Multimodal neuroprotection induced by PACAP38 in oxygen-glucose deprivation and middle cerebral artery occlusion stroke models.
Multimodal neuroprotection induced by PACAP38 in oxygen-glucose deprivation and middle cerebral artery occlusion stroke models.
复制标题
DOI：
10.1007/s12031-012-9818-1
复制
发表时间：
2012-11
期刊：
影响因子：
--
通讯作者：
Jiang H
中科院分区：
文献类型：
--
作者：
Lazarovici P;Cohen G;Arien-Zakay H;Chen J;Zhang C;Chopp M;Jiang H
垂体腺苷酸环化酶激活肽（PACAP）是一种穿过血脑屏障的有效神经肽，已知可通过值得澄清的机制在大脑中动脉闭塞（MCAO）大鼠中风模型中提供神经保护。我们确认了以下静脉注射。在暴露于 2 小时 MCAO 局灶性脑缺血和 48 小时再氧合的大鼠中注射 30 ng/kg PACAP38，通过降低 caspase-3 活性和脑梗塞体积来测量 50% 的神经保护作用。 PACAP38 治疗脑皮质神经元的氧-糖剥夺和再氧合时也测量到了类似的神经保护作用。神经保护作用暂时与脑源性神经营养因子表达增加、其受体原肌球蛋白相关激酶受体 B 型 (trkB) 磷酸化、磷酸肌醇 3-激酶和 Akt 激活以及细胞外信号调节激酶 1/2 磷酸化减少相关。 PACAP38 增加神经元标记物 β-微管蛋白 III、微管相关蛋白 2 和生长相关蛋白 43 的表达。 PACAP38 诱导 Rac 的刺激和 Rho GTPase 活性的抑制。 PACAP38 下调神经生长因子受体 (p75NTR) 和相关的 Nogo-（神经突生长-A）受体。总的来说，这些体外和体内结果表明，PACAP 通过三种机制在脑缺血中表现出神经保护作用：一种是直接的，由 PACAP 受体介导；另一种是间接的，由神经营养素释放、trkB 受体的激活和神经元生长抑制信号分子 p75NTR 和 Nogo 受体的减弱诱导。
Pituitary adenylate cyclase activating peptide (PACAP), a potent neuropeptide which crosses the blood–brain barrier, is known to provide neuroprotection in rat stroke models of middle cerebral artery occlusion (MCAO) by mechanism(s) which deserve clarification. We confirmed that following i.v. injection of 30 ng/kg of PACAP38 in rats exposed to 2 h of MCAO focal cerebral ischemia and 48 h reoxygenation, 50 % neuroprotection was measured by reduced caspase-3 activity and volume of cerebral infarction. Similar neuroprotective effects were measured upon PACAP38 treatment of oxygen–glucose deprivation and reoxygenation of brain cortical neurons. The neuroprotection was temporally associated with increased expression of brain-derived neurotrophic factor, phosphorylation of its receptor—tropomyosin-related kinase receptor type B (trkB), activation of phosphoinositide 3-kinase and Akt, and reduction of extracellular signal-regulated kinases 1/2 phosphorylation. PACAP38 increased expression of neuronal markers beta-tubulin III, microtubule-associated protein-2, and growth-associated protein-43. PACAP38 induced stimulation of Rac and suppression of Rho GTPase activities. PACAP38 down-regulated the nerve growth factor receptor (p75NTR) and associated Nogo-(Neurite outgrowth-A) receptor. Collectively, these in vitro and in vivo results propose that PACAP exhibits neuroprotective effects in cerebral ischemia by three mechanisms: a direct one, mediated by PACAP receptors, and two indirect, induced by neurotrophin release, activation of the trkB receptors and attenuation of neuronal growth inhibitory signaling molecules p75NTR and Nogo receptor.
登录
查看更多内容
影响因子：
5.3
作者：
Kozma, R;Sarner, S;Lim, L
通讯作者：
Lim, L
影响因子：
3.3
作者：
Davoli, MA;Fourtounis, J;Xu, D
通讯作者：
Xu, D
影响因子：
25
作者：
Kao, HT;Song, HJ;Greengard, P
通讯作者：
Greengard, P
影响因子：
6.3
作者：
Chen, JL;Zhang, CL;Chopp, M
通讯作者：
Chopp, M
影响因子：
3.3
作者：
Koumura, A.;Nonaka, Y.;Hara, H.
通讯作者：
Hara, H.