Evaluation of NMDA receptor-mediated neuroprotection in the endothelin-1 model of upper extremity impairment in stroke

Upper extremity impairment after focal ischemic stroke represents the most prominent functional deficit for surviving stroke victims. Recently, this condition has been modeled in rats by injecting the vasoconstrictive peptide endothelin-1 (ET-1) to forelimb representation areas of the brain, such as the forelimb sensorimotor cortex and the dorsolateral striatum. This ET-1 model may be a valuable experimental tool for investigating functional neuroprotection after ischemia-induced forelimb impairment in rats. However, there are only a few published studies regarding the use of this model for neuroprotection in stroke research, and compounds that target NMDA receptor-mediated excitotoxicity remain to be tested in this model. Using adult, male Sprague-Dawley rats, initial experiments were performed using different volumes, concentrations, and stereotaxic coordinates of injected ET-1 to the forelimb sensorimotor cortex and dorsolateral striatum. During these preliminary studies, rats were subjected to a behavioural test battery that measured various aspects of forelimb sensorimotor function.In conclusion, the primary finding from this thesis is that the ET-1 model of upper extremity impairment in stroke is suitable for neuroprotection studies using NMDA receptor antagonists as therapeutic compounds. Thus, given its experimental advantages, the ET-1 model may be a useful tool for investigating the therapeutic effect of NMDA receptor antagonists on forelimb recovery after focal cerebral ischemia in the rat.Using the surgical and behavioural protocols developed during preliminary experimentation, the ET-1 model was then evaluated for neuroprotection using a single dose of MK-801 (5mg/kg i.p.) and R025-6981 (6mg/kg i.p.). Results revealed that both compounds conferred marked neuroprotection to the cortex and improved forelimb function relative to a vehicle control group when measured over two weeks post-stroke. Using a separate group of rats, an ET-1-induced lesion was placed in the homotopic contralesional hemisphere in order to investigate its functional contribution to forelimb recovery subsequent to the initial lesion. Whether the functional neuroprotection provided by R025-6981 was related to diminished contralesional hemispheric involvement during recovery was also examined. Results from this experiment demonstrated that the introduction of a second, homotopic lesion significantly reinstated forelimb impairment when measured 3 hr post-stroke.