Postischemic regulation of central histamine receptors.

This study characterizes changes occurring in the central histaminergic system associated with ischemia-reperfusion pathology in the rat. Specifically, after a postocclusion time period of 48 h, we have analyzed histamine H(1) receptor mRNA expression, histamine H(2) receptor protein amount and binding densities, and histamine H(3) receptor mRNA expression and binding densities in brain regions that have been suggested to be selectively vulnerable to transient global ischemia, i.e. hippocampus, thalamus, caudate-putamen, and cerebral cortex. We found an increase in H(1) receptor mRNA expression in the caudate-putamen: given that ischemia reduces glucose uptake and H(1) receptor activation has been shown to decrease this effect, an increase of expression levels may result in mitigating tissue damage due to energy failure observed in ischemia. A decrease in H(2) receptor binding densities in the caudate-putamen was also observed; the ischemia-induced decrease in H(2) receptor protein was also detectable by Western blot analysis. This phenomenon may underlie the previously reported ischemia induced striatal dopamine release. H(3) receptor mRNA expression was increased in the caudate putamen of the postischemic brain but was decreased in the globus pallidus and the thalamus; in association with this, H(3) receptor binding densities were increased in the cortex, caudate-putamen, globus pallidus, and hippocampus. The upregulation of H(3) receptor ligand binding may be involved in the previously reported continuous neuronal histamine release. Our data suggest that central histamine receptor expression and ligand binding are altered in brain ischemia in distinct areas, and may participate in neuroprotection and/or ischemia-associated neuronal damage.

Tolerization against loss of neuronal function after ischemia-reperfusion injury.

To investigate whether sublethal ischemia preserves neuronal function otherwise lost after stroke, anesthesized rabbits were subjected to clamping of abdominal aorta to cause lumbar spinal cord ischemia. An occlusion period of 12.5 min was followed 12 or 48 h later by a second occlusion for 30 min. When scored 24 h later for hindlimb function on a 0-6 scale, the rabbits that underwent tolerizing ischemia 12 h before infarction had better motor function (n = 7; 4.29+/-0.21,p < 0.0001) than sham-operated controls (n = 7; 1.00+/-0.27), but those infarcted at 48 h had mixed outcomes (n = 5; 2.20+/-0.21, ns). In correlation, the proportion of neurons with histological evidence of damage was lower in the tolerized rabbits (0.15+/-0.04) than in sham-operated controls (0.74+/-0.09, p < 0.001). We conclude that ischemic tolerance also improves neurological function of infarcted spinal cord and could be studied for clinical application.