激活多巴胺 2 受体可调节小鼠中风恢复过程中的谷氨酸脱羧酶 65 和 67

Neuroprotection Pub Date : 2023-12-14 DOI:10.1002/nep3.28
D. Talhada, Robert Nilsson, Severin Walser, Georgios Michalettos, K. Ruscher
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引用次数: 0

摘要

左旋多巴能促进临床前中风模型和患者丧失的神经功能的恢复。在此,我们研究了多巴胺信号转导是否会调节实验性脑卒中后副发光体阳性中间神经元的GABA能神经传递。小鼠在中风两天后,分别接受 D1 受体拮抗剂 R(+)-SCH-23390 (0.1 mg/kg)、选择性 D1 受体激动剂 (R)-(+)-SKF-38393 盐酸盐(1 mg/kg)、D2 受体激动剂 R(-)-2,10,11- 三羟基-N-丙基-去甲吗啡氢溴酸盐(TNPA)(1 mg/kg)、D2 受体拮抗剂 S-(-)-eticlopride 盐酸盐(0.3毫克/千克)或载体(生理盐水),每天腹腔注射,连续五天。术前、术后第2天和第7天,通过脚掌放置和脚错试验评估小鼠的功能恢复情况。与所有其他治疗条件相比,接受TNPA治疗的小鼠的恢复情况有显著的统计学改善。γ-氨基丁酸(GABA)的合成通过梗死周围区域和对侧皮层同型区域的全长和裂解谷氨酸脱羧酶67和65(GAD65和GAD67)的水平进行量化。与其他治疗方法相比,TNPA 能显著降低缺血半球和对侧半球中 GAD67 同工酶的水平。我们的结果表明,在 D2 受体介导的机制中,GABA 合成减少可能有助于抵消中风后的功能抑制。
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Activation of dopamine 2 receptors modulates glutamate decarboxylases 65 and 67 during stroke recovery in mice
Treatment with levodopa enhances recovery of lost neurological functions in preclinical stroke models and patients. Here, we studied whether dopamine signaling modulates GABAergic neurotransmission in parvalbumin‐positive interneurons after experimental stroke.Following block randomization, mice were subjected to experimental stroke induced by photothrombosis (PT). Two days after the insult, mice were treated either with the D1 receptor antagonist by R(+)‐SCH‐23390 (0.1 mg/kg), the selective D1 receptor agonist (R)‐(+)‐SKF‐38393 hydrochloride (1 mg/kg), the D2 receptor agonist R(−)‐2,10,11‐trihydroxy‐N‐propyl‐noraporphine hydrobromide hydrate (TNPA) (1 mg/kg), the D2 receptor antagonist S‐(−)‐eticlopride hydrochloride (0.3 mg/kg), or vehicle (saline) by daily intraperitoneal injection for five consecutive days, respectively. Recovery of function was assessed by paw placement and foot fault test before and on Days 2 and 7 after surgery.Mice treated with TNPA showed a statistically significant improvement of recovery compared to all other treatment conditions. Synthesis of gamma‐aminobutyric acid (GABA) was quantified by levels of full‐length and cleaved glutamate acid decarboxylase 67 and 65 (GAD65 and GAD67) in the peri‐infarct area and homotypic regions of the contralateral cortex. Compared to the other treatments, TNPA significantly reduced the level of the GAD67 isoform both in the ischemic and contralateral hemispheres. Levels of GAD65 were found significantly higher in the contralateral hemisphere in TNPA‐treated mice after PT accompanied by an increase in the 58 kDa‐truncated form.Our results point toward reduced GABA synthesis in a D2 receptor‐mediated mechanism possibly contributing to counteract functional inhibition after stroke.
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