p38 MAPK Inhibition Improves Synaptic Plasticity and Memory in Angiotensin II-dependent Hypertensive Mice.
The pathogenesis of hypertension-related cognitive impairment has not been sufficiently clarified, new molecular targets are needed. p38 MAPK pathway plays an important role in hypertensive target organ damage. Activated p38 MAPK was seen in AD brain tissue. In this study, we found that long-term potentiation (LTP) of hippocampal CA1 was decreased, the density of the dendritic spines on the CA1 pyramidal cells was reduced, the p-p38 protein expression in hippocampus was elevated, and cognitive function was impaired in angiotensin II-dependent hypertensive C57BL/6 mice. In vivo, using a p38 heterozygous knockdown mice (p38(KI/+)) model, we showed that knockdown of p38 MAPK in hippocampus leads to the improvement of cognitive function and hippocampal synaptic plasticity in angiotensin II-dependent p38(KI/+) hypertensive mice. In vitro, LTP was improved in hippocampal slices from C57BL/6 hypertensive mice by treatment with p38MAPK inhibitor SKF86002. Our data demonstrated that p38 MAPK may be a potential therapeutic target for hypertension-related cognitive dysfunction.
Department of Cardiology, Yan'an Affiliated Hospital of Kunming Medical University, Kunming, China.|Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China.|Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.
Hai-Long
HL
Dai
Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China.
Wei-Yuan
WY
Hu
Department of Cardiothoracic Surgery, Yan'an Affiliated Hospital of Kunming Medical University, Kunming, China.
Li-Hong
LH
Jiang
Department of outpatient, Ganmei Affiliated Hospital of Kunming Medical University, Kunming, China.
Le
L
Li
Department of Cardiology, Yan'an Affiliated Hospital of Kunming Medical University, Kunming, China.
Xue-Feng
XF
Gaung
Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China.|Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.
Zhi-Cheng
ZC
Xiao
D000804:Angiotensin II / Q000235:genetics*; D000818:Animals; D049229:Dendritic Spines / Q000187:drug effects; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D007093:Imidazoles / Q000008:administration & dosage; D017774:Long-Term Potentiation / Q000187:drug effects; D051379:Mice; D009473:Neuronal Plasticity / Q000235:genetics*; D017966:Pyramidal Cells / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000008:administration & dosage; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*
D007093:Imidazoles; D013844:Thiazoles; D000804:Angiotensin II; C052026:6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole; D048051:p38 Mitogen-Activated Protein Kinases