American Journal of Animal and Veterinary Sciences 6 (4): 166-170, 2011 ISSN 1557-4555 2011 Science Publications Anticonvulsant Effect of
Pitavastatin in Mice Induced by Pentylenetetrazole
Department of Pharmacology and Toxicology, Faculty of Veterinary, Tabriz Branch, Islamic Azad University, Tabriz, Iran Abstract: Problem statement: The 3-Hydroxy-3-Methylglutaryl-CoA (HMG-CoA) reductase
inhibitors (statins) have been unequivocally shown to reduce cardiovascular morbidity and mortality
by their lipid-lowering actions. It has been suggested that statins appear to have therapeutic benefits in
diseases that are unrelated to elevated serum cholesterol levels. The aim of this study was to evaluation
the effect of intraperitoneally injection of different doses of pitavastatin on PTZ-induced seizure
threshold in mice. Approach: Mice were divided into 9 groups randomly: the first group received
saline normal (ip) (control group); the second group received Carboxymethylcellulose (CMC) 0.5%
(ip) (vehicle group) and the next groups received respectively different doses of pitavastatin (1, 5, 10,
20, 40, 80 and 100 mg kg daily ) for 4 days (ip) before determination of seizure threshold induced by
PTZ. Results: Results showed that PTZ-induced seizure threshold in control mice was 35.48±1.39 mg
kg . Intraperitoneal injection of pitavastatin showed significant (p<0.05) increase of PTZ-induced
seizure threshold in a dose dependently manner. Conclusion: According to our results, pitavastatin has
anticonvulsant effects on mice. Nevertheless, new studies must be carried out in order to determine the
beneficial effects of statins in treatment of epilepsy.
Key words: Threshold, Franeyltransferase Inhibitor (FTI), neurological diseases, PTZ-induced
seizure, elevated serum, lipid-lowering, control group, seizure threshold INTRODUCTION
dysfunction, anti-thrombosis and anti-oxidant actions, prevention of Alzheimer’s disease and antineoplasic Epilepsy is one of the major neurological diseases actions (Goncalves et al., 2011). Statins might exert in humans and about one percent of the population is beneficial effects beyond cholesterol reduction; include improving endothelial function, decreasing vascular (HMG-CoA) reductase inhibitors (statins) have been inflammation, inhibiting smooth-muscle proliferation and immunomodulation. Most of these effects are morbidity and mortality (NIH, 1994). Statins are mediated through inhibition of isoprenoid synthesis, with among the most widely used prescription drugs and subsequent effects on multiple downstream signaling exert their lipid-lowering actions by reversible and pathways (Wang et al., 2008). Also statins might exert competitive inhibition of the enzyme 3-hydroxy-3- beneficial neuroprotective effects in various animal disease models and clinical studies (Rangel et al., reductase), the rate-limiting step in the conversion of 2005). Furthermore, recent studies have shown that 3-Hydroxy-3-Methylglutaryl-coenzyme A (HMG- statins reduces the extent of brain damage after CoA) to mevalonate, a precursor of cholesterol ischemic insult (Sironi et al., 2003). Therefore the aim (McTaggart et al., 2001). It has been suggested that of this study was to evaluation the effect of statins appear to have therapeutic benefits in diseases intraperitoneally injection of different doses of that are unrelated to elevated serum cholesterol pitavastatin on PTZ-induced seizure threshold in mice. levels, such as rheumatologic diseases and ischemic stroke (McCarey et al., 2004). Statins are also known MATERIALS AND METHODS
for their pleiotropic effects, which are independent of their lipid-lowering properties. Among the effects of Animals: Experiments were performed on 22-25 g
statins, the most relevant are anti atherosclerotic and adult NMRI male mice in their 8-9 week (n = 8 for each anti-inflammatory actions, improvement of endothelial group), purchased from Razi Institute (Iran). Animals American J. Animal & Vet. Sci., 6 (4): 166-170, 2011 were housed 8 per cage in the Animal House of Veterinary Faculty of Tabriz Branch, Islamic Azad University in a temperature (20-22°C) and humidity (50±10%) controlled environment under a 12-h light dark cycle (lights on at 7 am). Food and water were available ad libitum. This study was performed in accordance with the Guide for the Care and Use of Laboratory Animals of Research affairs of Tabriz University of Medical Sciences, Tabriz-Iran. All efforts were made to minimize the number of animals which were used and their suffering degree. Animals were divided into 9 groups randomly: the first group received Fig. 1: PTZ-induced seizure threshold in mice (mg/kg). saline normal (ip) (control group); the second group Effect of intraperitoneally injection of different received Carboxymethylcellulose (CMC) 0.5% (ip) doses of pitavastatin on seizure threshold. Each (vehicle group) and the next groups received respectively different doses of pitavastatin (1, 5, 10, 20, *P<0.05, **P<0.01 and ***P<0.001 compared 40, 80 and 100 mg kg daily ) for 4 days (ip) before DISCUSSION
Chemicals: PTZ (Pentylenetetrazole) was purchased
from Sigma-Aldrich. Pitavastatin was provided from Pentylenetetrazole (PTZ) has been used widely to Kowa Pharmaceuticals. All other reagents were of produce the animal model of chemically induced analytical grade. Pitavastatin was prepared by being seizure because this model is highly sensitivity for dissolved in 0.5% Carboxymethylcellulose (CMC) and the comparing different chemical under standardized vehicle group was given an equal volume of vehicle. conditions (Shafaroodi et al., 2004). In this study PTZ- induced seizure threshold in control mice was PTZ-induced clonic seizure threshold: Behavioral
35.48±1.39 mg kg and pitavastatin increased PTZ- experiments were done in a quiet, temperature- induced seizure threshold in a dose dependently controlled (20-22°C) room between 10 am and 4 pm. manner. Anti-nociceptive and anti-inflammatory effects PTZ-induced clonic seizure threshold was determined of statins have been shown in different experimental by inserting a 30-gauge needle into the tail vein of mice animal models of pain and inflammatory and clinical and infusion of 0.5% PTZ solution at a constant rate of studies (Dantas et al., 2010; Massaro et al., 2010; Nezic 1 ml/min to unrestrained freely moving animals. et al., 2009; Sparrow et al., 2001; Weitz-Schmidt et al., Minimal dose of PTZ (mg kg ) needed to induce 2001), but so fare effects of statins on epilepsy are very forelimb clonus followed by full clonus of the body was limited (Rangel et al., 2005; Lee et al., 2008). Results recorded as an index of clonic seizure threshold of this study showed that pitavastatin has beneficial neuroprotective effects on PTZ seizure model in mice Data analysis: Group data are presented as mean±
that in agreement with a recent study that reported an SEM and analyzed statistically using student test. Time effective neuroprotective action of statins after an acute course data were analyzed using one-way ANOVA brain injury and epilepsy (Daimon et al., 2004; Lee et followed by Tukey’s post hoc test. The level for al., 2008; Rangel et al., 2005). Furthermore, recent statistical significance was set at a p<0.05. studies have shown that lovastatin partially suppressed acute experimental autoimmune Encephalomyelitis (EAE) in rat spinal cord injury model (26). Also, studies reported that statin treatment provided anti- PTZ-induced seizure threshold in control mice was inflammatory effects on human multiple sclerosis and 35.48±1.39 mg kg . In vehicle group, CMC have not X-linked adrenoleukodystrophy (Nath et al., 2004; shown significant change on PTZ-induced seizure Paintlia et al., 2005; Pannu et al., 2007; Shepherd et al., threshold compared with control group (Fig. 1). 1995; Singh et al., 1998; Stanislaus et al., 2002; 1999; 2001; Vollmer et al., 2004). Moreover, other research significant (p<0.05) increase of PTZ-induced seizure groups have reported the similar neuroprotective role of threshold in a dose dependently manner compared with statins in other neurological disease models, such as traumatic brain injury, brain ischemia and Alzheimer’s American J. Animal & Vet. Sci., 6 (4): 166-170, 2011 disease (Endres et al., 1998; Kirsch et al., 2003; Lu et thus, their biological roles are expected to be mediated al., 2004). Rangel et al. (2005) demonstrated that by their inhibitory roles in cholesterol and isoprenoid lovastatin treatment was able to prevent hippocampal synthesis. Indeed, the inhibitory role of statins in neuronal loss in CA1 subfield after an epileptic insult cholesterol biosynthesis previously reported to inhibit (Rangel et al., 2005). The molecular mechanisms of the NMDA mediated excitotoxicity in vitro neuron culture anticonvulsant and immunomodulatory properties of study. Also has been reported that statin treatment of statins have not been fully clarified. Rangel et al. cultured neuron cells leads to instability of AMPA (2005) suggested that Reactive Oxygen Species (ROS) receptor by disruption of cholesterol and sphingolipid are a part of normal human metabolism; however, when rich membrane microdomains called “Detergent produced in excess, ROS can cause tissue injury Resistant/Insoluble Membrane domains (DRM/DIM)” including lipid peroxidation, DNA damage and enzyme or “lipid rafts”. Therefore, they had suggested that the inactivation. ROS is a common denominator among possible involvement of cholesterol biosynthesis in acute neurological conditions, including epilepsy. In the statin-mediated anti-excitotoxic activity (Lee et al., pilocarpine model, there is an involvement of 2008). At present, whether cholesterol biosynthesis excitotoxic neuronal injury and ROS production has plays a role in statin-mediated anti-seizure and anti- been considered to be a part of mechanisms involved excitotoxicity in the in vivo animal model is not known. with glutamatergic excitotoxicity in vitro and in vivo. In the brain, cholesterol has a very long half life (up to Moreover, it was demonstrated that lovastatin treatment several months). Therefore, statins are not expected to inhibits free radical injury. Thus, this antioxidant effect change brain cholesterol level readily. Previous studies of statins could explain the neuroprotective properties have reported that systemic statin treatment does not found in their study (Rangel et al., 2005). Also, they affect cholesterol levels in the brain of guinea pigs. had been suggested that there is one classical argument supporting a possible role of Nitric Oxide (NO) in cholesterol levels in lipid raft fractions of synaptosomal convulsive phenomena: excitatory amino acids, such as plasma membrane suggests that statin treatment may N-Methyl-D-Aspartate (NMDA) and kainate, are affect intercellular or intracellular distribution of known to be potent convulsants and the activation of cholesterol which is associated with glutamate receptor NMDA receptors is accompanied by the formation of function in induction of status epilepticus and NO. In fact, the role of NO in epileptogenesis has been excitotoxicity (Lee et al., 2008). Along with examined in a number of studies, suggesting being a proconvulsive endogenous substance. Furthermore, pyrophosphate and geranylgeranylpyrophosphate are some studies have revealed that statins inhibit the lipid byproducts produced by the mevalonate pathway production of NO in brain parenchyma, indicating that and implicated in membrane attachment and function of statins, secondarily, may play the role of an small GTPases. Since the small GTPases (i.e., RhoA and H-Ras) are involved in various neuronal functions glutamate-mediated neurotoxicity. Other possibility is and excitotoxic signaling cascades, statins are also that the inhibition of brain endothelial Nitric Oxide expected to exert their anti-seizure and anti-excitotoxic Synthase (eNOS) leads to increased blood pressure, activities through inhibition of isoprenoid synthesis and which, in turn, may affect the excitability of central interfering with small GTPase signaling. Recent in vivo nervous system; however, it was demonstrated that reports have demonstrated that inhibition of H-Ras statins are able to upregulate eNOS, may be pivotal in farnesylation by Franeyltransferase Inhibitor (FTI) treatment inhibits NMDA-mediated excitotoxicity in decreasing with this, the firing threshold (Rangel et al., the rat brain. This report supports that statins may 2005). Also, they had been suggested that anti- inflammatory effects of statins could also contribute to isoprenylation. However, whether statins exert their epilepticus. Moreover, several studies have implicated a number of cytokines in seizure-related pathology. inhibiting synthesis of isoprenoid or cholesterol or both Therefore lovastatin treatment may provide an of them is not known at present (Lee et al., 2008). Also, important approach to suppression of the inflammatory Lee et al. (2008) reported that neuroprotective responses after status epilepticus (Rangel et al., 2005). efficacies of statins are mediated by their anti- In other study, Lee et al. (2008) reported that statins are inflammatory activity under various neurological inhibitors of HMG-CoA reductase, a rate limiting disease conditions such as human multiple sclerosis and enzyme for synthesis of cholesterol and isoprenoids, its animal models, Spinal cord injury, X-linked American J. Animal & Vet. Sci., 6 (4): 166-170, 2011 adrenoleukodystrophy, Alzheimer’s disease, traumatic Endres, M., U. Laufs, Z. Huang, T. Nakamura and P. brain injury and stroke. In these studies, statins Huang et al., 1998. Stroke protection by 3-hydroxy- inhibited inflammatory signal cascades and gene 3-methylglutaryl (HMG)-CoA reductase inhibitors expression through inhibition of isoprenylation of small mediated by endothelial nitric oxide synthase. Proc. GTPase (Ras and RhoA). A similar inhibitory role of Natl. Acad. Sci., 95: 8880-8885. PMID: 9671773 statins in inflammatory reactions was observed in KA- Goncalves, D.O., I.B.F. Calou, R.P. Siqueira, A.A. treated rats. However, they do not expect that the Lopes and L.K.A. Leal et al., 2011. In vivo and in observed statin-mediated reduction in inflammatory reactions as well as apoptotic cell death in KA-treated activities of lovastatin in rodents. Braz J. Med. rat is mediated by its own anti-inflammatory activity Biol. Res., 44: 173-181. DOI: 10.1590/S0100- observed in their previous studies. Since post-seizure inflammation and leakage of blood-brain barrier are Kirsch, C., G.P. Eckert, A.R. Koudinov and W.E. known to directly correlate with activity and frequency Muller, 2003. Brain cholesterol, statins and of status epilepticus, the decreased status epilepticus by Alzheimer's Disease. Pharmacopsychiatry, 36: statin treatment appears to attenuate inflammatory reaction in KA-treated rats (Lee et al., 2008). Statins Lee, J.K., J.S. Won, A.K. Singh and I. Singh, 2008. have been used to reduce inflammation, tame immune Statin inhibits kainic acid-induced seizure and cell activation, or arrest degenerative processes. associated inflammation and hippocampal cell Because of their widespread use and long-term safety death. Neurosci. Lett., 440: 260-264. DOI: record, some physicians prescribe statin therapy for non approved indications. A number of case reports describe Lu, D., A. Goussev, J. Chen, P. Pannu and Y. Li et al., the dramatic effects of statins added to standard therapies, 2004. Atorvastatin reduces neurological deficit and but beneficial effects need to be confirmed in controlled studies (Dinarello, 2010). Nevertheless, new and neuronal survival in rats subjected to traumatic completely studies must be carried out in order to brain injury. J Neurotrauma, 21: 21-32. PMID: determine in more detail the beneficial actions of statins Massaro, M., A. Zampolli, E. Scoditti, M.A. Carluccio and C. Storelli et al., 2010. Statins inhibit CONCLUSION
cyclooxygenase-2 and matrix metalloproteinase-9 in human endothelial cells: anti-angiogenic actions According to our results, pitavastatin has Cardiovasc. Res., 86: 311-320. PMID: 19946014 anticonvulsant effects on mice. Nevertheless, new McCarey, D.W., I.B. Mclnnes, R. Madhok, R. studies must be carried out in order to determine the Hampson and O. Scherbakov et al., 2004. Trial of beneficial effects of statins in treatment of epilepsy. atorvastatin in rheumatoid arthritis (TARA): double-blind, randomized placebo-controlled trial. REFERENCES
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