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  • br Introduction Epilepsy is characterized by spontaneous rec

    2024-04-01


    Introduction Epilepsy is characterized by spontaneous recurrent seizures and represents one of the most frequent neurological diseases affecting about 60 million people worldwide (McNamara, 1999). It is estimated that up to 50% of all cases are triggered by “initial precipitating injuries”, such as status epilepticus (SE), stroke, and traumatic brain injury (TBI) (DeLorenzo et al., 2005, Hauser and Annegers, 1991, Hauser et al., 1991). The underlying pathophysiological process that is triggered by these and other initiating events and that transforms a healthy brain into an epileptic brain is termed epileptogenesis. This process involves changes in the equilibrium between excitatory and γ-aminobutyric Quinacrine hydrochloride hydrate (GABA)-ergic inhibitory neurotransmission, changes in ionotropic receptor function, alterations in calcium-homeostasis, or dysfunction of endogenous anticonvulsant or neuroprotective regulatory systems (DeLorenzo et al., 2007, Kohling, 2006). Consequently, currently used antiepileptic drugs largely act on neuronal and postsynaptic targets involved in the regulation of neurotransmission. This is also true for newer antiepileptic drugs, such as gabapentin and pregabalin, which have recently been demonstrated to act on the α2–δ subunit of a voltage-gated calcium channel, thus attenuating the calcium flux into neurons (Davies et al., 2007, Field et al., 2007, Taylor et al., 2007). Apart from dysfunction of neuronal networks (Holmes and Ben-Ari, 2003), dysfunction of astrocytes has recently emerged as a critical component of epileptogenesis adding an additional layer of complexity to the underlying disease process (Borges et al., 2006, Tian et al., 2005). Current epilepsy therapies largely rely on pharmacotherapy or surgical intervention, both symptomatic strategies aimed at the suppression of seizures but not at the suppression of epileptogenesis (Loscher and Schmidt, 2004). Thus, to date no effective prophylaxis or true pharmacotherapeutic cure is available. In addition, the progression of epileptogenesis to chronic epilepsy often leads to pharmacoresistance and intractable seizures, which afflict up to 30% of all patients with epilepsy in particular those with temporal lobe epilepsy (TLE), the most prevalent form of refractory symptomatic epilepsy (Engel, 2001, Jallon, 1997). These patients are often severely disabled by their condition, have an unsatisfactory quality of life, and are at increased risk of sudden unexpected death. Thus, therapeutic strategies, which prevent or retard epileptogenesis and disease progression, would constitute a major therapeutic advance (Pitkanen and Halonen, 1998) with the goal to achieve seizure control without side effects. A prerequisite for the development of rational antiepileptogenic therapies is the understanding of the pathophysiological mechanisms underlying epileptogenesis. Based on rational consideration of these mechanisms several gene and cell therapies have been proposed making use of endogenous antiepileptic and antiepileptogenic compounds of the brain (Boison, 2007b, Noe et al., 2007). This review will critically evaluate dysfunction of the adenosine-based endogenous seizure control system (i) as a key component of epileptogenesis and (ii) as a rational target for therapeutic intervention aimed at the prevention of epilepsy.
    Epileptogenesis Whether hippocampal neuronal cell loss and/or hippocampal sclerosis is the cause or consequence of seizures has been a recurring question in human epilepsy research for more than a century. According to the current understanding of epileptogenesis, three major phases are involved (Pitkanen, 2002, Pitkanen and Sutula, 2002): (i) the acute injury (e.g. status epilepticus, prolonged febrile seizures, stroke, or traumatic brain injury); (ii) a latent phase of epileptogenesis; and (iii) chronic epilepsy with spontaneous recurrent seizures. A major challenge in epilepsy research is to understand how the initial injury involved in the induction of epileptogenesis can produce long-term changes in neuronal excitability. Although different types of injuries may lead to epileptogenesis, some of the underlying mechanisms may still be the same. The search for such common pathways of epileptogenesis may thus provide the foundation for the development of novel antiepileptogenic and thus preventive therapies. A common consequence of brain injury is the development of an astrogliotic scar. Thus, reactive astrogliosis is the most prominent macroglial response to diverse forms of CNS injury (Pekny and Nilsson, 2005). In addition, astrogliosis is known to be a prominent feature of epileptic foci being evident in up to 90% of surgically resected epileptic hippocampi (Thom et al., 2002), and may play a causal role in the development of seizures and the persistence of seizure disorders (Khurgel and Ivy, 1996). Astrogliosis as seen in hippocampal sclerosis in TLE is considered to be a hallmark of epileptogenesis. Hippocampal sclerosis is characterized by intensive gliosis combined with a selective loss of neurons in the hippocampal formation. This includes loss of glutamatergic neurons in the granular and pyramidal cell layers of the hippocampal formation and the loss of inhibitory interneurons in the dentate hilus and the CA1 region. Neuronal cell loss and gliosis can spread to other components of the limbic system, such as amygdala or the entorhinal or perirhinal cortex (Wieser, 2004); in particular the loss of GABAergic interneurons is thought to contribute to the increased excitability of the epileptic hippocampus (Thompson et al., 1998).