Cannabinoids and Neuroprotection in Cerebral Ischemia

描述(由申请人提供)：内源性大麻素(内源性大麻素)信号通路与正常大脑功能以及脑缺血后的神经保护有关。我们发现，大麻素受体激动剂减少了大鼠全脑和局灶性脑缺血造成的神经元丢失，在CB1大麻受体(CB1R)基因敲除(KO)小鼠大脑中动脉阻塞(MCAO)后脑梗塞面积增加，大脑对缺血的反应涉及神经元CB1R上调和内源性抗炎内源性大麻素相关化合物的产生。从脑缺血中恢复可能不仅涉及促进细胞存活的神经保护机制，还涉及通过新细胞的生成(神经再生)取代致命损伤的神经元。最近的证据表明，内源性大麻素可能调节神经发生。我们发现，与年龄和品系匹配的野生型小鼠相比，CB1R-KO小鼠在成年脑的两个主要神经增殖区--海马齿状回颗粒下区(SGZ)和头端脑室下区(SVZ)的基础神经发生减少了50%，这表明CB1R的激活促进了神经发生。因此，我们假设内源性大麻素信号系统在调控局灶性脑缺血后的神经保护和神经再生方面具有重要作用。我们工作的长期目标是寻找治疗中风的新方法。为进一步实现这一目标，我们提出了以下具体目标：(1)确定缺失脂肪酸酰胺水解酶(FAAH)基因对大麻素局灶性脑缺血的组织学和功能结局的影响；(2)探讨一氧化氮合酶异构体(nNOS、eNOS和iNOS)在大麻素对局灶性脑缺血的神经保护作用中的作用；(3)表征大麻素在正常情况下和MCAO后对神经元增殖、死亡、迁移、分化和与成体神经发生相关的功能的影响；以及(4)评估生长因子(BDNF、TGFα、VEGF和FGF2)在大麻素刺激的成人神经发生中的作用。

DESCRIPTION (provided by applicant): Endogenous cannabinoid (endocannabinoid) signaling pathways have been implicated in normal brain function, as well as in neuroprotection following cerebral ischemia. We have shown that cannabinoid receptor agonists reduce neuronal loss from global and focal cerebral ischemia in rats, that the size of cerebral infarcts after middle cerebral artery occlusion (MCAO) is increased in CB1 cannabinoid receptor (CB1R)-knockout (KO) mice, and that the brain's response to ischemia involves up-regulation of neuronal CB1R and increased production of endogenous anti-inflammatory endocannabinoid-related compounds. Recovery from cerebral ischemia may involve not only neuroprotective mechanisms that promote cell survival, but also the replacement of lethally injured neurons by the generation of new cells (neurogenesis). Recent evidence suggests that endocannabinoids may regulate neurogenesis. We found that in CB1R-KO compared to age- and strain-matched wild-type mice, basal neurogenesis was reduced by 50% in the two principal neuroproliferative zones of the adult brain, the subgranular zone (SGZ) of the hippocampal dentate gyrus and the rostral subventricular zone (SVZ), suggesting that CB1R activation promotes neurogenesis. Thus, we hypothesize that the endocannabinoid signaling system has an important role in regulating both neuroprotection and neurogenesis after focal cerebral ischemia. The long term objective of our work is to identify new treatments for stroke. In furtherance of this objective, we propose to pursue the following Specific Aims: (1) Determine the effect of deleting the gene for fatty acid amide hydrolase (FAAH), which inactivates the endocannabinoid anandamide (AEA), on histological and functional outcome from focal cerebral ischemia; (2) Investigate the role of nitric oxide synthase isoforms (nNOS, eNOS and iNOS) in the neuroprotective effect of cannabinoids against focal cerebral ischemia; (3) Characterize the effects of cannabinoids on neuronal proliferation, death, migration, differentiation and function associated with adult neurogenesis, under normal conditions and after MCAO; and (4) Evaluate the role of growth factors (BDNF, TGFalpha, VEGF and FGF2) in cannabinoid-stimulated adult neurogenesis.