Zepeda Rodrigo, Contreras Valentina, Pissani Claudia, Stack Katherine, Vargas Macarena, Owen Gareth I, Lazo Oscar M, Bronfman Francisca C
MINREB and Center for Aging and Regeneration (CARE UC), Faculty of Biological Sciences, Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile.
Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile.
Neuropharmacology. 2016 Aug;107:131-145. doi: 10.1016/j.neuropharm.2016.03.011. Epub 2016 Mar 8.
Neuromodulators, such as antidepressants, may contribute to neuroprotection by modulating growth factor expression to exert anti-inflammatory effects and to support neuronal plasticity after stroke. Our objective was to study whether early treatment with venlafaxine, a serotonin-norepinephrine reuptake inhibitor, modulates growth factor expression and positively contributes to reducing the volume of infarcted brain tissue resulting in increased functional recovery. We studied the expression of BDNF, FGF2 and TGF-β1 by examining their mRNA and protein levels and cellular distribution using quantitative confocal microscopy at 5 days after venlafaxine treatment in control and infarcted brains. Venlafaxine treatment did not change the expression of these growth factors in sham rats. In infarcted rats, BDNF mRNA and protein levels were reduced, while the mRNA and protein levels of FGF2 and TGF-β1 were increased. Venlafaxine treatment potentiated all of the changes that were induced by cortical stroke alone. In particular, increased levels of FGF2 and TGF-β1 were observed in astrocytes at 5 days after stroke induction, and these increases were correlated with decreased astrogliosis (measured by GFAP) and increased synaptophysin immunostaining at twenty-one days after stroke in venlafaxine-treated rats. Finally, we show that venlafaxine reduced infarct volume after stroke resulting in increased functional recovery, which was measured using ladder rung motor tests, at 21 days after stroke. Our results indicate that the early oral administration of venlafaxine positively contributes to neuroprotection during the acute and late events that follow stroke.
神经调节剂，如抗抑郁药，可能通过调节生长因子表达来发挥抗炎作用并支持中风后的神经元可塑性，从而有助于神经保护。我们的目的是研究血清素-去甲肾上腺素再摄取抑制剂文拉法辛的早期治疗是否能调节生长因子表达，并对减少梗死脑组织体积从而促进功能恢复产生积极作用。我们在文拉法辛治疗5天后，通过定量共聚焦显微镜检查对照和梗死脑内脑源性神经营养因子（BDNF）、成纤维细胞生长因子2（FGF2）和转化生长因子-β1（TGF-β1）的mRNA和蛋白质水平以及细胞分布，来研究它们的表达情况。文拉法辛治疗对假手术大鼠这些生长因子的表达没有影响。在梗死大鼠中，BDNF的mRNA和蛋白质水平降低，而FGF2和TGF-β1的mRNA和蛋白质水平升高。文拉法辛治疗增强了仅由皮质中风诱导的所有变化。特别是，在中风诱导后5天，星形胶质细胞中FGF2和TGF-β1水平升高，并且这些升高与文拉法辛治疗的大鼠在中风后21天星形胶质细胞增生减少（通过胶质纤维酸性蛋白（GFAP）测量）和突触素免疫染色增加相关。最后，我们表明文拉法辛可减少中风后的梗死体积，从而在中风后21天通过阶梯式运动试验测量促进功能恢复。我们的结果表明，早期口服文拉法辛对中风后急性和晚期事件期间的神经保护有积极作用。
