thioperamide and Reperfusion-Injury

In view of the recent evidence for the involvement of histamine in cerebral ischemia, the present study evaluated the effect of thioperamide (THP), a selective histamine H3-receptor antagonist, on middle cerebral artery occlusion (MCAO) induced focal cerebral ischemia in rats. The rats were subjected to 2 h of MCAO followed by 22 h reperfusion after which the grip strength, locomotor activity and spontaneous alternation performance were assessed. Animals were then killed and oxidative stress markers were estimated in the whole brain. An elevation of thiobarbituric acid reactive substance (TBARS) and a reduction in glutathione (GSH) and antioxidant enzymes, such as glutathione-S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR) and superoxide dismutase (SOD), was observed following MCAO, the last two being statistically insignificant. Pretreatment with THP (5.5 mg/kg i.p. and 11 mg/kg i.p.) significantly reversed the MCAO-induced increase in TBARS, but could not reverse the other parameters. Paradoxically, it further reduced the levels of GPx, GR and SOD. No significant changes were observed in the catalase levels and in the grip strength and spontaneous alternation behavior of rats. Locomotor activity was reduced slightly, but reversed on pretreatment with THP. The dual effect of THP on oxidative stress requires further investigation and raises doubts on its possible use in cerebral ischemia.

Topics: Animals; Biomarkers; Disease Models, Animal; Dose-Response Relationship, Drug; Glutathione; Histamine H3 Antagonists; Infarction, Middle Cerebral Artery; Lipid Peroxidation; Male; Maze Learning; Middle Cerebral Artery; Motor Activity; Muscle Strength; Oxidative Stress; Oxidoreductases; Piperidines; Rats; Rats, Wistar; Reperfusion Injury; Thiobarbituric Acid Reactive Substances

An increase in the histamine concentration in the brain has been demonstrated to provide protective effects against ischemia/reperfusion brain injury. Since hypothermia and barbiturates are also regarded to protect ischemic brains, effects of postischemic treatments were compared in gerbils between mild hypothermia and intraperitoneal administration of L-histidine, a precursor of histamine. Furthermore, effects of thioperamide, a histamine H(3) receptor antagonist, were evaluated in histidine-treated gerbils after 60 days. Transient forebrain ischemia for 4 min at 37 degrees C provoked severe neuronal damage in the hippocampal CA1 pyramidal cells after 7 days. Postischemic hypothermia (33 degrees C) for 3 h under pentobarbital anesthesia alleviated neuronal death, and the number of preserved neurons was 77+/-56/mm (mean+/-S.D., n=14). The effect of L-histidine injected three times, immediately, 6 h, and 24 h after reperfusion (1,000 mg/kg, i.p., each), was more prominent than that of hypothermia, and the number of preserved neurons was 142+/-55/mm (n=14). When the histologic outcome was evaluated after 60 days, most neurons were damaged in both the hypothermic and histidine groups. The improvement of the histologic outcome was observed even after 60 days in animals injected with thioperamide, immediately and 6 h after reperfusion (5 mg/kg, s.c., each), with three injections of l-histidine. The number of preserved neurons was 133+/-88/mm (n=10), while that in the hypothermic group was 7+/-15 (n=10). Activation of the central histaminergic system provides beneficial effects against cerebral ischemia.

Topics: Animals; Brain Ischemia; Drug Therapy, Combination; Gerbillinae; Hippocampus; Histamine; Histamine Antagonists; Histidine; Hypnotics and Sedatives; Hypothermia, Induced; Male; Neuroprotective Agents; Pentobarbital; Piperidines; Prosencephalon; Pyramidal Cells; Reperfusion Injury; Time Factors

We examined the renoprotective effects of l-carnosine (beta-alanyl-l-histidine) on ischemia/reperfusion (I/R)-induced acute renal failure (ARF) in rats. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. In vehicle (0.9% saline)-treated rats, renal sympathetic nerve activity (RSNA) was significantly augmented during the renal ischemia, and renal function was markedly decreased at 24 h after reperfusion. Intracerebroventricular injection of l-carnosine (1.5 and 5 pmol/rat) to ischemic ARF rats dose-dependently suppressed the augmented RSNA during ischemia and the renal injury at 24 h after reperfusion. N-alpha-Acetyl-l-carnosine [N-acetyl-beta-alanyl-l-histidine; 5 pmol/rat intracerebroventricular (i.c.v.)], which is resistant to enzymatic hydrolysis by carnosinase, did not affect the renal injury, and l-histidine (5 pmol/rat i.c.v.), a metabolite cleaved from l-carnosine by carnosinase, ameliorated the I/R-induced renal injury. Furthermore, a selective histamine H(3) receptor antagonist, thioperamide (30 nmol/rat i.c.v.) eliminated the preventing effects by l-carnosine (15 nmol/rat intravenously) on ischemic ARF. In contrast, a selective H(3) receptor agonist, R-alpha-methylhistamine (5 pmol/rat i.c.v.), prevented the I/R-induced renal injury as well as l-carnosine (5 pmol/rat) did. These results indicate that l-carnosine prevents the development of I/R-induced renal injury, and the effect is accompanied by suppressing the enhanced RSNA during ischemia. In addition, the present findings suggest that the renoprotective effect of l-carnosine on ischemic ARF is induced by its conversion to l-histidine and l-histamine and is mediated through the activation of histamine H(3) receptors in the central nervous system.

Topics: Acute Kidney Injury; Animals; Blood Pressure; Carnosine; Histidine; Injections, Intraventricular; Kidney; Male; Piperidines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sympathetic Nervous System

Previously, we showed that an elevated production of histamine promotes the healing of injured intestinal mucosa after ischemia-reperfusion. The aim of the present study was to determine whether histamine-mediated repair of the intestinal mucosa after ischemia-reperfusion involves the engagement of H1 or H2 receptors.. The superior mesenteric artery was occluded for 15 minutes followed by reperfusion, and H1- or H2-receptor antagonists were infused intraduodenally. After ischemia-reperfusion, ornithine decarboxylase activity in the jejunal mucosa and lipid transport to mesenteric lymph were examined.. In jejunal mucosa, ornithine decarboxylase activity markedly increased at 6 hours after reperfusion and remained elevated at 48 hours. The ischemia-reperfusion-induced increase in ornithine decarboxylase activity was attenuated (in a dose-dependent manner) by an H1-receptor antagonist (chlorpheniramine maleate) but not by an H2 antagonist (cimetidine). Intraperitoneal injection of an H3 antagonist (thioperamide) increased histamine output in mesenteric lymph and stimulated intestinal ornithine decarboxylase activity. Transport of dietary lipid into mesenteric lymph was depressed 24 hours after an ischemic insult, yet it returned to the normal level 48 hours after ischemia-reperfusion. The recovery of the lipid transport normally observed at 48 hours after ischemia-reperfusion was attenuated by the H1 antagonist.. The beneficial effects of histamine on the repair of intestinal mucosa after ischemia-reperfusion results from the engagement and activation of the H1 receptor.

Topics: Animals; Biological Transport; Chlorpheniramine; Cimetidine; Dietary Fats; Histamine Antagonists; Histamine Release; Intestinal Mucosa; Intestines; Lymph; Male; Ornithine Decarboxylase; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H2; Reperfusion Injury