The emerging role for chemokines in epilepsy Paolo F. Fabene a, ⁎, Placido Bramanti b , Gabriela Constantin c a Department of Morphological and Biomedical Sciences, Section of Anatomy and Histology, University of Verona, Verona, Italy b IRCCS Centro Neurolesi “Bonino-Pulejo”, Messina, Italy c Department of General Pathology, Section of Pathology, University of Verona, Verona, Italy abstract article info Article history: Received 26 April 2010 Accepted 4 May 2010 Keywords: Seizures Chemokines Pilocarpine Epileptogenesis Leukocyte trafficking Epilepsy has been considered mainly a neuronal disease, without much attention to non-neuronal cells. In recent years growing evidence suggest that astrocytes, microglia, blood leukocytes and blood–brain barrier breakdown are involved in the pathogenesis of epilepsy. In particular, leukocyte–endothelium interactions and eventually subsequent leukocyte recruitment in the brain parenchyma seem to represent key players in the epileptogenic cascade. Chemokines are chemotactic factors controlling leukocyte migration under physiological and pathological conditions. In the light of recent advances in our understanding of the role of inflammation mechanisms in the pathogenesis of epilepsy, pro-inflammatory chemokines may play a critical role in epileptogenesis. © 2010 Elsevier B.V. All rights reserved. 1. Epilepsy Epilepsy is a neurological condition characterized by a paroxysmal event due to abnormal and hypersynchronous discharges from an aggregate of neurons in the central nervous system (CNS). Epilepsy affects 1% of the general world population, resulting in a condition in which a person has recurrent seizures due to a chronic, underlying pathologic process. Epilepsy affects around 50 million people world- wide, and nearly 90% of them are found in developing areas (WHO Fact sheet N°999; http://www.who.int/mediacentre/factsheets/ fs999/en/index.html). Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy in adults, and often represents a treatment-refractory disorder (Hauser et al., 1996; Engel, 2001; Wieser, 2004). Given the fact that, by definition, epilepsy is a neuronal malfunctioning, many of the studies have been historically focused almost exclusively on the consequences on neuronal alterations (see Fig. 1), and, in particular, on the unbalance between excitability and inhibition (Holmes, 2005). TLE is often associated with a characteristic pattern of selective and extensive hippocampal atrophy, referred as hippocampal sclerosis (HS; see, e.g., Meldrum and Bruton, 1992). The sclerotic hippocampus is considered to be the source of the electrical events that cause spontaneous epileptic seizures (Spencer, 1998). The indirect evidence that surgical removal of HS produces clinical improvement (Falconer and Taylor, 1968) strengthened the concept that HS itself is an epileptogenic area (Falconer, 1974). However, whether hippocampal sclerosis is the consequence of repeated seizures, or whether it plays a role in the development of the epileptic focus is still debated (Jefferys, 1999). Both clinical and preclinical data suggest that HS can be associated but not necessary for long-lasting epileptic condition. In particular, we recently demonstrated the occurrence of spontaneous recurrent seizures (SRSs) in rats with preserved hippocampal (and extrahippocampal) morphology and even in absence of status epilepticus (SE) (Navarro Mora et al., 2009). Furthermore, we have provided evidences that modulating leukocyte–endothelium interac- tion we can reduce the SRSs frequency up to 60%, even in presence of a severe HS (Fabene et al., 2008). These considerations indicate that we should carefully interpret the experimental data obtained in animal models of epilepsy and that neuroinflammation has a more important role in the etiopathogenesis of epilepsy than previously considered. 1.1. Pilocarpine model of TLE Systemic administration of single dose of pilocarpine, a muscarinic cholinergic agonist, leads to SE and, after a seizure-free period, to a chronic condition determined by SRSs (see, for review, Turski et al., 1989). Pilocarpine, which, together with kainic acid (KA), is probably the most commonly studied chemical-inductive model for TLE, has been recently also proposed as a model of pharmacoresistance in TLE (Chakir et al., 2006) and for a non-SE SRSs model (Navarro Mora et al., 2009). Pilocarpine-induced SE is usually characterized by lesions similar to those of patients with TLE, like HS, loss of GABAergic interneurons in the dentate hilus and pyramidal cell death within CA3 and CA1 strata of hippocampus (Sarkisian, 2001). Furthermore, an enhancement of Journal of Neuroimmunology 224 (2010) 22–27 ⁎ Corresponding author. Department of Morphological and Biomedical Sciences, Section of Anatomy and Histology, Faculty of Medicine, Strada Le Grazie 8, 37134 Verona, Italy. Tel.: +39 045 8027 267; fax: +39 045 8027163. E-mail address: paolo.fabene@univr.it (P.F. Fabene). 0165-5728/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2010.05.016 Contents lists available at ScienceDirect Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim