Send Orders for Reprints to reprints@benthamscience.ae Current Drug Targets, 2015, 16, 000-000 1 1389-4501/15 $58.00+.00 © 2015 Bentham Science Publishers Statins and Epilepsy: Preclinical Studies, Clinical Trials and Statin- Anticonvulsant Drug Interactions Francesca Scicchitano 1 , Andrew Constanti 2 , Rita Citraro 1 , Giovambattista De Sarro 1 and Emilio Russo 1,* 1 Science of Health Department, School of Medicine, University “Magna Graecia” of Catanzaro, Italy; 2 Department of Pharmacology, UCL School of Pharmacy, 29/39 Brunswick Square, London, United Kingdom Abstract: 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) are potent cho- lesterol-lowering drugs which also possess beneficial antioxidant, antiinflammatory, immunomodula- tory, and antiexcitotoxic effects. In addition, statins have proven neuroprotective effects in several neu- rological diseases: stroke, cerebral ischemia, Alzheimer’s and Parkinson’s disease, multiple sclerosis and traumatic brain injury. Relatively few studies have investigated the potential anti-seizure proper- ties of statins in epilepsy and the possible underlying protective mechanisms that may be involved. This review summarizes the currently available data concerning statin effects in modulating seizure activity (sometimes adversely) and epileptogenesis in different experimental models as well as in clinical studies. Furthermore, we analyze the consequences of some of the more commonly reported statin–anticonvulsant drug interactions in the literature, discuss some of the adverse effects of statins encountered in clinical practice and comment on the potential future usefulness of statins in epilepsy therapy. Keywords: Adverse effects, atorvastatin, epileptogenesis, fluvastatin, lovastatin, pravastatin, seizures, simvastatin, statin- antiepileptic drug (AED) interactions, statins. 1. INTRODUCTION Epilepsy is a chronic neurological disorder characterized by a tendency towards spontaneous recurrent seizures; it affects ~1% of the human population world-wide. Although this disease is suitably treated with a number of established antiepileptic drugs (AEDs) according to etiology, age, and pattern of onset, ~30% of patients still do not respond to the standard AED treatments and are therefore not effectively controlled [1,2]. Monotherapy is the treatment of choice for newly diagnosed epilepsy, but after therapeutic failure, poly- therapy with more than one AED is considered. This thera- peutic approach can lead to excessive drug use and increased incidence of toxicity, considering the common use of poly- pharmacy in elderly patients with epilepsy [3]. Accordingly, these patients may not be free of the consequences of poten- tial drug interactions and in many patients, concomitant dis- eases or other conditions may require co-administration of non-AED drugs [4]. The need for new anticonvul- sant/antiepileptic drugs with novel (ideally more selective) targets therefore still remains in clinical and preclinical re- search. Experimental and clinical findings support a crucial role for neuroinflammatory processes in epilepsy, particularly in *Address correspondence to this author at the Department of Science of Health, School of Medicine, University of Catanzaro, Via T. Campanella, 115; 88100 Catanzaro, Italy; Tel: +39 0961 3694191; Fax: +39 0961 3694192; E-mail: erusso@unicz.it the mechanisms underlying seizure development (epilepto- genesis) [5]. Some drugs used clinically for other treatments also have the potential indication for inhibiting neuroin- flammation, so in principle, deserve to be investigated for potential antiepileptogenic activity. One such class of drugs is the statins. These are potent lipid-lowering medications used for treating hypercholesterolemia and coronary heart disease; they exert protective effects in non-cardiovascular disorders, including neurological conditions ([6] and intrac- ranial hemorrhage [7]. Despite their widespread use, statins can exhibit some serious adverse side effects during treat- ment which can affect patient compliance. These include: gastrointestinal problems (diarrhoea, abdominal pain, consti- pation, flatulence), myopathy, muscle aches or pains, rhab- domyolysis, hepatotoxicity, proteinuria, rash, peripheral neu- ropathy, insomnia, unusual dreams, sleep and concentration problems, as well as asymptomatic increases in serum transaminase enzymes. They are also known to slightly in- crease the incidence of type 2 diabetes mellitus in some pa- tients [8]. Nevertheless, their cardiovascular benefits are considered to outweigh their potential harmful effects in pa- tients with a high risk of cardiovascular disease. In addition to their cholesterol-lowering action, statins exhibit many cholesterol-independent “pleiotropic” effects that include anti-thrombotic, anti-inflammatory and antioxi- dative actions [9]. Moreover, numerous studies reported in the literature have demonstrated the neuroprotective action of statins in acute stroke, cerebral ischemia, traumatic brain Please provide corresponding author(s) photograph size should be 4" x 4" inches