Stroke and Neurovascular Research Laboratory
Stroke and Neurovascular Regulation

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This laboratory studies mechanisms and mediators of tissue injury relating to cerebral ischemia and migraine.

Our interest in stroke focuses on the role of nitric oxide (NO) as an important mediator of cytotoxicity and regulator of cerebral blood flow. To this end, we have established models of cerebral ischemia in mice and developed a computerized monitoring system for the study of the cerebral circulation in knockouts lacking the neuronal or vascular isoforms of nitric oxide synthase. These knockouts, developed by Drs. Paul Huang, Mark Fishman of the MGH Cardiovascular Institute and their collaborators at Johns Hopkins Medical School, have been useful for both clarifying the role of NO in ischemic brain disease and for determining the relative contribution of NO derived from various tissue compartments. The neuronal knockouts exhibit normal systemic arterial blood pressures, autoregulation, and a normal brain vascular supply. The volume of brain damage is significantly attenuated following middle cerebral artery occlusion, despite blood flow reductions equivalent to the wild type. The decreased tissue damage is accompanied by improved neurological function 24 hrs after injury. cGMP production does not increase after ischemia as in the wild type mice. Somewhat paradoxically, NOS inhibitors increase ischemic injury in mutant mice. We believe this reflects drug-induced inhibition of vascular NO and attendant negative hemodynamic consequences on ischemia. Hence, neuronal NO production appears to exacerbate acute ischemic injury whereas vascular NO protects after middle cerebral artery occlusion. The data emphasize the importance of developing selective inhibitors of the neuronal NOS isoform.

The discovery of the sensory innervation to the circle of Willis from the trigeminal ganglia more than 10 years ago stimulated our interest in mechanisms of vascular head pain. Since that time, we characterized the neurotransmitters within this pathway and established the relevance of the "trigeminovascular pathway" to the pathophysiology and treatment of migraine. In the past few years, we discovered a novel mechanism by which serotoninergic drugs block headache. Pharmacological and molecular evidence established that trigeminal fibers possess 5-HT1D-alpha receptors which inhibit neuropeptide release and the development of neurogenic inflammation within the meninges. The newest antimigraine drug (sumatriptan) works predominantly through this mechanism. We are now developing novel drugs which alleviate pain but lack intrinsic vasoconstrictor potency [postjunctional receptor mechanisms promoting vasoconstriction are mediated by a distinct, albeit related receptor (5-HT1Dbeta)]. For these studies models of both neurogenic inflammation and activation of trigeminal system using c-fos expression have been established.

 

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