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 a n behavior and CA1 neuronal death after traumatic brain injury (TBI) with a cute (1 h after TBI) forebrain ischemia has not been systematically assesse d. We examined cognitive and motor dysfunction and the relationship of beha vior deficits to neuronal death in this model using muscarinic and NMDA ant agonists. Three behavioral groups (n = 10/group) of Wister rats were subjec ted 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/grou p) were evaluated only for CA1 death after 7 days survival following sham, individual or combined injury with and without drug treatments. Rats were g iven 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-da y 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 h ypothermia that decreased CA1 death and likely influenced behavioral morbid ity. M-S given before TBI (p < 0.01) decreased memory deficits on day 15, w hile M-S treatment given after TBI was ineffective. Unexpectedly, M-S treat ment before or after TBI produced transient motor deficits (p < 0.01). Memo ry improvement occurred independent of CA1 death. (C) 1999 Elsevier Science B.V. All rights reserved.