Natural products from marine organisms with neuroprotective activity in the experimental models of Alzheimer's disease, Parkinson's disease and ischemic brain stroke: their molecular targets and action mechanisms.

Arch. Pharm. Res. DOI 10.1007/s12272-014-0503-5

REVIEW

Natural products from marine organisms with neuroprotective activity in the experimental models of Alzheimer’s disease, Parkinson’s disease and ischemic brain stroke: their molecular targets and action mechanisms Dong-Young Choi • Hyukjae Choi

Received: 3 September 2014 / Accepted: 14 October 2014 Ó The Pharmaceutical Society of Korea 2014

Abstract Continuous increases in the incidence of neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and brain stroke demand the urgent development of therapeutics. Marine organisms are well-known producers of natural products with diverse structures and pharmacological activities. Therefore, researchers have endeavored to identify marine natural products with neuroprotective effects. In this regard, this review summarizes therapeutic targets for AD, PD, and ischemic brain stroke and marine natural products with pharmacological activities on the targets according to taxonomies of marine organisms. Furthermore, several marine natural products on the clinical trials for the treatment of neurological disorders are discussed. Keywords Marine natural products Neurological diseases Neuroprotective Alzheimer’s disease Parkinson’s disease Ischemic brain stroke

Introduction Neurodegenerative diseases, such as AD and PD are characterized by progressive loss of neurons leading to various neurological symptoms. Such diseases continuously caused huge economic and social impacts in many countries (Ernst and Hay 1994; Findley et al. 2003). Neurodegenerative diseases become more prevalent as populations age, and currently we face aging of the baby boomer generation (Farooqui and Farooqui 2009). D.-Y. Choi H. Choi (&) College of Pharmacy, Yeungnam University, 280 Daehak-ro, Gyeongsan, Gyeongbuk 712-749, Republic of Korea e-mail: [email protected]

Although our understanding of these disorders has been substantially improved over recent years, no known medication can halt or cure the progressive neurodegeneration that underlies the pathogeneses of these diseases. Furthermore, drugs approved for the treatment of neurodegenerative diseases only offer marginal and transient symptomatic benefits (Lansbury 2004). Stroke is the second cause of disability in developed countries and of death after ischemic heart disease worldwide (van der Worp and van Gijn 2007). The incidence of stroke tends to increase exponentially with age (Truelsen et al. 2006), and despite years of continuous research and pioneering clinical work, stroke remains a major public health concern. Ischemia in the brain results in neuronal injury through cascade of detrimental events, but no neuroprotectant has been successfully developed into a cerebral ischemic stroke therapy (Sutherland et al. 2012). The only pharmacologic treatments proven to be effective at improving clinical outcome following ischemic stroke are aspirin and acute thrombolytic agents (Goldstein 2007; Balami et al. 2013). The marine environment offers a rich source of structurally novel natural products with significant anti-cancer, anti-inflammatory, analgesic, immuno-modulatory, and neuroprotective effects (Newman and Cragg, 2004). Several marine natural products and their derivatives in Fig. 1, such as cytarabin (1), trabectedin (2), eribulin mesylate (3), and brentuximab vedotin (4), have been approved by the U. S. Food and Drug Administration (U.S. FDA) or European Medicines Agency (EMEA) for the treatment of cancer (Martins et al. 2014). Furthermore, marine natural products with diverse bioactivities have been successfully developed as products, such as, omega-3-acid ethyl esters (5, U.S. FDA and EMEA approved drugs for the treatment of hypertriglyceridemia), ziconotide (6, neuropathic pain), and iota-carrageenan (7, an over-the-counter drug used to

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D.-Y. Choi, H. Choi Table 1 Marine natural products with neurological activities and their mode of action Compound

Mechanism of action

IC50 (lM)

Disease

Reference

Mannosylglycerate (29)

Inhibition of a-syn aggregation

NEa

PD

Faria et al. (2013)

Inhibition of tau hyperphosphorylation

NE

a

AD

Chai et al. (2013)

BACE inhibition, a-secretase activation Inhibition of H2O2 induced neurotoxicity

NEa

AD

Liu et al. (2014)

NEa

PD

Mena et al. (2009)

Betaine (30)

NP7 (31) Marinoquinoline A (32)

Inhibition of AChE activity

4.9

AD

Sangnoi et al. (2008)

Saproxanthin (33)

Inhibition of N-glutamate toxicity

3.1

Ischemia

Shindo et al. (2007)

Myxol (34)

Inhibition of N-glutamate toxicity

8.1

Ischemia

Shindo et al. (2007)

Tasiamide B (35)

Inhibition of BACE1

0.189

AD

Liu et al. (2012)

Tasiamide B analog (36)

Inhibition of BACE1

0.0488

AD

Liu et al. (2012)

Tasiamide B analog (37)

Inhibition of BACE1 and Ab40 production Antagonizing a7nAChR

0.0572

AD

Liu et al. (2012)

NEa

AD

Kharrat et al. (2008)

Inhibition of tau protein hyperphosphorylation

NEa

AD

Alonso et al. (2011a)

NEa

AD

Alonso et al. (2011b)

NEa

AD

Alonso et al. (2013a)

NEa

AD

Alonso et al. (2013b)

NEa

AD

Alonso et al. (2012)

AD

Choi et al. (2007)

Gymnodimine (38)

Inhibition of intracellular Ab accumulation Protection of glutamate-induced neurotoxicity 13-Desmethyl spirolide C (39)

Inhibition of Ab accumulation Inhibition of tau protein hyperphosphorylation Inhibition of GSK3b Protection of glutamate-induced neurotoxicity Increase in N-acetyl aspartate level

Yessotoxin (40)

Increase of inactive GSK3 Inhibition of tau protein hyperphosphorylation

Gambierol (41)

Reduction in the levels of Ab

Inhibition of Ab accumulation Inhibition of tau protein hyperphosphorylation Sargaquinoic acid (42)

Inhibition of AChE

23.2

Inhibition of BChE

0.026

Sargachromenol (43)

Inhibition of AChE Inhibition of BChE

32.7 7.3

AD

Choi et al. (2007)

A chromone (44)

Inhibition of GSK3b

\10

AD

Zhang et al. (2012b)

Spiralisone A (45)

Inhibition of GSK3b

\10

AD


Spiralisone B (46)

Inhibition of GSK3b

\10

AD


Eckstolonol (47)

Inhibition of AChE

42.66

AD

Yoon et al. (2008)

Inhibition of BChE

230.27

Eckol (48)

Inhibition of AChE

20.56

AD

Yoon et al. (2008)

Phlorofucofuroeckol-A (49)

Inhibition of AChE

4.89

AD

Yoon et al. (2008)

Inhibition of BChE

136.71

Dieckol (50)

Inhibition of AChE

17.11

AD

Yoon et al. (2008)

2-Phloroeckol (51)

Inhibition of AChE

38.13

AD

Yoon et al. (2008)

7-Phloroeckol (52)

Inhibition of AChE

21.11

AD

Yoon et al. (2008)

123

Natural products from marine organisms Table 1 continued Compound

Mechanism of action

IC50 (lM)

Disease

Reference

Homotaurine (53)

Reduction of amyloid plaque formation

NEa

AD

Gervais et al. (2007)

Inhibition of Ab aggregation

NEa

AD

Gupta-Bansal et al. (1995)

Neuroprotection against PD-inducing neurotoxin

NEa

PD

Akashi et al. (2011)

Ab42 induced neuroinflammation

NEa

AD

Dewapriya et al. (2013)

Inhibition of AChE

2.01

AD

Deng et al. (2013)

Decrease in cerebral Ab levels

Neoechinulin A (54)

Anhydrojavanicin (55) 8-O-methylbostrycoidin (56)

Inhibition of AChE

6.71

AD

Deng et al. (2013)

NGA0187 (57)

Inhibition of AChE

1.89

AD

Deng et al. (2013)

Induction of neurite outgrowth

NEa

Beauvericin (58)

Inhibition of AChE

3.09

AD

Deng et al. (2013)

Alaternin (59)

Inhibition of AChE

2.9

AD

Wen et al. 2007

Paeciloxanthone (60)

Inhibition of AChE

6.94

AD

Wen et al. (2008)

Xyloketal A (61)

Inhibition of AChE

NEa

AD

Lin et al. (2001)

Ischemia

Zhao et al. (2009)

PD

Lu et al. (2010)

Xyloketal B (62)

a

Neuroprotection against ischemiainduced cell injury

NE

Neuroprotection against MPP?induced neurotoxicity

NEa

Secalonic acid A (63)

Neuroprotection in PD model

NEa

PD

Zhai et al. (2013)

JBIR-59 (64)

DPPH radical scavenging activity

25

Ischemia

Kawahara et al. (2012)

JBIR-124 (65)


30

Ischemia

Kawahara et al. (2012)

Leucettamine B (66)

Inhibition of DYRKs/CLKs

NEa

AD

Tahtouh et al. (2012)

a

AD

Tahtouh et al. (2012)

AD

Bidon-Chanal et al. (2013)

AD

Meijer et al. (2000)

Leucettine L41 (67)

Inhibition of GSK3b

NE

Reuroprotection against glutamateinduced HT22 cell death Reuroprotection against APP-induced cell death in brain Palinurin (68)

Hymenialdisine (69)

Inhibition of GSK3b

4.5


NEa

Inhibition of GSK3b

0.035


NEa

Debromohymenialdisine (70)

Inhibition of GSK-3b

0.2

AD

Zhang et al. (2012a)

Manzamine A (71)


10

AD

Hamann et al. (2007)

(Z)-5-(4-hydroxybenzylidene)hydantoin (72)


13.7

AD

Khanfar et al. (2009) Khanfar et al. (2009)

A synthetic analog of 72 (73)


4.2

AD

Lamellarin O (74)

Inhibition of BACE1

[10

AD

Zhang et al. (2012c)

Lamellarin O1 (75)

Inhibition of BACE1

\10

AD


Lamellarin O2 (76)

Inhibition of BACE1

[10

AD


Ianthellidone F (77) Dictyodendrin F (78)

Inhibition of BACE1 Inhibition of BACE1

[10 1.5

AD AD

Zhang et al. (2012c) Zhang et al. (2012d)

Dictyodendrin H (79)

Inhibition of BACE1

2

AD

Zhang et al. (2012d)

Dictyodendrin I (80)

Inhibition of BACE1

2

AD

Zhang et al. (2012d)

Dictyodendrin J (81)

Inhibition of BACE1

2

AD

Xestosaprol D (82)

Inhibition of BACE1

93

AD

Zhang et al. (2012d) Millań-Aguinãga et al. (2010)

123

D.-Y. Choi, H. Choi Table 1 continued Compound

Mechanism of action

IC50 (lM)

Disease

Reference

Xestosaprol H (83)

Inhibition of BACE1

82

AD

Dai et al. (2010a)

29-Hydroperoxystigmasta5,24(28)-dien-3-ol (84)

Inhibition of PGC-1

32

PD

Zhou et al. (2014)

Topsentinol K trisulfate (85)

Nonspecific inhibition of BACE1

1.2

AD

Dai et al. (2010b)

4-Acetoxy-plakinamine B (86)

AChE inhibitor

3.75

AD

Langjae et al. (2007)

Fascaplysin (87)

Inhibition of AChE

1.49

AD

Bharate et al. (2012a)

Inhibition of BChE

90.47 AD

Orhan et al. (2012)

Oroidin (88)

Inhibition AChE activity

500


64

Inhibition of CDK1

0.06

AD

Simone et al. (2005)

Inhibition of CDK9 Inhibition of GSK3

0.026 0.07

AD

Echalier et al. (2008)

Saraine 1 (90)

Inhibition of AChE

NEa

AD

Defant et al. (2011)

Saraine 3 (91)

Inhibition of AChE

NEa

AD


Saraine A (92)

Inhibition of AChE

NE

a

AD


Saraine B (93)

Inhibition of AChE

NEa

AD


Saraine C (94)

Inhibition of AChE

NEa

AD


Isosaraine 1 (95)

Inhibition of AChE

NEa

AD


Platisidine A (96)

Inhibition of AChE

NEa

AD

Kubota et al. (2010)

Platisidine B (97)

Inhibition of AChE

NEa

AD


Platisidine C (98)

Inhibition of AChE

NE

a

AD


Petrosamine (99)

Inhibition of AChE

0.091

AD

Nukoolkarn et al. (2008)

Ilimaquinone (100)

Activation of HIF-1

NEa

Ischemia

Du et al. (2013)

5,8-Diepi-ilimaquinone (101)

Activation of HIF-1

NEa

Ischemia

Du et al. (2013)

4,5-Diepi-dactylospongiaquinone (102)

Activation of HIF-1

NEa

Ischemia

Du et al. (2013)

Gracilin A (103)

Inhibition of H2O2 induced neurotoxicity

NEa

AD/PD

Leiro´s et al. (2014)

Gracilin H (104)


NEa

AD/PD


Gracilin J (105)


NEa

AD/PD


Gracilin K (106)


NEa

AD/PD


Gracilin L (107)


NEa

AD/PD


Tetrahydroaplysuphurin-1 (108)


NEa

AD/PD


11-Dehydrosinulariolide (109)

Activation of PI3 K, inhibition of caspases 3/7

NEa

PD

Chen et al. (2012)

Waixenicin (26)

Neuroprotection of the cerebral ischemia-induced neuronal injury

NEa

Ischemia

Zierler et al. (2011)

Anabaseine (110)

Agonist/antagonist of nAChR

NEa

AD

Kem et al. (1997)

GTS-21 (111) 4-OH-GTS-21 (112)

Partial agonist of a7 nAChR Partial agonist of a7 nAChR

NEa NEa

AD AD

Neuroprotective effects against Ab

NEa

Papke et al. (2004) Papke et al. (2004), Meyer et al. (1998b)

Reduction of Ab40 and Ab42 production

NEa

AD

Etcheberrigaray et al. (2004)

Prevention of the cerebral ischemiainduced neuronal injury

NEa

Ischemia

Tan et al. (2013)

Variolin B (89)

Bryostatin 1 (113)

123

Natural products from marine organisms Table 1 continued Compound

Mechanism of action

IC50 (lM)

Disease

Reference

(–)–Debromoflustramine B (115)

BChE inhibition

1.37

AD

Rivera-Becerril et al. (2008)

6-Bromoinduribin (116)

Inhibition of GSK3b

0.045

AD


6-Bromoinduribin-30 -oxime (117)

Inhibition of GSK3b

0.005

AD


Ischemia

Williams et al. (2000)

Conantokin-G (118)

Neuroprotection against hypoxia/ hypoglycemia, NMDA, glutamate or veratridine induced toxicity

NE

a

a-Conotoxin BuIA (119)

Inhibition of AChR

0.00026

AD

Azam et al. (2005)

x-Conotoxin MVIIA (120)

Blockage of calcium channel

0.00055

Ischemia

Lewis et al. (2000)

Didemnaketal D (121)

Inhibition of GSK3

[11

AD

Mohamed et al. (2014)

Didemnaketal E (122)

Inhibition of GSK3

[11

AD

Mohamed et al. (2014) Plisson et al. (2012)

Ningalin B (123)

Inhibition of GSK3b

0.8

AD

Ningalin C (124)

Inhibition of GSK3b

\0.2

AD

Plisson et al. (2012)

Ningalin D (125)

Inhibition of GSK3b

\0.2

AD


Ningalin E (126)

Inhibition of GSK3b

1.6

AD


Ningalin F (127)

Inhibition of GSK3b

3.1

AD


Ningalin G (128)

Inhibition of GSK3b

\0.5

AD


Meridianine E (129)

Inhibition of GSK3a

0.90

AD

Radwan and ElSherbiny (2007)

Inhibition of GSK3b

2.50

HTP-1 (130)

Neuroprotection against Ab42 on PC12

NEa

AD

Pangestuti et al. (2013)

DHA (131)

Reduction of Ab deposition

NEa

AD

Calon et al. (2004)

Neuroprotectin D1 (132)

Reduction of Ab42 production via BACE1, a-secretase, and PPARc

NEa

AD

Zhao et al. (2011)

a

Not evaluated

treat viral infections). Currently, a number of marine natural products and their derivatives are either undergoing clinical trials, or have reached an advanced preclinical status (Newman and Cragg 2014). Several marine natural products have been demonstrated to be effective in experimental models of neurologic disorders, but not one has been demonstrated to be therapeutically effective by clinical trial for the treatment of neurologic diseases (Martinez 2007; Ryu and Kim 2013). We performed PubMed and SCIfinder searches using the keywords ‘marine natural products’ and ‘marine compound’ and identified articles published from 1990 to 2014 on the effectiveness of marine products in vivo and in vitro models of neurologic diseases. Articles were further examined after selecting those that addressed AD, PD, or ischemic brain stroke. In this review, potential therapeutic targets are described and marine natural products are organized with respect to the taxonomy of marine organisms (Archaea, Bacteria, Protozoa, Chromista, Plantae, Fungi, and Animalia) and their chemical structures and biological effects on therapeutic targets are reviewed. In addition, the plausibility of their pharmacological uses for the treatment or prevention of progressive neurodegeneration is discussed.

Therapeutic targets for AD, PD and ischemic brain stroke AD Amyloid-b (Ab) and the enzymes involved in its synthesis Ab is generated via the sequential endoproteolysis of amyloid precursor protein (APP) by the b-secretase (BACE1) and c-secretase (Huse et al. 2003). BACE cuts first at the extracellular domain of APP generating a sAPP-b and the membrane bound APP C-terminal fragment C99, and in turn c-secretase cleaves C99 producing Ab. Evidence suggests that Ab peptides play a critical or even causal role in the pathogenesis of AD, but the underlying mechanisms remain elusive (McLean et al. 1999; Klein et al. 2001; Morgan et al. 2000). It has been shown that synapse abnormalities as well as memory impairments correlate poorly with Ab plaque burden and that these impairment can occur before plaque formation in transgenic animal models of AD (Lacor et al. 2007; Jacobsen et al. 2006). Immunization against Ab was found to have a neuroprotective effect and to attenuate memory deficits in transgenic mice without decreasing Ab plaques burden (Buttini et al. 2005; Dodart et al. 2002).

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D.-Y. Choi, H. Choi

N

O N

O HO

O

HO

NH2

O HO

O

OH

O

H O

O H

H O

S N

O

O

1

O

O

N

N H

O

H N

3

O

H N

N

O

NH

N

N O

O

N H

H2 N

H

O

O

O

O

O

O O

H

OH

2

O S

H 2N

S

N

OH

cAC10

O

NH HO

O AcO O

O

NH

O

OH

O

4

O

O O O 5

-

O3SO H O

O

H

OH O

HHO H H

O

H O H H

H O

H

O

OSO3-

7 C-K-G-K-G-A-K-C-S-R-L-M-W-D-C-C-T-G-S-C-R-S-G-K-C-NH 2 6

Fig. 1 Marine natural products derived drugs

These results suggest that Ab in plaques might not be responsible for synapse degeneration and that other forms of Ab critically contribute to neurotoxicity in the Alzheimer’s brains (Klein et al. 2001). Based on the evidence that Ab plays a pivotal role in the pathogenesis of AD, several clinical trials involving passive and active immunizations to Ab were carried out (Lobello et al. 2012). However, neither method turned out to be successful in clinical trials due to poor therapeutic efficacy and adverse effects such as encephalitis. The action of BACE1 and c-secretase on the APP is essential for deposition of Ab peptide which probably contributes to pathology of AD. Prior to the identification of BACE1, activity the enzyme was observed in cells and tissues (Vassar and Kandalepas 2011). In 1999, BACE1 was cloned by five different groups and variously named BACE, Asp2, or memapsin 2 (Wang et al. 2013). Different cloning methods were employed, but all involved agreed that they had identified the same enzyme. BACE1

123

overexpression increases the production of Ab and BACE1-cleaved APP fragments, respectively (Li et al. 2006). In addition, the activity of BACE1 on wild-type and mutant APP substrates is consistent with its sequence specificity (Cole and Vassar 2007). Notably, BACE1 cleaves APP containing the Swedish familial AD-causing mutation approximately 10- to 100-fold more efficiently than it cleaves wild-type APP (Vassar and Kandalepas 2011). Some BACE1 inhibitors have been tried to develop as therapeutics for AD (Zhang 2012). LY2811376 (8) significantly decreased Ab levels in human cerebrospinal fluid and in animal models. However, treatment with LY2811376 had a toxic effect on and led to the enlargement and toxicity in retinal epithelial cells in animal-based studies, which prevented further clinical examinations (May et al. 2011). A BACE1 inhibitor, MK-8931 (9) developed by Merck is still in clinical trial (Fig. 2). Mutations on genes of presenilins are responsible for early-onset AD (De Strooper et al. 2012). Subsequently, it

Natural products from marine organisms N

N

S

N

N F

NH HN

NH2 S

F 8

CF3

OH

N F

O

O O S N

H2N

O

O 10

9

Cl

N

F N

11

O

HN F

OH

N NH

N NH

F 12

Cl

O S

S

O 13

O

N N

N

CF3

O

CF3

HN

OH

14

O

O O O

N

N

O

H HO

15

16

N H

N

O O

17

Fig. 2 Compounds in clinical trials for AD treatments

was found that presenilins (the multipass membrane proteins) are catalytic components of c-secretase, that is, the membrane-embedded aspartyl protease complexes responsible for generating the carboxyl terminus of Ab from APP (Wolfe et al. 1999). Protease complex also cleaves a variety of other type I integral membrane proteins, most notably Notch receptor, which generates signal involved in many cell differentiation events (De Strooper et al. 2012). Thus, although c-secretase is a major target for the development of a treatment for AD, Notch signaling should not be disrupted. Compounds that alter Ab production by c-secretase without affecting Notch proteolysis and signaling have been identified and are currently at various stages in the drug development pipeline. A c-secretase modulator, flurbiprofen (10) was the first to undergo a clinical trial, but failed due to a lack of therapeutic efficacy. A number of potent Notch-sparing inhibitors have recently been reported and some of them are now in early- to midstage clinical trials (Kreft et al. 2009). Examples include BMS-708163 (11) from Bristol-Myers-Squibb (Gillman et al. 2010), PF-3084014 (12) from Pfizer (Lanz et al. 2010), and GSI-953 (13) from Wyeth (Mayer et al. 2008).

disorders, termed tauopathies, in which tau is deposited in affected brain regions (Hanger et al. 2009). In AD, pathologic tau is a hyperphosphorylated form and is aberrantly cleaved (Kolarova et al. 2012). The protein also has abnormal conformations and is prone to aggregation to produce neurofibrillary tangles (Ross and Poirier 2004). In recent studies, early changes in the forms of soluble tau proteins including their phosphorylation have been associated with neurodegeneration (Santacruz et al. 2005; Andorfer et al. 2005). GSK3 is a candidate kinase responsible for phosphorylation of tau protein which regulates tau binding to microtubules, tau degradation and tau aggregation (Hernandez et al. 2010). In AD, it has been proposed that beta amyloid promotes GSK3 activation and results in tau phosphorylation (Lee et al. 2009). Currently, a number of GSK3 inhibitors have been examined for its therapeutic efficacy in AD, and it has been demonstrated that AZD1080 (14), a potent and selective GSK3 inhibitor attenuates tau phosphorylation in cells expressing human tau and in the intact rat brain (Georgievska et al. 2013).

Tau protein and glycogen synthase kinase 3 (GSK3)

In addition to the complex pathological and biological alterations involved in the neuronal manifestations of AD, such as Ab aggregation and development of neurofibrillary tangles, cholinergic deficit due to basal forebrain

The microtubule-associated protein tau is known to be involved in the pathogeneses of AD, and several related

Acetylcholine related molecules

123

D.-Y. Choi, H. Choi

degeneration is observed in Alzheimer’s brains (SerranoPozo et al. 2011). Furthermore, there is a large decrease in cerebral nicotinic acetylcholine receptor (nAChR) levels in AD, due to a preferential loss of neurons expressing nAChRs (Sugaya et al. 1990). Binding of acetylcholine to nAChR and their interactions are critical in cognitive processes, and activation of nAChRs by nicotinic ligands can also protect neurons (Kihara et al. 1998). Therefore, interest has been focused on increasing acetylcholine levels and directly stimulating nAChRs using novel compounds for the purpose of restoring cognitive deficits and protecting neurons from Ab neurotoxicity (Buckingham et al. 2009). This has led to identifying acetylcholinesterase (AChE) inhibitors which prevent acetylcholine hydrolysis and specific agonists for nAChRs. Intriguingly, evidence suggests that a7nAChRs antagonists protect neurons from Ab-induced neurotoxicity (Alonso et al. 2011a). AChE has proven to be a pivotal therapeutic target for achieving symptomatic improvement in AD because cholinergic deficit is a consistent and early finding during the disease course (Mehta et al. 2012). In fact, three of the four drugs current available for AD treatment are AChE inhibitors, which are galantamine (15), rivastigmine (16) and donepezil (17). Interestingly, galantamine (15) was derived from bulbs of the common snowdrop and several Amaryllidaceae, and has been approved in several countries for the symptomatic treatment of AD-associated senile dementia (Sramek et al. 2000). PD Alpha-synuclein (a-syn) Physiologically a-syn is believed to regulate neurotransmitter release, possibly via calcium-dependent binding and its subsequent dissociation from lipid domains on secretory vesicles (Sulzer 2010). a-Syn is a major constituent of Lewy bodies and has been associated with both familial and idiopathic cases of PD (Spillantini et al. 1997; Trojanowski and Lee 1998). Three rare missense mutations in asyn—A30P (Kruger et al. 1998), A53T (Polymeropoulos et al. 1997), and E46K (Zarranz et al. 2004)—have been discovered in families with an autosomal dominant earlyonset form of PD. It is also believed that elevated levels of wild-type (triplication mutation) a-syn (Singleton et al. 2003) and a-syn damaged during the aging process or through environmental exposure (Dawson and Dawson 2003) contribute at least partially to familial and sporadic PD, respectively. Accumulation of wild-type a-syn may also play a causal role in sporadic PD and related conditions (Masliah et al. 2000). In addition, mutations in Parkin, DJ-1, and ubiquitin carboxyl-terminal esterase L1 (UCH-L1) genes associated with PD are considered to

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affect the structure and/or clearance of a-syn, supporting the idea that a-syn is crucial in the pathophysiology of PD (Maries et al. 2003). Although it is not clear how a-syn exerts neurotoxicity, substantial evidence suggests that some oligomeric species serve as neuron killers. Evidence indicate that overexpression of wild-type a-syn and pathogenic mutations of a-syn promote toxic interaction between a-syn oligomers and lipids that may disrupt transmembrane concentration gradients across secretory vesicles and other organelles and interfere with normal lysosomal or ubiqutin/proteasome mediated protein degradation or mitochondrial function (Lashuel et al. 2013; Sulzer 2010; Zhang et al. 2009). Therefore, reducing the amount of a-syn in the brains is thought to be beneficial in PD. The first clinical trial with vaccine against a-syn was commenced in 2012 and the results are expected later this year (Dolgin, 2012). Monoamine oxidase B Monoamine oxidase B (MAO-B) inhibitors are used for the symptomatic treatment of PD as they increase synaptic dopamine by blocking its degradation (Schapira 2011). Two MAO-B inhibitors, selegiline (18) and rasagiline (19), are currently licensed in Europe and North America for treating the early symptoms of PD and for reducing ‘off-time’ in patients with more advanced PD and motor fluctuations related to levodopa (Fig. 3) (Fernandez and Chen 2007). A third MAO-B inhibitor, safinamide (20) which has additional non-dopaminergic properties of potential benefit to PD patients, is currently undergoing in phase III clinical trials as an adjuvant in combination with a dopamine agonist or levodopa (Schapira 2011). MAO-B inhibitors have also been studied extensively for possible neuroprotective or disease-modifying actions, and abundant laboratory evidence that MAO-B inhibitors have some neuroprotective properties, at least in the PD models currently available (Zhu et al. 2008; Binda et al. 2011).

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Fig. 3 Compounds in clinical trials for PD treatments

Natural products from marine organisms

Peroxisome proliferator-activated receptor c coactivator-1 alpha (PGC-1a) PGC-1a was discovered in brown adipose tissue as a peroxisome proliferator-activated receptor c (PPARc) coactivator during thermogenic response to cold (Hondares et al. 2011). Two other coactivators have been identified, PGC1b and PGC-1-related coactivator (Finck and Kelly 2006). PGC-1a, which is involved in mitochondrial biogenesis and respiration, has been implicated in PD (Pacelli et al. 2011; Austin and St-Pierre 2012). PGC-1a induces the expression of reactive oxygen species (ROS) scavenging enzymes (glutathione peroxidase-1, catalase and superoxide dismutase) and reduces oxidative stress (Mcgill and Beal 2006). In PGC-1a knockout mice, increased vulnerability to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced degeneration of nigral dopaminergic neurons, suggesting that PGC-1a has a critical neuroprotective role (Corona and Duchen 2014). Furthermore, increasing PGC-1a levels dramatically protected neural cells from oxidative stress and cell death (St-Pierre et al. 2006), and activation of PGC-1a reduced the dopaminergic neuron loss induced by mutant a-syn or the pesticide rotenone (Zheng et al. 2010). These studies provided compelling evidence that PGC-1a plays a pivotal role in PD and it is a good candidate treatment for the neurodegenerative disease (Corona and Duchen 2014).

ganglion sensory neurons, which has stimulated its development as an agent for the treatment of chronic pain. The potential therapeutic properties of neurotrophic factors are complicated by their peptidic structures, which impairs penetration into the brain parenchyma, and thus makes their pharmaco-therapeutic properties difficult to evaluate (Mocchetti and Brown 2008). One possible way of overcoming this difficulty is to increase the function of endogenous neurotrophins using pharmacological compounds that induce the synthesis and release of neurotrophins in relevant brain areas or by small synthetic molecules that bind to and activate specific neurotrophin receptors (Mocchetti and Brown 2008; Longo and Massa 2013). In this context, the ability of natural compounds to mimic neurotrophic factors is of potential therapeutic importance for the prevention of neuronal damage in chronic neurodegenerative diseases like PD. PYM50028 (21, Cogane) was derived from the extract of the sasparilla plant and oral administration of the drug was found to induce GDNF and brain-derived neurotrophic factor (BDNF) in the brains of mice (Worth 2013). Furthermore, PYM50028 significantly reduced MPTP-induced dopaminergic neurodegeneration in mice (Visanji et al. 2008). However, PYM50028 (21) fail to exhibit significant beneficial effect over placebo in a clinical trial. Ischemic brain stroke

Neurotrophic factors Oxidative stress Most neurotrophic factors can be grouped into families of structurally and functionally related molecules (Ibanez 1995). These include the nerve growth factor (NGF) superfamily, the neurokine superfamily and the glial cell line-derived neurotrophic factor (GDNF) superfamily. The GDNF superfamily has generated particular interest. It consists of four structurally homologous members, GDNF, neurturin (NTN), persephin (PSP) and artemin (Art), which are distantly related to transforming growth factor beta (TGF-b) (Alfano et al. 2007). GDNF was the first member of this family discovered by Lin and colleagues in 1993 (Lin et al. 1993). Subsequent studies with in vitro and in vivo models have demonstrated that GDNF enhances the morphological differentiation and survival of dopaminergic neurons, although its actions are not exclusive to this neuronal population (Bourque and Trudeau 2000; Mount et al. 1995). NTN has a similar function, and has been shown to be expressed in the nigrostriatal system and increase survival of midbrain dopaminergic neurons. On the other hand, PSP promotes the survival of both dopaminergic neurons and motor neurons in culture and in vivo whereas Art, whilst supporting ventral midbrain neurons in vitro, seems to have a more potent effect on dorsal root

Accumulating evidence suggests that lipid peroxidation, and the accumulations of conjugated dienes and thiobarbiturate-reactive material, are consistently found after cerebral ischemia and subsequent reperfusion. Oxidative stress seems to be exaggerated by deficient a-tocopherol and vitamin C levels, and supplementation with these vitamins can attenuate the effect (Gariballa et al. 2002). Furthermore, plasma alpha- and beta-carotene concentrations were found to be lower in patients with acute ischemic stroke (Chang et al. 2005). Accordingly, it appears that enhanced antioxidant capacity after acute stroke might protect against the free radical-induced adverse effects during ischemia and reperfusion (Gariballa et al. 2002). The most promising antioxidants are dehydroascorbic acid (22), a-tocotrienol (23), c-tocopherol (24), and resveratrol (25) which have exhibited positive effects in animal models of acute ischemic stroke (Fig. 4) (Cherubini et al. 2008). However, the results of experimental and clinical studies in this context are discrepant, and recent data suggest that total dietary antioxidant capacity does not appear to have a preventative effect on the sequelae of ischemic brain stroke (Devore et al. 2013).

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For example, waixenicin A (26), a naturally occurring compound from the soft coral Sarcothelia edmondsoni, has been shown to inhibit TRPM7 without significantly affecting other TRPM channels (Zierler et al. 2011) and notably, psalmotoxin (PcTx1), a peptide of molecular weight 4,689 purified from the venom of the South American tarantula, Psalmopoeus cambridgei, potently inhibits the homomeric ASIC1a current at a concentration of 1 nM (Escoubas et al. 2000). Furthermore, a recent study conducted in a rat cardiac model of global ischemia showed that the ASIC inhibitor amiloride, reduced neurodegeneration (Tai and Truong 2013).

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Fig. 4 Compounds in clinical trials for ischemia ischemic brain stroke treatments

Calcium channels During stroke, disruption of blood flow to the brain deprives cells of energy and disturbs cellular ionic homeostasis (Siesjo¨ 1992). In particular, the inhibition of oxidative phosphorylation and depletion of ATP result in the loss of ATP substrate for Na?–K?-ATPase, which leads to the dissipation of transmembrane K? and Na? gradients and subsequent membrane depolarization (Lipton 1999). Furthermore, sustained depolarization causes excessive Ca2? entry through voltage-sensitive Ca2? channels, which initiates an excessive release of glutamate (Benveniste et al. 1984; Nicholls and Attwell 1990), resulting in the overstimulation of N-methyl-D-aspartate (NMDA) receptors. The resulting Ca2? overload (Choi 1992) then triggers secondary signal cascades, which activate proteases and phospholipases, and produce free radicals (Puyal et al. 2013). This cascade constitutes the well-known excitotoxicity mechanism that contributes to the cerebral ischemia-induced neuronal injury. In addition, studies have shown other Ca2? permeable channels such as the acid-sensing ion channel 1a (ASIC1a), transient receptor potential melastatin 7 (TRPM7), and Na?/ H? exchanger isoform 1 (NHE1), contribute to neuronal injury after ischemia and reperfusion (Nedergaard et al. 1991). A number of natural compounds have been reported to suppress activities of ASIC or TRPM7 (Leng et al. 2014).

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It has been reported that a local rapid increase in central adenosine might be involved in acute neuronal ischemic preconditioning, which suggests that adenosine-based preconditioning might be a general protective mechanism (Cunha 2005). Adenosine kinase (ADK) is the major adenosine regulating enzyme and catalyzes conversion of adenosine to AMP and ADP using ATP (Boison 2006). In addition, ADK has recently been identified as a novel therapeutic target in the context of preventing ischemic neuronal cell death (Boison 2006). Overexpression of ADK makes animals susceptible to ischemic brain injuryinduced neuronal death (Pignataro et al. 2007), whereas ADK down-regulation in ischemic brains appears to afford endogenous neuroprotection increasing ambient levels of adenosine (Pignataro et al. 2008). It has also been shown that pharmacological inhibition of ADK potentiates adenosine-based neuroprotection in animal models of cerebral ischemia (Kowaluk and Jarvis 2000; Jiang et al. 1997). From the pharmacologic perspective, ADK inhibitors including 5-iodotubercidin (5-ITU, 27) and GP683 (28) were have been demonstrated to provide effective neuroprotection in animal models for cerebral ischemia (Miller et al. 1996; Tatlisumak et al. 1998). Hypoxia inducible factor (HIF) Disturbance in cerebral blood flow during stroke is followed by multiple cellular and molecular processes resulting in neuronal necrosis or apoptosis. In addition to the detrimental cascades, some endogenous adaptive and regenerative responses occur to rescue damaged cells from these ischemic events (Singh et al. 2012). Among regulators of these processes, HIF essentially mediates oxygen homeostasis by activating various transcription factors (Semenza and Wang 1992). HIF is composed of two subunits, a (oxygen-regulated) and b (oxygen-independent). Under oxygen-deficient cellular condition, a and b subunits are dimerized in the nucleus which in turn binds to the cis-acting hypoxia-


(Thompson et al. 2012). It was found that activity of HIF is controlled by multiple regulators such as prolyl hydroxylase, ubiquitin–proteasome system, and regulatory factors that modify hydroxylation, acetylation, and phosphorylation of HIF-1a (Singh et al. 2012). Thus, pharmacologic HIF-1 activator and compounds that modify activity of HIF regulators could be decent drug candidates for treating stroke.

responsive element in target genes with transcriptional coactivator p300/CBP (CREB-binding protein) and DNA polymerase II (Singh et al. 2012). Then the transcription complex transcribes a number of genes responsible for angiogenesis, vascular tone, glycolysis, mitochondrial function, and cell survival. There are three major HIFa isoforms in humans: HIF-1a, HIF-2a, and HIF-3a. The two predominant isoforms are HIF-1 and HIF-2, and these are proposed as the main HIF molecules that confer adaptation to hypoxic stress (Semenza 2007). Ischemic preconditioning treatment protects neurons from ischemic condition through increasing levels of HIF-1a and HIF-1b suggesting that ischemic preconditioning-mediated protection might be achieved through HIF-1 mediated pathways (Bergeron et al. 2000). Cobalt chloride and desferrioxamine have been known as HIF-1 activators and protected neonatal rat brains from lethal ischemia Fig. 5 Marine natural products (Archaea and Bacteria) and their derivatives with neurologic activities

Marine natural products with pharmacological activity on therapeutic targets of AD, PD and ischemic brain stroke Archaea Hyperthermophiles inhabiting extremely harsh environments typified by high temperatures and osmotic pressures

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are known to possess zwitterionic natural products (possessing a cationic and an anionic group) that prevent the thermal denaturation and aggregation of proteins (Santos et al. 2007; Faria et al. 2008). (2R)-2-(a-D-mannopyranosyl)glyceric acid (29), a widespread solute in hyperthermophiles has been reported inhibited a formation of a-syn inclusions in a yeast model of PD (Fig. 5, Faria et al. 2013). Bacteria Glycine betaine (30) is a N,N,N-trimethylglycine zwitterionic entity (Fig. 5). This compound was first isolated from the sugar beet (Beta vulgaris), but it has been found in diverse marine organisms, including halophilic bacteria (Actinopolyspora halophile and Ectothiorhodospira halochloris), the red alga (Ceratodictyon spongiosum), and mollusca (Patella vulgate) (Crmwell and Rennie 1953; Nyyssola et al. 2000; Takemoto and Sai 1964; Etienne 1956). Glycine betaine (30) has been reported to promote homocysteine metabolism and has been used to treat hyperlipidemia, coronary atherosclerosis and fatty liver. Recently, compound 30 was found to reduce tau hyperphosphorylation and Ab deposition by inhibiting BACE1 and the activation of a-secretase (Kharbanda et al. 2007; Chai et al. 2013; Liu et al. 2014). NP7 (31) is a marine-derived antioxidant, which discovered by lead optimization system from Streptomyces spp. NP7 (31) has been reported to be a potent free radical scavenging agent in the nM–lM range and to cross the mammalian blood–brain barrier effectively (Garcıá-Palomero et al. 2007). NP7 (31) at concentrations of 5–10 lM protected midbrain neuronal and glial cultures from wild type and Parkin null mice from H2O2-induced cell death (Mena et al. 2009). Marinoquinoline A (32) is a pyrroloquinoline reported from the marine gliding bacterium Rapidithrix thailandica found in the Andaman Sea (Sangnoi et al. 2008). The structure of 32 is closely related to a potent AChE inhibitor tacrine and Sangnoi et al. found that it effectively inhibits AChE (IC50 = 4.9 lM). Two rare carotenoids (3R)-saproxanthin (33) and (3R,20 S)-myxol (34) isolated from marine bacteria of the Flavobacteriaceae family, showed potent antioxidative properties against lipid peroxidation in a rat brain homogenate model with IC50 values of 2.1 and 6.2 lM, respectively. In addition, they showed potent neuroprotective properties against L-glutamate-induced toxicity in N18-RE-105 cells with EC50 values of 3.1 and 8.1 lM, respectively. By comparison the EC50 values of b-carotene and zeaxanthin were over 100 and 500 lM, respectively (Shindo et al. 2007). Tasiamide B (35), is a cyanobacterial metabolite with a phenyl-statine structure and an aspartic protease inhibitor,

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which inhibits BACE1 and cathepsins D and E with IC50 values of 0.189, 0.182, and 0.066 lM, respectively (Liu et al. 2012). A series of BACE1 inhibitors (36, 37) were synthesized based on structural considerations, and these exhibited different selectivities for BACE1 and cathepsins D and E. The crystal structures of complexes between BACE1 and 35, 36, and 37 allowed relations to be identified between structures and BACE1 inhibition. Compounds 36 and 37 were also found to be stable in vitro and in vivo (mice), and 37 effectively reduced Ab40 levels when administered to CF-1 mice (Liu et al. 2012). Protozoa Gymnodimine (38) is a macrocyclic imine metabolite, which was first isolated from the dinoflagellate Karenia selliformis (formerly named Gymnodinium selliforme) and from New Zealand oysters (Fig. 6) (Seki et al. 1995; Stewart et al. 1997). It was reported that 38 bound to muscular and neuronal nAChRs with high affinity (Kharrat et al. 2008). In addition, gymnodimine (38) is revealed to antagonize human a7nAChR expressed in Xenopus oocytes (Bourne et al. 2010). Later, long term exposure of 3 9 Tg cortical neurons to 38 at 50 nM was found to reduce the intracellular accumulation of Ab, hyperphosphorylated tau protein levels, and prevent glutamate-induced neuronal death (Alonso et al. 2011a). Spirolides are marine toxins produced by the dinoflagellate Alexandrium ostenfeldii and accumulate in shellfish (Falk et al. 2001). One spirolide, 13-desmethyl spirolide C (39) reduced intracellular Ab accumulation and the protein levels of hyperphosphorylated tau, GSK3b and ERK in 3 9 Tg cortical neurons. In addition, 39 abolished glutamate-induced neurotoxicity in 3 9 Tg cortical neurons (Alonso et al. 2011b), and i.p. treatment of 39 to 3 9 Tg mice increased N-acetyl aspartate levels (a biomarker of AD) (Alonso et al. 2013a). Furthermore, in vivo neuromuscular excitability experiments showed 39 was 300-fold more active than 38 (Marrouchi et al. 2013). Yessotoxin (40) is a marine toxin produced by the dinoflagellates Protoceratium reticulatum and Lingulodinium polyedrum and a protein kinase C activator (Satake et al. 1997; Paz et al. 2004; Miles et al. 2005; Lo´pez et al. 2011). Pretreatment of 3 9 Tg cortical neurons with 1 nM of 40 decreased the intracellular accumulations of Ab and hyperphosphorylated tau protein through by interacting with GSK3 in a protein kinase C (PKC) activation mediated manner (Alonso et al. 2013b). Gambierol (41) is a polycyclic ether type of neurotoxin, and was first isolated from Gambierdiscus toxicus in 1993 (Satake et al. 1993). The target of gambierol (41) was later identified as the voltage-gated potassium channels. Gambierol inhibited voltage-gated potassium ion currents in


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Fig. 6 Marine natural products (Protozoa) with neurologic activities

mouse taste cells with an IC50 of 1.8 nM (Ghiaroni et al. 2005). Furthermore, in vitro pretreatment of 3 9 Tg cortical neuronal cells with 41 reduced extra- and intracellular Ab and hyperphosphorylated tau protein levels, and decreased the steady-state level of NMDA receptor subunit 2A (Alonso et al. 2012). Chromista (brown algae) Brown algae in the genus of Sargassum are a rich source of prenylated compounds. Sargaquinoic acid (42) and sargachromenol (43) are plastoquinones found in Sargassum sagamianum (Fig. 7) (Kusumi et al. 1979). Sargaquinoic acid (42) inhibits AChE with IC50 value of 23.2 lM and potently inhibits butyrylcholinesterase (BChE) with IC50 value of 0.026 lM (Choi et al. 2007). Sargachromenol (43), which possesses a chromone group, has also been reported to potently inhibit both AChE and BChE with IC50 values of 32.7 and 7.3 lM, respectively (Choi et al. 2007). 5,7-Dihydroxy-2-(4Z,7Z,10Z,13Z,16Z-nonadecapentaenyl) chromone (44) is a phloroglucinol-derived chromone type lipid found in Zonaria tournefortii and Zonaria spiralis (Tringali and Piatelli 1982; Zhang et al. 2012b), and spiralisones A (45) and B (46) are phloroglucinol-derived lipid metabolites isolated from brown alga, Zonaria spiralis (Zhang et al. 2012b). Compounds 44, 45, and 46 showed kinase inhibitory activities against CDK5/p25 (IC50 = 10.0, 10.0, and 3.0 lM, respectively), CK1d (all IC50 values \ 10.0 lM), and GSK3b (all IC50 values \ 10.0 lM), which are related to the pathology of AD. In addition, compounds 44 and 45 displayed antibacterial activities against Bacillus subtilis (ATCC 6051 and 6633) (Zhang et al. 2012b).

Phlorotannins are polyphenolic compounds and are frequently found in the extracts of brown algae; they are formed by the polymerization of the phloroglucinol subunit (Ragan and Glombitza 1986; Fukuyama et al. 1985; Okada et al. 2004). Six phlorotannins, eckstolonol (47), eckol (48), phlorofucofuroeckol-A (49), dieckol (50), 2-phloroeckol (51) and 7-phloroeckol (52) were isolated from the brown algae Ecklonia stolonifera and found to have showed AChE inhibitory activities (IC50 values of 42.66, 20.56, 4.89, 17.11, 38.13, and 21.11 lM, respectively) (Yoon et al. 2008). Eckstolonol (47) and phlorofucofuroeckol-A (49) were also found to possess BChE inhibitory activities with IC50 values of 230.27 and 136.71 lM, respectively (Yoon et al. 2008). Plantae (red alga) Homotaurine (53, tramiprosate, Alzhemed) is an aminosulfonate metabolite found in marine red alga Grateloupia livida, although it was first discovered by chemical synthesis (Fig. 8) (Miyasawa et al. 1970; Sen 1962). Due to the structural similarities of 53 and the neurotransmitter gamma aminobutyric acid (GABA), 53 binds to GABA receptor (Fariello et al. 1982). In an in vitro study, homotaurine (53) showed preferential binding to soluble Ab, and thus, inhibited Ab aggregation and maintained Ab in non-toxic non-fibrillar form (Gupta-Bansal et al. 1995). In addition, the administration of 53 to an AD transgenic mouse model (TgCRND8 mice) significantly reduced amyloid plaque formation in brain and decreased cerebral Ab levels (Gervais et al. 2007). Furthermore, 53 produced promising results in preclinical and human phase II clinical trials (Aisen et al. 2006). However, 53 was not found to be

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D.-Y. Choi, H. Choi Fig. 7 Marine natural products (Chromista) with neurologic activities

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clinically effective in mild-to-moderate AD patients in phase III clinical trials (Aisen et al. 2011). Fungi Neoechinulin A (54), a diketopiperazine alkaloid containing a prenylated indole was isolated from the red algaeassociated fungi Microsporum sp. and Aspergillus sp. (Fig. 9) (Dewapriya et al. 2013; Casnati et al. 1972; Kimoto et al. 2007; Li et al. 2004). In an in vitro study, 54 ameliorated neurotoxicities in PC12 cells induced by the PD-inducing neurotoxins, 1-methyl-4-phenylpyridinium

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and rotenone (Kajimura et al. 2008; Akashi et al. 2011). Moreover, in Ab42-activated BV-2 microglia cells, 54 reduced the productions of reactive oxygen species and nitric oxide and suppressed the expressions of pro-inflammatory cytokines. In addition, the activated microglia induced apoptosis of PC12 pheochromocytoma cells was significantly repressed by neoechinulin A (54, Dewapriya et al. 2013). Anhydrojavanicin (55) is a fungal pigment found in Fusarium javanicum, and F. Solani. It was first identified as an antibacterial natural product possessing a quinone moiety in F. Javanicum (Arnstein and Cook 1947; Kimura


et al. 1988). 8-O-Methylbostrycoidin (56) is an azaanthraquinone pigment that was first reported in the fungus F. Moniliforme (Steyn and Wessels 1979). Recently, anhydrojavanicin (55), and 8-O-methylbostrycoidin (56) were also reported in the extract of mangrove endophytic fungus Aspergillus terreus, and both compounds were found to inhibit AChE activity in an in vitro study with IC50 values of 2.01 and 6.71 lM, respectively (Deng et al. 2013). NGA0187 (57) is a natural sterol found in the fermentation broth of Acremonium sp. TF-0356, which induces neurite outgrowth from PC12 cells (Nozawa et al. 2002). Beauvericin (58) is a depsipeptide that was first isolated as an antibiotic mycotoxin from a mycelium culture of Beauveria bassiana (Hamill et al. 1969). Recently NGA0187 (57) and beauvericin (58) were isolated from an extract of the endophytic fungus Aspergillus terreus and found to be AChE inhibitors with IC50 values of 1.89 and 3.09 lM, respectively (Deng et al. 2013). Fig. 8 Structure of homotaurine from a red alga Grateloupia livida

+

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Alaternin (59) is an anthraquinone found in the plants Rhamnus alaternus and Cassia tora, and in fungi, such as, Alternaria solani and Alternaria porri (Abou-Chaar and Shamlian 1980; Choi et al. 1994, 1998; Suemitsu et al. 1975). Recently, alaternin (59) was isolated from the marine mangrove fungus Paecilomyces sp. (Wen et al. 2007). Alaternin has been reported to inhibit AChE with an IC50 value of 0.87 lg/mL and to have an in vivo neuroprotective effect (Wen et al. 2007; Shin et al. 2010). In addition, it has been reported to have diverse bioactivities including antioxidant effects, antimutagenic effects, antitumor activity (IC50 of 7.0 lg/mL) (Choi et al. 1994, 1998; Wen et al. 2007). A mangrove-associated metatrophic fungus Paecilomyces sp. (Tree1–7) has been reported to produce a cytotoxic xanthone, paeciloxanthone (60) (Wen et al. 2008). This compound also showed in vitro AChE inhibitory activity (IC50 = 2.25 lg/mL), a cytotoxic effect on HepG2 cells (IC50 = 1.08 lg/mL) and antimicrobial activities against Curvularia lunata, Candida albicans and E. Coli (Wen et al. 2008). A series of xyloketals were isolated from the broth of the cultured mangrove-associated fungus Xylaria sp. These compounds have a highly substituted core aromatic ring and one or more ketals. In particular, xyloketal A (61),

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Fig. 9 Marine natural products (Fungi) with neurologic activities

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antioxidant property of 62 is due to the induction of heme oxygenase-1 (HO-1) expression via phosphoinositide 3 kinase (PI3 K), AK mouse plus Transforming or Thymoma, and nuclear factor erythroid 2-related factor 2 associated pathways (Li et al. 2013). Secalonic acid A (63) has been described as a phlogistic and cytostatic natural product. It is present in marine fungi, including Aspergillus ochraceus and Paecilomyces sp. (Harada et al. 1974; Kurobane et al. 1987; Zhai et al. 2011). Pretreatment of cultured rat cortical neurons with 63 provided neuroprotection against colchicine-induced neurotoxicity (Zhai et al. 2011). In a PD mouse model, 63 protected against MPTP-induced dopaminergic neuronal cell death, and in nigral neurons and SH-SY5Y cells

which has C3 symmetry about a core hexa-substituted benzene ring substituted with three ketals, inhibited AChE at a concentration of 1.5 lM (Lin et al. 2001). Xyloketal B (62) is structurally closely related to xyloketal A (61). Xyloketal B (62) directly scavenged di(phenyl)-(2,4,6-trinitrophenyl)iminoazanium (DPPH) free radicals and protected PC12 cells against ischemiainduced cell injury without inducing cell proliferation or cytotoxicity (Zhao et al. 2009; Chen et al. 2009). Xyloketal B (62) showed neuroprotective activities against 1-methyl4-phenylpyridinium (MPP?)-induced neurotoxicity in Caenorhabditis elegans and PC12 cells mainly due to its antioxidant properties and restoration of total glutathione levels (Lu et al. 2010). Recently, it was reported that the O

O O

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Fig. 10 Marine natural products (Porifera) with neurologic activities

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O

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90 R = -CH=CH- (Z form) 91 R = -CH2-CH=CH- (Z form)

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Fig. 10 continued

protected against MPP?-induced neurotoxicity (Zhai et al. 2013). JBIR-59 (64) and JBIR-124 (65) were isolated from the mycelium of a marine sponge-derived fungus Penicillium citrinum SpI080624G1f01 (Ueda et al. 2010; Kawahara et al. 2012). Both JBIR-59 (64) and JBIR-124 (65) are hexaketides of the sorbicillinoids class and scavenged the DPPH radical with IC50 values of 25 and 30 lM, respectively (Kawahara et al. 2012). Animalia Porifera (marine sponges) Leucettamine B (66) is an imidazolone containing alkaloid that was isolated from the marine sponge Leucetta

microraphis, and has been reported to inhibit AD-related protein kinases, such as, DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) (Fig. 10) (Chan et al. 1993; Watanabe et al. 2000). Later the medicinal chemistry study led to the discovery of synthetic analogs of 66 in the leucettines class. Leucettine L41 (67), an optimized analog of 66, were cocrystalized with a number of protein kinases (DYRKs, CLK3, PIM1 and GSK3b) related to AD development. Leucettine L41 (67) protected HT22 cells against the glutamate-induced neurotoxicity (Tahtouh et al. 2012). In the rat brain, leucettine L41 (67) reduced APP-induced cell death (Tahtouh et al. 2012). Palinurin (68) is a furanosesquiterpene isolated from the marine sponge Ircinia variabilis (Alfano et al. 1979). Palinurin (68) inhibited the activity of GSK3b. However

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the activity is achieved not by competing with ATP or peptide substrates but by allosteric mechanism. Therefore, 68 inhibited GSK3b with a high degree of selectivity with the IC50 value of 4.5 lM (Bidon-Chanal et al. 2013; Gordillo et al. 2004). Furthermore 68 reduced the hyperphosphorylation of tau protein (Bidon-Chanal et al. 2013; Gordillo et al. 2004). Hymenaldisine (69) is an alkaloid found from the extract of marine sponge Axinella verrucosa and Acanthella aurantiaca (Supriyono et al. 1995). The compound 69 found to compete with ATP for binding to GSK3b and to be a potent GSK3b inhibitor with the IC50 value of 35 nM (Meijer et al. 2000). Hymenaldisine (69) blocked the hyperphosphorylation of tau protein both in vitro and in vivo (Meijer et al. 2000). Debromohymenialdisine (70), a naturally occurring analog of 69 lack of bromine atom, was originally isolated from the marine sponge Phakellia flabellate (Sharma et al. 1980). Likewise 69, debromohymenialdisine (70) also inhibited the activities of diverse protein kinases including CDK5/p25 (IC50 = 0.4 lM), CK1d (IC50 = 0.1 lM), and GSK3b (IC50 = 0.2 lM) without antibacterial activities (Zhang et al. 2012a). Manzamine A (71) is also an alkaloid from the marine sponge Haliclona sp. And it was first reported with the cytotoxicity against cancer cells (Sakai et al. 1986). Later, it has been found that manzamine A (71) was an inhibitor of GSK3b with the IC50 value of 10 lM (Hamann et al. 2007). (Z)-5-(4-hydroxybenzylidene)-hydantoin (72) was isolated from the Red Sea sponge Hemimycale arabica and first reported with its anti-methastatic activity against prostate cancer (Mudit et al. 2009; Shah et al. 2009). In an in vitro study, 72 was revealed to inhibit the activity of GSK3b with the IC50 of 13.7 lM via direct binding (Khanfar et al. 2009). A synthetically modified analog (73) also inhibited the activity of GSK3b with the IC50 of 4.2 lM in an in vitro experiment. Furthermore, 73 inhibited the activity of GSK3b and increased hepatic glycogen level significantly in vivo (Khanfar et al. 2009). Three series of alkaloids in the classes of lamellarins, ianthellidones, and dictyodendrins were reported from the Australian marine sponge Ianthella sp. (Zhang et al. 2012c, d). These three structure classes are speculated to be biosynthetically related one another. Lamellarins O (74), O1 (75) and O2 (76) are pyrrole-containing alkaloids, while ianthellidone F (77) is a pyrrolidone containing molecule. The BACE1 inhibitory activities of these four structurally related compounds were evaluated at the concentration of 10 lM. The compounds 74, 75, 76, and 77 showed reduction of BACE1 activity 40, 60, 40, and 40 %, respectively (Zhang et al. 2012c). Dictyodendrins are also pyrrolidone-containing alkaloids which were speculated to

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be produced from three units of 4-hydroxy phenyl residues with a tryptophan. Dictyodendrins F (78), H (79), I (80), and J (81) showed BACE1 inhibitory activities with the IC50 values of 1.5, 1.0, 2.0 and 2.0 lM, respectively. In particular, the compound 81 showed no significant cytotoxicity against human colon cancer cell line (SW620) (Zhang et al. 2012d). Xestosaprols are pentacyclic compounds isolated from an Indonesian marine sponge in the genus of Xestospongia (Millań-Aguinãga et al. 2010; Dai et al. 2010a). Two compounds in the xestosaprols class, xestrosaprols D (82) and H (83) were weakly inhibited the activity of BACE1 with the IC50 values of 93 and 82 lM, respectively. 29-Hydroperoxystigmasta-5,24(28)-dien-3-ol (84) was isolated from Xestospongia testudinaria (Zhou et al. 2014). This hydroperoxy steroid showed diverse inhibitory activities against PGC-1a (IC50 = 32 lM) and the other enzymes including Foxo3a, GFP-tagged human 3-hydroxy3-methylglutaryl-CoA reductase, luciferase tagged nuclear factor kappa-light-chain-enhancer of activated B cells, and protein-tyrosine phosphatase 1B, with the IC50 ranges between 8.5 and 43 lM. A sulfated sterol, topsentinol K trisulfate (85) was first isolated from an undescribed marine sponge Topsentia sp. Topsentinol K trisulfate (85) was found to inhibit BACE1 with IC50 value of 1.2 lM. However, it was also revealed that the BACE1 inhibition of 85 was achieve by nonstoichiometric aggregation of 85 with the target enzymes (Dai et al. 2010b). 4-Acetoxy-plakinamine B (86) is a stigmastane-type steroid found from the Thai sponge Corticium sp. (Langjae et al. 2007). This marine steroidal alkaloid reversibly inhibited AChE activity with the IC50 of 3.75 lM in a mixed-competitive mode. Fascaplysin (87) is a bis-indole alkaloid found from marine sponge Fascaplysinopsis sp. (Roll et al. 1988). This compound was reported as an antimicrobial pigment, a cytotoxin against cancer cell lines and a selective inhibitor of CDK4/cyclin D1 with the IC50 of 350 nM (Roll et al. 1988; Segraves et al. 2004; Soni et al. 2000). Fascaplysin (87) noncompetitively inhibited AChE with the IC50 and ki values of 1.49 and 2.28 lM, respectively (Bharate et al. 2012a). The compound 87 also showed selective inhibitory activity against AChE over BChE about 60-fold. Furthermore molecular docking experiments revealed that fascaplysin (87) docked into the AChE active site (Bharate et al. 2012a). Oroidin (88) is an antimalarial marine natural product isolated from Agelas oroides (Forenza et al. 1971; Garcia et al. 1973). The compound 88 also possessed antioxidant property to scavenge DPPH radical with the IC50 of 64 lM and weakly inhibited AChE activity with the IC50 around 500 lM (Orhan et al. 2012).


Variolin B (89) is a marine natural product isolated from the Antarctic sponge Kirkpatrickia vaialosa (Perry et al. 1994). This alkaloid was first reported with its potent antitumor and anti-viral activities and has been in the anticancer drug discovery pipeline for a while. Later variolin B (89) was revealed as the inhibitor of CDKs such as CDK1 (IC50 = 60 nM), CDK2 (IC50 = 80 nM), CDK5 (IC50 = 90 nM), and CDK9 (IC50 = 26 nM) and other protein kinases including GSK3b (IC50 = 70 nM), CK1 (IC50 = 5.0 nM) and DYRK1A (IC50 = 80 nM) (Simone et al. 2005; Echalier et al. 2008). A series of diamine alkaloids including the saraines and the isosaraines were isolated from the Mediterranean marine sponge Reniera sarai (Cimino et al. 1986a, b, 1989a, b; Guo et al. 1996, 1998). Saraines 1 (90), 3 (91), A–C (92–94) showed insecticidal activity, toxicity to brine shrimp and antibacterial activities (Caprioli et al. 1992). In addition, the compound 90 had good anti-fouling activity (Blihoghe et al. 2011). The mixtures of saraines A–C (92– 94), isosaraine 1 (95), saraines 1 (90) and 3 (91) inhibited the activity of AChE in a competitive mode with reversible manner (Defant et al. 2011). Platisidines A–C (96–98) are alkaloids isolated from an Okinawan marine sponge in the genus of Plakortis (Kubota et al. 2010). They contain N-methylated pyridinium structures and they are N-methyl nicotinic acid derivatives with a hexadecanoyl chain. Platisidines A–C (96–98) showed inhibitory activity against AChE (Kubota et al. 2010). Petrosamine (99) was isolated from marine sponge in the genus of Petrosia (Molinski et al. 1988). The compound 99 is a colored pentacyclic alkaloid in the class of pyridoacridine and showed potent AChE inhibitory activity with the IC50 value of 91 nM which is six times lower value than that of galantamine (IC50 = 590 nM) (Nukoolkarn et al. 2008). A number of sesquiterpene including ilimaquinone (100), 5,8-diepi-ilimaquinone (101), and 4,5-diepi-dactylospongiaquinine (102) were isolated from the extracts of the sponge Dactylospongia elegans (Luibrand et al. 1979; Capon and MacLeod, 1987; Du et al. 2013). These three sesquiterpene quinones (100–102) activated HIF-1 and increased the level of vascular endothelial growth factor proteins in T47D cells at the concentration of 10 lM (Du et al. 2013). At the higher concentration of 30 lM, compounds 100–102 suppressed cell proliferation/viability (Du et al. 2013). Five gracilins (103–107) and tetrahydroaplysulphurin-1 (108) were first reported from Spongionella gracilis with the effect against tyrosine kinase (Rateb et al. 2009). They possess diterpene structures with the high levels of oxidation. On an oxidative in vitro stress model, tetrahydroaplysulphurin-1 (108), gracilins A (103), H (104), J (105), K (106), and L (107), showed anti-oxidant activity

and protected primary cortical neurons from H2O2 induced cytotoxicity. In particular, the compound 108 showed complete neuroprotective effect at 1.0 and 0.1 lM (Leiro´s et al. 2014). Cnidaria 11-Dehydrosinulariolide (109) is a diterpene macrolide with an epoxide isolated from the cultured soft coral, Sinularia flexibilis (Fig. 11) (Chen et al. 2012). The compound 109 down-regulated the expressions of inducible nitric oxide synthase and cyclooxygenase-2 in lipopolysaccharide-stimulated macrophage cells (Chen et al. 2012). In an in vitro PD model study, 11-dehydrosinulariolide (109) also protected a human neuroblastoma cells against 6-hydroxydopamine-induced cytotoxicity and apoptosis (Chen et al. 2012). In addition, the compound 109 regulated PI3 K/Akt pathway and reduced the activity of caspases 3/7. Waixenicin A (26) is a diterpenoid isolated from the soft coral Sarcothelia edmondsoni (formerly known as Anthelia edmondsoni) (Coval et al. 1984). Originally, the structure of waixenicin A (26) with a nine-membered ring has been reported without any biological activities. Recently, its pharmacological potential on the inhibition of cancer cell proliferation and the prevention of the cerebral ischemiainduced neuronal injury through TRPM7 inhibition has been found (Zierler et al. 2011). Annelida Anabaseine (110) is an alkaloid toxin originally isolated from a marine ribbon-worm Paranemertes peregrine and also found in the other animals such as Aphaenogaster ants

O

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O O 109

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Fig. 11 Marine natural products (Cnidaria) with neurologic activities

N O N H+

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111 R = CH3 112 R = H

Fig. 12 A marine natural product (Annelida) and its derivatives with neurologic activities

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(Fig. 12) (Kem and Abbott, 1971; Wheeler et al. 1981). Anabaseine (110) is a nonselective mixed agonist/antagonist for diverse types of nAChR (Kem et al. 1997). Two benzylidene derivatives of 110, 3-(2,4-dimethoxybenzylidene)anabaseine (GTS-21, 111) and 3-(2-methoxy,4-hydroxybenzylidene)anabaseine (4-OH-GTS-21, 112) showed highly selective agonistic activity for the a7 receptor subtype, while compound 110 showed potent activity with muscle-type and neuronal a3b4 and a4b2 nAChR (Papke et al. 2004). GTS-21 (111) showed improve behavioral actions of patients under AD and protect rat neurons from apoptotic and necrotic insults both in vitro and in vivo (Martin et al. 1994; Meyer et al. 1998a; Shimohama et al. 1998). The compound 112 showed neuroprotective effects against amyloid-toxicity in both human and rat cell lines (Meyer et al. 1998b). Bryozoa Bryostatin 1 (113) is a macrolide lactone isolated from a bryozoan Bugula neritina (Fig. 13) (Pettit et al. 1982). The compound 113 was first reported with the potent anticancer activity in both in vivo and in vitro experiments. Later bryostatin 1 (113) was also reported to agonize PKC isoforms at subnanomolar concentrations and to reduce the production of Ab40 and Ab42 in AD double-transgenic mice (Hennings et al. 1987; Mutter and Wills 2000; Etcheberrigaray et al. 2004). In acute cerebral ischemia rat model, bryostatin 1 (113) administration protected the brain from neurological injury after reversible occlusion of the right middle cerebral artery (Tan et al. 2013). A series of pyrrolidinoindoline alkaloids have been known as potent inhibitors of cholinesterase inhibitors. A representative of this class is physostigmine (114), also known as eserine, which was isolated from the seeds of Physostigma venenosum (Rodin, 1947). A series of prenylated physostigmine type marine natural products has been reported from a cheilostome bryozoan Flustra

foliacea (Carle and Christophersen 1979; Holst et al. 1994). The debromoflustramine B (115) showed potent BChE inhibition with the IC50 of 1.37 lM (Rivera-Becerril et al. 2008). Mollusca The indirubins are pigments in the class of bis-indole alkaloids isolated from mollusca. 6-Bromoindirubin (116) was found from the Mediterranean mollusca Hexaplex trunculus and reported as a selective inhibitor of GSK3b with the IC50 value of 45 nM (Fig. 14) (Meijer et al. 2003). 6-Bromoindirubin-30 -oxime (117), a synthetic analog of 116, interacted with the ATP binding pocket of GSK3b and inhibited the phosphorylation of GSK3b. Furthermore, the compound 117 reduced the phosphorylation of b-catenin on GSK3 specific site in cellular models (Meijer et al. 2003). Fish-hunting cone snail in the genus Conus are well known to possess the polypeptide venoms. Conantokin-G (118), a peptide with 17 amino acids including five ccarboxyglutamates was isolated from the cone snail Conus geographus and found to induce sleep-like state in mice (McIntosh et al. 1984). The compound 118 was also reported as a NMDA antagonist with high affinity (Skolnick et al. 1992). In the in vitro experiments, Conantokin-G (118) decreased excitotoxic calcium response to NMDA and exhibited neuroprotective effects against hypoxia/ hypoglycemia-, NMDA-, glutamate-, or veratridineinduced toxicity in primary cerebellar neurons. Furthermore, the compound 118 showed neuroprotective effects in vivo rat ischemia model (Williams et al. 2000). However, it failed in the phase II clinical trials for the treatment of epilepsy. a-Conotoxin BuIA (119) is one of the conopeptide isolated from Conus bullatus and inhibited several types of Br O

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Fig. 13 Marine natural products (Bryozoa) with neurologic activities and physostigmine

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Fig. 14 Marine natural products (Mollusca) and a derivative with neurologic activities


the mice and found later as a blocker of N-type voltage sensitive calcium channel with the IC50 of 0.055 nM (Olivera et al. 1987; Kristipati et al. 1994; Lewis et al. 2000). Later, it has been approved as an analgesic drug for patients with intractable pain (Lynch et al. 2006; Williams et al. 2008). A single bolus i.v. Injection of the compound 120 after 24 h of the onset of stroke showed potent neuroprotective activity in a rat model of transient forebrain ischemia (Valentino et al. 1993). Also, i.v. Infusion of the compound 117 in a rat focal ischemia model reduced the neocortical infarct volume effectively by inhibition of glutamate release from presynaptic sites (Takizawa et al. 1995).

neuronal nAChRs (Jin et al. 2007; Azam et al. 2005). The compound 119 blocked nAChR a6a3b2(b3) with the IC50 of 0.26 nM without clear specificity (Azam et al. 2005). However, this compound showed very slow off-times with b4 subunits compared with that with b2 subunits of neuronal nAChRs and the difference of wash-off time allowed the differentiation between those two functionally important subunits by a-conotoxin BuIA (119) (Azam and McIntosh 2006; Shiembob et al. 2006). x-Conotoxin MVIIA (120) was also isolated from another species of fish-hunting marine snail Conus magus by intracerebral bioassay guided isolation (Olivera et al. 1987). This marine toxin elicited the shaking behavior of

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Fig. 15 Marine natural products (Chordata) and a derivative with neurologic activities

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Chordata Ascidiaceae (acidians, tunicates) Didemnaketals D (121) and E (122) were isolated from a Red Sea ascidian Didemnum sp. And they possessed spiroketal terpenoids with an additional ketal (121) or a hemiketal (122) (Fig. 15). They showed moderate protein kinases inhibition against CDK5, CK1, DYRK1A and GSK3 with all the IC50 values of both compounds over 11 lM (Mohamed et al. 2014). Aromatic alkaloids in the class of ningalins were isolated from the Australian ascidian of the genus Didemnum (Plisson et al. 2012; Kang and Fenical 1997). They possess a number of catechol structures derived from 3,4-dihydroxyphenylalanine (DOPA). Ningalins B (123), E (126), and F (127) were identified as the modest protein kinase inhibitors against CK1d and GSK3b with the IC50 ranges between 0.8–3.9 lM. Ningalins C (124), D (125), and G (128) were found as more potent inhibitors against three protein kinases, CK1d (IC50 = 0.2–1.4 lM), GSK3b (IC50 = 0.2–0.5 lM), and CDK5 (IC50 = 0.5–2.4 lM) (Plisson et al. 2012). Meridianins are indole alkaloids first isolated from tunicate Aplidium meridianum and some of meridianins have also been reported from the Antarctic tunicate in the genus of Synoicum (Bharate et al. 2012b; Franco et al. 1998; Lebar and Baker 2010). Meridianins were reported as inhibitors of protein kinases including CDKs, GSK3, cyclic nucleotide-dependent kinases and CK1 related to AD (Bharate et al. 2012b; Gompel et al. 2004). Among the known meridianins, meridianin E (129) were found most potent inhibitor of protein kinases, CDK1/B (IC50 = 0.18 lM), CDK5/p25 (IC50 = 0.15 lM), GSK3a (IC50 = 0.90 lM), GSK3b (IC50 = 2.50 lM), and CK1 (IC50 = 0.40 lM) (Radwan and El-Sherbiny, 2007). Chordata—actinopterygi Seahorses have been used as traditional medicine for anti-aging, anti-fatigue, strengthening the kidney and neuroprotective effects in many countries (Li et al. 2008). HTP-1 (130) has been isolated from the heavily traded species of seahorse, Hippocampus trimaculatus as a bioactive natural product (Fig. 15). HTP1 (130) is a peptide with a sequence of Gly-Thr-Glu-AspGlu-Leu-Asp-Lys and showed neuroprotective effects against Ab42 on PC12 cells (Pangestuti et al. 2013). Docosahexaenoic acid (131, DHA; C22:6) is an essential fatty acid widely found in fish (Watters et al. 2012). This polyunsaturated fatty acid is also found in the central nerve system, synaptic and other cellular membranes. DHA is closely related to the function of CNS, synaptogenesis, cognition, neuroprotection, synaptic function and vision (Bazan, 2006; Lim et al. 2005; Lukiw et al. 2005; Salem et al. 2001). In particular, DHA treatment did not prevent

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AD-related dementia, but it retarded the progression of cognitive decline in aged individuals without dementia (Fotuhi et al. 2009; Quinn et al. 2010). Additionally, in an in vivo AD animal model, dietary DHA ameliorated Ab pathology by reduction of Ab deposition (Calon et al. 2004; Green et al. 2007). Recently, the DHA-derived neuroprotectin D1 (132) was identified as the modulator of DHA-dependent neuroinflammation and neuroprotection. Neuroprotection D1 decreases Ab42 production via the modulation of asecretase and b-secretase as well as the activation of PPARc (Zhao et al. 2011). Marine natural product and the derivatives in clinical trials for the treatment of neurological disorders Historically, eight compounds of marine natural products or their derivatives have been approved as drugs to treat viral infection (vidarabine; iota-carrageenan 7), cancer (cytarabine 1; trabectedin 2; eribulin mesylate 3; brentoximab vedotin, 4), neuropathic pain (ziconotide), hypertriglyceridemia (omega-3-acid ethyl esters, 5). Among them, ziconotide (6, tradename: Prialt) was discovered for the treatment of neuropathic pain. The other neuropeptide of cone snail in the genus of Conus such as x-conotoxin CVID and contulakin-G are also in the phase II trials for neuropathic pain treatment (Mortari et al. 2007). Several marine natural products and their derivatives are currently in the drug discovery pipeline to treat neurological diseases. Homotaurine (tramiprosate, 3APS, 53) was in phase III clinical trials (NCT00314912) for the patients with mild-to-moderate AD, but this compound showed not enough clinical efficacy (Aisen et al. 2011). GTS-21 (DMXBA, 111), a synthetic derivative of anabaseine (110) is in phase II for participants with probable AD (NCT00414622) and for Schizophrenia patients (NCT01400477). Bryostatin 1 (113) is also in the clinical trials for the AD patients (phase II, NCT00606164) and the patients in diverse cancers (phase II) (Lam et al. 2010). DHA (131) is also in phase III clinical trials (NCT00440050) for slowing the progression of AD.

Conclusion In this review, 104 compounds (26, 29–113, 115–132) isolated or derived from marine organisms possessing pharmacological activities on the therapeutic targets for neurodegenerative diseases including AD, PD, and ischemic brain-stroke are included (Table 1). Among these compounds, 67 marine natural products (26, 66–113, 115– 132) have been reported from marine organisms in the kingdom of Animalia. However, many of natural products


found in macroorganisms are speculated to be biosynthesized by microorganisms (Gerwick and Moore 2012). Therefore, the number of neuropharmacologically active compounds from marine microorganisms such as bacteria and fungi could be increased. Currently, no pharmacologically effective treatment to block or cure the progression of neurodegenerative diseases and ischemic brain-stroke has been developed. With an explosively increasing mortality and morbidity rate of these diseases, the discovery and development of new drugs to treat them is highly demanding. The marine natural products have been known for their structural diversity, due to high biodiversity and genetic uniqueness of marine organisms as well as severe competition for survival in their habitat. Therefore, the marine natural products could be a very promising chemical pool to discover neuropharmacologically active compounds with new structures as potential drug leads for AD, PD, and ischemic brain stroke. Acknowledgments This work was supported by the 2014 Yeungnam University Research Grant.

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