Experimental focal cerebral ischemia:optimization of models and therapeutic interventions

Stroke is the second most common cause of death and leading cause of adult disability, accounting for 11% of total deaths worldwide. Ischemic stroke (80% of all cases) results from a blood clot formation in an artery to or in the brain resulting in ischemic damage and neurological impairment. Many drugs that prevent brain cells from dying have worked well in animal models of stroke, but failed clinically. There is a need for novel therapeutics, as the only effective therapy known, i.e. revascularisation of the blocked cerebral artery, serves at best up to 15 % of all ischemic stroke patients. We adapted the rat permanent focal brain ischemia model using an intravascular filament approach by modifying the occluding tip and substantially improved survival, while mimicking the features of a severely progressive form of stroke. To study electrolyte changes after brain ischemia, we employed a cryogenic copper-based surface resonator cooled down by liquid nitrogen to 77 oK (-196 oC) using a custom built cryostat housing to measure tissue potassium (39K) signal comparing healthy and stroke-affected rat brain with a 9.4 Tesla MRI. This cryogenic coil had an improved signal-to-noise ratio in comparison to the measurement obtained from a coil at room temperature. Further we identified 2 experimental drugs to reduce brain infarct size: pigment epithelial-derived growth factor (PEDF) using MRI, while SUL121 (a chromanol-based compound) reduced ischemic damage, increased endogenous hydrogen sulfide (H2S) synthesizing enzymes, especially CBS, and improved aortic vasorelaxant function. Finally, dopamine treatment of murine microglial cells reduced hypothermia/rewarming-induced injury, partially via a dopamine D1 receptor-mediated action, and through maintenance of H2S synthesizing enzymes