Fingolimod (FTY720) attenuates social deficits, learning and memory impairments, neuronal loss and neuroinflammation in the rat model of autism
Fingolimod (FTY720) attenuates social deficits, learning and memory impairments, neuronal loss and neuroinflammation in the rat model of autism
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芬戈莫德 (FTY720) 可减轻自闭症大鼠模型的社交缺陷、学习和记忆障碍、神经元损失和神经炎症
DOI：
10.1016/j.lfs.2017.01.012
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发表时间：
2017-03
期刊：
影响因子：
6.1
通讯作者：
Wu Lijie
中科院分区：
文献类型：
--
作者：
Wu Hongmei;Wang Xuelai;Gao Jingquan;Liang Shuang;Hao Yanqiu;Sun Caihong;Xia Wei;Cao Yonggang;Wu Lijie
目的探讨FTY 720对丙戊酸（Valproic acid，VPA）诱导的大鼠孤独症模型的影响。从出生后第15天至第35天，每天以0.25、0.5和1 mg/kg的剂量经口给予幼仔FTY 720。在FTY 720治疗结束时评估社会行为、空间学习和记忆。FTY 720（1 mg/kg）可改善VPA染毒大鼠的社会行为、空间学习记忆障碍，减少海马CA 1区神经元丢失和锥体细胞凋亡，降低海马CA 1区神经元凋亡率，降低海马CA 2区神经元凋亡率，降低海马CA 1区神经元凋亡率，降低海马CA 2区神经元凋亡率，降低海马CA 3区神经元凋亡率。（3）抑制海马小胶质细胞的活化，降低促炎细胞因子IL-1 β和IL-6的水平;（4）改变海马组织中丙二醛（MDA）、谷胱甘肽（GSH）含量、超氧化物歧化酶（SOD）和谷胱甘肽过氧化物酶（GSH-Px）活性;（6）抑制海马Bax和caspase-3蛋白的表达，提高Bcl-2蛋白的相对表达水平;和（7）增加磷酸钙/钙调素依赖性蛋白激酶II（p-CaMKII）、磷酸化cAMP反应元件结合蛋白（p-CREB）和脑源性神经营养因子（BDNF）在海马中的蛋白表达。重要性FTY 720挽救社交缺陷，VPA暴露大鼠的空间学习和记忆障碍。FTY 720发挥对神经元的直接保护作用，并间接调节炎症介导的神经元损失作为神经保护的可能机制。
AimsTo investigate the effect of FTY720 on the valproic acid (VPA) rat model of autism.Main methodsAs an animal model of autism, we used intraperitoneal injection of VPA on embryonic day 12.5 in Wistar rats. The pups were given FTY720 orally at doses of 0.25, 0.5 and 1 mg/kg daily from postnatal day 15 to 35. Social behavior, spatial learning and memory were assessed at the end of FTY720 treatment. The histological change, oxidative stress, neuroinflammatory responses, and apoptosis-related proteins in the hippocampus were evaluated.Key findingsFTY720 (1 mg/kg) administration to VPA-exposed rats (1) improved social behavior, spatial learning and memory impairment; (2) resulted in a reduction in neuronal loss and apoptosis of pyramidal cells in hippocampal CA1 regions; (3) inhibited activation of microglial cells, in turn lowering the level of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-6 in the hippocampus; (4) changed Malondialdehyde (MDA) levels, Glutathione (GSH) levels, superoxide dismutase (SOD) activity and Glutathione Peroxidase (GSH-Px) activity in the hippocampus; (6) inhibited the elevated Bax and caspase-3 protein levels and enhanced the relative expression level of Bcl-2 in the hippocampus; and (7) increased phospho-Ca2 +/calmodulin-dependent protein kinase II (p-CaMKII), phospho-cAMP-response element binding protein (p-CREB) and Brain Derived Neurotrophic Factor (BDNF) protein expression in the hippocampus.SignificanceFTY720 rescues social deficit, spatial learning and memory impairment in VPA-exposed rats. FTY720 exerts both a direct protection for neurons and an indirect modulation of inflammation-mediated neuron loss as a possible mechanism of neuroprotection.
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DOI：
10.1503/jpn.140009
发表时间：
2016
期刊：
Journal of psychiatry & neuroscience : JPN
影响因子：
--
作者：
Han Wang;S. Liang;Maoqing Wang;Jingquan Gao;Caihong Sun;Jia Wang;W. Xia;Shiying Wu;S. Sumner;Fengyu Zhang;Changhao Sun;Lijie Wu
通讯作者：
Han Wang;S. Liang;Maoqing Wang;Jingquan Gao;Caihong Sun;Jia Wang;W. Xia;Shiying Wu;S. Sumner;Fengyu Zhang;Changhao Sun;Lijie Wu
影响因子：
--
作者：
Benjamin Zablotsky;Lindsey I. Black;M. Maenner;L. Schieve;S. Blumberg
通讯作者：
Benjamin Zablotsky;Lindsey I. Black;M. Maenner;L. Schieve;S. Blumberg
影响因子：
9.3
作者：
Tye C;Bolton P
通讯作者：
Bolton P
DOI：
10.1074/jbc.m111.240481
发表时间：
2011-05
期刊：
The Journal of Biological Chemistry
影响因子：
--
作者：
T. Than;H. Lou;C. Ji;S. Win;N. Kaplowitz
通讯作者：
T. Than;H. Lou;C. Ji;S. Win;N. Kaplowitz
影响因子：
2.7
作者：
Fukumoto, Kazuya;Mizoguchi, Hiroyuki;Suzumura, Akio
通讯作者：
Suzumura, Akio