Neuroprotective strategies using antiepileptic drugs

Seizures induce neuronal damage/death via a variety of mechanisms, including glutamate-induced excitotoxicity, oxidative stress, and mitochondrial dysfunction. Antiepileptic drugs (AEDs) have long been used to control seizure activity; however, interest in the neuroprotective actions of AEDs is growing. During seizure activity, elevated levels of excitatory amino acids (EAAs), such as glutamate, activate α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptors, which cause depolarization. This increase in EAA (glutamate surge) can also lead to the activation of voltagedependent Na⁺ channels, leading to further depolarization resulting from increased Na⁺ entry into the cell and osmotic swelling of the neuron as Cl⁻ passively enters the cell, causing an influx of water. Aberrant depolarization can also result in the removal of the Mg²⁺ block from N⁻methyl-daspartate (NMDA) receptors, allowing them to be activated by glutamate. Activation of NMDA receptors and group I metabotropic glutamate receptors allows Ca²⁺ influx into the neuron, subsequently activating downstream mediators of programmed cell death (Sullivan, 2005; Walker, 2007). This disruption of Ca²⁺ homeostasis is believed to underlie glutamate-mediated toxicity. Based on several distinct animal models of excitotoxicity and injury, it has become apparent that several antiepileptic drugs may possess neuroprotective properties (Trojnar et al., 2002). Although their sites of action may be very distinct, generally AEDs displaying neuroprotective properties inhibit components of the excitotoxic cascade (Sullivan, 2005). Several of the AEDs shown to be neuroprotective are known to enhance GABA-meditated inhibition at the synapse, including barbiturates, benzodiazepines, vigabatrin, tiagabine, felbamate, and topiramate. Others, such as phenytoin, carbamazepine, oxcarbazepine, lamotrigine, zonisamide, and valproate, are able to inactivate voltage-dependent Na⁺ channels. Lamotrigine, felbamate, and valproate may act as Ca²⁺ channel blockers, and AEDs such as felbamate, gabapentin, lamotrigine, tiagabine, topiramate, and valproate all exert antiseizure and neuroprotective actions at numerous sites (or combinations of sites), including inhibition of Na⁺ and Ca²⁺ channels, enhancing GABAmediated inhibition, and acting as antagonists of the AMPA receptors (for a full review of AED mechanisms, see Chapter 8 in this volume; for reviews of neuroprotection by AEDs, see Sullivan, 2005; Trojnar et al., 2002). Zonisamide, in addition to inhibition of Na⁺ channels, may also act as an antioxidant, which could enhance its neuroprotective properties. The complex pharmacology of many of these AEDs results in a blanket-type approach being used in the treatment of epilepsy which has proven beneficial in reducing seizure severity; however, this approach has proven controversial with regard to the proposed neuroprotective benefits of AEDs. Valproate, tiagabine, and even benzodiazepines, for example, have been shown to be neurotoxic and can exacerbate neuronal damage in some paradigms, particularly in immature animal models of CNS injury (Table 11.1) (Olney et al., 2002; Trojnar et al., 2002). Furthermore, in several cases, neuroprotection is limited unless the dosage is raised considerably above the clinical range, and efficacy can vary greatly (even becoming neurotoxic) depending on treatment initiation and the therapeutic window that is targeted. In addition, concerns about adverse neurobehavioral effects have been raised and demonstrated in several animal models of epilepsy (Sankar and Holmes, 2004). Even though the precise mechanisms underlying these adverse effects are unknown, they may hinder the potential for using AEDs as neuroprotective agents. However, if one moves downstream of the receptor-mediated events currently utilized by AEDs, it becomes apparent that Ca²⁺- mediated mitochondrial dysfunction may be a prime target for neuroprotective interventions. In short, the overall pharmacological target for AEDs is to decrease neuronal excitation (Landmark, 2007). By decreasing neuronal excitation, AEDs may exert their neuroprotective mechanisms of action through inhibition of the excitotoxic cascade. It is important to note that not all AEDs are neuroprotective in every paradigm, and some have been shown to be neurotoxic, especially in immature animal models of injury (Olney et al., 2002; Trojnar et al., 2002). This chapter focuses on reviewing the main neuroprotective mechanisms of action for AEDs, first discussing AEDs that act at the GABAergic synapse followed by those functioning at the glutamatergic synapse (Figure 11.1; see also figures in Chapter 8 in this volume). Given the emergent role of Ca²⁺- mediated mitochondrial dysfunction in epilepsy, we begin by covering the pivotal role mitochondria can play in neuronal cell survival or death during excitotoxic insults through their regulation of both energy metabolism and apoptotic pathways.