Ellagic Acid Reverses Alterations in the Expression of AMPA Receptor and Its Scaffolding Proteins in the Cerebral Cortex and Memory Decline in STZ-sporadic Alzheimer' s Disease Mouse Model.

IF 3.5 3区医学 Q2 NEUROSCIENCES Psychopharmacology Pub Date : 2024-10-01 Epub Date: 2024-06-06 DOI:10.1007/s00213-024-06622-9

Nidhi Anand K Singh, S Prasad

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Abstract

Rationale: Alzheimer's disease (AD), an age-dependent devastating neuropsychiatric disorder, is a leading cause of learning, memory and intellectual disabilities. Current therapeutic approaches for the amelioration of the anomalies of AD are not effective.

Objective: In the present study, the molecular mechanisms underlying sporadic AD (sAD), the memory related behavioral analysis and neuroprotective effects of Ellagic acid (EA) were investigated.

Method: sAD mouse model was developed by intracerebroventricular (ICV) injection of Streptozotocin (STZ). The efficacy of EA, a naturally occurring polyphenol, in amelioration of anomalies associated with sAD was assessed. EA was administered once daily for 28 days at a dose of 75 mg/kg body weight followed by neurobehavioral, biochemical, molecular and neuronal count analysis to delineate the mode of action of EA.

Result: The ICV injection of STZ in mice significantly increased the expression of AD biomarkers in addition to enhanced oxidative stress. A decline in the discrimination index in Novel Object Recognition Test was observed indicating the compromise of recognition memory in AD. Studies on the expression of genes involved in synaptic plasticity reveal the dysregulation of the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) of the glutamate and its scaffolding proteins in the postsynaptic density and thereby synaptic plasticity in AD. ICV-STZ led to significant upregulation of apoptotic markers which led to decrease in neuronal density of the cerebral cortex. EA significantly reversed the above and improved anomalies of sAD.

Conclusion: EA was observed to profoundly modulate the genes involved in AD pathophysiology, restored antioxidant enzymes activity, reduced lipid peroxidation and neuronal loss in the sAD brain. Further, EA was observed to effectively modulate the genes involved in apoptosis and synaptic plasticity. Therefore, EA possesses promising anti-AD properties, which may improve AD-associated anomalies by modulating synaptic plasticity via AMPAR signaling.

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鞣花酸可逆转 STZ 散发性阿尔茨海默病小鼠模型大脑皮层中 AMPA 受体及其支架蛋白的表达变化和记忆衰退。

理由阿尔茨海默病（AD）是一种与年龄相关的破坏性神经精神疾病，是导致学习、记忆和智力障碍的主要原因。目前改善阿尔茨海默病异常的治疗方法并不有效：方法：通过脑室内注射链脲佐菌素（STZ）建立散发性 AD（sAD）小鼠模型。方法：通过脑室内注射链脲佐菌素（STZ）建立小鼠模型，评估天然多酚 EA 在改善与 sAD 相关的异常情况方面的功效。以 75 毫克/千克体重的剂量连续 28 天每天给药一次，然后进行神经行为、生化、分子和神经元计数分析，以确定 EA 的作用模式：结果：小鼠 ICV 注射 STZ 后，除了氧化应激增强外，AD 生物标志物的表达也明显增加。结果：小鼠ICV注射STZ后，除了氧化应激增强外，AD生物标志物的表达也明显增加，新颖物体识别测试中的辨别指数下降，表明AD患者的识别记忆受到影响。对突触可塑性相关基因表达的研究表明，谷氨酸α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）及其支架蛋白在突触后密度中的表达失调，从而影响了AD的突触可塑性。ICV-STZ导致细胞凋亡标志物显著上调，从而导致大脑皮层神经元密度下降。EA明显逆转了上述情况，并改善了sAD的异常现象：结论：据观察，EA 能显著调节参与 AD 病理生理学的基因，恢复抗氧化酶的活性，减少脂质过氧化和 sAD 大脑神经元的损失。此外，还观察到 EA 能有效调节参与细胞凋亡和突触可塑性的基因。因此，EA具有良好的抗AD特性，可通过AMPAR信号调节突触可塑性来改善AD相关异常。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Psychopharmacology 医学-精神病学

CiteScore

7.10

自引率

5.90%

发文量

257

审稿时长

2-4 weeks

期刊介绍： Official Journal of the European Behavioural Pharmacology Society (EBPS) Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields: Human Psychopharmacology: Experimental This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered. Human Psychopharmacology: Clinical and Translational This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects. Preclinical psychopharmacology: Behavioral and Neural This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels. Preclinical Psychopharmacology: Translational This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways. Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.