Progress in neuroprotective strategies for preventing epilepsy
Introduction
Epilepsy is one of the oldest neurological conditions known to humankind. The term “epilepsy” is derived from Greek word “epilambanein”, which means “to seize upon” or “to attack”. In this modern era, epilepsy is the most frequent neurodegenerative disease after stroke. It afflicts more than 2 million Americans and 50 million people worldwide (Strine et al., 2005), and the temporal lobe epilepsy (TLE) is among the most frequent types of drug-resistant epilepsy (Engel, 2001, Litt et al., 2001, McKeown and McNamara, 2001). In a population of new patients presented with epilepsy, almost 30% of them have seizures originating from the temporal lobe of the brain (Manford et al., 1992). Individuals affected with TLE typically have comparable clinical description, including an initial precipitating injury (IPI) such as the status epilepticus (SE), head trauma, encephalitis or childhood febrile seizures (Harvey et al., 1997, Fisher et al., 1998, Cendes, 2002). There is usually a latent period of several years between this injury and the emergence of the chronic TLE characterized by spontaneous recurrent motor seizures (SRMS) originating from temporal lobe foci, and learning and memory impairments (Devinsky, 2004, Detour et al., 2005). Further, the TLE is frequently associated with hippocampal sclerosis, mainly exemplified by significant neurodegeneration in the dentate hilus (DH), and the CA1 and CA3c sub regions (Sloviter, 2005). Human studies suggest that the hippocampal sclerosis likely initiates or contributes to the generation of most TLEs (Engel, 1996). A significant number of people (∼25%) afflicted with epilepsy have seizures that cannot be controlled by anti-epileptic drugs (Litt et al., 2001, McKeown and McNamara, 2001). Moreover, anti-epileptic drugs (AEDs) merely provide symptomatic treatment without having any influence on the course of the disease. Thus, there is a pressing need to develop alternative therapeutic approaches that prevent the epileptogenesis after the SE or an IPI. From this perspective, identification of compounds or approaches that are efficacious for providing neuroprotection to the hippocampus after the onset of SE has great significance.
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Definition, causes and consequences of seizures
A seizure is a convulsive episode, which starts of as atypical, excessive hyper-synchronous discharges from an aggregate of neurons in the brain and then recruits surrounding neurons to comprise one or both hemispheres of the brain (Kandel et al., 2000, Carey and Fuchs, 2001). In most patients presenting TLE, the development of seizures is preceded with an IPI such as the head trauma, stroke, SE, and infections like meningitis (Harvey et al., 1997, Fisher et al., 1998, Cendes, 2002).
Hippocampal neurodegeneration and synaptic reorganization after seizures
Acute seizures in the adult brain may lead to alterations in the synaptic plasticity, including the long-term potentiation of synaptic responses. A wide range of neuropsychological deficits may follow the SE, which typically include learning and memory dysfunction and other cognitive deficits (Holmes et al., 2004, Holmes, 2006). Although multiple regions of the brain are affected with the SE induced through chemoconvulsants such as KA or pilocarpine, the hippocampal region has received the most
Changes in GABA-ergic interneurons after seizures
The prevailing hypothesis pertaining to links between GABA-ergic interneurons, epileptogenesis and TLE is that epileptogenesis results from a diminished GABA-mediated inhibition occurring through the degeneration of fractions of GABA-ergic interneurons. Inhibitory inputs from GABA-ergic hippocampal interneurons prevent the principal excitatory hippocampal neurons from becoming hyperexcitable under normal conditions (Freund and Buzsaki, 1996). This is mediated by direct inhibitory inputs from
Dentate neurogenesis and temporal lobe epilepsy (TLE)
Addition of new neurons to the dentate granule cell layer from proliferating neural stem/progenitor cells (NSCs) in the subgranular zone (SGZ) of the DG is maintained all through life in the mammalian CNS (Kaplan and Hinds, 1977, Kuhn et al., 1996, Cameron et al., 1998, Eriksson et al., 1998, Kornack and Rakic, 1999, Gage, 2002, Gould and Gross, 2002, Song et al., 2002, Emsley et al., 2005). Interestingly, hippocampal functions of learning and memory are closely linked to the extent of dentate
Neuroprotective strategies for preventing chronic epilepsy
The onset of chronic epileptic seizures (also refereed to as SRMS) after brain insults such as SE, stroke or head trauma occurs after a delay. It is believed that multiple epileptogenic changes occur during this latent period. Thus, the latent period after an IPI provides an opportunity for applying effective intervention strategies that are capable of preventing the progression of initial seizure or injury induced neurodegeneration into chronic epilepsy, characterized by SRMS and learning and
Neuroprotection using anti-epileptic drugs
The anticonvulsive mechanisms of conventional and newly introduced drugs vary considerably. The most common actions were shown on ion channels, GABA-ergic and glutamatergic metabolism, receptors or secondary messengers (Macdonald and Kelly, 1994, Macdonald and Kelly, 1995). Extensive efforts have been made to achieve neuroprotection through effective seizure suppression with anticonvulsants and new compounds that may be neuroprotective through mechanisms other than anticonvulsant actions. A
Neuroprotection using the ketogenic diet
In spite of new developments in the AED research and availability of almost 20 AEDs, seizures remain unmanageable in many types of epileptic manifestations. Moreover, the AED therapy is associated with significant side-effects (Porter et al., 1997, Browne and Holmes, 2001, Wheless et al., 2001). From this perspective, since 1990s, the ketogenic diet (KD) is emerging as one of the effective therapies with relatively reduced side effects particularly in difficult-to-control epilepsies (Freeman et
Neuroprotection via administration of neurotrophic factors
The neurotrophic factors appear to play key roles in pathophysiological conditions such as seizures (Jankowsky and Patterson, 2001). A variety of neurotrophic factors has potent effects on neuronal survival, differentiation, neurite outgrowth, neurotransmitter synthesis, synaptic plasticity and excitability (Weisenhorn et al., 1999). However, the epileptogenic or anti-epileptogenic effects of various neurotrophic factors following brain insults like seizures are still being studied. The major
Efficacy of antioxidants as neuroprotective compounds against epilepsy
Oxidative injury, resulting from excessive release of free radicals, likely contributes to the initiation and progression of epilepsy after brain injury. Therefore, antioxidant therapies aimed at reducing oxidative stress have received considerable attention in the treatment of epilepsy. These approaches may also restrain tissue damage and favorably alter the clinical course of the disease (Costello and Delanty, 2004). In this section, we discuss the efficacy of two distinct antioxidants
Hormones and neuroprotection
The effects of hormones, either peripheral or endogenous on the nervous system have been well established. Especially, gonadal steroids like estrogen, progesterone and their precursors are proven to have direct effects on neurotransmitter receptors (Hoffman et al., 2006). The cyclical changes in these steroids are believed to be important in the pathogenesis of catamenial epilepsy because susceptibility to seizures during menstrual cycle are linked to serum hormone levels (Reddy, 2004).
Neuroprotective effects of neural cell transplants
Although multipotent and self-renewing neural stem cells (NSCs) persist in both neurogenic (neuron producing) and non-neurogenic regions of the adult CNS, the capacity of the adult mammalian CNS for self-repair is limited (Turner and Shetty, 2003, Shetty and Hattiangady, 2007b). This is because, in conditions such as injury or disease, the endogenous NSCs fail to form adequate new neurons to replace the lost neurons. Moreover, the plasticity of residual neurons in response to injury and
Overall conclusions
The epileptogenesis is a dynamic process with major modifications taking place at multiple levels, which include synaptic plasticity, aberrant reorganization of the neuronal circuitry, alterations in interneuron number and function, and changes in dentate neurogenesis. The latency period found between the initial precipitating insult and the development of chronic epilepsy offers a useful window for application of promising neuroprotective strategies. Ideally, the initial insult modification
Acknowledgements
This work was supported by grants from the Department of Veterans Affairs (VA Merit Review Award to A.K.S.), the National Institute of Neurological Disorders and Stroke (NS054780 & NS043507 to A.K.S.), and the National Institute for Aging (AG20924).
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