Cellular and molecular mechanisms of ischemic brain damage in hyperglycemic rats

Detta är en avhandling från Experimental Brain Research, Lund University

Sammanfattning: The present study is centered on mechanisms of ischemic brain damage in hyperglycemic animals, and in those in which exaggerated intraischemic acidosis was induced by superimposed hypercapnia in normoglycemic animals. The initial experiments were focussed on the pathophysiology of postischemic seizures. Since hyperglycemic animals developed delayed postischemic hyperthermia, the question arose whether the hyperthemia was responsible for the postischemic seizures which usually occurred after a delay of 18-26 h. However, even if the delayed hyperthermia was prevented by physical cooling or by acetaminophen,the seizures were unaffected suggesting that both the delayed seizures and the delayed ischemic damage were due to aggravation of the tissue damage during the ischemic insult. This contention was supported by results demonstrating that the initial insult, and not the secondary damage appearing many hours after the initiation of recirculation, is what triggers epileptiform activity that ”matures” into status epileptics. In a subsequent project, it was explored whether the severity of the insult influences BDNF gene expression after transient forebrain ischemia. The results indicated that the aggravation caused by hyperglycemia and hypercapnia, was related to a transiently decreased expression of BDNF mRNA levels in vulnerable brain areas. The immunosuppressant cyclosporin A (CsA) has previously been found to block, in a virtually specific manner, the permeability transition (PT) of the inner mitochondrial membrane which is observed when mitochondria are loaded with calcium in the presence of certain inducers. It has been speculated that the MPT triggers secondary mitochondrial failure and reperfusion injury. When allowed to penetrate the blood-brain barrier, CsA dramatically ameliorated delayed neuronal death in the CA1 pyramidal cell layer after both 7 and 10 min of normoglycemic ischemia, supporting a pathogenetic role of MPT. A similarly beneficial effect of CsA was observed when animals with plasma glucose concentrations of = 13 mM were subjected to 10 min of ischemia; postischemic seizures did not occur. However, the effect of CsA was less impressive when plasma glucose was raised to = 20 mM, even though the duration of ischemia was reduced to 5 min.

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