Pharmacological approaches for Alzheimer's disease: neurotransmitter as drug targets.

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SPECIAL FOCUS y The Current and Future Use of Alzheimer’s Disease Therapeutics

Review

Pharmacological approaches for Alzheimer’s disease: neurotransmitter as drug targets Expert Rev. Neurother. Early online, 1–19 (2014)

Atish Prakash*1–3, Jaspreet Kalra2, Vasudevan Mani1, Kalavathy Ramasamy3, Abu Bakar Abdul Majeed1 1 Brain Research Laboratory, Faculty of Pharmacy, Campus Puncak Alam, Universiti Teknologi MARA (UiTM), 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia 2 Department of Pharmacology, ISF college of Pharmacy, Ghal kalan, Moga 142-001, Punjab, India 3 Brain Degeneration and Therapeutics Group, Brain and Neuroscience Communities of Research, Universiti Teknologi MARA (UiTM), 40450 Shah Alam, Selangor Darul Ehsan, Malaysia *Author for correspondence: [email protected]; [email protected]

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Alzheimer’s disease (AD) is the most common CNS disorder occurring worldwide. There is neither proven effective prevention for AD nor a cure for patients with this disorder. Hence, there is an urgent need to develop safer and more efficacious drugs to help combat the tremendous increase in disease progression. The present review is an attempt at discussing the treatment strategies and drugs under clinical trials governing the modulation of neurotransmitter. Therefore, looking at neurotransmitter abnormalities, there is an urge for developing the pharmacological approaches aimed at correcting those abnormalities and dysfunctioning. In addition, this review also discusses the drugs that are in Phase III trials for the treatment of AD. Despite advances in treatment strategies aimed at correcting neurotransmitter abnormalities, there exists a need for the development of drug therapies focusing on the attempts to remove the pathogenomic protein deposits, thus combating the disease progression. KEYWORDS: Alzheimer’s disease • neurotransmitter • neurotransmitter dysfunction • pharmacological approaches

Alzheimer disease (AD) is the most common chronic progressive neurodegenerative disorder affecting elderly population above 65 years of age [1]. Clinically, AD typically begins with slight decline in memory and gradually progresses to global deterioration in cognitive and adaptive functioning like diminished executive functioning, faulty judgment, deterioration in self-care and ultimately the lack of ability to manage life independently [2,3]. According to WHO, more than 35 million individuals are living with AD worldwide [4]. Current estimates suggests that 5.4 million Americans have AD, and this increased prevalence is anticipated to get triple over the next 40 years due to demographic changes and longer life expectancies of individuals [5,6]. On the basis of etiology, onset of symptoms, pathophysiological, biochemical and genetic alterations, AD is classified into two subtypes, familial AD and sporadic AD [7,8,2]. Familial AD is caused by missense mutations in the amyloid precursor protein gene, presenilin (PS)1 gene, presenilin (PS)-1 gene on chromosome

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21, 14 and 1 [7,9]. Whereas sporadic AD is linked with inherent changes in cerebral ATP production, energy metabolism, regulation and pathways associated with it at cellular, molecular and genetic levels [10]. Extracellular synaptotoxic b-amyloid (Ab) peptide, neuritic plaques composed of aggregated Ab and intracellular neurofibrilary tangles composed of hyperphosphorylated tau protein are believed to be central to the pathogenesis of AD [11]. Apart from these two mechanisms, chronic oxidative stress, mitochondrial dysfunction, hormone imbalance, neuroinflammation, mitotic dysfunction, calcium overload and genetic disturbances play a crucial role in the disease process. The mechanisms are diverse, accompanied by number of inevitable event resulting in AD [12]. Neuropathological studies have demonstrated that dementia involves loss of neuron in distinct brain areas with an associated alteration in different neurotransmitters [13]. It has been reported that several neurotransmitter systems, including the cholinergic,

2014 Informa UK Ltd

ISSN 1473-7175

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Review

Prakash, Kalra, Mani, Ramasamy & Majeed

glutamatergic, serotonergic, GABAergic and possibly dopaminergic neurons, are disturbed in AD [14]. Numerous postmortem studies have revealed that neurotransmitter systems are not consistently affected in AD [15–17]. Cholinergic, serotonergic and glutamatergic deficits are present at relatively early stages of AD, while dopaminergic and GABAergic systems appear to be affected later in the pathogenesis of AD [18,19]. Neuropeptides, angiotensin-converting enzyme, histamine, oxygen free radicals, platelet-activating factor (PAF) and neurotropic factor have also been implicated in the process of learning and memory [20–24]. However, of changes in those systems, the cholinergic abnormality is the most severe and intimately related to the severity of the disease [14]. So, here we have tried to summarize the dysfunction of various neurotransmitters and the role of its modulators for proper functioning of the abnormal neurotransmitters in AD. Pharmacological approaches modulating multiple neurotransmitters release

There are many hypotheses indicating that multiple neurotransmitters pathways could be linked to the development of AD. Previously, it was demonstrated that a single neuron produced only a single type of neurotransmitter. However, there is now convincing evidence that many types of neurons contain and release two or more different neurotransmitters. When more than one transmitter is present within a nerve terminal, the molecules are called co-transmitters. Because each class of transmitter tends to be packaged in a separate population of synaptic vesicles, co-transmitters typically are segregated within a presynaptic terminal. Cholinergic system

Approximately all the neurotransmitters, and neuropeptides, play a significant role in regulation of normal functioning of brain [25]. Neurodegenerative alterations in any of the neurotransmitter system of specific brain region have been interrelated with specific disease. AD is particularly interrelated with neuronal degeneration and hypofunction of basal forebrain cholinergic neurons [26,27]. Acetylcholine (Ach) is a neurotransmitter that acts as selective agonist for cholinergic receptors. Nicotinic receptors and muscarinic receptors are the two subtypes of cholinergic receptors. Muscarinic receptors are expressed in the brain and parasympathetic effector organs, whereas nicotinic receptors are located in the skeletal neuromuscular junction and autonomic ganglia [28,29]. The two main nicotinic acetylcholine receptor (nAChR) subtypes expressed in the CNS are the a7 and a4b2 receptors [30]. Decreased expression of nicotinic receptors has been found in AD brains [31–33]. Growing body of evidence also shows the significance of muscarinic receptors in AD. Tsang et al. showed that M1 receptor densities are not affected in AD patients, but M1/ G-protein pairing in the frontal cortex was markedly decreased and linked with the severity of cognitive decline [34]. The degree of cholinergic neurodegeneration correlates completely with severity of memory impairment, particularly doi: 10.1586/14737175.2015.988709

short-term memory in AD patients [18,35]. Thus, the various strategies for enhancing cholinergic transmission are proposed including the use of ACh precursors, inhibitors of cholinesterases, muscarinic and nicotinic agonists and ACh releasers. ACh precursor

Preclinical studies have reported choline as a prime component for the synthesis of Ach and lecithin, choline increases the production of brain ACh hence supporting the fact that they can be used in the treatment of cholinergic diseases like AD [36–38]. Many of clinical studies indicated that choline administration does not increase ACh synthesis but make brain rich in choline by increasing its availability [39,40]. According to Amenta and Tayebati, cholinergic precursors for biosynthesis of Ach should be stored and incorporated in phospholipids, such as cytidine 5´-diphosphocholine (CDPcholine) or a-glyceryl phosphorylcholine (choline alphoscerate), both of them accounts for increased levels of Ach and improvement in cognitive dysfunction [41]. Acetylcholinesterase inhibitors

These are the inhibitors of enzyme acetylcholinesterase, which facilitate the working of Ach via prolonging its interaction with cholinergic receptors and potassium ion channels, and affect the uptake, synthesis and release of neurotransmitters [42]. Since 1993, the FDA approved four cholinesterase inhibitors and one NMDA blocker for treatment of mild to moderate AD, tacrine (Cognex 1993), donepezil (Aricept 1996), rivastigmine (Exelon 2000) and galantamine (Razadyne 2001), memantine (Namenda 2003). Tacrine, an acridine derivative, was found to be a potent acetylcholinesterase inhibitor. It is an orally active amine readily crosses blood–brain barrier. It increases the release of Ach from cholinergic nerve endings, inhibits enzyme monoamine oxidase, decreases the release of GABA and increases the release of noradrenaline, dopamine (DA) and 5-HT from nerve endings, therefore, proving its beneficial role in AD patients [43]. Tacrine was later discarded because of its hepatotoxicity, gastrointestinal adverse reactions, poor oral bioavailability and frequent dosing requirements. Meta-analyses have revealed that acetylcholinesterase inhibitors have a modest beneficial effect on cognition and memory [44]. Donepezil offers neuroprotection by attenuating glutamate excitotoxicity, diminishing Ab load, toxicity and consequently increasing cell longevity [45,46]. Rivastigmine is an inhibitor of both AChE and butylcholinesterase, and clinical trials have shown that it is effective in improving cognition and functional impairment without apparent side effects in AD patients compared with placebo [44]. Muscarinic receptor 1 agonist

The cholinergic deficiency in AD appears to be mainly presynaptic. Therefore, pharmacological stimulation of the postsynaptic M1 R (muscarinic receptors), which are preserved until late stages of AD, may counteract the degeneration of presynaptic cholinergic terminals unable to suitably synthesize and release Ach [47]. Expert Rev. Neurother.

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Aβ

Aβ deposition in neuron

sAPPβ

Aβ

γ α β-secretase β

C99

Ca++

Intracellular Ca++

NMDA receptor

Amyloid precursor protein processing

Selective M1 agonist AF267B which is under clinical evaluation for its safety and tolerability reduces memory impairment, Ab42 load and tau hyperphosphorylation in AD triple transgenic mice [48]. Talsaclidine, AF-102B and AF-267B (NGX-267) are M1 R agonists that can affect Ab production [47]. Talsaclidine and AF-102B decreased CSF Ab concentrations in patients with AD [49], but these compounds can have potentially undesirable cholinergic receptor-mediated effects, such as increased salivary flow, although for this reason AF-102B and AF-267B have been tested in patients with xerostomia [50]. In addition to N-alkyl/aryl-substituted thiazolidinone arecoline analogs [51], N-aryl carboxamide-, sulfonamide- and thioureasubstituted 3-morpholino arecoline derivatives are novel analogs developed as M1 R agonist for treating dementing illness like AD [52–54].

Enzyme activation, Aβ plaque formation

Alzheimer’s disease

P

P

Tau hyperphosphorylation

Mitochondrial membrane potential

AMPA/KA receptor


Pharmacological approaches for AD

ROS Mitochondrial calcium

Astrocytes

Glutamate release

Alzheimer’s disease

Figure 1. Diagrammatic representation of pathways involved in glutamate excitotoxicity.

Nicotinic agonists

Enhancement of cholinergic transmission with nicotinic receptor agonists has also been investigated. Ispronicline (AZD-3480) is a selective agonist of the a4b2 -nicotinic receptor that has shown positive effects on memory impairment [55]. ABT-089, partial agonist of nicotinic a4b2 and a6b2 receptors causes reversal of cognitive deficits induced by hyoscine (scopolamine) in healthy volunteers [56]. ZY-1, a newer nicotinic analog has shown significant decrease in escape latency in transgenic mice model of AD [57]. Researchers have also illustrated the role of pre- and postsynaptic a7 nAChRs involved in modulating the release of neurotransmitter in brain via Ca2+-dependent mechanisms with conclusion that a7 nAChRs are responsible for regulating neuronal growth and differentiation in the developing CNS [58–61]. a7 nAChRs have also high affinity for Ab [62]. This interaction leads to intraneuronal accumulation of Ab1-42 (Ab1-42) a7 nAChR complexes [63], rapid tau phosphorylation [64] impairment of a7 nAChR channels [65,66], defects in cholinergic neurotransmission [67] and neuronal cell death [68]. Hence, disrupting Ab1-42 a7 nAChR interaction may characterize the novel approach for reducing Ab42-mediated functional memory deficits. a7 nicotinic receptor agonistsThree analogs of anabaseine, 3-(2,4)-dimethoxybenzilidine anabaseine (DMXB-A; also known as GTS-21), 3-(4)-dimethylaminobenzylidine anabaseine and 3-(4)-dimethylaminocinnamylidine, have been reported to be functionally selective for the a7 nAChRs. DMXB-A improved the cognitive function in young adult volunteers. It has also been reported that DMXB-A improved long-term memory as well as working memory and attention against memory impairment [69,70]. EVP-6124 agonist is safe and well tolerated in patients with AD. AD is accompanied by informahealthcare.com

disturbances in behavioral and psychological functions, agitation and anxiety being common symptoms. PNU-282987 a7 nAChR agonist has shown positive effect on motor, anxiety and stress in an animal model of AD [71]. Glutamatergic system

Excitotoxicity refers to a process of neuronal cell death caused by disproportionate or prolonged activation of receptors for the excitatory amino acid neurotransmitter glutamic acid, results in various neurodegenerative disorders including, AD, Parkinson’s disease and Huntington’s disease [72,73]. Glutamate is the major excitatory neurotransmitter in the mammalian CNS, primarily acts through NMDA receptor, a-(amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) AMPA, kainate and group 1 metabotropic receptors (mGluR1), but excitotoxicity is specifically mediated by NMDA receptors [74,75]. Therefore, modulation of NMDA and AMPA receptors considerably affects synaptic plasticity [75]. It has been reported that both competitive such as (R)-3(2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid and noncompetitive NMDA receptor antagonist like MK-801 and thienylcyclohexyOpiperidine produce impairment of spatial learning in rats [76]. The Ab causes the disturbance in the functioning of postsynaptic NMDA receptor leading to excessive calcium influx in neurons followed by activation of NMDA-dependent downstream pathways. The cytosol and mitochondrial calcium overload results in cascade of oxidative cytotoxicity and apoptosis (FIGURE 1) [77,78]. Memantine, an NMDA antagonist, is a novel agent for treating AD that is thought to be protected against elevated levels of glutamate by blocking NMDA receptors, which ultimately lead to cell death. Memantine has 100% bioavailability with low protein binding and minimal metabolism [79,80]. doi: 10.1586/14737175.2015.988709

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Serotonin & memory

It has been confirmed over the past few years that the neurotransmitter, serotonin plays a major role in cognition [81] and data from post-mortem studies, cerebrospinal fluid and serotonin synapse studies indicate serious impairment of the serotoninergic system in patients with AD [82–84]. Decreased levels of the 5-HT metabolite 5-hydroxyindoleacetic acid have also been correlated with aggressive behavior, which may further complicate management of these patients [85]. Furthermore, it has been described that the loss of serotoninergic pathways from the raphe nuclei has been well reported to be linked with AD [86]. Serotonin acts on 16 different types of serotonin receptors, divided into seven subfamilies, 5-HT1 to 5-HT7, based on their physiological mechanisms [87,88]. The serotonin 5-HT1A receptor is interesting receptor subtype due to its unique distribution and multiple modulating mechanisms in the CNS. It has been reported that 5-HT1A antagonist lecozotan (SRA-333) enhances cognition in primates and is now being tested for its clinical use in AD [89–91]. The procognitive effects of 5-HT1A antagonists are probably due to the facilitation of glutamatergic and cholinergic transmission after reduction of the inhibitory effects of serotonin [92]. In addition to this, 5-HT6 receptor is also expressed in the striatal, hippocampal and cortical areas of the brain [93]. 5-HT6 receptors are involved in modulation of neurotransmitters, glutamate and Ach, and facilitate learning and memory processes [94,95]. Since the discovery and subsequent development of selective antagonists in 1993, several evidences support the use of serotonin 5-HT6 receptor antagonists as a potential mechanism for treating cognitive dysfunction. Later, it was shown that not only antagonists, but also 5-HT6 receptor agonists improve learning and memory in animal models. In fact, an antagonist, SB-742457, also exists that has completed its Phase II trials for the treatment of AD [96].

significant improvement in motility indicating a neuroprotective role of D2 receptor by its antagonism. Growing body of evidence suggests that activation of D3 receptors controlled DAergic system and also reduces cortical acetylcholine release which may play a significant role in modulating cognitive processes exerted by the frontal cortex [103]. GABAergic system & memory

GABA is a major inhibitory neurotransmitter in the CNS, regulates functioning in neuronal and non-neuronal tissues. GABA mediates its effect via ionotropic (GABAA and GABAC) and metabotropic GABAB receptors. GABAergic ionotropic receptors are ligand gated ion channels, involved in fast axonal transport, whereas metabotropic GABAB receptors are G-protein coupled receptors, and are responsible for the neuromodulatory effect of GABA [104,105]. Hence, over- or underactivation of GABAergic system has been implicated in the pathophysiology of neuropsychiatric and neurodegenerative disorders including AD [19,106,107]. Drug therapies targeting the GABAergic system may be proven beneficial for treatment of dementia. In terms of specificity, GABAB receptor antagonists seem to be potential candidates as compounds falling under this class known for enhancing cognitive function over a wide range of tasks in experimental models as well as in subjects [108–110]. GABAB receptors (GABAB R) are located both pre- and postsynaptically in the hippocampal neurons and activation of presynaptic GABAB R leads to inhibition of neurotransmitter release, whereas activation of postsynaptic GABAB R leads to inhibition of postsynaptic potential [111]. SGS742 is a GABAB antagonist that showed promising results in preclinical and Phase I studies but have not reached beyond Phase II. Etazolate, modulator of GABAA receptor too contributes for its neuroprotective action thus producing improvement in learning and memory [112]. Histaminergic system

Dopaminergic system & memory

DA is a neurotransmitter involved in regulating brain functions ranging from behavioral thoughts, movement orientation to memory formation, finally governing the synaptic plasticity. However, its role in AD pathogenesis is still not clear [97]. DA is synthesized in midbrain neurons and reaches to the hippocampus, neocortex and basal ganglia via diffusion [98]. DA acts through five different types of receptors, classified into two subclasses: D1-like and D2-like [99]. Activation of DA D2 receptor reduces cortical excitability [100,101]. Therefore, antagonism of D2 receptor can be a newer neuroprotective approach for dealing with tauopathy. The above fact was further supported by the studies of McCormick et al. [102], who employed genome of Caenorhabditis elegans encoding two D2-like receptors, DOP-2 and DOP-3 in their study and strains containing lesions within these genes were generated by combining with tau transgene: T337;dop-2 and T337;dop-3 as well as T337;dop-2;dop-3, which concluded that animals lacking both worm D2 receptors (DOP-2 and DOP-3) had shown doi: 10.1586/14737175.2015.988709

Histamine is an organic nitrogenous compound, mediates local immune responses and act as functional neurotransmitter in the CNS [22,113]. Elevated levels of histamine have also been noted in cerebrospinal fluid and serum of AD patients, although this may originate from mast cells as well as from the [113–115]. The effects of neuronal histamine are mediated via G-protein coupled receptors (H1–H4 receptors). Among all the known histamine receptor subtypes, H3 receptors are predominantly expressed in the CNS. It has been reported that there exists a crosslinking between H3 autoreceptors and H3 heteroreceptors, activation of the former can inhibit histamine synthesis and release from histaminergic neurons whereas activation of latter (Arrang et al.) [116] inhibits release of neurotransmitters such Ach, noradrenaline, DA and 5-HT from non-histaminergic neurons [115,114]. On the contrary, blockade of H3 receptors with selective antagonists can enhance the release of above-mentioned neurotransmitters involved in controlling thought and emotions [117]. Da Silveira et al. conferred the role of histaminergic system in Expert Rev. Neurother.



consolidation of object recognition memory by means of H1, H2 and H3 receptors in brain [118]. Preclinical studies had also shown cognition-enhancing properties of novel H3 antagonists, including BF2.649, PF-03654746, GSK189254, MK-0249, JNJ-17216498 and ABT-288 in several animal models of AD [119–123]. ABT-288 was found safe and well tolerated in healthy adults [124]. A small pilot trial with GSK239512, selective H3 antagonist showed excellent safety profile with positive effects on attention and memory [125]. Potent H3 receptor antagonist SAR110894 has shown improvement in the memory in scopolamine-induced memory dysfunction as well as those produced by central infusion of toxic amyloid fragment Ab25–30 [126]. Currently, newer drugs and compounds are being tested and developed for enhancing learning and memory, more recently the effects of b-histine a H3 antagonist/H1 agonist on learning and memory, and related brain activity were assessed and measured in healthy volunteers for clinical use [127]. COX & memory

Normal brain consumes approximately 17.8 mg/day of arachidonic acid, and this consumption is anticipated to increase in several neurodegenerative diseases including AD [128]. Some amount of intracellular free arachidonic acid is metabolized by the two cyclooxygenases (COX-1 and COX-2) to liberate biologically active prostaglandins and leukotrienes, respectively. In CNS, COX-1 is expressed constitutively in most tissues and in brain it expresses primarily in microglia [129], whereas in brain COX-2 is expressed constitutively in hippocampal neurons and in dendritic spines. Neuronal COX-2 expression is altered by changes in synaptic activity [130] as well as by various pathological conditions together with the Ab peptide-triggered neurotoxicity [131,132]. It has been reported that AD brain exhibits increased protein levels of COX-1 in both cytosolic and particulate fractions and that COX-2 protein was also reported to be increased in the particulate fraction accompanied by elevated levels of cytokines, interleukins, soluble TNF receptors, TNF-a converting enzyme, leucocyte elastase, a-1-proteinase, levels of C-reactive protein [133]. In a study analyzing the post-mortem brains of AD patients, it was found that in AD patients, neurons of CA1 region of hippocampus exhibited increased COX-2 immunoreactivity that linked with the severity of AD pathology [134,135]. Thus, the selective inhibition of COX-1 and COX-2 enzyme in the brain may represent such approach for treating AD. Epidemiological studies suggest that long-term use of antiinflammatory drugs might reduce the risk of developing AD [25]. The main mechanism of action of NSAID is inhibition of COX-1 and COX-2 enzymes responsible for the production of prostaglandins and other inflammatory agents [136,137]. The administration of ibuprofen at an early stage of pathological process resulted in reduction of the Ab burden, dystrophic neuritis, activated microglia, inhibiting the synaptic failure induced by Ab [138,139]. Potent NSAID like indomethacin has suffered high withdrawal rates in clinical trials due to gastrointestinal toxicity. Some trials with COX-2 selective (celecoxib and rofecoxib) or informahealthcare.com

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unselective (naproxen) NSAID or other anti-inflammatory drugs such as dapsone, hydroxychloroquine and prednisone have not shown a beneficial effect [140]. Renin–angiotensin system & memory

Existence of brain renin–angiotensin system is well documented despite its presence at the periphery [141]. Brain renin–angiotensin system performs several functions linked with basic physiologies including reabsoption, uptake of body fluid, blood pressure maintenance and vasopressin release [141,142]. AT I receptors are present more densely than AT II receptors, in brain areas regulating autonomic and hormonal response [141]. Recently, AT4 receptors have been identified and characterized. Three different angiotensin receptors, AT I, AT II and AT IV, are implicated in various physiologies of CNS [21]. In AD and other neurodegenerative disorders, it has been demonstrated that there is increased synthesis of angiotensin II (Ang II) creating a hindrance on Ach release from cholinergic neurons [143]. In contrast, angiotensin-converting enzyme (ACE) inhibitors such as captopril and enalapril have been demonstrated to improve cognition in various animal models of learning and memory by reducing the synthesis of Ang II, thereby removing a hindering barrier on Ach release. It has been demonstrated that telmisartan and lisinopril have preventive effect on cognitive impairment produced by AD [144]. Moreover, Ang II-mediated improvement in retention, in active and passive avoidance paradigms is prevented by bicuculline (a GABAA receptor antagonist) suggesting the involvement of GABA receptor in memory enhancing effect of Ang II [145]. Recent studies have implicated the role of brain angiotensin receptor subtype AT IV in acquisition of spatial learning conferring its nootropic and amnesic effect ultimately causing an increase in cognition [146]. High density of AT IV receptors (activated by Ang IV) are found in brain structure such as CA1-CA3 area of hippocampus, neocortex, cerebellum, claustrum, choroid plexus and pontine nucleus, which are involved in memory function [147,148]. Preclinically, it has been demonstrated that chronic intracerebroventricular (icv) administration of AT4-specific agonists like norleucine1-Ang IV has been reported to improve acquisition of spatial memory on circular maze, however, chronic icv administration of AT IV-specific antagonist divalinal impaired the acquisition [149,147]. Norleucinal promotes increase in cerebral blood flow due to vasodilatation of arterioles and this fact has been positively correlated with its memory improving effects [149]. Nitric oxide & memory

Nitric oxide (NO) is produced in the neuronal cells as a co-product of the conversion of the L-arginine to L-citrulline via enzyme nitric oxide synthase (NOS) with calcium and calmodulin as cofactors. Three distinct NOS (eNOS, nNOS and iNOS) have been recognized in the hippocampus, cortex, cerebellum, corpus striatum and medulla of rat brain. Functioning as a neurotransmitter in the brain NO is synthesized by neurons in response to the NMDA receptor activation by the doi: 10.1586/14737175.2015.988709


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excitatory amino acid glutamate, acts as one of the contributors of Ab peptide-induced cognitive deficits [150]. Rate of synthesis of NO in hippocampus is considered essential for maintaining long-term potentiation and long-term depression [151]. Proper nitric oxide signaling is an essential event in memory process, synaptic transmission and plasticity of memory process [152]. Reducing Ab production is the main aim in the treatment of AD. Therefore, the usage of enzyme inhibitors, subtype selective, targeting NOS isoforms causing damage to brain cells in AD may represent potential approach to untangle the pathophysiologic enigma of AD [153]. In regards of increased levels of NO, NMDA receptor antagonist dizocipline (MK-801) and AP5 have been found to be beneficial by inhibiting its synthesis in the brain [154]. N-NitroL-arginine methyl ester (L-NAME) and N-nitro-L-arginine (L-NA), N-monomethyl-L-arginine (L-NMMA) [150] and the nitro-indazole compound, 7-nitroindazole (7-NI) are the synthetic analogs of L-arginine that are known to decrease NO concentration via inhibition of nNOS and eNOS, ultimately inhibiting the synthesis of NO in the brain [155]. Neurotrophic factors & memory

These are target-derived proteins capable of affecting survival, target innervation and function of neuronal cell populations. The NGF, brain-derived neurotrophic factor (BDNF), neurotrophin 3 and neurotrophin 4 are the members of neurotrophin family [24]. Hippocampal extracellular ERK and Ras-signaling responsible for synaptic plasticity in hippocampus are found to be activated by BDNF [156]. However, the brains of AD patients show reduced expression of BDNF and NGF [157–159]. BDNF is predominantly expressed in the frontal cortex and the entorhinal cortex, which specifically provides the support to the basal forebrain cholinergic neurons but in AD its expression is markedly reduced participating in disease progression [159]. The facts discussed above provide strong rationales signifying that increasing supply of neurotrophins to degenerating neurons may be effective way to repair impaired neuronal function in neurodegenerative conditions like AD. Therefore, AD-like dementing illness may be treated by administration of potent NGF synthesis stimulator like propentofylline, idebenone induces the synthesis of NGF protein, mRNA and choline acetyltransferase activity in basal forebrain region of AD brains [160]. Moreover, in AD brains it has also been reported that decreased levels of NGF and BDNF are further accompanied by impaired TGF-b1 signaling [161], reduced levels of TGF-b1 seem to induce microglial activation and ectopic cellcycle re-activation in neurons [162]. Several drugs may induce TGF-b1 release by glial cells, including estrogens [163], mGlu2/ 3 agonists [164], lithium [165] and antidepressant venlafaxine [166]. All showed neuroprotective potential in different in vitro and in vivo models of AD pathology [161]. NAP (NAPVSIPQ), an eight amino acid peptide [167], derived from activity neuroprotective protein and ADNF-9 peptide, doi: 10.1586/14737175.2015.988709

derived from activity-dependent neurotrophic factor (ADNF) [168,169] are implicated in neurodegenerative disorders including AD. In AD, ADNF-9 has been found to be protective against Ab, apoE deficiencies, oxidative insults as well as in enhancing synapse formation [170–173]. Neuroprotective effect of ADNF is mimicked by NAP via its interaction with tubulin, increasing assembly of microtubules, resulting in improved neuronal outgrowth [174–176]. NAP modulates Ca2+ signaling in neurons, stimulates MAPK/ ERK and PI3-K/Akt pathways and promotes phosphorylation of the transcription factor, which produces neuronal outgrowth and differentiation [177,178]. Platelet-activating factor & memory

PAF is present in mammalian brain cells and specific binding sites for PAF have identified in cortex, hippocampus and midbrain region of rats producing memory enhancer effect [23]. PAF is considered to play a vital role in mediating long-term potentiation as a retrograde messenger [179]. Hippocampal and intra-amygdala infusions of PAF analog have been shown to facilitate long-term potentiation process in CA3 region of hippocampus by stimulating perforant path and to enhance learning and memory in experimental animals [179,180], whereas PAF receptor antagonists, BN50730 and BN52021 have been reported to impair memory in rodents [181,182]. BN52021 induced retrograde amnesia in mice has been shown to be reversed by icv injection of PAF and by a non-selective PAF hydrolase inhibitor [181]. Neuropeptides in AD

Neuropeptides are small protein-like molecules (peptides) utilized by neurons to communicate with each other. Neuropeptides are distributed throughout the whole nervous system, act as neurotransmitter, neuromodulator or neurohormone [183]. Hippocampus, basal forebrain, amygdala regions of brain show wide distribution of neuropeptides, hence they are expected to modulate learning and memory process at varying levels. In brain, these neuropeptides are involved in providing strength and neuroprotection, ultimately promoting cell longevity to the neurons. In neurodegenerative disorders like Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and AD, expression of these neuropeptides are markedly reduced, causing cell death followed by disease progression. So administration of these neuropeptides can combat their reduced levels in neurodegenerative disorders via increased rate of cell survival [184]. Drug therapies aimed at restoring reduced levels of neuropeptides utilize exogenous administration of arginine, vasopressin and adrenocorticotropic hormone, which have been linked to facilitate consolidation and retrieval process of memory [20,185]. Earlier vasopressin and its analogs had shown memory improvement in animal model of memory [186]. Estrogen acts as a neuroprotective agent and has been found to enhance memory in female mice and women [187]. Peripheral administration of insulin causes increase in ACh level in amygdala, providing an evidence for improved cholinergic transmission in brain [188]. Expert Rev. Neurother.


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Table 1. Drugs under clinical trials aimed at correcting neurotransmitter abnormalities for the treatment of Alzheimer’s disease. Product name

Sponsor

Indication

Development phase

Ref.

AZD1446 (a-4/b-2 neuronal nicotinic receptor agonist)

AstraZeneca Wilmington, DE, USA Targacept Winston-Salem, NC, USA

AD

Phase I

[211,212]

ABT-126 (a-7-NNR antagonist)

AbbVie North Chicago, IL, USA

AD

Phase II

[213]

TC-5619 (a-7 nAChR)

Targacept Winston-Salem, NC, USA

AD

Phase I

[212]

AZD1446 (a-4/b-2 neuronal nicotinic receptor agonist)

AstraZeneca Wilmington, DE, USA Targacept Winston-Salem, NC, USA

AD

Phase I

[211,212]

ABT-288(neurotransmitter receptor modulator)

AbbVie North Chicago, IL, USA

AD

Phase II completed

Donepezil/memantine extended release (fixed-dose combination)

Adamas Pharmaceuticals Emeryville, CA Forest Laboratories New York, NY, USA

moderate to severe AD

Phase II

[214,215]

GSK742457 (5-HT6 receptor antagonist)

GlaxoSmithKline Rsch. Triangle Park, NC, USA

Dementia

Phase II

[216]

Lu AE58054 (5-HT6 receptor antagonist)

Lundbeck Deerfield, IL, USA Otsuka America Pharmaceutical Rockville, MD, USA

AD (cognition)

AVN 322 (serotonin 5-HT6 receptor antagonist)

Avineuro Pharmaceuticals San Diego, CA, USA

AD

Phase I

[219]

AVN 101 (serotonin 5-HT6 receptor antagonist)

Avineuro Pharmaceuticals San Diego, CA, USA

AD

Phase II

[219]

PRX-3140 (serotonin 5-HT4 receptor agonist)

Nanotherapeutics Alachua, FL, USA

AD

Phase II

[220]

SB-742457 (5-HT6 antagonist)


AD

Phase II

[216]

RG1577 (MAO-B inhibitor)

Roche Nutley, NJ, USA

AD

Phase I

[221]

SAR110894 (H3 antagonist)

Sanofi US Bridgewater, NJ, USA

AD

Phase II

[222]

APH-0703 (protein kinase C stimulant)

Aphios Corporation Woburn, MA, USA

AD

Phase I/II

[223]

PF-05212377 (SAM-760)

Pfizer New York, NY, USA

AD

Phase II

[224]

PRX-3140 (serotonin 5-HT4 receptor agonist)

Nanotherapeutics Alachua, FL, USA

AD

Phase II

[220]

Posiphen R-phenserine

QR Pharma Berwyn, PA, USA

AD,

Phase II

[225]

ABT 957 (calpain inhibitor)

Abb Vei North Chicago, IL, USA

AD

Phase II

[213]

Rilapladib (Lp-PLA2 inhibitor)


AD

Phase II

[216]

[213]

[217,218]

AD: Alzheimer’s disease.


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Review



Table 1. Drugs under clinical trials aimed at correcting neurotransmitter abnormalities for the treatment of Alzheimer’s disease (cont.). Product name

Sponsor

Indication

Development phase

Ref.

GM6 (peptide therapeutic)

Genervon Biopharmaceuticals Pasadena, CA, USA

AD

Phase I

[226]

RVX-208

Resverlogix Calgary, Canada

AD

Phase I

[227]

SAR110894 (H3 antagonist)


AD

Phase II

[222]

SB-742457 (5-HT6 antagonist)


AD

Phase II

[216]

AC-1204 (glucose stimulant)

Accera Broomfield, CO, USA

AD

Phase II/III

[228]

ACC-001/PF-05236806

Janssen Alzheimer Immunotherapy South San Francisco, CA, USA Pfizer New York, NY, USA

AD

Phase II

[224,229]

DSP-8658 (PPARa/g agonist)

Sunovion Pharmaceuticals Marlborough, MA, USA

AD

Phase I

[230]

Pioglitazone companion diagnostic

Takeda Pharmaceuticals U.S.A. Deerfield, IL Zinfadel Pharmaceuticals Chapel Hill, NC, USA

AD (diagnosis)

Phase I

[231]

T3D-959 (dual PPAR agonist

T3D Therapeutics Rsch. Triangle Park, NC, USA

AD

Phase I completed

[232]

AD: Alzheimer’s disease.

Neuropeptide Y inhibits the formation of long-term potentiation when applied on hippocampus, mediated by Y2 receptors located presynaptically [189]. In comparison with neuropeptide Y, neuropeptide K increases memory retention power when injected into rostal and caudal portion of the hippocampus [190]. Moreover, post-training administration of substance P is found to enhance memory in rats, potentiation of this effect is noted by naloxone signifying the contribution of endopioids in memory enhancement [190]. Drugs under Phase III of clinical trials for AD

Multiple potential treatments for AD are currently under investigation, including several compounds being studied in different phases of clinical trials. The most important clinical research is focused on treatment strategies governing the modulation of neurotransmitter functioning by the use of several antagonists/ agonists to the attempts to remove the pathogenomic protein deposits, thus combating the disease progression. This review enlists the drugs that are under clinical trials aimed at correcting neurotransmitter abnormalities (TABLE 1) [191,192] and removing the pathogenomic protein deposits (TABLE 2) [191,192]. It has been known since earlier times that calcium signaling pathways play a vital role in the cell survival. With increasing age, oxidative insults and several other factors, calcium homeostasis can be disrupted in the brain, which leads to cognitive

doi: 10.1586/14737175.2015.988709

and functional decline [193]. Thus, it raises the possibility of protecting neurons by identifying chemicals able to regulate calcium homeostasis in neurons during aging and several neurodegenerative disorders like AD and Parkinson’s disease [194]. Various calcium channel blockers such as nicardipine, nimodine and mibefradil have been reported for their neuroprotective potential [195,193]. Recently, nilvadipine, a calcium channel blocker, is being tested for the treatment of AD and it is under Phase III of clinical trials. And the basic mechanism by which it will be acting primarily is the increased Ab clearance from brain restoring cortical perfusion in mouse models of AD. Nilvadipine is safe and well tolerated in AD patients having potential of stabilizing the cognitive decline and thus reducing incidence of AD, pointing to both symptomatic and diseasemodifying benefits [196]. In the previous decade, new therapeutic approaches targeting Ab have been discovered and developed with the expectations of modifying the natural history of AD patients [197]. The most revolutionary of these approaches comprise removal of brain Ab via anti-Ab antibodies. Several second-generation active Ab vaccines and passive Ab immunotherapies have been developed and are under clinical investigation with the main aim of accelerating Ab clearance from the brain of AD patients. Bapineuzumab is an anti-Ab monoclonal antibody drug and is being studied as a treatment for patients with mild-to-moderate

Expert Rev. Neurother.


Review


Table 2. Drugs under clinical trials aimed at removing pathogenomic protein deposits for the treatment of Alzheimer’s disease. Product name

Sponsor

Indication

Development phase

Ref.

AAB-003/PF-05236812 (Ab protein inhibitor mAb)

Janssen Alzheimer Immunotherapy South San Francisco, CA, USA Pfizer, New York, NY, USA

AD

Phase I

[224,233]

AD02 vaccine

Affiris, Vienna, Austria GlaxoSmithKline Rsch. Triangle Park, NC, USA

AD

Phase II

[216,234]

AD03 vaccine

Affiris, Vienna, Austria GlaxoSmithKline Rsch. Triangle Park, NC, USA

AD

Phase I

[216]

ARC031 (soluble amyloid reducing/clearing agent)

Archer Pharmaceuticals Sarasota, FL, USA

AD

Phase I

[235]

ARC031 SR (soluble amyloid reducing/clearing agent)

Archer Pharmaceuticals Sarasota, FL, USA

AD

Phase I

[235]

AD4833/TOMM40

Takeda Pharmaceuticals International Deerfield, IL, USA

AD prevention

Phase I

[231]

ASP0777

Astellas Pharma US Northbrook, IL, USA

AD

Phase I

[236]

BACE inhibitor

Janssen Pharmaceuticals Titusville, NJ, USA Shionogi Florham Park, NJ, USA

AD

Phase I

[237,238]

b-Secretase inhibitor (LY2886721)

Eli Lilly Indianapolis, IN, USA

AD (slow disease progression)

Phase II

[205]

SAR228810 (anti-protofibrillar Ab mAb)


AD

Phase I

[222]

Solanezumab (Ab protein inhibitor)

Eli Lilly Indianapolis, IN, USA

Mild AD

Phase III

[205]

BAN2401 (Ab protein inhibitor)

Eisai Woodcliff Lake, NJ, USA

Early stage AD

Phase II

[239]

BAY 85-8101 (18F-labeled radiopharmaceutical)

Piramal Healthcare Mumbai, India

AD (diagnosis)

BIIB037 (human anti-A b mAb)

Biogen Idec Weston, MA, USA

AD

Phase I

[240]

BMS-241027 (microtubule stabilizer)

Bristol-Myers Squibb Princeton, NJ, USA

AD senile dementia

Phase I

[241]

CAD106 (A b protein inhibitor)

Novartis Pharmaceuticals East Hanover, NJ, USA

AD

Phase II

[242]

V950 vaccine

Merck Whitehouse Station, NJ, USA

AD

Phase I

[243]

Vanutide cridificar (ACC-001/PF-05236806)

Janssen Alzheimer Immunotherapy South San Francisco, CA, USA Pfizer New York, NY, USA

AD

Phase II

[224,229]

Ab: b-Amyloid; AD: Alzheimer’s disease; mAb: Monoclonal antibody.


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Review



Table 2. Drugs under clinical trials aimed at removing pathogenomic protein deposits for the treatment of Alzheimer’s disease (cont.). Product name

Sponsor

Indication

Development phase

Ref.

XEL 001HP (transdermal patch)

Xel Pharmaceuticals Drapre, UT, USA

AD

Phase I

[244]

VI-1121

VIVUS Mountain View, CA, USA

AD

Phase II

[245]

V950 vaccine


AD

Phase I

[243]

TTP4000

Transtech Pharma High Point, NC, USA

AD

Phase I

[246]

TTP488

Transtech Pharma High Point, NC, USA

AD (fast track)

Phase II

[246]

T-817MA

Toyama Chemical Tokyo, Japan

AD

Phase II

[247]

ST101

Sonexa Therapeutics San Diego, CA, USA

AD

Phase II

[248]

sGC 1061 (nomethiazole)

sGC Pharma Wellesley, MA, USA

AD

Phase I

[249]

AZD2184 (PET enhancer)

Navidea Pharmaceuticals Dublin, OH, USA

AD (diagnosis)

Phase I

[250]

AZD2995 (PET enhancer)

Navidea Pharmaceuticals Dublin, OH, USA

AD (diagnosis)

Phase I

[250]

Bisnorcymserine (BNC)

QR Pharma Berwyn, PA, USA

AD

Phase I

[225]

Davunetide intranasal

Allon Therapeutics Vancouver, Canada

AD

Phase II

[251]

E2212 (amyloid precursor protein secretase modulator)


AD

Phase I completed

[239]

E2609 (BACE1 protein inhibitor)


AD

Phase I

[239]

EVP-0962 (g-secretase modulator)

EnVivo Pharmaceuticals Watertown, MA, USA

AD

Phase II

[252]

Exebryl-1 A b protein/tau protein inhibitor

ProteoTech Kirkland, WA, USA

AD

Phase I

[253]

F-18 T808 (PET imaging)

Siemens Medical Solutions Malvern, PA, USA

AD (diagnosis)

Phase 0

[254]

F18-flutemetamol (PET imaging agent)

GE Healthcare Waukesha, WI, USA

AD (diagnosis)

Application submitted

[255]

Gammagard immune globulin

Baxter International Deerfield, IL, USA

Early-stage, mid-stage AD

Phase III

[256]

g-Secretase modulator, Ab modulator

Bristol-Myers Squibb Princeton, NJ, USA

AD, senile dementia

In clinical trials

[241]


doi: 10.1586/14737175.2015.988709



Review


Table 2. Drugs under clinical trials aimed at removing pathogenomic protein deposits for the treatment of Alzheimer’s disease (cont.). Product name

Sponsor

Indication

Development phase

Ref.

Gantenerumab (Ab protein inhibitor)

Roche Nutley, NJ, USA

Early-stage AD

Phase II/III

[221]

GM6 (peptide therapeutic)

Genervon Biopharmaceuticals Pasadena, CA, USA

AD

Phase I

[226]

HPP 854 (BACE1 protein inhibitor)

High Point Pharmaceuticals High Point, NC, USA

AD

Phase I

[257]

Human immunoglobulin (intravenous)

Grifols Los Angeles, CA, USA

AD

Phase III

[258]

JNJ-54861911

Janssen Research and Development Raritan, NJ, USA

AD

Phase I

[233]

KU-046 (Ab protein modulator)

Kareus Therapeutics La Chaux-deFonds, Switzerland

AD

Phase I

[259]

LMTX (TRx-0238)

TauRx Pharmaceuticals Singapore

AD, frontotemporal dementia

Phase III

[260]

Lym Pro neurotrophic factor companion diagnostic

Amarantus BioSciences Sunnyvale, CA, USA

AD (diagnosis)

Phase II

[261]

Masitinib (AB-1010)

AB Science USA Short Hills, NJ, USA

AD

Phase III completed

[262]

MCD-386

Mithridion Madison, WI, USA

AD

Phase I

[263]

MK-3328 (PET imaging)

Merck Whitehouse Station, NJ

AD (diagnosis)

Phase I completed

[243]

MK-8931 (BACE1 protein inhibitor)


AD

Phase II/III

[243]

MSDC-0160

Metabolic Solutions Development Kalamazoo, MI, USA

AD (see also diabetes)

Phase II

[264]

NAV4694 (fluorine18-labeled precision radiopharmaceutical)

Navidea Biopharmaceuticals Dublin, OH, USA

AD (diagnosis)

Phase II

[250]

NAV5001 (123I-labeled imaging agent)

Navidea Biopharmaceuticals Dublin, OH, USA

Dementia with Lewy bodies (diagnosis)

Phase II

[250]

NIC5–15 (amyloid precursor protein secretase inhibitor)

Humanetics Minneapolis, MN, USA

AD

Phase II

[265]

PF-05212377 (SAM-760)

Pfizer New York, NY, USA

AD

Phase II

[224]


AD. It is currently in Phase III trials. Other monoclonal antibodys targeting Ab are gantenerumab and solanezumab, former has shown reduced brain Ab levels in Phase I, but vasogenic edema was seen but still it is in Phase III, relevant data are expected in 2015, and in latter case data are expected to be generated in 2016 under DIAN-TU and A4 trials for AD [198]. informahealthcare.com

Dimebon, initially developed as an anti-histamine drug, is being re-introduced for new indications as an effective treatment for patients suffering from neurodegenerative disorders including AD [199]. Currently, dimebon is being studied in combination with donepezil in patients with mild-to-moderate AD. The mechanistic approach behind its provoked effects is doi: 10.1586/14737175.2015.988709


Review


blockade of calcium currents in intestinal cells, inhibition of acetylcholinesterase enzyme and acting as a glutamate receptor blocker. In addition to blockade of mitochondrial dysfunction, there is also another approach for generating its neuroprotective effect [200]. The drug is currently in Phase III trials. Various serotonin receptors are expressed in brain region including 5-HT6 receptor. This serotonin receptor subtype is expressed in brain regions involved in cognition, such as the cortex and the hippocampus, and modulates activity of multiple neurotransmitter systems [201]. Lu-AE58054 is 5-HT6 antagonist, which is under clinical trial and has shown improved cognition in Phase I trials. It is used in combination with donepezil as an adjunctive therapy to acetylcholinesterase inhibitors. Phase III data for mild-to-moderate AD are expected from the Study of Lu AE58054 in patients with mild - moderate alzheimer’s disease treated with donepezil (STARSHINE) trial in September 2015, and from the STARBEAM and STARBRIGHT trials in January 2016 [202]. Ab soluble oligomers are neurotoxic and believed to be a major cause of neurodegeneration in AD. Ab is derived from amyloid precursor protein by two sequential cleavage steps involving b- and g-secretases. These two proteolytic enzymes represent rational drug targets for treating AD [203]. b-Secretase was identified as the membrane-anchored aspartyl protease BACE (or BACE1) with an associated increase in brain cortex of patients with sporadic AD. MK-8931, BACE inhibitor which is under Phase III of clinical trials; EPOCH trial for mild-to-moderate AD data are expected in 2017; Phase III data from APECS trial for prodromal AD are expected in 2018. PBT2 is a drug designed to stop the formation of Ab plaques. It is being studied in patients with early-stage AD, currently in Phase II trials and is expected to reach Phase III [204]. g-Secretase is an enzyme that is required in the formation of a sticky protein called Ab, thus inhibiting this enzyme is one such approach for treating AD. Recently, LY450139, investigational g-secretase inhibitor is under Phase III (IDENTITY clinical trial) for the treatment of mild-to-moderate AD [205]. Recently, insulin analogs are under clinical trials for the treatment of AD, preparations include intranasal insulin, which primarily acts at all insulin pathways. Promising data have been obtained in Phase II; data from the Phase II/III SNIFF trial in mild AD are expected in 2014 [206]. Another drug, investigational low-dose pioglitazone (designated AD-4833); insulin sensitizing PPARg agonist is under Phase III TOMMORROW trial for AD prevention in cognitively normal subjects at high risk of AD was initiated in August 2013 with data expected in 2019 [207]. MSDC-0160, having low PPARg affinity has passed Phase II and data showed that the drug maintained glucose metabolism in brain regions associated with cognitive decline in mild AD. Further trials like for liraglutide, Novo Nordisk GLP -1 analog, reported positive data from preclinical AD models. Drug is likely to be assessed in the Phase IIb ELAD

doi: 10.1586/14737175.2015.988709

trial for mild AD, which is to be started soon with an expected completion in 2016. If successful, Novo Nordisk will consider Phase III studies [208]. In addition to this, Mitsubishi Tanabe Pharma announced the start of global Phase III clinical trial program assessing encenicline hydrochloride (EVP-6124), an acetylcholinesterase inhibitors for AD in collaboration with EnVivo Pharmaceuticals. Mitsubishi Tanabe licensed EVP-6124 from EnVivo and is currently developing the drug under the code MT-4666 [209,210]. The drug is intended to improve cognition in patients affected with AD and it is a new a-7 potentiator. This drug is being tested in Phase III COGNITIV clinical trials in two categories: COGNITIV AD in patients with AD and COGNITIV CIAS in patients with cognitive impairment associated with schizophrenia. Phase III of COGNITIV AD clinical trial program consists of about 1600 patients with mild-to-moderate AD who are presently receiving stable treatment with or have undergone previous acetylcholinesterase inhibitor treatment. The trials will be divided into placebocontrolled, double-blind and randomized. Patients in the trial will be randomized to receive either one of two doses of MT-4666 once daily against a placebo-controlled group to assess safety and efficacy of the drugs [209,210]. Furthermore, potential links between AD and neurotransmitter pathways continue to be explored, with a number of Phase II or III trials in progress and preparation. Crucially though, AD remains a disease desperately in need of a cure. Expert commentary & five-year view

The occurrence of AD in aging population is increasing day by day producing widespread societal implications. This has led to immense development in the field of therapeutics aimed at correcting abnormalities in neurotransmitter release and modulation. Although treatment therapy for modulating the dysfunction of cholinergic and glutametergic system are known since long time, still none of them has been claimed to be a profitable one. Moreover, with increasing age besides abnormalities in cholinergic and glutametergic system, abnormalities in histaminergic, dopaminergic, serotonergic and GABAergic system has been noted. In addition to this, numerous drug therapies focused on removing underlying pathogenomic protein deposits are under clinical trials for AD treatment. Furthermore, there is a strong urge for developing drugs that may prove their beneficial action and may serve as a landmark in controlling disease progression with the possible outcomes. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.



Review

Key issues • Alzheimer’s disease (AD) pathology is characterized by the abnormal functioning of different neurotransmitters like acetylcholine, glutamate, serotonin and GABA. • There are many hypotheses indicating that multiple neurotransmitters pathways could be linked to the development of AD. • The alteration of these receptors may be associated with oxidative stress, amyloid plaque formation and tau phosphorylations in AD. • Several different neurotransmitters can be released from a single nerve terminal, including neuropeptides and small molecule neurotransmitters. Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Washington University Library on 12/21/14 For personal use only.

• Experimental and clinical conditions which have been associated with altered release pattern of neurotransmitter in the AD are well noted.

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Aphios. Available from: www.aphios.com/

224.

Pfizer. Available from: www.pfizer.com

225.

QR Pharma. Available from: www. qrpharma.com

226.

GENERVON. Available from: www. genervon.com

227.

RESVERLOGIX. Available from: www. resverlogix.com

242.

228.

Accera. Available from: www.accerapharma. com/

229. 230.

Review

238.

SHIONOGI INC. Available from: www. shionogi.com

253.

Proteo Tech. Available from: www. proteotech.com

239.

Eisai. Available from: www.eisai.com

254.

240.

Biogenidec. Available from: www. biogenidec.com

SIEMENS. Available from: www.usa. healthcare.siemens.com

255.

Bristol-Myers Squibb. Available from: www. bms.com

GE Healthcare. Available from: www. gehealthcare.com

256.

Baxter. Available from: http://baxter.com/

NOVARTIS. Available from: www.novartis. com/

257.

Highpointpharma. Available from: www. highpointpharma.com

243.

MERCK. Available from: www.merck.com

258.

GRIFOLS. Available from: www grifols.com

Janimm. Available from: www.janimm.com

244.

XEL Pharmaceuticals. Available from: www. xelpharmaceuticals.com

259.

Sunovion. Available from: www.sunovion. com

KAREUS Therapeutics; SA. Available from: www.kareustherapeutics.com

245.

Vivus. Available from: www.vivus.com

260.

231.

Takeda. Available from: www.takeda.com

246.

TAU Rx Therapeutics. Available from: www.taurx.com

232.

T3D Therapeutics. Available from: http:// www.t3dtherapeutics.com/

TransTech Pharma. Available from: www. ttpharma.com

261.

247.

Amarantus. Available from: www.amarantus. com

Janssen. Available from: www.janssenrnd. com

FUJI FILM. Available from: www.toyamachemical.co.jp

262.

248.

Sonexa. Available from: www.sonexa.com

AB-SCIENCE. Available from: www.abscience.com

234.

Affiris. Available from: www.affiris.com

249.

263.

235.

Archer Pharmaceuticals. Available from: www.archerpharma.com

SGC Pharma. Available from: www. sgcpharma.com

Mithridion. Available from: www. mithridion.com

250.

Navidea. Available from: www.navidea.com

264.

236.

Astellas. Available from: www.astellas.com

251.

237.

Janssen Pharmaceuticals, Inc. Available from: www.janssenpharmaceuticalsinc.com

Allon therapeutics. Available from: www. allontherapeutics.com

Metabolic Solutions Development Company. Available from: www.msdrx.com

265.

Humanetics. Available from: www. humaneticscorp.com

233.


241.

252.

Forum Pharmaceuticals. Available from: www.envivopharma.com

doi: 10.1586/14737175.2015.988709

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