Cellular responses to the generation of free-radical oxidants after decompartmentalization of hemoglobin or iron-containing heme compounds may depend on the induction of protective mechanisms. For example, strains of Escherichia coli may be differentiated on observation of responses to peroxide. Induction of enzymes to repair DNA damage induced by Fenton-derived free radicals appears to be critical for cellular survival.80,81 Some speculate that continuing alterations causing focal epileptiform discharges may result from free-radical injury to neuronal nuclear or mitochondrial DNA. Differences in susceptibility to developing epilepsy after a given trauma dose may be related to the ability of repair-response induction after initiation of lipid peroxidation.
Specific brain genetic factors that cause a liability to develop post-traumatic epilepsy remain unknown. A possible genetic predisposition has been observed, however, with the detection of decreased levels of serum haptoglobin in familial epilepsy.82 Haptoglobins are acute phase glycoproteins in the alpha L–globulin fraction of serum that form stable complexes with hemoglobin.83 Because antioxidants such as superoxide dismutase and peroxidases are not found in high concentrations in extracellular fluid, containment of initiators of oxidation must depend on binding of reactive metals to carrier proteins, including transferrin, lactoferrin, ceruloplasmin, and haptoglobins.83 Because one mechanism of protection against the induction of oxidant stress is sequestration of free hemoglobin with haptoglobins, impairment in the synthesis of these glycoproteins may produce an inherent susceptibility to the development of epilepsy after head trauma.
Regulation of glutamate may be critical in the process of epileptogenesis. Microdialysis measurements from humans with spontaneous seizures from the hippocampus show transient release of glutamate.84 Most glutamate is cleared from the extrasynaptic space by the action of high-affinity transporters called GLAST and GLT-1. These proteins are found predominantly in glia.85,86 Decreasing GLAST and GLT-1 expression would be the result of down-regulation, because the messenger RNAs of these proteins were decreased even though progressive gliosis is a characteristic found in the hippocampus of rats that are spontaneously seizing.87,88 Down-regulation of glial glutamate transporter with expected increase in tissue glutamate concentration contributes to excitatory synaptic transmission, associated occurrence of seizures, and neurodegeneration in the hippocampus. Animals with spontaneous iron-induced amygdalar seizures89 have down-regulation of glutamate transporter production as a component of their chronic epileptogenesis.90,91
Molecular changes appear to correlate with depolarization-induced elevation of extracellular glutamate levels in the hippocampus, as determined by in vivo microdialysis. A protein called GAT-1 transports GABA. This transporter protein is reported to be responsible for approximately 85% of GABA reuptake.92 GAT-1 is widely distributed in neurons and astrocytes in hippocampal and limbic regions.93–95 Alterations in GABA uptake may be important to the process of chronic epileptogenesis after head trauma.96
Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.
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