Cyclic nucleotides in stroke and related cerebrovascular disorders.
Evidence has steadily accumulated to indicate that the rapid fluctuations in cyclic nucleotides during primary and secondary stroke are more than epiphenomena of the disease. During acute phases of ischemia, anoxia or hypoxia cyclic AMP rapidly accumulates in cerebral tissue, cerebrospinal fluid (CSF) and venous plasma, while cyclic GMP either remains unchanged or declines. The massive release of transmitters (catecholamines and adenosine) or ionic fluxes (Na+ and K+) may account for these observations. If reflow is established through a previously occluded vessel cyclic AMP content rises even higher in conjunction with a sharp rise in cyclic GMP. It is during this reflow period subsequent to longer term stroke (30-60 min) that the synaptic membrane enzyme, adenylate cyclase, is especially vulnerable. Presumably the cause of injury to cell membrane systems results from excess lactic acid accumulation and/or Ca++ entry through the damaged blood-brain barrier. The latter initiates breakdown of membrane phospholipids with resultant synthesis of vasoactive prostaglandins and formation of free radicals causing further insult to membrane phospholipids. Thus drugs acting to inhibit formation of prostaglandins, scavenge free radicals, reduce lactate formation, inhibit Ca++ entry or stabilize cell membranes have been shown to possess varying degrees of protective action toward adenylate cyclase. Moreover, cyclic AMP has been found to reverse stroke-induced vasospasm in central vessels. Reduced cyclic AMP content in CSF has been used to monitor the severity of coma, whereas clinical improvement was associated with predictable increases in the cyclic nucleotide. Therefore, cyclic nucleotides and related membrane enzyme systems might be used as target molecules in which to develop future therapeutic strategies for prevention or treatment of stroke.
Palmer
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D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000378:metabolism; D000241:Adenosine / Q000502:physiology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism; D002196:Capillaries / Q000378:metabolism; D002561:Cerebrovascular Disorders / Q000378:metabolism*; D000242:Cyclic AMP / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000652:urine; D006152:Cyclic GMP / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D002534:Hypoxia, Brain / Q000378:metabolism; D066298:In Vitro Techniques; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D009638:Norepinephrine / Q000502:physiology; D010743:Phospholipids / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D013570:Synaptic Membranes / Q000378:metabolism; D014018:Tissue Distribution; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D007773:Lactates; D010743:Phospholipids; D019344:Lactic Acid; D005680:gamma-Aminobutyric Acid; D000242:Cyclic AMP; D011494:Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000262:Adenylyl Cyclases; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D000241:Adenosine; D009638:Norepinephrine