Receptor Agonist And Antagonist

Mechanisms of bloodvessel growth after injury have similarities to abnormal angiogenesis in brain tumours.Gliomas grow rapidly, creating a hypoxic environment with increased HIF concentrations; angiogenesis compensates for the absence of oxygen.Malignant glioma cell lines have increased MMP concentrations and low TIMP concentrations.The targeting of HIF with small interfering RNA in glioma cells decreased the expression of MMP and raised TIMP concentrations.Glioma cells have a high level of the angiogenic regulator angiopoietin, which is associated with high MMP concentrations, suggesting that angiopoietin might promote tumour cell in ltration through activation of MMP.Angiogenesis is important in arteriovenous malformations.Concomitant intracerebral injection of adenoviral vectors Naloxone hydrochloride expressing VEGF and angiopoietin in rats increased angiogenesis; the combination of these molecules increased angiogenesis and production of MMP more than VEGF alone.When viral vectors that deliver VEGF stimulate the growth of blood vessels, treatment with the tetracycline derivative doxycycline, an inhibitor of MMP, Benzyl alcohol reduces the growth of blood vessels.However, once angiogenesis begins, which seems to be within days of the initial insult in stroke, MMP inhibitors can hinder recovery.The migration of neural progenitor cells and the growth of vessels after stroke is dependent on multiple factors, including the stimulation of bloodvessel growth by HIF in the presence of decreased oxygen tension in the tissues.Cells in the subventricular zone are the source of neuroblasts that migrate to the site of injury after a stroke; these cells secrete MMP to facilitate movement, which would be blocked with MMP inhibitors.Acute cerebral ischaemia has been most intensively studied.Autoimmune and infectious diseases have been successfully treated with MMP inhibitors in animals.Damage to the bloodbrain barrier seen in experimentally induced meningitis and experimental allergic encephalomyelitis can be reduced with MMP inhibitors.Doxycycline blocks secondary damage in experimental bacterial meningitis in rodents.Tetracycline derivates, such as doxycycline and minocycline, inhibit in ammation and reduce MMP concentrations.Minocycline given to patients with multiple sclerosis reduces the number of gadoliniumenhancing lesions on MRI.Tetracyclines can be given in low doses for several years without adverse e ects and, when given in combination with interferon beta, were e ective in controlling in ammation in mice with experimental allergic encephalomyelitis.A caveat is that MMP might be important in remyelination, as oligodendrocyte regrowth is facilitated by MMP.Although there are MMP inhibitors that are selective for MMP and MMP, most available MMP inhibitors are broadspectrum drugs.For the shortterm treatment strategies envisioned for acute neurological diseases, such as early opening of the bloodbrain barrier in ischaemia and infection, a broadspectrum inhibitor might be useful.The problem with broadspectrum inhibitors is that they might block important functions, such as remodelling of the extracellular matrix.In trials of MMP inhibitors in cancer, joint sti ness was the sidee ect that limited treatment.For longterm use, selective MMP inhibitors might be needed to avoid prolonged broadspectrum e ects.Metabolism and e cacy of MMP inhibitors vary in di erent species.For example, drugs that e ectively close the bloodbrain barrier in rats after lipopolysaccharide challenge are ine ective in mice.In vascular cognitive impairment, decreasing white matter damage caused by ischaemic injury and hypoxic hypoperfusion is a likely therapeutic aim.

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