Reduction of neural damage in irreversible cerebral ischemia by calcium antagonists

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Abstract
Because of the complexity and cost of clinical investigations and the virtual lack of pharmacological leads, drugs for the treatment of strokes have to be tested extensively in animal models closely mimicking the human disorder. With the recent introduction of in vivo NMR imaging (MRI) and spectroscopy (MRS), it is now possible to evaluate the consequences of strokes and to monitor the effects of therapeutic interventions in animals with the same methodology as in humans. The appearance and evolution of brain infarcts in spontaneously hypertensive rats (SHR), after occlusion of the middle cerebral artery (MCA), were detected with MRI. In coronal sections through the rat brain, regions with increased MRI signal started to become discernible after 6 h and turned out to be largely necrotic already after 24 h, as revealed by histology. The location (fronto-parietal cortex, caudateputamen) and total infarct size, as determined from MR images or histology, were highly reproducible. Posttreatment with the dihydropyridine calcium antagonist isradipine (PN 200-110), at a daily dose of 3×0.3jmg/kg sc, reduced the total infarct size by 30–40%, determined by quantitative MRI and confirmed by histology. Biochemical markers of necrosis, such as the increased brain wet wt, the levels of sodium, potassium, dopamine, and noradrenaline, were changed toward normal values. The functional consequences of these morphological effects of isradipine were reflected by the parallel improvement of a neurological score. Follow-up observations made by MRI and histology indicated that the morphological differences between treated and control animals were still present to the same extent after 2 wk and, therefore, seem to be permanent. In order to elucidate the putative mechanisms involved, the influence of calcium antagonists on cerebral blood flow (CBF) and high energy phosphates (HEPs) was investigated. CBF was measured quantitatively with [14C] iodoantipyrine in MCA-occluded SHRs. Although isradipine had no effect on CBF in the contralateral hemisphere, at a dose reducing infarct size, it increased the reduced blood flow in the lesioned hemisphere toward normal values. HEPs (PCr and ATP) as well as inorganic phosphate (Pi) and intracellular pH were measured noninvasively in the rat brain by31P MRS using a surface coil. Under normal conditions, calcium antagonists had no effect on these parameters. However, the disappearance of HEPs and concomitant build-up of Pi following cardiac arrest were slowed down by isradipine, suggesting that calcium antagonists reduce the utilization of HEPs. It can be concluded from these experiments that at least two mechanisms might be responsible for the beneficial effects of isradipine in stroke: a vascular effect, i.e., the improvement of collateral blood supply to the ischemic area without producing a steal effect and a neuronal effect decreasing the energy demand of the cell, presumably by reduction of the excessive calcium influx occurring in stroke.