Epileptogenesis in Experimental Models

Abstract

Summary: Epileptogenesis refers to a phenomenon in which the brain undergoes molecular and cellular alterations after a brain-damaging insult, which increase its excitability and eventually lead to the occurrence of recurrent spontaneous seizures. Common epileptogenic factors include traumatic brain injury (TBI), stroke, and cerebral infections. Only a subpopulation of patients with any of these brain insults, however, will develop epilepsy. Thus, there are two great challenges: (1) identifying patients at risk, and (2) preventing and/or modifying the epileptogenic process. Target identification for antiepileptogenic treatments is difficult in humans because patients undergoing epileptogenesis cannot currently be identified. Animal models of epileptogenesis are therefore necessary for scientific progress. Recent advances in the development of experimental models of epileptogenesis have provided tools to investigate the molecular and cellular alterations and their temporal appearance, as well as the epilepsy phenotype after various clinically relevant epileptogenic etiologies, including TBI and stroke. Studying these models will lead to answers to critical questions such as: Do the molecular mechanisms of epileptogenesis depend on the etiology? Is the spectrum of network alterations during epileptogenesis the same after various clinically relevant etiologies? Is the temporal progression of epileptogenesis similar? Work is ongoing, and answers to these questions will facilitate the identification of molecular targets for antiepileptogenic treatments, the design of treatment paradigms, and the determination of whether data from one etiology can be extrapolated to another. Key Words: Endothelin-1-Gene arrayLateral fluid-percussion injury-Magnetic resonance imagingPhotothrombotic stroke-Traumatic brain injury-Video-EEG monitoring.According to the World Health Organization, approximately 0.8% (50 million) of the world population has epilepsy (available from http://www.who.int/ mediacentre/factsheets/fs165/en/). Epilepsies can be divided into three major categories based on etiology: idiopathic, symptomatic, and presumed symptomatic (previously called "cryptogenic") (Engel, 2001). In idiopathic epilepsies, genetic factors causing, for example, channelopathies, are presumed to have a major causative role in the development of seizures. In symptomatic epilepsies, there is an identifiable lesion in the brain that triggers seizures. The lesion can be a genetically programmed cellular alteration like neuronal migration disorder in cortex or an acquired lesion like traumatic brain injury (TBI) or stroke. Presumed symptomatic epilepsies are those most likely to be symptomatic, but the lesions cannot be identified using currently available methods (Engel, 2001).

The adenosine kinase hypothesis of epileptogenesis

“…Although the role of mossy fiber sprouting in epileptogenesis has been challenged (Elmer et al, 1997;Nissinen et al, 2001), in addition to astrogliosis, mossy fiber sprouting is one of the characteristic histopathological findings in TLE (Kharatishvili et al, 2006;Pitkanen et al, 2007;Represa et al, 1993;Sloviter et al, 2006;Sutula et al, 1988). The loss of normal postsynaptic targets of granule neurons may be the cause for mossy fiber sprouting, an hypothesis supported by findings that the degree of mossy fiber sprouting is correlated to the degree of neuronal cell loss (Cavazos and Cross, 2006).…”

Silk polymer-based adenosine release: Therapeutic potential for epilepsy

“…Despite the availability of an armamentarium of antiepileptic drugs, about 30% of all epilepsies cannot be treated with systemic pharmacotherapy for a variety of reasons including pharmacoresistance and intolerable side effects [1]. In contrast to systemic drug delivery, focal drug delivery to the brain is generally devoid of systemic side effects and holds great promise for the therapy of 1 Both authors contributed equally to this studyepilepsy [2], which frequently is of focal origin [3][4][5]. Therefore, various cell and gene therapies are currently in development for the treatment of intractable epilepsy [6][7][8][9][10].…”

Novel Animal Models of Pediatric Epilepsy

“…Spontaneous seizures develop after a "silent" period, which may last between several days and several months [15]. Whether cell injury to the immature brain is required to induce epileptogenesis remains an active topic of debate [16,17].…”