Dexmedetomidine improves the histological and neurological outcomes 48 h after transient spinal ischemia in rats.

Dexmedetomidine, an α2 adrenoceptor agonist, provides neuroprotection against various cerebral ischemia models through its anti-apoptotic effects. Dexmedetomidine also improves paraplegia induced by intrathecal morphine after short-term spinal ischemia. However, there are no reports regarding dexmedetomidine׳s ability to provide neuroprotection solely against transient spinal ischemia. We investigated whether dexmedetomidine would provide spinal protection following transient spinal ischemia in rats. Adult male Sprague Dawley rats were randomly assigned to one of the following five groups: (1) intravenous infusion of 0.9% NaCl at the rate of 0.5 mL/h (control), (2) dexmedetomidine 0.1 µg/kg/h, (3) dexmedetomidine 1 µg/kg/h, (4) dexmedetomidine 10 µg/kg/h, or (5) intravenous infusion of 0.9% NaCl without spinal ischemia (sham). The rats received saline solution or dexmedetomidine from 30 min before spinal cord ischemia to 48 h after ischemia. Spinal cord ischemia was induced by intraaortic balloon occlusion combined with proximal arterial hypotension for 10 min. Ischemic injury was assessed by neurological deficit scores and the number of viable motor nerve cells in the anterior spinal cord at 48 h after reperfusion. Neurological deficit scores in the dexmedetomidine-treated rats were significantly lower than the scores in the control group at 24 and 48 h after ischemia (P<0.05). The number of viable motor nerve cells was significantly larger in the dexmedetomidine-treated rats than in the control rats (P<0.05), but the number of motor nerve cells in the dexmedetomidine group was significantly smaller than the sham group. Our results indicate that the continuous administration of dexmedetomidine improves neurological and histological outcomes 48 h after transient spinal ischemia in rats.

Neuroprotective effects of selective ß-1 adrenoceptor antagonists, landiolol and esmolol, on transient forebrain ischemia in rats; a dose-response study.

Although selective beta-1 adrenoceptor antagonists are known to provide neuroprotective effects after brain ischemia, dose-response relationships of their neuroprotective effects have not been examined. The present study was conducted to evaluate whether the degree of brain protection against transient forebrain ischemia would be influenced by different doses of selective beta-1 adrenoceptor antagonists, esmolol and landiolol, in rats. Adult male S.D. rats received intravenous infusion of saline 0.5 ml/h, esmolol 20, 200, 2,000 µg/kg/min, or landiolol 5, 50, 500 µg/kg/min. Infusion was initiated 30 min prior to ischemia and continued for 24h. Ten-minute forebrain ischemia was induced by hemorrhagic hypotension and occlusion of the bilateral carotid arteries. Neurological and histological examinations were performed. Neurological deficit scores at 1, 4 and 7 days were lower, and the number of intact neurons in CA1 hippocampal region was larger in the rats treated with esmolol and landiolol after ischemia, compared with saline-treated rats (P<0.05), whereas no difference was found among different doses of esmolol and landiolol. These results suggested that selective beta-1 adrenoceptor antagonists improved neurological and histological outcomes following forebrain ischemia in rats, irrespective of their doses.

Neuroprotective effects and suppression of ischemia-induced glutamate elevation by ß1-adrenoreceptor antagonists administered before transient focal ischemia in rats.

BACKGROUND: ß-Adrenoreceptor antagonists provide neuroprotective effects after focal cerebral ischemia in experimental settings. This study was conducted to compare the neuroprotective effects of low-dose and high-dose of selective ß1-adrenoreceptor antagonists in rats after focal cerebral ischemia. We also investigated whether glutamate and norepinephrine contribute to neuroprotection of the ß-adrenoreceptor antagonists. METHODS: Sprague-Dawley rats were subjected to 120 minutes middle cerebral artery occlusion. The rats received intravenous infusion of saline 0.5 mL/h, esmolol 200, esmolol 2000, landiolol 50, or landiolol 500 µg/kg/min. Infusion of all the drugs were started 30 minutes before ischemia and continued for 24 hours. Neurological deficit scores were evaluated at 1, 4, and 7 days, whereas the brains were removed and stained at 7 days after ischemia. In the esmolol 200, and landiolol 50 µg/kg/min groups of additional rats, glutamate and norepinephrine concentrations in the striatum were measured separately by microdialysis during ischemia (glutamate, 120 min; norepinephrine, 110 min) and reperfusion (40 min). RESULTS: Neurological deficit scores were smaller in rats treated with esmolol or landiolol than in saline-treated rats at 1, 4, and 7 days. The cortical and striatal infarct volumes were smaller in rats receiving ß-adrenoreceptor antagonists than in the saline-treated rats. There were no significant differences in neurological score or infarct volume between the groups receiving the different doses of ß1-adrenoreceptor antagonists. The area under the curve of glutamate in the esmolol-treated or landiolol-treated rats was significantly smaller than that in the saline-treated rats, whereas no significant differences were noted in the norepinephrine concentration among the groups. CONCLUSIONS: This study indicates that the improvement in neurological and histologic outcomes by selective ß1-adrenoreceptor antagonists after transient focal cerebral ischemia is partly attributed to attenuation of glutamate release.

Post-treatment with selective ß1 adrenoceptor antagonists provides neuroprotection against transient focal ischemia in rats.

We have reported the neuroprotective effects of pre-treatment with beta-adrenoceptor antagonists on the cerebral infarction at 1 and 7 days after focal ischemia in rats. However, the protective effect of post-treatment with beta-adrenoceptor antagonists has not been investigated yet. This study was conducted to evaluate the post-treatment effects of selective beta(1)-adrenoceptor antagonists in the rat focal cerebral ischemia. Halothane anesthetized, normothermic adult male Sprague-Dawley rats were subjected to 2h of middle cerebral artery occlusion (MCAO) using the intraluminal suture technique confirmed by laser Doppler flowmetry. Rats received intravenous infusion of saline 0.5 mL/h, esmolol 200 microg/kg/min, or landiolol 50 microg/kg/min (n=8 in each group). Infusion was initiated 30 min after MCAO and continued for 24h. Rats were allowed to survive for 7 days, and the neurological deficit score was evaluated at 1, 4 and 7 days after reperfusion. The brains were removed and stained with triphenyltetrazolium chloride at 7 days after reperfusion. Neurological deficit scores were lower in the rats treated with esmolol or landiolol, compared with saline-treated rats at 1 day as well as 4 and 7 days. The infarct volumes of cortical and striatum were less in the rats receiving beta-adrenoceptor antagonists than in saline-treated rats (P<0.05). The current study indicates that administration of selective beta1-adrenoceptor antagonists after the onset of ischemia also improved neurological and histological outcomes following transient focal cerebral ischemia in rats.

Esmolol and landiolol, selective beta1-adrenoreceptor antagonists, provide neuroprotection against spinal cord ischemia and reperfusion in rats.

BACKGROUND: Paraplegia is a devastating and unpredictable complication occasionally resulting from surgery of the thoracic and thoracoabdominal aorta. Because ultrashort-acting selective beta(1)-adrenoreceptor antagonists provide neuroprotective effects after brain ischemia, we hypothesized that they would also ameliorate spinal cord injury after transient ischemia and reperfusion in rats. METHODS: Male Sprague-Dawley rats were randomly assigned to one of the following 4 groups: saline (received IV infusion of 0.9% saline at a rate of 0.5 mL/h, n = 8), esmolol (esmolol 200 microg/kg/min, n = 8), landiolol (landiolol 50 microg/kg/min), or sham surgical (n = 6). Infusion of saline or drugs was initiated 30 minutes before spinal cord ischemia and continued for the subsequent 24-hour reperfusion. Spinal cord ischemia was induced by intraaortic balloon occlusion combined with proximal arterial hypotension for 10 minutes. The spinal cord was then reperfused for 24 hours. Ischemic injury was assessed in terms of the motor deficit index score of the hindlimb and the number of viable motor nerve cells in the anterior spinal cord at 24 hours after reperfusion. RESULTS: The motor deficit index scores were significantly lower in the esmolol and landiolol groups compared with the saline group (P < 0.05). Histopathologic evaluation of the spinal cord showed less damage in the esmolol and landiolol groups than in the saline group (P < 0.05). CONCLUSIONS: These data show that ultrashort-acting selective beta(1)-adrenoreceptor antagonists can reduce neurological injury in a rat model of spinal cord ischemia-reperfusion.

Beta-adrenoreceptor antagonists attenuate brain injury after transient focal ischemia in rats.

Beta-adrenoreceptor antagonists experimentally reduce cardiac and renal injury after ischemia and are also clinically useful for myocardial infarction and severe burns. In addition, beta-adrenoreceptor antagonists provide neuroprotective effects after focal cerebral ischemia in experimental settings. We conducted the present study to compare the neuroprotective effects of several beta-adrenoreceptor antagonists in rat transient focal cerebral ischemia. Halothane-anesthetized normothermic adult male Sprague-Dawley rats were subjected to 2 h of middle cerebral artery occlusion using the intraluminal suture technique confirmed by laser Doppler flowmetry. Rats received an IV infusion of saline 0.5 mL/h, propranolol 100 microg x kg(-1) x min(-1), carvedilol 4 microg x kg(-1) x min(-1), esmolol 200 microg x kg(-1) x min(-1), or landiolol 50 microg x kg(-1) x min(-1) (n = 6 in each group). Infusion was initiated 30 min before middle cerebral artery occlusion and continued for 24 h. Additional rats received esmolol 50 microg x kg(-1) x min(-1) or landiolol 10 microg x kg(-1) x min(-1) intrathecally (IT) via the cisterna magna (n = 5 in each group), according to the same experimental protocol. The neurological deficit score was evaluated at 22 h after reperfusion, and the brains were removed and stained with triphenyltetrazolium chloride for evaluation of infarct volume. Additional rats that received saline, esmolol, and landiolol IV (n = 6 in each group) were allowed to survive for 7 days followed by measurement of infarct size. Neurological deficit scores were smaller in rats treated with propranolol-IV, carvedilol-IV, esmolol-IV, landiolol-IV, esmolol-IT, and landiolol-IT compared with saline-treated rats (P < 0.05). Cortical and striatum infarct volumes were less in the rats receiving beta-adrenoreceptor antagonists via either IV or IT than in saline-treated rats (P < 0.05). We conclude that beta-adrenoreceptor antagonists improve neurological and histological outcomes after transient focal cerebral ischemia in rats independent of administration route.