Epilepsy and Seizures: Excitotoxicity or Excitotrophicity?

Abstract

Excitotoxic neuronal death has been clearly documented in the adult brain following status epilepticus (SE), a state of uninterrupted seizure activity that may last for hours. The severity and duration of SE determine the extent of neuronal injury; in most animal models damage is observed with durations of one hour or longer. Severity, duration and rate of onset may also influence the extent to which the neuronal death is mediated by apoptotic or necrotic processes. In contrast to the adult brain, the immature brain is resistant to SE-induced damage; nevertheless long-term deleter ious effects of SE have been observed in animals that experienced SE in infancy without exhibiting neuronal loss. Likewise, in adult animals, long-term abnormalities such as spontaneous seizures have been documented following SE even under conditions in which the brain was protected from damage. This suggests that SE-induced excitotoxic injury is not required for the development of long-term disrupt ion of neuronal function in the aftermath of SE. In contrast to SE, recurrent intermittent brief seizures such as those typically associated with epilepsy, do not necessar ily cause neuronal inj ury. In patients with epilepsy it is often difficult to determine whether brain lesions are a cause or consequence of the seizure condition; little or no injury has been observed with chronic brief seizures in several animal models. In fact, exposure to repeated brief noninjurious seizures has been shown to exert a neuroprotective action, possibly as a consequence of induction of expression of neurotrophic factors. This “excitotrophic” effect of seizures extends beyond protection against SE-induced injury to include protection in models such as adrenalectomy-induced granule cell death. It is therefore possible that seizures may serve to protect against neurodegeneration and promote regrowth and remodeling in the face of insults to the nervous system. Thus, seizures can span a spectrum from trophic and adaptive to toxic and maladaptive, depending upon the conditions of their occurrence and the extent to which they are regulated. In this context, seizures may be analogous to fever: adaptive and protective in specific settings, with the capacity to become maladaptive and injurious in their own right if they develop into SE or a long lasting epileptic condition.