Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020440 (hypercapnia)
 7,939 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Babies are frequently exposed to cerebral hypoxia and ischemia (H/I) during the perinatal period as a result of stroke, problems with delivery, or postdelivery respiratory management. The sole approved treatment for acute stroke is tissue type plasminogen activator. H/I impairs pial artery dilation (PAD) induced by hypercapnia and hypotension, the impairment aggravated by type plasminogen activator and attenuated by the plasminogen activator inhibitor-1-derived peptide EEIIMD. Mitogen-activated protein kinase (MAPK), a family of at least three kinases, ERK, p38, and JNK, is upregulated after H/I and ERK contribute to impaired cerebrovasodilation. This study determined the roles of p38 and JNK MAPK in the impairment of dilation post-H/I in pigs equipped with a closed cranial window and the relationship between alterations in MAPK isoforms and EEIIMD-mediated cerebrovascular protection. Cerebrospinal fluid-phosphorylated (activated) p38 MAPK, but not JNK MAPK, was increased after H/I, an effect potentiated by intravenous EEIIMD administered 1 h postinjury. PAD in response to hypercapnia and hypotension was blunted by H/I, but dilation was maintained by EEIIMD. PAD was further impaired by the p38 antagonist SB-203580 but unchanged by the JNK antagonist SP-600125. Isoproterenol-induced PAD was unchanged by H/I, EEIIMD, SB-203580, and SP-600125. These data indicate that postinjury treatment with EEIIMD attenuated impaired cerebrovasodilation post-H/I by upregulating p38 but not JNK. These data suggest that plasminogen activator inhibitor-1-based peptides and other approaches to upregulate p38 may offer a novel approach to increase the benefit-to-risk ratio of thrombolytic therapy for diverse central nervous system disorders associated with H/I.
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PMID:PAI-1-derived peptide EEIIMD prevents impairment of cerebrovasodilation by augmenting p38 MAPK upregulation after cerebral hypoxia/ischemia. 2043 43

The cerebral blood flow is tightly regulated by myogenic, endothelial, metabolic, and neural mechanisms under physiological conditions, and a large body of recent evidence indicates that inflammatory pathways have a major influence on the cerebral blood perfusion in certain central nervous system disorders, like hemorrhagic and ischemic stroke, traumatic brain injury, and vascular dementia. All major cell types involved in cerebrovascular control pathways (i.e., smooth muscle, endothelium, neurons, astrocytes, pericytes, microglia, and leukocytes) are capable of synthesizing endocannabinoids and/or express some or several of their target proteins [i.e., the cannabinoid 1 and 2 (CB1 and CB2) receptors and the transient receptor potential vanilloid type 1 ion channel]. Therefore, the endocannabinoid system may importantly modulate the regulation of cerebral circulation under physiological and pathophysiological conditions in a very complex manner. Experimental data accumulated since the late 1990s indicate that the direct effect of cannabinoids on cerebral vessels is vasodilation mediated, at least in part, by CB1 receptors. Cannabinoid-induced cerebrovascular relaxation involves both a direct inhibition of smooth muscle contractility and a release of vasodilator mediator(s) from the endothelium. However, under stress conditions (e.g., in conscious restrained animals or during hypoxia and hypercapnia), cannabinoid receptor activation was shown to induce a reduction of the cerebral blood flow, probably via inhibition of the electrical and/or metabolic activity of neurons. Finally, in certain cerebrovascular pathologies (e.g., subarachnoid hemorrhage, as well as traumatic and ischemic brain injury), activation of CB2 (and probably yet unidentified non-CB1/non-CB2) receptors appear to improve the blood perfusion of the brain via attenuating vascular inflammation.
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PMID:Endocannabinoids in cerebrovascular regulation. 2682 17