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PHAREP 112 1–8 Pharmacological Reports xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Pharmacological Reports journal homepage: www.elsevier.com/locate/pharep 1 2

Review article

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Statins – Are they anticonvulsant?

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Q1 Monika

Banach a, Stanisław J. Czuczwar b,c, Kinga K. Borowicz a,*

a

Experimental Neuropathophysiology Unit, Department of Pathophysiology, Medical University, Lublin, Poland Department of Pathophysiology, Medical University, Lublin, Poland c Department of Physiopathology, Institute of Rural Health, Lublin, Poland b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 14 August 2013 Received in revised form 11 February 2014 Accepted 25 February 2014 Available online xxx

Statins are the most popular and effective lipid-lowering medications beneficial in hypercholesterolemias and prevention of cardiovascular diseases. Growing evidence supports theory that statins exhibit neuroprotective action in acute stroke, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis or epilepsy. Hereby, we present available experimental data regarding action of this group of drugs on seizure activity and neuronal cell death. The most commonly examined statins, such as atorvastatin and simvastatin, display anticonvulsant action with only inconsiderable exceptions. However, the mechanism of this effect remains unexplained. Simvastatin, as a lipophilic statin, which can pass blood–brain barrier easily, was recommended as the best candidate for an anticonvulsant agent. Nevertheless, it is still indistinct, whether the protective activity of statins depends on cholesterol lowering properties or its pleiotropic characteristics. One of the most interesting of 3-hydroxy-3methylglutaryl-coenzyme A inhibitor’s actions involves influence on nitric oxide metabolism. ß 2014 Published by Elsevier Urban & Partner Sp. z o.o. on behalf of Institute of Pharmacology, Polish Academy of Sciences.

Keywords: Statins HMGCoA inhibitors Epilepsy Seizures Neuroprotection

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Contents Introduction . . . . . . . . . . . . . . . . . . . . Statins . . . . . . . . . . . . . . . . . . . . . . . . Cholesterol metabolism in brain . . . . In vitro studies . . . . . . . . . . . . . . . . . . Animal studies . . . . . . . . . . . . . . . . . . Atorvastatin . . . . . . . . . . . . . . . . . . . . Simvastatin . . . . . . . . . . . . . . . . . . . . Fluvastatin . . . . . . . . . . . . . . . . . . . . . Lovastatin . . . . . . . . . . . . . . . . . . . . . . Pravastatin . . . . . . . . . . . . . . . . . . . . . Human studies . . . . . . . . . . . . . . . . . . Mechanisms of statin action in brain Conclusions . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .

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28 Abbreviations: AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ATV, atorvastatin; CBZ, carbamazepine; CNS, central nervous system; CRMP-2, collapsin responsive mediator protein-2; CSF, cerebrospinal fluid; DZP, diazepam; FBM, felbamate; FLUV, fluvastatin; GABA, gamma-aminobutyric acid; GBP, gabapentin; GGPP, geranylgeranyl-pyrophosphate; GSK-3b, glycogen synthase kinase-3 beta; HDL, high-density lipoproteins; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; KA, kainic acid; QA, quinolinic acid; ip, intraperitoneal; icv, intracerebroventricular; iNOS, inducible nitric oxide synthetase; iv, intravenous; LDL, low-density lipoprotein; LEV, levetiracetam; L-NAME, NG-nitro-L-arginine methyl ester; LOV, lovastatin; LTG, lamotrigine; MFS, mossy fiber sprouting; NMDA, N-methyl-D-aspartic acid; NO, nitric oxide; nNOS, neuronal nitric oxide synthetase; OXC, oxcarbazepine; PB, phenobarbital; PHT, phenytoin; po, per os; PRAV, pravastatin; PTZ, pentylenetetrazole; SE, status epilepticus; SIMV, simvastatin; s.c., subcutaneous; TPM, topiramate; VPA, valproate. * Corresponding author. E-mail address: [email protected] (K.K. Borowicz). http://dx.doi.org/10.1016/j.pharep.2014.02.026 1734-1140/ß 2014 Published by Elsevier Urban & Partner Sp. z o.o. on behalf of Institute of Pharmacology, Polish Academy of Sciences.

Please cite this article in press as: Banach M, et al. Statins – Are they anticonvulsant? Pharmacol Rep (2014), http://dx.doi.org/10.1016/ j.pharep.2014.02.026

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Introduction

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Epilepsy, one of the most common neurological disorders, affects almost 1% of human population. Although in the 21st century we can choose among several therapies and plenty of antiepileptic drugs, still 30% of patients do not respond to the treatment. On the other hand, the worldwide population is aging, which is strongly tied with increased prevalence of other diseases, including a variety of cardiovascular disorders. It is not surprising that with increased number of drugs in polytherapy, the risk of drug interactions and unwanted side effects also increases. The recommended in such cases rational polytherapy is based on co-administration of drugs acting synergistically in respect of their therapeutic action and not potentiating each others’ side effects [6]. In accordance with this golden rule, antiepileptic drugs should be combined with statins increasing the seizure threshold or at least not influencing this parameter. Statins, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are the most popular cholesterol-lowering agents, beneficial in hypercholesterolemia and related diseases. They are recommended as a first line treatment in primary and secondary prevention of cardiovascular diseases. Nevertheless, this group of drugs exhibits other properties that extend far beyond their leading mechanism of action. Statins exert pleiotropic action on endothelium, inflammatory response or free radical production. They showed neuroprotective and anti-inflammatory effects in experimental cell and animal studies. The wellestablished anti-inflammatory properties include decreased release of pro-inflammatory cytokines, chemokines, metalloproteinases and adhesion molecules. Not less important seem to be antioxidant actions of statins expressed in decreased superoxide production and lipid peroxidation. Immunosuppressant action of statins is based on suppression of T-cell and antigen-presenting cell activation. In humans, statins were proved to reduce ischemic stroke incidence and mortality. Recently, statins were proved to exert neuroprotective action during acute stroke, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis or epilepsy [25,34,38]. Excitotoxic cell death, seizure generation and propagation may share common etiopathogenesis, therefore neuroprotective compounds may display anticonvulsant activity and vice versa [2,9]. Furthermore, statin-induced cholesterol depletion in cell membranes can change their physicochemical properties and neural excitability. Under such circumstances, it seems reasonable to survey available data regarding possible action of statins on seizure phenomena and excitotoxicity.

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Statins

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Statins act as competitive inhibitors of HMG-CoA reductase, a rate limiting enzyme necessary for the production of L-mevalonate, an intermediate product in the synthesis of cholesterol. Inhibition of endogenous cholesterol production results in up-regulation of low-density lipoprotein (LDL) receptors on cell surface. The final effect is increased uptake of LDLs from the blood and reduced LDL cholesterol concentration. Additionally, statins increase levels of high-density lipoproteins (HDLs) and decrease those of triglycerides [29]. All of these lipid-modifying effects are dose-dependent [25]. Statins are hepatoselective; the main place of their action is the liver. Some of them, like simvastatin (SIMV) and lovastatin (LOV) need to be metabolized before activation [38]. Due to extensive first-pass extraction, peripheral exposure to free drug molecule is low. The majority of HMG-CoA inhibitors are eliminated with bile, only pravastatin (PRAV) and rosuvastatin are excreted both by the liver and kidneys [29].

Statins are believed to be well-tolerated and safe. Possible side effects include myopathy, hepatotoxicity, gastrointestinal symptoms, proteinuria, rash, peripheral neuropathy, insomnia, unusual dreams, sleep and concentration problems [29,38]. Unfortunately, statins may increase a risk for development of diabetes mellitus [28]. Depending on the origin, statins are divided into three groups: synthetic (atorvastatin – ATV, cerivastatin, fluvastatin – FLUV, pitavastatin, and rosuvastatin), semi-synthetic (SIMV, mevastatin, PRAV) and fungus-derived (LOV) [32]. Another classification is based on lipophilicity: lipophilic drugs (SIMV, ATV, LOV) are capable of crossing blood–brain barrier, whereas lipophobic medications (PRAV, rosuvastatin) are not. FLUV has intermediate characteristics [25]. According to Sierra et al. [32], the most lipophilic is ATV, followed by SIMV, whereas regarding potential to cross blood–brain barrier, SIMV seems to have better access to brain than ATV [32,38]. It is widely believed that the mechanism of cardiovascular risk reduction during statin treatment is not limited to lipidlowering action, but also due to variety of pleiotropic effects, such as inhibition of inflammatory responses, improvement of endothelial function, antioxidant, antithrombotic and anti-apoptotic effects [25]. A question arises, which of the aforementioned mechanisms are mostly responsible for neuroprotective properties of HMGCoA-inhibitors in acute stroke, neurodegenerative diseases, multiple sclerosis or epilepsy [37,38].

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Cholesterol metabolism in brain

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In the central nervous system, cholesterol is present not only in all plasma membranes of glial cells and neurons, but also in specialized membranes of myelin. It accounts for almost 25% of the unestrified cholesterol in the human body. It is considered that brain cholesterol is synthesized entirely in the brain. This assumption is supported by growing evidence indicating no uptake of LDL or HDL from plasma to brain. Furthermore, brain cholesterol synthesis takes place almost exclusively in astrocytes and oligodendrocytes, which explains why nonsignificant reduction of total brain cholesterol might mask a large change in neuronal cholesterol [21]. Brain cholesterol production is independent on peripheral cholesterol concentration [32]. Only 0.02% (in humans) to 0.4% (in mice) turns over each day. The rate of cholesterol flux across the central nervous system is approximately 0.9% of that across the rest of human or mouse body [7]. One of the most important output pathways of cholesterol from the central nervous system is 24-hydroxylation, since this cholesterol derivative can cross blood–brain barrier and enter plasma [7].

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In vitro studies

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In vitro studies are usually a great source of knowledge about molecular mechanisms of drug action. Therefore, it seems disappointing that available literature provides rather inconsistent data reporting possible effects of statins on cultured neurons, its electrophysiologic properties and excitotoxicity, which is a well defined mechanism of neuronal death following epileptic seizures. Some well-known excitatory agents, like kainic acid (KA) or N-methyl-D-aspartic acid (NMDA) were used to assess effects of statins on neuronal excitability and survival or NMDA receptor function. LOV reduced neuronal cell death in cultured hippocampal cells, induced by KA and glutamate [16]. Also, subsequent extended studies in vitro revealed neuroprotective properties of five statins: rosuvastatin, SIMV, ATV, mevastatin, and PRAV. Pretreatment with one of statins (100 and 300 nM for 6 days) protected cultured mouse neurons from excitotoxic cell death induced by NMDA.

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Please cite this article in press as: Banach M, et al. Statins – Are they anticonvulsant? Pharmacol Rep (2014), http://dx.doi.org/10.1016/ j.pharep.2014.02.026

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This action of statins developed after 2–4 days of treatment and was concentration-dependent. The rank order of potency proposed [41] was: rosuvastatin = SIMV > ATV = mevastatin > PRAV. In the same experiment, neuronal cultures were co-treated with SIMV alone, or with statin in combination with mevalonate or cholesterol. Both mevalonate and cholesterol reversed the neuroprotective action of the statin. Moreover, manipulation of cell cholesterol without HMG-CoA inhibitors resulted in alterations in susceptibility to NMDA-induced excitotoxicity. Acute cell membrane cholesterol depletion with cyclic glucose oligomer, methyl-b-cyclodextrin, exerted a protective effect similar to chronic SIMV pretreatment, whereas cholesterol replacement restored NMDA-induced lactate dehydrogenase release to control levels. Additionally, electrophysiological measurements with calcium microfluorimetry were performed to assess NMDA receptor function of mouse cortical neurons during chronic exposure to SIMV. The statin slightly decreased NMDA-induced whole-cell current but it was not followed by reduction in intraneuronal calcium concentration [41]. Authors of the cited report [41] tried to explain discrepancies between their own and previous results [10,17,30,36]. They suggested that previously observed neurotoxic action of statins could be a consequence of too high statin concentration (micromolar vs. nanomolar concentration), which inhibits geranylgeranyl-pyrophosphate (GGPP) synthesis. Cholesterol biosynthesis is inhibited by much lower doses of statins than other mevalonate derivatives so toxic effects of a statin at higher concentration, which is reversed by GGPP, may depend on lack of isoprenylation of proteins. Actually, such effects were in most cases reversed by GGPP [24]. According to Zacco et al. [41], another possible reason of these divergences could be differences in preparation of neuronal cultures, alterations of lipid rafts sterol composition resulting in changes in NMDAR function or neuronal nitric oxide synthetase (nNOS) activation. The most important message from this study was, however, assumption that neuroprotective effects of statins seem to depend on cholesterol synthesis inhibition. Slightly wider research was conducted by Bo¨sel et al. [4], who discovered that 2–4-day pre-treatment with ATV, but not mevastatin, applied at low concentrations (100 nm and 1 mm but not 10 mm), exhibits neuroprotective effects against glutamate-induced excitotoxicity. Moreover, ATV remained ineffective against oxygen–glucose deprivation (model of ischemic cell death) or camptothecin-induced apoptosis (this was even augmented). Since co-treatment with mevalonate or isoprenoid intermediates did not reverse nor attenuate the protective properties of ATV, neuroprotection seems to be unrelated to HMG-CoA reductase inhibition. On the contrary, mevalonate reversed toxic effect of ATV applied at the concentration of 20 mm. The anti-excitotoxic effect of ATV was correlated with reduced NMDA-induced whole cell currents and, in contrast to Zacco et al. [41], ATV diminished intracellular calcium concentration. This discrepancy, according to the authors, could be due to differences in experimental setup and/or suggest indirect action of statins on calcium currents that may be mediated by changes in gene expression, posttranslational mechanisms or receptor subunit composition [4]. Ponce et al. [21] have found that a 4-day pretreatment with SIMV or AY9944, an inhibitor of the last step in cholesterol synthesis, attenuated NMDA-induced cell death in primary cultures of neurons. This anti-excitotoxic effect was reversed by addition of cholesterol. SIMV, in a concentration-dependent manner, significantly reduced cholesterol level in neurons, but did not influence NMDAR1 expression. Ponce et al. [21] have revealed for the first time, that statins and AY9944, reduced association of NMDA receptors with lipid rafts [21]. Mossy fiber sprouting (MFS), a pathological phenomenon associated with temporal lobe epilepsy, is believed to play a

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critical role in epileptogenesis. The molecular mechanism of MFS is not known, however, increased expression of glycogen synthase kinase-3 beta (GSK-3b) and collapsin responsive mediator protein-2 (CRMP-2) signaling pathway observed after SE may suggest one possible explanation, since both play a role in axonal growth. Lovastatin, administered intraperitoneally at dose of 20 mg/kg 3 h after termination of pilocarpine-induced SE in rats, significantly reduced MFS in dentate gyrus and CA3 area in the hippocampus. Additionally, LOV reversed alterations in GSK-3b and CRMP-2 expression level 3 and 7 days after SE in rat’s brain. In the same study, in electrophysiologic experiment direct action of LOV on NMDA receptor was excluded [15]. Summing up, studies in vitro indicate that statins may present neuroprotective or neurotoxic properties, depending on the type of drug applied, drug concentration or methodology employed in experiments. Statin-induced neurotoxicity seems to be cholesterol-dependent, whereas exact mechanism of their protective action remains unclear. It should be stressed once again that in vitro studies dealt mainly with neuroprotective effects of statins. Considered mechanisms of such effects include reduction of cholesterol or isoprenoid content in neurons, decreased production of pro-inflammatory mediators, enhanced release of neurotrophic factors, increased NO production by endothelial nitric oxide synthase (eNOS), and decreased coagulation. Some mechanisms may be common for neuroprotection and anticonvulsant action, among them reduced association of NMDA receptor with lipid rafts and decreased release of excitatory neurotransmitters [38].

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Animal studies

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Multiple animal seizure models were used to assess possible effects of statins on seizures. Most of them were chemically induced by administration of glutamate agonists (KA, quinolinic acid – QA), gamma-aminobutyric acid (GABA) receptor antagonists (pentylenetetrazole – PTZ) or evoked by electrical impulse. Preclinical studies suggested that SIMV would be the best candidate for a neuroprotectant. The most commonly examined drug in experimental models was, however, ATV.

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Atorvastatin

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ATV is one of the most potent HMG-CoA inhibitors. In majority of chemically-induced convulsions and audiogenic seizures, the statin presented protective effects and enhanced the action of antiepileptic drugs. On the contrary, ATV was entirely ineffective in electrically evoked seizures. Lee et al. [16] reported that 7-day pretreatment with ATV (10 mg/kg po), but not post-treatment (0.5 h after KA injection), significantly reduced the severity of KA-induced status epilepticus (from stage 4 to less than 3 according to Racine’s scale) and wet dog shaking behavior in rats. Moreover, cell death in CA1 and CA3 hippocampal regions, the macrophage infiltration and expression of genes encoding cytokines, inducible nitric oxide synthetase (iNOS) in hippocampus were also inhibited. This confirms anti-inflammatory properties of the statin [16]. In contrast, higher dose of ATV (50 mg/kg), administered 24 h and then 30 min before ip KA injection, enhanced convulsions in mice, increasing seizure scores, percentage of mice with developed SE, and shortening the latency period. Moreover, the statin did not protect against excitotoxicity after SE [23]. Further, ATV (10 mg/kg) administered for 7 days, but not at a single dose, protected mice from QA-induced tonic and/or clonic seizures, promoted neuronal cell survival and inhibited reduction of glutamate uptake in hippocampal slices after QA icv infusion [20].

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Please cite this article in press as: Banach M, et al. Statins – Are they anticonvulsant? Pharmacol Rep (2014), http://dx.doi.org/10.1016/ j.pharep.2014.02.026

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¨ zu¨m et al. [37], 4-week pretreatment with ATV According to U (5 mg/kg ip) prevented PTZ kindling development in rats as well as the long-term memory deficits. Funck et al. [9] showed that single oral dose of ATV (10 mg/kg) did not alter the latency to PTZ-induced seizures, whereas chronic treatment (for 7 days) delayed PTZ-induced generalized seizures. The statin remained, however, ineffective against clonic seizures. Abrupt cessation of chronic administration of ATV facilitated convulsions in this model. Additionally, the authors assessed plasma and brain cholesterol concentrations after 7-day treatment with ATV (10 mg/kg). Both were unaltered in comparison to control. Possible changes in blood–brain barrier permeability to the convulsant were also excluded. In another experiment, chronic administration of ATV at doses of 0.1, 0.5, and 1 mg/kg, but not at higher doses of 5 and 10 mg/kg, significantly increased the seizure threshold in intravenous PTZ-induced convulsions. This effect was inhibited by both acute and chronic administration of NOS inhibitors: nonselective NG-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine – a selective inhibitor of iNOS). On the other hand, only a higher dose of chronic ATV (5 mg/kg) prolonged latency to PTZ generalized tonic seizures. This effect was also reversed by acute administration of NOS inhibitors [19]. Subsequent report provides some complimentary data. Acute oral ATV at the dose of 5 mg/kg significantly increased the seizure threshold in PTZ-induced convulsions. It should be stressed that either lower (0.5, 1 mg/kg) or higher (10 and 15 mg/kg) doses of ATV were ineffective in this respect. Furthermore, acute co-administration of L-NAME (5 and 10 mg/kg) antagonized the protective effect of ATV. Additionally, combination of L-arginine, a precursor of NO, with subeffective doses of ATV (1 mg/kg) significantly increased the PTZ seizure threshold in mice [18]. Chronic ATV (10 mg/kg applied 7 days before and 7 days after induction of SE) did not affect electrically-evoked temporal lobe epilepsy in rats. The triglyceride plasma level, blood–brain barrier permeability, hilar cell loss, CD68 immunoreactive cells, microglia activation and gliosis were also assessed. Among them only triglyceride levels in rats after 2-week sucrose/fructose regimen were reduced to control levels by ATV treatment. The authors suggest that the lack of anticonvulsant effect of the statin may depend on prolonged SE, which was not terminated in this experiment. On the other hand, the lack of expected beneficial effect of ATV on the restoration of blood–brain barrier, cell death and inflammation may be explained by the greater effectiveness of the statin on adaptive immune response and its less pronounced influence on innate response that is essential in the pathomechanism of temporal lobe epilepsy [39]. In another study, neither acute nor chronic ATV (20 and 80 mg/kg) affected the electroconvulsive threshold in mice. Moreover, 7-day administration of the statin at the dose of 80 mg/kg significantly decreased the anticonvulsant action of carbamazepine (CBZ), but did not influence these of phenytoin (PHT) or valproate (VPA) against maximal electroshock in mice. It is worth stressing that ATV given in a single injection remained ineffective on the protective action of antiepileptic drugs. Since chronic ATV (80 mg/kg) did not alter the total brain concentration of CBZ, the reduced action of this antiepileptic is probably due to a pharmacodynamic interaction between the two drugs [35]. In audiogenic seizures in DBA/2 mice, another model of generalized tonic–clonic seizures, single injection of ATV displayed anticonvulsive action against tonus at doses 80–100 mg/kg, remaining ineffective against clonus. Both phases of seizures were inhibited by co-administration of the ineffective dose of ATV (25 mg/kg) with VPA, CBZ, diazepam (DZP), topiramate (TPM) and lamotrigine (LTG) [27]. Summing up this subsection, ATV failed to raise the threshold for electrically-induced seizures seem, whereas in most chemical

models the statin exerted anticonvulsant activity. Such an activity was observed after chronic, and sometimes acute, treatment with ATV. Interestingly, chronic administration of lower doses of ATV (up to 10 mg/kg) were sufficient to inhibit KA- and PTZ-induced convulsions, whereas acute ATV at the dose of 50 mg/kg presented proconvulsive effects in KA-induced seizures. ATV, applied at relatively high doses (80–100 mg/kg), was also effective against audiogenic seizures.

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Simvastatin

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On the basis of pharmacological properties and in vitro studies, SIMV seemed to be the most promising candidate for a neuroprotective drug. Surprisingly, only limited data reporting effects of this statin on animal seizures is available. SIMV in KA-, picrotoxin-induced and audiogenic seizures exerted anticonvulsant activity whereas it was ineffective in PTZ model [9,23]. Ramirez et al. [23] observed that a single dose of SIMV (50 mg/kg) significantly reduced seizure scores, percentage of mice convulsing and developing SE as well as delayed the latency period to ip KA-induced convulsions. Additionally, SIMV displayed a protective action against structural disruption of the pyramidal neuron layer of the hippocampus and limbic structures of the cortex after KA administration. Similarly, in picrotoxin model of clonic seizures in Balb/c mice, SIMV administered orally at the dose of 10 mg/kg exerted anticonvulsant action, lowering the number of convulsing mice and shortening duration of seizures. Additionally, hippocampal neuronal cells of CA1 and CA3 regions were protected from death [13]. In the experiment performed by Funck et al. [9], neither acute nor chronic treatment with SIMV (10 mg/kg po) affected PTZinduced seizures. The authors did not observe any changes in plasma and brain cholesterol concentration after 7-day treatment with this HMG-CoA reductase inhibitor. Recent, unpublished yet, our data suggest that acute but not chronic treatment with SIMV significantly increase the electroconvulsive threshold. On the contrary, chronic, but not acute, administration of SIMV enhanced the anticonvulsant activity of PHT against maximal electroshock-induced seizures in mice. SIMV (20–100 mg/kg) was the only statin effective against both tonic and clonic phases of audiogenic seizures in DBA/2 mice. Moreover, SIMV, at a low dose of 10 mg/kg, enhanced the anticonvulsant action of VPA, felbamate (FBM), gabapentin (GBP), TPM, CBZ, DZP, LTG and PB in this seizure model [27]. Interestingly, ATV and SIMV did not always act unidirectionally. In KA seizure model, ATV presented pro- or anticonvulsant effects, depending on the dose used and animal species, while SIMV exhibited protective properties. SIMV, but not ATV, raised the electroconvulsive threshold in mice. In contrast, only ATV inhibited PTZ-induced seizures. SIMV remained ineffective in this respect [9,16,23].

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Fluvastatin

397

FLUV, a synthetic statin, did not affect KA- or electricallyinduced convulsions, but instead of this potentiated the anticonvulsant action of some antiepileptic drugs against maximal electroshock and audiogenic seizures [23,35]. In KA-induced seizures in mice, FLUV did not influence the latency period, seizure score and only slightly (but not significantly) reduced percentage of mice with seizures and SE. Moreover, the statin did not protect against excitotoxicity after SE [23]. Neither acute nor chronic FLUV applied at doses of 20 and 80 mg/kg affected the threshold for electroconvulsions. Acute administration of FLUV (10, 20, 40, and 80 mg/kg)

398 399 400 401 402 403 404 405 406 407 408

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Table 1 Effects of statins on seizure activity. Statin

Seizure model

Dose/animals

Atorvastatin

QA (icv)

Acute 10 mg/kg po/mice Chronic (7 days) 1 mg/kg po/mice Chronic (7 days) 10 mg/kg po/mice Acute 50 mg/kg ip/mice Chronic (7 days) 10 mg/kg po/rats Acute 10 mg/kg po/rats Chronic (7 days) 10 mg/kg po/rats Chronic (4 weeks) 5 mg/kg ip/rats Chronic (7 days) 0,1; 0,5; 1 mg/kg po/mice Chronic (7 days) 5; 10 mg/kg po/ mice Chronic (7 days) 1 mg/kg po/mice

KA (ip) KA (ip) PTZ (ip) PTZ kindling (ip) PTZ-treshold (iv)

PTZ (ip) treshold

PTZ-treshold (iv)

Chronic (7 days) 5 mg/kg po/mice Chronic (7 days) 1, 10 mg/kg po/ mice Chronic (7 days) 5 mg/kg po/mice

Acute 5 mg/kg po/mice Acute 1 mg/kg po/mice

Electrically induced rat temporal lobe epilepsy MEST

MES

Audiogenic seizures

Simvastatin

KA (ip) Picrotoxin (po) PTZ (ip) Audiogenic seizures

Acute 20 and 80 mg/dl ip/mice Chronic (7 days) 20 and 80 mg/kg ip/ mice Acute 80 mg/kg ip/mice Chronic 80 mg/kg ip/mice Acute ip 80-100 mg/kg/DBA/2 mice Acute 25 mg/kg

KA (ip) MEST

MES

Audiogenic seizures

Pravastatin

KA (ip) Audiogenic seizures

L-NAME ip (acute 5 mg/kg and chronic 2 mg/kg) Aminoguanidine ip (acute 100 mg/kg and chronic 50 mg/kg)

Acute 50 mg/kg ip/mice Acute ip up to 150 mg/kg/DBA/2 mice Acute 30 mg/kg ip/DBA/2 mice

References

No effect No effect Anticonvulsant Proconvulsant Anticonvulsant No effect Anticonvulsant Anticonvulsant Anticonvulsant

[20]

[23] [16] [9] [37] [19]

Inhibition of the anticonvulsant activity of atorvastatin Inhibition of the anticonvulsant activity of atorvastatin Anticonvulsant No effect

Acute L-NAME 5 mg/kg ip Acute aminoguanidine 100 mg/kg ip Acute L-NAME 5; 10 mg/ kg ip Acute L-arginine 60; 100 mg/kg ip

Inhibition of the anticonvulsant activity of atorvastatin Inhibition of the anticonvulsant activity of atorvastatin Inhibition of the anticonvulsant activity of atorvastatin Potentiation of the anticonvulsant activity of atorvastatin No effect No effect No effect

Acute CBZ, PHT, VPA Acute CBZ Acute PHT, VPA Acute VPA, TPM, CBZ, DZP, LTG, Acute FBM Acute GBP, LEV, OXC, PB, PHT

Acute 50 mg/kg ip/mice Acute 10 mg/kg Acute 10 mg/kg po/rats Chronic (7 days) 10 mg/kg po/rats Acute ip 20–100 mg/kg/DBA/2 mice

Acute 50 mg/kg ip/mice Acute 20 and 80 mg/dl ip/mice Chronic (7 days) 20 and 80 mg/kg ip/ mice Acute 10, 20, 40, 80 mg/kg ip/mice Acute 40, 80 mg/kg ip/mice. Acute 80 mg/kg ip/mice Chronic 80 mg/kg ip/mice Acute ip 80–100 mg/kg/DBA/2 mice Acute 25 mg/kg ip/DBA/2 mice

Effect

No effect

Chronic (14 days) 10 mg/kg po/rat

Acute 10 mg/kg ip/DBA/2 mice

Fluvastatin

Co-administered drug

acute VPA, FBM, GBP, TPM, CBZ, DZP, LTG, PB, acute PHT acute LEV, OXC

acute acute acute acute

CBZ VPA PHT CBZ, PHT, VPA

acute CBZ, DZP, LTG, TPM, VPA acute FBM acute GBP, LEV, OXC, PHT, PB

acute LTG, TPM, VPA acute CBZ, FBM acute LEV, GBP, DZP, OXC, PB, PHT

No effect Proconvulsant No effect Anticonvulsant against tonus Anticonvulsant against tonus and clonus Anticonvulsantagainst tonus No effect

[18]

[39] [35]

[27]

Anticonvulsant Anticonvulsant No effect No effect Anticonvulsant against tonus and clonus Anticonvulsant against tonus and clonus Anticonvulsant against tonus No effect

[23] [13] [9]

No effect No effect No effect

[23] [35]

[27]

Anticonvulsant Anticonvulsant No effect No effect Anticonvulsant against tonus Anticonvulsant against tonus and clonus Anticonvulsant against tonus No effect

[27]

Proconvulsant No effect

[23] [27]

Anticonvulsant against tonus and clonus Anticonvulsant against tonus No effect

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6 Table 1 (Continued ) Statin

Seizure model

Dose/animals

Lovastatin

AY-induced atypical absence seizures KA (ip)

Subchronic 50, 100 mg/kg po/rat

Co-administered drug

Acute 50 mg/kg ip/mice acute CBZ, PHT, PB

PTZ threshold (iv) Audiogenic seizures

Subchronic 1, 5, 10, 20, 40, 80, 100 mg/kg ip/mice Acute ip 30–100 mg/kg/DBA/2 mice Acute 20 mg/kg/DBA/2 mice

acute VPA, FBM, TPM, CBZ, DZP, LTG acute GBP, PB, PHT acute LEV, OXC

Effect

References

Proconvulsant

[31]

Anticonvulsant No effect Anticonvulsant

[23]

Anticonvulsant against tonus Anticonvulsant against tonus and clonus Anticonvulsant against tonus No effect

[27]

[14]

QA, quinolinic acid; PTZ, pentylenetetrazole; KA, kainic acid; MEST, maximal electroshock threshold; MES, maximal electroshock; icv, intracerebroventricularly; ip, intraperitoneal; iv, intravenous; po, per os; L-NAME, NG-nitro-L-arginine methyl ester; CBZ, carbamazepine; PHT, phenytoin; VPA, valproate; PB, phenobarbital; TPM, topiramate; GBP, gabapentin; FBM, felbamate; LEV, levetiracetam; DZP, diazepam; LTG, lamotrigine; OXC, oxcarbazepine.

409 410 411 412 413 414 415 416 417 418 419 420 421 422 423

significantly potentiated the anticonvulsant action of CBZ, but not PHT, in maximal electroshock-induced seizures in mice. In the same experiment, FLUV at doses of 40 and 80 mg/kg enhanced the anticonvulsant effect of VPA. However, 7-day treatment with the statin did not influence the action of any of the examined antiepileptic drugs. The nature of interaction between FLUV and CBZ seems to be pharmacokinetic, while that between FLUV and VPA is probably pharmacodynamic. This assumption was based on data indicating that FLUV (80 mg/kg) significantly elevated CBZ total brain concentration, remaining without effect on the brain concentration of VPA [35]. Finally, FLUV at doses of 80–100 mg/kg reduced the tonic phase of audiogenic seizures in DBA/2 mice and increased the anticonvulsant action of CBZ, DZP, LTG, TPM, and VPA against both tonic and clonic convulsions [27].

424

Lovastatin

425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441

LOV, fungus-derived statin, exerted anticonvulsant action in most studies regarding KA-, PTZ-induced seizures, electroconvulsions or audiogenic seizures with the exception of atypical absence seizures, which in contrast were augmented [14,23, 27, 31, unpublished data]. LOV at doses of 50 and 100 mg/kg exacerbated atypical absence seizures in rats, increasing spike-and-wave discharge duration similarly to another cholesterol synthesis inhibitor, AY-9944. Since LOV only slightly reduced the total brain cholesterol level, it is not clear what is the exact mechanism of the proconvulsive action observed in this study. The authors suggested probable disruption of inhibitory neurosteroid synthesis or rapid transient or localized reduction in brain cholesterol that was difficult to detect by measuring its total concentration [31]. In another experiment, the statin administered orally at dose of 20 mg/kg prevented hippocampal neuronal loss in CA1 area immediately or 24 h after pilocarpine induction of SE in rats [24].

In KA-induced seizures, lovastatin exerted a protective activity, reduced the percentage of mice with seizures and developed SE, but did not change the latency period to the onset of seizures. Similarly to SIMV, LOV tended to protect against neuronal damage after KA administration [23]. Lovastatin at doses of 40, 80 and 100 mg/kg, but not lower, administered intraperitoneally for four days before test, significantly increased the threshold in PTZ-induced convulsions in mice [14]. Our recent unpublished data indicate that acute, but not chronic treatment with LOV, decreases seizure threshold in mice. In spite of this, both acute and chronic LOV potentiated the anticonvulsant action of VPA and PHT against maximal electroshock-induced seizures. In audiogenic seizures, acute LOV was the second after SIMV in order of the antiseizure potency. At doses of 30–100 mg/kg, LOV attenuated tonic seizures, whereas at a dose of 20 mg/kg it enhanced the anticonvulsant effects of VPA, FBM, TPM, CBZ, DZP, and LTG [27]. Aforementioned data show that LOV may act bidirectionally on seizures, which depends on the type of experimental model, but in most of them the statin acts as an anticonvulsant.

442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463

Pravastatin

464

There are only two available articles regarding effects of PRAV in seizure models. In KA-induced convulsions, PRAV significantly increased seizure score, shortened latency period and increased percentage of mice with SE. It did not show any neuroprotective activity [23]. PRAV remained the only statin examined in the mouse model of audiogenic seizures that did not affect the tonic phase of seizures at all (at doses up to 150 mg/kg). Acute administration of PRAV at the dose of 30 mg/kg augmented the anticonvulsant action of VPA against tonus and clonus, and CBZ or FBM against tonus [27]. To the

465 466 467 468 469 470 471 472 473 474

Table 2 Effects of statins on neurons (in vitro). Statin

Model of excitotoxicity/SE

Effect

References

SIMV

NMDA

[41]

SIMV Rosuvastatin, SIMV, ATV, PRAV, mevastatin ATV

NMDA NMDA glutamate-induced exciotoxicity

LOV

KA, glutamate Picrotoxin-induced SE

Decreased whole-cell current, no reduction in intraneuronal calcium concentration Reduced association of NMDAR to lipid rafts Decreased NMDA-induced whole current Reduced whole-cell current followed by diminished intracellular calcium concentration Anti-excitotoxic Reduced MFS, GSK-3b and CRMP-2 expression

[21] [41] [4] [16] [15]

ATV, atorvastatin; CRMP-2, collapsin responsive mediator protein-2; GSK-3b, glycogen synthase kinase-3 beta; KA, kainic acid; LOV, lovastatin; MFS, mossy fiber sprouting; NMDA, N-methyl-D-aspartic acid; NMDAR, N-methyl-D-aspartic acid receptor; PRAV, pravastatin; SIMV, simvastatin; SE, status epilepticus.

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extent of our knowledge, there is no available data concerning possible action of mevastatin, cerivastatin (withdrawn due to increased risk of rhabdomyolysis) [29] or rosuvastatin on seizures. Effects of statins on seizure activity are listed in Table 1.

479

Human studies

480 481 482

Two observational human studies reported that the use of statins decreased the risk of hospitalization for epilepsy in older people [8,22].

483

Mechanisms of statin action in brain

484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536

Consideration of possible influence of statin on cholesterol metabolism in brain and seizures should be started from the question of whether statins can pass the blood–brain barrier and inhibit cholesterol synthesis in situ. From the theoretical point of view, penetration of lipophobic statins should be at least problematic. However, as it was reported, HMG-CoA reductase inhibitors administered in a form of lactone prodrug (i.e. SIMV) are transported to the brain via simple diffusion, while those applied in the active form of hydroxyl-acid require a carriermediated transport system. Nevertheless, it seems that both lipophobic and lipophilic statins can reach the brain circulation, although to different extent. Admittedly, another problem emerges, because HMG-CoA reductase inhibitors undergo extensive first-pass metabolism and have relatively short plasma halflife of 1–2 h. In spite of this pharmacokinetic characteristics, LOV and PRAV have been detected in human cerebrospinal fluid [5]. According to numerous studies, statins are able do reduce brain cholesterol synthesis in both animals and humans. However, only long-term treatment (preferably more than 6 months) may reduce cholesterol level in the cerebrospinal fluid of experimental animals or examined patients [5,38]. HMG-CoA reductase inhibitors administered in rodents for 4–7 days did not lower the brain cholesterol concentration significantly [9,16,31]. Some experiments, carried out on animals, showed that high doses of statins alter brain cholesterol production but not brain cholesterol content [5,38]. Possibly, it can be explained by the extremely long half-life of brain cholesterol (up to several months) [16,38]. Moreover, it was reported that either lipophilic or hydrophilic statins, administered at high enough doses, decrease both cholesterol synthesis and elimination, thus reducing cholesterol turnover in the brain [5]. Finally, Sierra et al. [32] compared in vitro cholesterol lowering effects of statins on human neurons, glial and hepatic cells, indicating the greatest decrease in lipid level in neurons and Q2 SIMV as the most potent statin (Table 2). In a nutshell, all brain cholesterol is produced in situ; statins, regardless of lipid solubility, can pass the blood–brain barrier and inhibit the sterol synthesis; chronic treatment with statins can reduce the CSF concentration of cholesterol, however, the brain content of cholesterol is probably not affected [5,38]. The question arises, whether it is enough to trigger secondary cholesterol-dependent actions. Although there is mounting evidence that statins do influence seizure activity and neuronal survival, it is still not clear what is the exact mechanism of their action. The authors quoted in this review suggested plenty of plausible mechanisms of the statin action. The first theory is based on modulation of neurotransmission in the brain. Cholesterol is the only source of all steroids, including neurosteroids. A number of neurosteroids and steroid hormone derivatives were reported to behave as neuroprotectants, some of them also exhibit anticonvulsant properties. They are so called ‘inhibitory’ neurosteroids, which may positively modulate GABAA and/or negatively modulate NMDA receptors. However, it should not be forgotten that some

7

other neurosteroids may have just an opposite action on cell membrane receptors and exhibit proconvulsant and excitotoxic action [3]. Whether a statin is proconvulsant, or anticonvulsant, should be dependent on its net effect on local neurosteroid production in a given brain area involved in seizures. It is worth mentioning that on one hand, inhibition of cholesterol synthesis in rat neonates by AY-9944 results in a development of atypical absence seizures [31], but on the other one, cholesterol depletion leads to neuroprotection against NMDA-induced neuronal death in primary neuronal cultures [21]. Lipid rafts are cell membrane domains facilitating formation of protein complexes and activation of specific signaling pathways. Depletion of cholesterol in lipid rafts results in alterations of both inhibitory (like GABAA) and excitatory a-amino-3-hydroxy-5methyl-4-isoxazolepropioinic acid (AMPA) or NMDA receptors [11,21,41]. For instance, inhibition of NMDA-induced excitotoxicity in cortical neurons due to modulation of NMDA receptor function and dynamics of intracellular calcium was reported after the treatment with several HMG-CoA reductase inhibitors [4,41]. Another way of statin action regards inhibition of isoprenoids synthesis, lipid byproducts of cholesterol synthesis involved in membrane attachment and function of small GTPases (Rho, Rac, Ras), which are an important link in excitotoxic signaling cascade and other neuronal function [16,25,26]. Statins are also believed to modulate signaling pathways involving Bax and Bcl, pro- and antiapoptotic protein expression and inhibit caspase-dependent pro-apoptotic pathway, promoting cell survival [20,23]. Statins increase Akt phosphorylation which has been implicated in cell survival [12,20]. It should be underlined, however, that statins inhibit prenylation in much higher doses when compared to inhibition of cholesterol synthesis [21]. Inflammation, one of the most widely recognized pathology during epileptogenesis, enhances neuronal excitability and increases blood brain barrier permeability. Anti-inflammatory action of statins may explain their neuroprotective function [40]. Statins were proved to reduce expression of pro-inflammatory genes, they also attenuate release of pro-inflammatory cytokines, chemokines, adhesion molecules, and matrix metalloproteinases [16,24,25,38,39]. Nevertheless, some studies cited in this review did not confirm significant restoration of blood brain barrier nor prevention against brain inflammation during and after statin administration [9,23,39,40]. Inhibition of free radical formation and lipid peroxidation may be another explanation of neuroprotective and perhaps anticonvulsant properties of HMG-CoA inhibitors [23–25,38]. However, one of the most interesting theories regarding these actions concerns the statin-induced modulation of NO metabolism. NO is a small gaseous molecule, playing a variety of roles in the central nervous system. It was widely tested in terms of possible pro- or anticonvulsive action [1]. Statins influence NO production in brain through multiple mechanisms: 1. alleviating iNOS, 2. enhancing eNOS activity, and 3. involving Rho and PI3K/Akt pathway [12,25,38]. Experimental data showing anticonvulsant activity of ATV, which is augmented by NO precursor L-arginine and antagonized by L-NAME or aminoguanidine, could support the NO-related mechanism of the statin action. Unfortunately, this theory has been verified so far only in one model of epileptic seizures [18,19].

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Conclusions

595

In a vast majority of experimental seizure models, statins exhibited anticonvulsant action. ATV tended to act after chronic treatment, while SIMV, PRAV, FLUV, and LOV after a single injection. The most probable explanation of the observed anticonvulsant properties of statins is their influence

596 597 598 599 600

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on neurosteroid or NO synthesis in the brain. It cannot be excluded, however, that HMG-CoA inhibitors can act through unknown yet mechanisms, i.e. receptor action, particularly when the anticonvulsant action develops after a single injection.

605

Funding

606 607

There has been no funding body that provided financial support for this work and could influence its outcome.

608

Conflict of interest

609 610

There are no known conflicts of interests associated with publication.

611 Q3 Uncited reference 612

[33].

613

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