Protective effects of p38 MAPK inhibitor SB202190 against hippocampal apoptosis and spatial learning and memory deficits in a rat model of vascular dementia.
Vascular dementia (VaD) is a common age-related neurodegenerative disease resulting from chronic hypoxia. In the present study, we examined the protective effects of p38 MAPK inhibitor SB202190 against hippocampal apoptosis and spatial learning and memory deficits in a chronic hypoperfusion rat model of VaD established by permanent bilateral carotid occlusion (2-VO). Sixty rats were randomly divided into sham-operated, VaD model, and VaD plus SB202190 groups (n = 20/group). After sham/2-VO surgery, rats were administered 0.1% DMSO (sham-operated and VaD groups) or SB202190 by intracerebroventricular injection. One week after inhibitor/vehicle treatment, hippocampal p38 MAPK phosphorylation was higher in the model group than in the SB202190 group (P < 0.01). Compared to the model group, the SB202190 group exhibited significantly shorter escape latencies in the Morris water maze hidden platform trials (P < 0.01) and longer times in the original platform quadrant during probe trials (P < 0.01). The SB202190 group also showed significantly reduced neuronal apoptosis in the hippocampus compared to VaD model rats (P < 0.01) as well as higher (antiapoptotic) Bcl-2 expression and lower (proapoptotic) caspase-3 expression (P < 0.01 for both). In conclusion, blockade of the p38 MAPK signaling pathway by SB202190 following permanent 2-OV reduced apoptosis of hippocampal neurons and rescued spatial learning and memory deficits.
Department of Neurology, Shandong Provincial Hospital, Shandong University, Jinan 250012, China ; Department of Neurology, Taian Central Hospital, Taian 271000, China.
Shen
S
Yang
Department of Neurology, Taian Central Hospital, Taian 271000, China.
Guangan
G
Zhou
Department of Neurology, Liaocheng Hospital, Liaocheng 252000, China.
Hong
H
Liu
Department of Neurology, Taian Central Hospital, Taian 271000, China.
Bo
B
Zhang
Department of Neurology, Taian Central Hospital, Taian 271000, China.
Juan
J
Li
Department of Neurology, Taian Central Hospital, Taian 271000, China.
Ruiting
R
Cui
Department of Neurology, Shandong Provincial Hospital, Shandong University, Jinan 250012, China.
Yifeng
Y
Du
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000096:biosynthesis; D015140:Dementia, Vascular / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D007859:Learning Disabilities / Q000188:drug therapy* / Q000503:physiopathology; D008569:Memory Disorders / Q000188:drug therapy* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011725:Pyridines / Q000008:administration & dosage*; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D007093:Imidazoles; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole