多巴胺D1和D2受体激动剂和拮抗剂对脑缺血/再灌注损伤的影响

实验应用开阔法、组织病理学方法、原位末端标记(in situ terminal deoxynucleotidyl transferase-metliated de-oxy-UTP mick end labeling,TUNEL)法及免疫组织化学等方法,探讨多巴胺D1、D2受体激动剂和拮抗剂对沙土鼠前脑缺血／再灌注损伤海马CA1区神经元凋亡及凋亡相关基因bcl-2、bax表达的影响。结果显示：前脑缺血5min可引起沙土鼠探索活动增加;再灌注3d,海马CA1区约95％的锥体细胞凋亡;再灌注7d,海马CA1区仅残存约2％—7％的存活锥体细胞;前脑缺血5min可抑制bcl-2的表达并诱导bax表达增高;预先应用D2受体激动剂培高利特可减轻缺血后沙土鼠行为学异常、抑制海马CA1区锥体细胞凋亡、提高锥体细胞存活数、显著诱导bcl-2的表达并抑制bax的表达。预先应用SKF38393、SCH23390及螺哌隆对以上结果无明显影响。实验结果提示,培高利特具有确切的脑保护作用,诱导bcl-2并抑制bax的表达可能是其脑保护作用机制之一。

Effects of D1 and D2 dopamine receptor agonists and antagonists on cerebral ischemia/reperfusion injury

Gerbil forebrain ischemia/reperfusion(I/R) injury model was used to study the effects of D_1and D_2 receptor agonists and antagonists on neuronal apoptosis of hippocampal CA1 area. All animals weretested for habituation deficits in an open field test on the 1st, 3rd and 7th days after reperfusion. The animalswere then killed, and brains underwent paraffin embedding for hematoxylin-eosin staining, in situ terminaldeoxynucleotidyl transferase-mediated deoxy-UTP nick end labeling (TUNEL) staining and immunohisto-chemistry (bax, bcl-2). The result of open field test showed that the I/R group was significantly impaired(higher activity scores) when compared with the control group. Pretreatment with pergolide significantly re-duced this habituation impairment. Forebrain ischemia for 5 min resulted in extensive CA1 apoptosis on the3rd and 7th days after I/R injury. About 95% neurons in hippocampal CA1 area entered apoptosis and only2% - 7% pyramidal neurons stayed alive due to an inhibition of bcl-2 expression and an increase in bax ex-pression. Pretreatment of pergolide attenuated neuronal damage caused by transient ischemia. Infusion of per-golide could induce the expression of bcl-2 and reduce the expression of bax. Pretreatment with SKF38393,SCH23390 and spiperone had no effects on these changes in this transient I/R injury model. All these resultsindicate that pergolide plays an important role in the protection of hippocampal neurons from apotosis throughupregulating the expression of bcl-2 protein and reducing the expression of bax protein.