Histamine H2Receptor Antagonist Ranitidine Protects Against Neural Death Induced by Oxygen-Glucose Deprivation (original) (raw)
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Journal of Pharmacological Sciences, 2008
We have reported that facilitation of central histaminergic activity prevents the development of ischemia-induced brain injury. Since cerebral edema is a major cause of brain damage, we studied effects on brain edema of postischemic administration of L-histidine, a precursor of histamine, and thioperamide, a histamine H 3-receptor antagonist, both of which enhance central histaminergic activity. Focal cerebral ischemia for 2 h was provoked by transient occlusion of the right middle cerebral artery in rats, and the water content and infarct size were determined 24 h after reperfusion. Changes in the extracellular concentration of histamine were examined in the striatum by a microdialysis procedure, and effects of these compounds were evaluated. Repeated administration of L-histidine (1000 mg / kg × 2, i.p.), immediately and 6 h after reperfusion, reduced the increase in the water contents in ischemic regions. Simultaneous administration of thioperamide (5 mg / kg, s.c.) with L-histidine (1000 mg/ kg, i.p.) completely prevented edema formation and alleviated brain infarction, although a single dose of L-histidine, immediately after reperfusion, showed no benefits. The striatal histamine level was gradually increased after reperfusion as well as during ischemia. Simultaneous administration of thioperamide with L-histidine markedly increased the brain histamine concentration, and the value increased up to 230% of that in the saline group 5-6 h after reperfusion. L-Histidine alone did not affect the increase in the histamine output after ischemia. These findings suggest that further activation of the central histaminergic system after initiation of cerebral ischemia prevents development of ischemia-induced brain edema.
Histamine H3 receptors aggravate cerebral ischaemic injury by histamine-independent mechanisms
Nature Communications, 2014
The role of the histamine H3 receptor (H3R) in cerebral ischaemia/reperfusion (I/R) injury remains unknown. Here we show that H3R expression is upregulated after I/R in two mouse models. H3R antagonists and H3R knockout attenuate I/R injury, which is reversed by an H3R-selective agonist. Interestingly, H1R and H2R antagonists, a histidine decarboxylase (HDC) inhibitor and HDC knockout all fail to compromise the protection by H3R blockade. H3R blockade inhibits mTOR phosphorylation and reinforces autophagy. The neuroprotection by H3R antagonism is reversed by 3-methyladenine and siRNA for Atg7, and is diminished in Atg5 À / À mouse embryonic fibroblasts. Furthermore, the peptide Tat-H3R CT414-436 , which blocks CLIC4 binding with H3Rs, or siRNA for CLIC4, further increases I/R-induced autophagy and protects against I/R injury. Therefore, H3R promotes I/R injury while its antagonism protects against ischaemic injury via histamine-independent mechanisms that involve suppressing H3R/CLIC4 binding-activated autophagy, suggesting that H3R inhibition is a therapeutic target for cerebral ischaemia.
2021
The aim: to investigate the effect of a new derivative of 4-aminobutanoic acid (compounds KGM-5) on the level of neurotransmitters and neurotransmitter amino acids and the structural-functional state of the hippocampus of rats with acute cerebrovascular accident (ACVA). Materials and methods. ACVA was reproduced in rats by occlusion of the left carotid artery under anesthesia (sodium thiopental (35 mg/kg) intraperitoneally (i/p). 5 groups of animals were used: intact control (IC, n=6), untreated animals with ACVA (CP, n=13); animals with ACVA (n=14), which were treated for 5 days with KGM-5 at a dose of 30 mg/kg i/p, animals with ACVA (n=13), who received i/p comparison drug “Picamilon” (17 mg/kg). There was a group of pseudo-operated animals (POA, n=8). Withdrawal of animals from the experiment was performed on day 6 after modeling ACVA by painless euthanasia under anesthesia. Histological examinations of CA1 and CA3 zones of the ventral hippocampus were performed with staining of ...
Journal of Cerebral Blood Flow & Metabolism, 2011
We hypothesized that activation of the central histaminergic system is required for neuroprotection induced by hypoxic preconditioning. Wild-type (WT) and histidine decarboxylase knockout (HDC-KO) mice were preconditioned by 3 hours of hypoxia (8% O 2 ) and, 48 hours later, subjected to 30 minutes of middle cerebral artery (MCA) occlusion, followed by 24 hours of reperfusion. Hypoxic preconditioning improved neurologic function and decreased infarct volume in WT or HDC-KO mice treated with histamine, but not in HDC-KO or WT mice treated with a-fluoromethylhistidine (a-FMH, an inhibitor of HDC). Laser-Doppler flowmetry analysis showed that hypoxic preconditioning ameliorated cerebral blood flow (CBF) in the periphery of the MCA territory during ischemia in WT mice but not in HDC-KO mice. Histamine decreased in the cortex of WT mice after 2, 3, and 4 hours of hypoxia, and HDC activity increased after 3 hours of hypoxia. Vascular endothelial growth factor (VEGF) mRNA and protein expressions showed a greater increase after hypoxia than those in HDC-KO or a-FMH-treated WT mice. In addition, the VEGF receptor-2 antagonist SU1498 prevented the protective effect of hypoxic preconditioning in infarct volume and reversed increased peripheral CBF in WT mice. Therefore, endogenous histamine is an essential mediator of hypoxic preconditioning. It may function by enhancing hypoxia-induced VEGF expression.
European Journal of Pharmacology, 2007
Inflammation is a crucial factor in the development of ischemia-induced brain injury. Since facilitation of central histaminergic activity ameliorates reperfusion injury, effects of postischemic administration of L-histidine, a precursor of histamine, and thioperamide, a histamine H 3 receptor antagonist, on inflammatory cell infiltration were evaluated in a rat model of transient occlusion of the middle cerebral artery. After reperfusion for 12, 24, or 72 h following 2 h of occlusion, brain slices were immunohistochemically stained with antibodies against myeloperoxidase and CD68, which were markers of polymorphonuclear leukocytes and macrophages/microglia, respectively. After reperfusion for 12-24 h, the number of neutrophils on the ischemic side increased markedly, whereas the increase was not observed on the contralateral side. Administration of L-histidine (1000 mg/kg × 2, i.p.), immediately and 6 h after reperfusion, reduced the number of neutrophils to 52%. Simultaneous administration of thioperamide (5 mg/kg, s.c.) further decreased the number of neutrophils to 32%. Likewise, the ischemia induced increase in the number of CD68-positive cells after 24 h was suppressed by L-histidine injections. The L-histidine administration decreased the number of CD4 + T lymphocytes on both ischemic and contralateral sides after 12 h, and concurrent administration of thioperamide prolonged the effect. Although administration of mepyramine (3 nmol, i.c.v.) did not affect suppression of leukocyte infiltration, ranitidine tended to reverse the effect of L-histidine. These data suggest that enhancement of central histaminergic activity suppresses inflammatory cell recruitment after ischemic events through histamine H 2 receptors, which may be a mechanism underlying the protective effect of L-histidine.
Limiting Ischemic Injury by Inhibition of Excitatory Amino Acid Release
Journal of Cerebral Blood Flow & Metabolism, 1993
Excitatory amino acids (EAAs) are important mediators of ischemic injury in stroke. N.Methyl-D· aspartate (NMDA) receptor antagonists have been shown to be very effective neuroprotective agents in animal models of stroke, but may have unacceptable toxicity for human use. An alternative approach is to inhibit the re· lease of EAAs during stroke. BWI003C87 [5-(2,3,5trichlorophenyl)-2,4-diaminopyrimidine], a drug that in· hibits veratrine·induced release of the EAA glutamate in vitro, was tested in a rat model of proximal middle cere· bral artery (MCA) occlusion. BWlO03C87 significantly decreased ischemia· induced glutamate release in brain when given either 5 min before or 15 min following per-Brain injury following both focal and global isch· emia is mediated, at least in part, by glutamate or other endogenous excitatory amino acid (EAA) neurotransmitters gating a receptor·mediated neu· ronal calcium channel. Extracellular concentrations of the EAAs glutamate and aspartate are increased during ischemia due to both enhanced release of· EAAs from neurons and impaired reuptake (Ben· veniste et aI., 1984; Drejer et aI., 1985; Silverstein et aI., 1986). EAAs, acting pri marily via the N·methyl·D·aspartate (NMDA) re ceptor, increase intraneuronal calcium (MacDer mott et aI., 1986; Uematsu et aI., 1988) and are di-Abbreviations used: 2DG, 2-deoxyglucose; EAA, excitatory amino acid; GABA, -y-aminobutyric acid; HSP, heat shock pro tein; LCGU, local cerebral glucose utilization; MCA, middle ce rebral artery; NMDA, N-methyl-D-aspartate. 88 manent MCA occlusion. Pretreated and posttreated rats had smaller infarct volumes and preserved glucose me tabolism in the ischemic cortex at 24 h after MCA occlu· sion. BWI003C87 did not induce heat shock protein in the cingulate or retrosplenial cortex, suggesting that it does not injure neurons in these regions as do NMDA antago nists. These results demonstrate that drugs that inhibit glutamate release in ischemia may be nontoxic and show promise for the treatment of stroke.
The glutamate antagonist MK-801 reduces focal ischemic brain damage in the rat
Annals of Neurology, 1988
Excessive activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor has been implicated in the sequence of neurochemical events that results in irreversible neuronal damage in cerebral ischemia. The effects of the NMDA antagonist (+) -5-methyl-10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) upon the amount of ischemic brain damage has been assessed quantitatively in the lightly anesthetized rat. Focal cerebral ischemia was produced by the permanent occlusion of one middle cerebral artery (MCA), and the animals were killed 3 hours after the arterial occlusion. MK-801 (0.5 mg/kg) was administered intravenously either 30 minutes prior to MCA occlusion or 30 minutes after the induction of ischemia. Pretreatment with MK-801 reduced the volume of ischemic damage both in the cerebral cortex (by 38% compared with untreated rats with MCA occlusion; p < 0.01) and in the caudate nucleus (by 18% compared with controls; p < 0.05). Treatment with MK-801, initiated 30 minutes after MCA occlusion, reduced the volume of ischemic damage in the cerebral cortex (by 52% compared with controls; p < 0.01). The volume of ischemic damage in the caudate nucleus was minimally influenced by MK-801 treatment initiated after MCA occlusion. The antiischemic effects of MK-801 were readily demonstrable despite the hypotension that MK-801 induced in rats anesthetized with halothane (0.5%), nitrous oxide (70%), and oxygen (30%). The potency of MK-801 in reducing ischemic brain damage, even when administered after the induction of ischemia, highlights the potential use of NMDA receptor antagonists for the treatment of focal cerebral ischemia in humans.