Inoue M, McHugh M, Pappius H M
Goad Unit, Donner Laboratory of Experimental Neurochemistry, Montreal Neurological Institute, McGill University, Quebec, Canada.
J Cereb Blood Flow Metab. 1991 Mar;11(2):242-52. doi: 10.1038/jcbfm.1991.56.
Widespread decrease in local cerebral glucose utilization (LCGU) previously shown to occur 3 days after a local freezing lesion was interpreted as reflecting a depression of functional activity in the affected areas. In parallel experiments, cortical norepinephrine (NE) content of traumatized brain was found to be decreased. The effects of prazosin (PZ), an alpha 1-adrenergic receptor blocker, and yohimbine (YOH), an alpha 2-blocker, on glucose use and biogenic amine content of lesioned rat brain were studied to determine if the changes in the noradrenergic system associated with injury are of functional importance, to identify the receptors that may be involved in mediating the action of NE in injured brain, and to look for evidence of interaction between the noradrenergic and the serotonergic systems in traumatized brain. PZ (1 mg/kg) given 30 min before the lesion ameliorated the subsequent metabolic cortical depression seen in untreated animals. PZ given for 3 days starting before the lesion (3 mg/kg/day) was also effective in normalizing LCGU in areas where it was depressed by lesioning, despite the fact that this regimen induced significant global decrease in LCGU in normal animals. Once cortical metabolic depression had developed 3 days after the lesion, it could not be modified by PZ. YOH was less effective than PZ and was so only when given for 3 days (22.5 mg/kg/day in three divided doses). PZ (3 mg/kg/day in three divided doses) slightly but significantly decreased the accumulation of the serotonin (5-HT) metabolite 5-hydroxyindoleacetic acid in the traumatized hemisphere. These results provide evidence that blockage of alpha 1-adrenergic receptors prevents the development of cortical dysfunction associated with brain trauma. This implies that the noradrenergic system plays a role in the functional consequences of injury and that this effect is, at least in part, mediated by alpha 1-adrenergic receptors. Furthermore, alpha 1-adrenergic receptor blockage appears to modulate cortical turnover of 5-HT, previously also implicated in functional consequences of brain injury. The data are compatible with inhibitory effects of NE in the cortex and suggest a potential of alpha 1-adrenergic blockage in development of novel therapeutic approaches to brain injury.
先前的研究表明，在局部冷冻损伤3天后，局部脑葡萄糖利用率（LCGU）普遍下降，这被解释为反映了受影响区域功能活动的抑制。在平行实验中，发现创伤后脑皮质去甲肾上腺素（NE）含量降低。研究了α1肾上腺素能受体阻滞剂哌唑嗪（PZ）和α2阻滞剂育亨宾（YOH）对损伤大鼠脑葡萄糖利用和生物胺含量的影响，以确定与损伤相关的去甲肾上腺素能系统变化是否具有功能重要性，确定可能参与介导NE在损伤脑中作用的受体，并寻找创伤脑中去甲肾上腺素能系统与5-羟色胺能系统之间相互作用的证据。在损伤前30分钟给予PZ（1mg/kg）可改善未治疗动物随后出现的皮质代谢抑制。在损伤前开始给予PZ 3天（3mg/kg/天）也能有效使因损伤而降低的区域的LCGU恢复正常，尽管该方案在正常动物中导致了LCGU的显著整体下降。一旦损伤3天后出现皮质代谢抑制，PZ就无法对其进行改善。YOH的效果不如PZ，只有在给予3天（22.5mg/kg/天，分三次给药）时才有效。PZ（3mg/kg/天，分三次给药）轻微但显著地降低了创伤半球中5-羟色胺（5-HT）代谢物5-羟吲哚乙酸的积累。这些结果提供了证据，表明α1肾上腺素能受体的阻断可防止与脑损伤相关的皮质功能障碍的发展。这意味着去甲肾上腺素能系统在损伤的功能后果中起作用，并且这种作用至少部分是由α1肾上腺素能受体介导的。此外，α1肾上腺素能受体阻断似乎可调节5-HT的皮质更新，5-HT先前也与脑损伤的功能后果有关。这些数据与NE在皮质中的抑制作用相符，并表明α1肾上腺素能阻断在开发新型脑损伤治疗方法方面具有潜力。
