The Study Of The Role Of P38MAPK In Hypertension-related Cognitive Dysfunction

With the development of the population aging process and accelerated, the continuous improvement of living standards, the health of the elderly has been paid more and more attention, hypertension and cognitive dysfunction is a serious two problems affecting the health and quality of life of the elderly. In recent years, the condition of cerebral function damage caused by hypertension in elderly, namely from sequential mild cognitive impairment to dementia change has gradually become a hot research. But the research of the mechanism of hypertension-related cognitive impairment is not much, the mechanism of cognitive dysfunction caused by hypertension is not completely clear, treatment methods of hypertension-related cognitive impairment is very limited.The hippocampus is thought to be the main part of learning and memory. It plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Synaptic plasticity is the neurobiological basis of learning and memory. Recent studies show that p38MAPK signaling pathway plays important roles in hypertension, and cognitive dysfunction.In our study, angiotensin Ⅱ-dependent hypertensive model was used.We detected learning and memory ability in angiotensin Ⅱ-dependent hypertensive mice,detected the change of dendritic spine morphology and long-term potentiation (LTP) in hippocampal CAI, detected the changes of p38MAPK, and observe the changes of cognitive function and synaptic plasticity after inhibition of p38MAPK.This study investigated the role of p38MAPK pathway in hypertension-related cognitive dysfunction.It will help clear the mechanism of the disease,and provide new theoretical basis and new therapeutic target for prevention and treatment of hypertension-related cognitive dysfunction.Our study include the following three parts:1. The changes of cognitive function and hippocampal p38MAPK in angiotensin Ⅱ-dependent hypertensive mice.2. The effects of p38MAPK inhibition on cognitive function in angiotensin Ⅱ-dependent hypertensive mice in vivo.3. The effects of p38MAPK inhibition on hippocampal synaptic plasticity in angiotensin Ⅱ-dependent hypertensive mice.Chapter I:The changes of cognitive function and hippocampal p38MAPK in angiotensin Ⅱ-dependent hypertensive miceObjective:A mouse model of chronic angiotensin Ⅱ-dependent hypertension was used in the study. We investigated the changes of cognitive function and hippocampal p38MAPK in angiotensin Ⅱ-dependent hypertensive mice.Methods:Eight week-old C57BL/6 male mice were used for this study.The animals were randomly divided into two groups for the experiment: angiotensin Ⅱ infusion and controls receiving 0.9% saline solution. We used subcutaneous mini-pumps containing a concentration of angiotensin Ⅱ(1900 ng/kg/min) that induces malignant hypertension. Spatial memory was assessed using the Morris water maze test, the expression level of hippocampal p38MAPK and p-p38MAPK was detected by western-blot analysis.Results: Compared to the saline-treated control group, the treatment of Ang Ⅱ significantly raised the systolic blood pressure in adult male mice from the 1 st week (103.31±1.77 vs 154.58±8.74) mmHg, the 2nd week (104.96±3.11 vs 157.98± 6.81) mmHg, the 3rd week (103.58±1.98 vs 155.50±6.57) mmHg to the 4th week (105.73±2.35 vs 156.00±5.08) mmHg (all p< 0.01). The percentage of time spent in the target quadrant in probe test was significantly reduced in angiotensin Ⅱ-dependent hypertensive mice(52.61±13.34% vs 28.63±17.24%, p<0.01). The phosphorylation of p38MAPK was significantly higher in angiotensin Ⅱ-dependent hypertensive mice(p<0.01).Conclusions:Memory was impaired, and hippocampal p38MAPK was activated in angiotensin Ⅱ-dependent hypertensive mice.Chapter Ⅱ:The effects of p38MAPK inhibition on cognitive function in angiotensin Ⅱ-dependent hypertensive mice in vivoObjective:A mouse model of chronic angiotensin Ⅱ-dependent hypertension was used in the study. We investigated the effect of p38MAPK inhibiton on cognitive function in angiotensin Ⅱ-dependent hypertensive mice in vitro.Methods:Eight week-old C57BL/6 and p38KI/+ male mice were used for this study. The animals were randomly divided into four groups for the experiment:0.9% saline-treated C57BL/6 mice, angiotensin Ⅱ-treated C57BL/6 mice,0.9% saline-treated p38KI/+ mice, and angiotensin Ⅱ-treated p38KI/+ mice. We used subcutaneous mini-pumps containing a concentration of angiotensin Ⅱ(1900 ng/kg/min) that induces malignant hypertension. Spatial memory was assessed using the Morris water maze test.Results:Compared to the saline-treated control group, Ang Ⅱ significantly raised the systolic blood pressure (p<0.05) constant throughout the experiment. Compared to the angiotensin Ⅱ-treated C57BL/6 mice, the phosphorylation of p38MAPK was significantly lower in angiotensin Ⅱ-dependent hypertensive p38KI/+ mice(p<0.05), the percentage of time spent in the target quadrant in probe test was significantly increased in angiotensin Ⅱ-treated hypertensive p38KI/+ mice (p<0.05).Conclusions: p38MAPK inhibition can improve the cognitive function of hypertension-related cognitive dysfunction, p38MAPK inhibition may provide a new target for the treatment of hypertension-related cognitive dysfunction.Chapter Ⅲ:The effects of p38MAPK inhibition on hippocampal synaptic plasticity in angiotensin Ⅱ-dependent hypertensive miceSection 1 The effect of p38MAPK inhibition on hippocampal CA1 LTP in hippocampal slices from hypertensive mice in vitroObjective:A mouse model of chronic angiotensin Ⅱ-dependent hypertension was used in the study. We investigated the effect of p38MAPK inhibitor SKF86002 on hippocampal CA1 LTP in hippocampal slices from hypertensive mice in vitro.Methods:Eight week-old C57BL/6 male mice were used for this study.We used subcutaneous mini-pumps containing a concentration of angiotensin Ⅱ (1900 ng/kg/ min) that induces malignant hypertension. LTP was measured by vitro electrophysiology on hippocampal slices at the Schaffer-CA1 pathway. Comparison of LTP in p38MAPK inhibitor-treated hippocampal slices and non-treated hippocampal slices.Results:Compared to the non-treated hippocampal slices, hippocampal CA1 LTP was significantly increased in p38MAPK inhibitor-treated hippocampal slices from hypertensive mice (p< 0.05). Impaired LTP was improved in hippocampal slices from angiotensin Ⅱ-dependent hypertensive mice by p38MAPK inhibition in vitro.Section 2 The effects of p38MAPK inhibition on hippocampal synaptic plasticity in angiotensin Ⅱ-dependent hypertensive mice in vivoObjective: A mouse model of chronic angiotensin Ⅱ-dependent hypertension was used in the study. We investigated the effects of p38MAPK inhibition on hippocampal synaptic plasticity in hypertensive mice in vivo.Methods: Eight week-old C57BL/6 and p38KI/+ male mice were used for this study. The animals were randomly divided into four groups for the experiment:0.9% saline-treated C57BL/6 mice, angiotensin Ⅱ-treated C57BL/6 mice, 0.9% saline-treated p38KI/+ mice, and angiotensin Ⅱ-treated p38KI/+ mice.We used subcutaneous mini-pumps containing a concentration of angiotensin Ⅱ(1900 ng/kg/min) that induces malignant hypertension. The density of the dendritic spines on the CA1 pyramidal cells were examined by confocal microscopy after Golgi staining, LTP was measured by vitro electrophysiology on hippocampal slices at the Schaffer-CA1 pathway.Results:Compared to the saline-treated control group, Ang Ⅱ significantly raised the systolic blood pressure (p<0.05) constant throughout the experiment. Compared to the angiotensin Ⅱ-treated C57BL/6 mice, the density(/30μm) of the dendritic spines on the CA1 pyramidal cells and hippocampal CA1 LTP were significantly increased in angiotensin Ⅱ-treated hypertensive p38KI/+ mice (p<0.05).Conclusions of this Chapter: p38MAPK inhibition can improve the hippocampal synaptic plasticity, which might be one of its mechanism to improve the cognition function of hypertension-related cognitive dysfunction.