Combined therapy affects outcomes differentially after mild traumatic brain injury and secondary forebrain ischemia in rats

Muscarinic and NMDA receptors contribute to post-traumatic hypersensitivity to secondary ischemia. However, the effect of these receptor antagonists on behavior and CA1 neuronal death after traumatic brain injury (TBI) with acute (1 h after TBI) forebrain ischemia has not been systematically assessed. We examined cognitive and motor dysfunction and the relationship of behavior deficits to neuronal death in this model using muscarinic and NMDA antagonists. Three behavioral groups (n=10/group) of Wistar rats were subjected to mild TBI and 6 min of forebrain ischemia imposed 1 h after TBI with 45 days survival. Motor and spatial memory performance were assessed using the rotarod task and Morris water maze. Seven additional groups (n=6/group) were evaluated only for CA1 death after 7 days survival following sham, individual or combined injury with and without drug treatments. Rats were given 0.3 mg/kg MK-801 (M) and 1.0 mg/kg scopolamine (S) alone or combined (M-S) before or 45 min after TBI. Rotarod performance was tested at days 1-5 and maze performance on days 11-15 and 40-44 after M-S treatment. The 7-day studies showed M-S treatment (p<0.01) reduced CA1 neuronal death better than either S or M alone. Behavioral groups had inadvertent post-ischemic hypothermia that decreased CA1 death and likely influenced behavioral morbidity. M-S given before TBI (p<0.01) decreased memory deficits on day 15, while M-S treatment given after TBI was ineffective. Unexpectedly, M-S treatment before or after TBI produced transient motor deficits (p<0. 01). Memory improvement occurred independent of CA1 death.