Abstracts

Rationale: We have previously shown that mice susceptible to kainate-induced toxicity at a young age, exhibit greater excitotoxic damage with age, suggesting that susceptibility is regulated in a strain- and age-dependent manner. In the present study, we wanted to begin to determine the pharmacological mechanism that contributes to variability in the response to the neurotoxic effects of kainate. Thus, we compared the effects of the NMDA receptor antagonist, MK-801 and of the AMPA receptor antagonist, NBQX, on hippocampal damage following kainate administration in young, middle-aged, and aged C57BL/6 (B6) and FVB/N (FVB) mice. Methods: Young (2 month old), middle-aged (12 months) and old (18 months) male C57BL/6 (B6) and FVB/NJ (FVB) mice obtained from the NIA aging colony (B6) or aged in-house (FVB) received one subcutaneous injection of KA. Ninety minutes following kainate-induced status epilepticus, each age group was treated with i.p. injections of one of two antagonists (MK-801 or NBQX) at two different doses (0.5 mg/kg, 1.0 mg/kg; or 30 mg/kg, 60 mg/kg, respectively). We chose to administer the antagonists 90 minutes after onset of kainate-induced status epilepticus in order to control for individual animal differences in latency to seizures after kainate treatment. Following KA 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. 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: Administration of 0.5 mg/kg MK-801 was dramatically effective at reducing hippocampal cell damage in young FVB mice (no hippocampal cell death observed), while 1.0 mg/kg MK-801 was effective in 12 month old mice. In contrast, while 60 mg/kg NBQX was effective at significantly reducing hippocampal cell death in young FVB mice, it was not effective at all in 12 month old mice. Interestingly, in young FVB mice, 60 mg/kg NBQX was most effective at reducing cell death in area CA3 and within the dentate hilus, yet less effective within area CA1. In contrast, in 12 month old FVB mice, 60 mg/kg NBQX was only protective against hippocampal cell death within the dentate hilus. Conclusions: Our results suggest that aging may differentially affect the ability of neuroprotectants to protect against hippocampal damage. Such age-related decreases in tolerance to antagonist administration may depend on a variety of factors including the expression and distribution of glutamate receptor subtypes. Moreover, differences in the effectiveness of these two antagonists in the aged animal could result from differential regulation of glutamatergic neurotransmitter systems or ion channel specificity. Supported by AG25508 to PES and the Rose Hills Memorial Foundation to CSB.