Maity Dipan, Rahi Vikrant, Dorai Sandya Tambi, Chandrashekharappa Sandeep, Kaundal Ravinder K
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli (NIPER-R), Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, Uttar Pradesh 226002, India.
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research Raebareli (NIPER-R), Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, Uttar Pradesh 226002, India.
ACS Chem Neurosci. 2025 May 7;16(9):1815-1826. doi: 10.1021/acschemneuro.4c00886. Epub 2025 Apr 14.
Neuroinflammation is a key factor in age-related cognitive decline and memory impairment. UAS03, a potent synthetic analogue of Urolithin-A, has demonstrated anti-inflammatory and antioxidant properties. This investigation examined the neuroprotective effect of UAS03 on lipopolysaccharide (LPS) induced neuroinflammation, and its associated cognitive impairments, memory deficits, and depression-like behaviors. Intracerebroventricular administration of LPS (12 μg/kg) was performed to induce neuroinflammation in mice, followed by a 7 day treatment with UAS03 at 10 and 30 mg/kg doses. Mice were evaluated for depressive and anxiety-like behavior, spatial memory, and learning functions using a series of neurobehavioral test paradigms. Histopathological and molecular analyses were conducted using hematoxylin-eosin and cresyl violet staining, immunohistochemistry, ELISA, and Western blotting techniques. We have found that, UAS03 significantly enhanced cognitive and memory functions impaired by LPS while concurrently reducing depressive symptoms. Furthermore, the compound attenuated neuronal damage and decreased the expression of IBA-1 and GFAP in hippocampal region. Through the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, UAS03 effectively mitigated markers of oxidative stress and reduced levels of pro-inflammatory factors, including IL-1β, TNF-α, and COX-2. Cumulatively, this study provides compelling evidence that UAS03 exerts neuroprotective effects by regulating essential pathways involved in anti-inflammatory and neuroprotective mechanisms, suggesting its potential as a preventative measure against age-related cognitive decline and memory impairments associated with neuroinflammation.
神经炎症是与年龄相关的认知衰退和记忆障碍的关键因素。UAS03是一种强效的尿石素A合成类似物，已显示出抗炎和抗氧化特性。本研究考察了UAS03对脂多糖（LPS）诱导的神经炎症及其相关的认知障碍、记忆缺陷和抑郁样行为的神经保护作用。通过脑室内注射LPS（12μg/kg）诱导小鼠神经炎症，随后用10和30mg/kg剂量的UAS03进行7天治疗。使用一系列神经行为测试范式评估小鼠的抑郁和焦虑样行为、空间记忆和学习功能。使用苏木精-伊红和甲酚紫染色、免疫组织化学、ELISA和蛋白质印迹技术进行组织病理学和分子分析。我们发现，UAS03显著增强了LPS受损的认知和记忆功能，同时减轻了抑郁症状。此外，该化合物减轻了神经元损伤，并降低了海马区IBA-1和GFAP的表达。通过激活核因子红细胞2相关因子2（Nrf2）信号通路，UAS03有效减轻了氧化应激标志物，并降低了促炎因子的水平，包括IL-1β、TNF-α和COX-2。累积而言，本研究提供了令人信服的证据，表明UAS03通过调节参与抗炎和神经保护机制的关键途径发挥神经保护作用，表明其作为预防与神经炎症相关的年龄相关认知衰退和记忆障碍的潜在措施。
