SDF-1在丰富环境促进颞叶癫痫大鼠认知功能中的作用及机制研究

Enriched environment（EE）can effectively antagonize reduced neural plasticity associated with brain damage, but how enriched environment affecting adult temporal lobe epilepsy(TLE) is still in the blank. Our preliminary work found that EE could improve cognitive function, increase proliferation of the newborn cells in hippocampal dentate gyrus, and increase the hippocampal SDF-1 protein relative density in adult TLE rats. The recent researches demonstrated SDF-1/CXCR4 could enhance BDNF and neurogenesis in hippocampus. However, a high concentration of SDF-1 could be cleaved by matrix metalloproteinase (MMPs) to SDF-1(5-67), and SDF-1(5-67)/CXCR3 system could inhibit neurogenesis. Moreover, SDF-1 concentration in hippocampus is not low and SDF-1 (5-67) protein concentration is increased in the chronic phase of TLE. Accordingly, we will measure the expressions of SDF-1、SDF-1(5-67)、MMPs、CXCR4、CXCR3 and BDNF, and analyze neurogenesis in the hippocampus at different times after TLE and EE. We will demonstrate EE increases BDNF、neurogenesis and cognitive function after TLE by the enhancement on SDF-1/CXCR4 system and inhibition of SDF-1(5-67)/CXCR3 system under different interventions of these two systems.

丰富环境可以拮抗与脑损伤相关的神经可塑性降低，但对颞叶癫痫的影响尚不明确。我们发现：丰富环境能改善颞叶癫痫鼠的认知功能、提高齿状回新生细胞增殖、增加海马SDF-1表达。有研究表明SDF-1/CXCR4能提高BDNF促进神经发生，但高浓度SDF-1在MMPs的裂解下产生了SDF-1(5-67)，SDF-1(5-67)/CXCR3会抑制神经细胞再生。并且颞叶癫痫慢性期海马SDF-1浓度不降低且SDF-1(5-67)蛋白含量升高。据此，我们对颞叶癫痫及丰富环境后SDF-1、SDF-1(5-67)、BDNF等的表达以及海马神经发生情况进行检测，并对SDF-1/CXCR4与SDF-1(5-67)/CXCR3系统进行拮抗干预，从而揭示丰富环境可能是通过增强SDF-1/CXCR4，同时抑制SDF-1(5-67)/CXCR3，来提高BDNF水平、促进慢性期颞叶癫痫的神经发生和改善认知功能的一个新的分子机制

研究背景： .丰富环境对颞叶癫痫的影响尚不明确。我们对颞叶癫痫及丰富环境后SDF-1、SDF-1(5-67 )等的表达以及海马神经发生进行检测，并对SDF-1/CXCR4与SDF-1(5-67)/CXCR3系统进行拮抗干预，来研究其作用机制。.研究过程中还发现外消旋l-3-正丁基苯酞（DL-NBP）有助于提高癫痫小鼠的认知功能，降低癫痫发作的频率。.主要研究内容：.1观测癫痫大鼠在丰富环境下海马神经细胞的变性和学习记忆情况。.2检测癫痫组在丰富环境下SDF-1、CXCR4、SDF-1(5-67)在海马的表达。 .3注射SDF-1(5-67)拮抗剂后检测神经发生以及学习记忆的变化情况。.4 DL-NBP对癫痫鼠的影响。.重要结果:.1 丰富环境能够改善癫痫后的认知功能，促进神经发生。丰富环境组SDF-1、CXCR4的表达提高，SDF-1(5-67)的表达减少。.2 用SDF-1(5-67)拮抗剂会提高癫痫大鼠的神经发生和认知功能。.3 癫痫大鼠用DL-NBP治疗可增加新生神经元的增殖，逆转神经元的丢失，减轻认知障碍，减少苔藓纤维发芽和痫性发作的频率。.关键数据及其科学意义:.1 . 丰富环境组的逃避潜伏期 [(32.90±2.41)s vs (23.34±1.78)s]缩短；海马BrdU和BrdU/NeuN 阳性数[(17.89±1.18)个和(9.24±0.94)个]多于癫痫组[(12.93±0.93)个和(5.38±0.61)个]。.2 SDF-1(5-67)拮抗剂组新生神经元增加（10.5±1.3和3.0±0.4；P<0.05）。SDF-1(5-67)拮抗剂组逃避潜伏期降低（F[2,4]=35.581，P=0.016）。.3 DL-NBP组Nissl阳性神经元数量增加（分别为14.0±1.0和6.0±0.6；P<0.05）。.4 DL-NBP治疗降低癫痫发作的频率（分别为7.5±0.5和3.5±0.7次/2h；P<0.01）和持续时间（分别为79.3±4.8s和58.8±5.9s/2h；P<0.05）。.5 DL-NBP组Timm评分降低（分别为4.3±0.3 vs.2.7±0.3；P<0.05）。.通过我们一系列的研究表明了丰富环境、SDF-1(5-67)拮抗剂以及DL-NBP对颞叶癫痫均是有利的，并且进一步明确了其相关机制。