2003). But difficulties remain in understanding their specific mechanisms and efficiently counteracting them. A major clinical need for epilepsy is to develop new drugs intended for CK-636 controlling seizures in people with pharmacoresistant epilepsy. Moreover, the available treatments are symptomatic; therefore , disease-modifying therapies intended for preventing the onset or progression of the disease are missing. The key molecular mechanisms underlying the disease onset and its progression are still elusive, although some signaling pathways have recently been suggested to play a pathologic role (Pitkanen and Lukasiuk CK-636 2011). Experimental studies and clinical evidence obtained in animal models of epilepsy and human brain specimens from various drug-resistant forms of epilepsy show the activation of the innate and adaptive immunity mechanisms and the induction of the associated inflammatory processes in the epileptogenic foci (Aronica and Crino 2011; Vezzani et al. 2011b). A role of inflammatory molecules in the generation of seizures had been first envisaged when selected anti-inflammatory treatments, in particular, steroids, immunoglobulins, and adrenocorticotropic hormone (ACTH), were shown to control seizures in pediatric epilepsies refractory to conventional anticonvulsive drugs (e. g., infantile spasms, continuous spike and waves in sleep, and epilepsy in Rasmussen encephalitis [RE]). In addition , specific epileptic disorders have been associated with the presence of neuronal antigen-directed antibodies in plasma or cerebrospinal fluid (CSF). In some of these forms, the pathogenic role of some autoantibodies is suspected based on clinical and experimental findings (Bien et al. 2012). In recent years, immune cells producing inflammatory molecules were detected in surgically resected brain tissue from patients with pharmacoresistant epilepsies without an autoimmune etiology. A significant component of this inflammatory response was confined to brain resident cells (i. e., microglia, astrocytes, and neurons) and is defined as neuroinflammation (Vezzani et al. 2011b; Aronica et al. 2012b). Cytokines and related signaling molecules were among the most prominently overexpressed inflammatory mediators identified in epileptogenic brain tissue. Besides glial cells, inflammatory molecules are also produced and released by neurons and endothelial cells of the bloodbrain barrier (BBB). Leukocytes can also contribute to the inflammatory responses in epilepsy (Iyer et al. 2010a; Vezzani et al. 2011b; Bien et al. 2012). A notable finding is that the inflammatory mediators (i. e., cytokines, chemokines, prostaglandins, complement system) detected in epilepsy brain specimens are not only effector molecules of the immune system promoting local inflammation and tissue recruitment of peripheral immune cells, but they function as neuromodulators (Vezzani et al. 2011c). In fact , they activate their cognate receptors expressed by neurons, thus directly affecting neuronal function and excitability (Viviani et al. 2007; Vezzani et al. CK-636 2011c). Specific inflammatory mediators were reported to significantly contribute to the mechanisms of seizure generation and to pharmacoresistence in experimental models (van Vliet et al. 2010; Vezzani et al. 2011b). This article will describe the recent evidence related to the pathologic consequences of innate and adaptive immunity activation in human epilepsy, the mechanisms activated by inflammatory molecules or autoantibodies in target cells, and their relevance intended for the onset Rabbit polyclonal to CapG and progression of the disease. Finally, we will discuss the implications of these findings for epilepsy therapy. == ACTIVATION OF INNATE IMMUNITY IN EXPERIMENTAL MODELS OF EPILEPSY == Increasing evidence in animal models of epilepsy has shown a prominent role of glial cells in the biosynthesis and release of the inflammatory molecules (Aronica and Crino 2011; Vezzani et al. 2011b; Devinsky et al. 2013). These cells play the role of intrinsic innate immunity cells of the brain in concert with extravasated macrophages and granulocytes. In particular, epileptogenic brain injuries (i. e., brain insults leading to or increasing the risk of the development of epilepsy) or convulsive events (i. e., provoking acute seizures) rapidly activate microglia and astrocytes in the brain regions affected by the CK-636 pathologic event (Fig. 1). Glia activation occurs also in genetic models of epilepsy, such as in rats with spike-and-wave discharges mimicking absence seizures (Akin et al. 2011), models of tuberous sclerosis (Wong and Crino 2012), and progressive myoclonus epilepsy of UnverrichtLundborg type 1 (Tegelberg et al. 2012; Joensuu et al. 2014). Notably, glia activation occurs during epileptogenesis.