This article aimed to investigate the effects and related mechanisms of the 5-HT2A receptor reverse agonist LPM6690061 on a rat model of psychosis in Alzheimer's disease(ADP).A bilateral hippocampal injection of β-Amyloid protein(Aβ)was used to establish an AD rat model,and DOI was used to induce psychopathic behavior phenotypes in AD rats.Oral administration of 3.0 mg/kg LPM6690061 was used for in vivo pharmacological and mechanistic studies.The effects of LPM6690061 on the expression levels of phosphorylated protein kinase B(P-AKT),phosphorylated cyclic adenosine monophosphate effector element binding protein(P-CREB),and brain-de-rived neurotrophic factor(BDNF)in the hippocampus were examined by Western Blot(WB).Nissl staining was utilized to observe changes in the neuronal morphology and quantity of the hippocampal neurocytes.Golgi-Cox stai-ning was employed to assess the impact of LPM6690061 on the dendritic spine density in the hippocampus of rats.The results indicated that LPM6690061 significantly alleviated DOI-induced head-twitch response in rates.In the new object recognition test,LPM6690061 significantly improves cognitive impairments caused by Aβ.In the pre-pulse inhibition test,LPM6690061 significantly enhanced the pre-pulse inhibition rate in ADP rats.LPM6690061 increased the protein expression levels of P-AKT,P-CREB,and BDNF in the hippocampal region of AD rates,in-creased the number of neurons in the hippocampus,and significantly alleviated the decrease in dendritic spine den-sity caused by aggregated Aβ.These findings suggest that LPM6690061 can improve the synaptic plasticity affected by Aβ deposition through the AKT/CREB/BDNF pathway,thereby alleviating psychotic symptoms and improving cognitive impairments in ADP rats.
关键词
阿尔茨海默伴发精神病性症状/5-HT2A受体/BDNF/突触可塑性
Key words
psychosis in Alzheimer's disease/5-HT2A receptor/BDNF/synaptic plasticity
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