Stroke and Neurovascular Regulation
Michael A. Moskowitz, M.D.

Laboratory of Stroke and Neurovascular Regulation Recent Publications | Links

Michael Moskowitz, M.D. Stroke and Neurovascular Regulation Laboratory CNY 149-6403 Phone: 617-726-8442 E-Mail: moskowitz@helix.mgh.harvard.edu PPD Office Info Moskowitz Pubs 2001 Moskowitz Pubs 2000 Moskowitz Pubs 1999

This laboratory has had a long-standing interest in stroke pathophysiology and pharmacology and serves as the Core facility for the MGH Stroke Center sponsored by the NINCDS. To this end, the laboratory has adapted models of focal and global cerebral ischemia and has developed methods for detailed physiological monitoring in transgenic mice. Using these techniques, the laboratory is investigating the role of nitric oxide (NO) in the normal coupling between brain metabolism and blood flow, and in the development of brain injury. In stroke models, they have documented increases in blood flow within the ischemic penumbra and protection fro m ischemic injury by the NO precursor, 1-arginine. Clearly, the role of NO in ischemia is complex; under certain circumstances, NO serves as a free radical mediator of tissue injury and glutamate-mediated cell damage. Both eNOS and nNOS knockout mice have been intensively investigated in collaborative studies with Drs. Paul Huang and Marc Fishman at the Cardiovascular Research Center. Studies clearly document the protective role of eNOS and destructive role of nNOS during brain is ischemia. Physiological and pathophysiological mechanisms of protection and injury are being intensively studied.

A second major research area relates to the pathophysiology and pharmacology of vascular headaches. Unlike traditional investigations focusing on constrictor/dilator mechanisms within cranial vessels, research in this laboratory concerns the role of sensory fibers investing cranial blood vessels in the genesis of pain and the pharmacological actions of antimigraine drugs. Ten years ago, they discovered the trigeminal (sensory) innervation to the circle of Willis and have since described the existence of vasoactive neuropeptides contained within these perivascular unmy4elinated C-fibers. With knowledge concerning mechanisms of neuropeptide release and receptor interactions within the vessel wall, they have been exploring the formulation that ergot alkaloids and receptor specific serotonin analogues (and effective antimigraine agents) reduce pain by binding to 5-HT1 receptors on trigeminovascular fibers. As a consequence, tissue sensitization, hyperalgesia, and neurogenic inflammation become reduced with attendant relief of pain. To this end, the laboratory ahs documented the exist3nce fo prejunctional 5-HT heteroreceptors within trigeminal ganglion cells and a new receptor subty0pe using the tools of molecular biology and molecular receptor pharmacology. Based on structure activity of this newly discovered receptor, the laboratory is developing a new generation of therapeutic agents capable of blocking neural activity within the trigeminovascular system. Future investigations relate to the charcterization of this newly discovered 5-HT heteroreceptor and its molecular mechanism of action as well the actions of other receptors (e.g., histamine, NPY, alpha2 adrenoceptors, and opioids) recently identified within the trigeminovascular system.

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