Abstracts

Rationale: Inbred strains of mice differ in their susceptibility to excitotoxin-induced cell death, but the genetic basis of individual variation is unknown. We were interested in identifying the relationship between glycemic index and susceptibility to seizure-induced excitotoxic cell death and establishing whether modulation of glycemic index could modify the susceptibility to epilepsy. As a first step, we wanted to determine if glucose administration following kainate-induced status could reduce seizure-induced cell death in mice susceptible to excitotoxin-induced cell loss (FVB/N). Secondly, we wanted to determine if modulation of the glycemic index, in models of hypo- or hyperglycemia, could affect seizure susceptibility and its neuropathological consequences following kainate administration in a mouse strain previously found to be resistant to seizure-induced cell death (C57BL/6). Methods: C57BL/6 mice were purchased from Jackson Laboratories and injected with insulin (hypoglycemia), glucose (non-ketotic hyperglycemia) or streptozotocin (STZ; diabetic hyperglycemia) to modify their glycemic status. C57BL/6 mice with modified glycemic status or normoglycemic FVB/N mice, purchased from Jackson Laboratories, received one subcutaneous injection of kainic acid. Following kainate injections, mice were monitored continuously for 4 h for the onset of locomotor activity, behavioral manifestations of limbic seizure episodes, and scored for seizure activity as defined previously (Racine, 1972). Brains from animals in each age group were processed for light microscopic histopathologic evaluation seven days following kainate administration to evaluate the severity of seizure-induced brain damage. Results: Kainate administration to FVB/N mice resulted in a 2-fold reduction in blood glucose, which could be restored by glucose infusion following KA-induced status epilepticus. As well, glucose infusion post status epilepticus, also significantly reduced the extent of seizure-induced damage throughout the hippocampus. While hypoglycemia was without effect on kainate-induced seizure activity, it substantially increased the extent of seizure-induced cell death in C57BL/6 mice. In contrast, both diabetic hyperglycemia and non-ketotic hyperglycemia modulated seizure sensitivity and aggravated the extent of seizure-induced cell death in C57BL/6 mice post-kainate. Conclusions: We found that glycemic control could rescue hippocampal cells from seizure-induced excitotoxic cell death in an excitotoxin-susceptible mouse strain, FVB/N. As well, the results presented here illustrate that hyper- or hypoglycemia additively increased the extent of seizure-induced cell death in an excitotoxin-resistant mouse strain, C57BL/6. The ability of glucose dysregulation to elicit a phenotypic switch from excitotoxin resistant to susceptible after kainate administration implicates glucose dysfunction as a key event in the pathogenesis of seizure-induced excitotoxic cell death.