Molecule Man Vs Battle

The abnormal MRI signal in white matter is associated with cognitive decline in large population studies.Most of the patients with white matter changes have conditions that a ect the small blood vessels, such as hypertension and diabetes.The deep white matter, which forms a watershed circulation produced by the con uence of several end arteries that originate on the surface and that provide poor circulation to the deeper regions, is vulnerable to hypoxic events.In hypoxic tissue, MMP expression increases in di erent cell types.In rats with experimental allergic neuritis, a broadspectrum MMP inhibitor, BB, which also inhibits TACE, reduces damage to the nerves.During hypoxia, HIF increases, leading to expression of many genes implicated in injury and repair.HIF also stimulates expression of the same substances that mediate repair, including vascular endothelial growth factor and TGF.Because hypoxia seems to play a crucial part in vascular cognitive impairment, an understanding of the role of HIF is important.Myelin is lost, but U bres and cortical cells are spared.In the smallvessel form with extensive white matter disease, the astrocytes are reactive in the white matter and oligodendrocytes are lost. Hypertensive vascular disease and diabetes mellitus further reduce the perfusion of these vulnerable regions.Although development of animal models has been hampered by the heterogeneity of vascular cognitive impairment, the animal model most commonly used to study the hypoxic injury to the deep white matter is that of bilateral carotid artery occlusion in rats.The arrow shows an astrocyte immunostained with glial brillary acidic protein.Blood vessel exposed to longterm hypertension with damage to the bloodvessel wall and eosinophilic deposits.Rats with bilateral carotid artery occlusion have high expression of MMP in endothelial cells and microglia in white matter.In a recent study, treatment with a selective MMP inhibitor, AG, reduced bloodbrain Trilostane barrier injury to the white matter and resulted in less myelin damage, suggesting that disruption of the bloodbrain barrier by MMP was upstream of the myelin damage.The dual function of HIF in injury and repair suggests that, after the initial injury phase with induction of in ammatory molecules, recovery begins with the activation of molecules that will stimulate regrowth of cells and blood vessels.Chronic intermittent hypoxia results in recurrent apnoeas with periodic decreases in arterial blood oxygen, which predispose patients to cardiorespiratory morbidities.Patients with sleep apnoea can have white matter damage, like that seen on MRI in vascular cognitive impairment.In rodents and cell cultures, intermittent hypoxia activates various transcription factors, including HIF, cfos, nuclear factor of activated T cells, and NFB.Hypoxia secondary to Secnidazole hypoperfusion increases HIF concentration, which turns on cassettes of genes associated with injury such as FURIN, and increases expression of VEGF and TGF, which are important in repair.Furin leads to activation of MMP through activation of MTMMP.These ndings suggest that MMP can contribute to the clearance of soluble and brillar A.Inhibitors of secretases o er potential to reduce the production of A peptides.Deposition of amyloid peptides in tissues results in an in ammatory response that could be lessened with antiin ammatory drugs; however, nonsteroidal antiin ammatory drugs and freeradical scavengers have not proved useful.

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