Bommaraju Sumadhura, Dhokne Mrunali D, Rakeshkumar Patel Parthkumar, Datusalia Ashok Kumar
Laboratory of Molecular NeuroTherapeutics, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, Uttar Pradesh (UP), 226002, India.
Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, Uttar Pradesh (UP), 226002, India.
Neurochem Res. 2024 Dec 14;50(1):58. doi: 10.1007/s11064-024-04315-5.
Post-traumatic stress disorder (PTSD) poses significant neurological and psychiatric challenges. Investigations into the glutamatergic system, particularly the N-methyl-D-aspartate (NMDA) receptor, are crucial for understanding PTSD mechanisms. This study aimed to evaluate the therapeutic potential of the non-competitive NMDA receptor antagonist memantine in mitigating PTSD symptoms and to explore its underlying cellular and molecular impacts. Male Sprague Dawley rats were subjected to inescapable foot shock stress (FS-stress) to model PTSD. Following stress exposure, memantine was administered at doses of 5 mg/kg and 10 mg/kg six hours post-stress. Behavioural assessments, including fear conditioning and sucrose preference tests, were conducted. Golgi-Cox staining was used to assess neuroanatomical changes related to synaptic plasticity. Western blotting was used to analyse molecular markers associated with synaptic plasticity, while immunoassays measured proinflammatory cytokines and cortisol levels. Memantine treatment improved behavioral outcomes, restoring sucrose preference and reducing freezing behavior. Morphological analysis demonstrated that memantine enhanced dendritic spine structure, particularly increasing the proportion of mature mushroom spines, which are critical for synaptic stability. Additionally, memantine normalized cortisol levels, suggesting a regulatory effect on the hypothalamic-pituitary-adrenal (HPA) axis. Additionally, memantine treatment improved the inflammatory cytokine profile, reducing IL-6 and TNF-α levels. These results suggest that memantine has potential as a therapeutic intervention for PTSD by targeting critical pathways involved in stress responses.The findings indicate that memantine, an NMDA receptor antagonist, can counteract behavioral and functional disturbances induced by FS-stress.
创伤后应激障碍（PTSD）带来了重大的神经和精神挑战。对谷氨酸能系统，尤其是N-甲基-D-天冬氨酸（NMDA）受体的研究，对于理解PTSD机制至关重要。本研究旨在评估非竞争性NMDA受体拮抗剂美金刚在减轻PTSD症状方面的治疗潜力，并探索其潜在的细胞和分子影响。雄性Sprague Dawley大鼠接受不可逃避的足部电击应激（FS应激）以模拟PTSD。应激暴露后，在应激后6小时以5mg/kg和10mg/kg的剂量给予美金刚。进行了行为评估，包括恐惧条件反射和蔗糖偏好测试。高尔基-考克斯染色用于评估与突触可塑性相关的神经解剖学变化。蛋白质免疫印迹法用于分析与突触可塑性相关的分子标志物，而免疫测定法测量促炎细胞因子和皮质醇水平。美金刚治疗改善了行为结果，恢复了蔗糖偏好并减少了僵住行为。形态学分析表明，美金刚增强了树突棘结构，特别是增加了成熟蘑菇状棘的比例，这对突触稳定性至关重要。此外，美金刚使皮质醇水平正常化，表明对下丘脑-垂体-肾上腺（HPA）轴有调节作用。此外，美金刚治疗改善了炎性细胞因子谱，降低了IL-6和TNF-α水平。这些结果表明，美金刚通过靶向参与应激反应的关键途径，具有作为PTSD治疗干预措施的潜力。研究结果表明，NMDA受体拮抗剂美金刚可以抵消FS应激引起的行为和功能障碍。
