Mosalam Esraa M, Atya Soha M, Mesbah Noha M, Allam Shady, Mehanna Eman T
Biochemistry Department, Faculty of Pharmacy, Menoufia University, Shebin EL-Kom 32511, Menoufia, Egypt.
Department of Pharm D, Faculty of Pharmacy, Jadara University, Irbid 21110, Jordan.
Int J Mol Sci. 2025 Mar 28;26(7):3108. doi: 10.3390/ijms26073108.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, neuroinflammation and neuronal damage. This study aimed to investigate the neuroprotective effects of cilomilast (CILO), a phosphodiesterase-4 (PDE4) inhibitor, alone and in combination with chlorogenic acid (CGA), a natural polyphenol, against scopolamine (SCOP)-induced cognitive impairment in mice. Forty male albino mice were divided into five groups: normal control, SCOP control, CGA + SCOP, CILO + SCOP and CILO + CGA + SCOP. Behavioral assessments, including the Y-maze and pole climbing tests, demonstrated that SCOP significantly impaired cognition, while treatment with CILO and CGA reversed these deficits, with the combination group showing the greatest improvement. Histopathological analyses revealed that CILO and CGA reduced neuronal damage and amyloid beta (Aβ) accumulation. Immunohistochemical and biochemical assessments confirmed a decrease in neuroinflammatory markers, including tumor necrosis factor-alpha (TNF-α) and nuclear factor kappa B (NF-κB). Molecular analyses showed that CILO restored cyclic adenosine monophosphate (cAMP) levels, leading to activation of protein kinase A (PKA), cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), key regulators of neuronal plasticity and survival. CGA enhanced these effects by further inhibiting PDE4, amplifying the neuroprotective response. These findings suggest that PDE4 inhibitors, particularly in combination with CGA, may represent promising therapeutic strategies for AD-related cognitive impairment.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征为认知功能下降、神经炎症和神经元损伤。本研究旨在探究西洛司特（CILO，一种磷酸二酯酶-4（PDE4）抑制剂）单独使用以及与天然多酚绿原酸（CGA）联合使用时，对东莨菪碱（SCOP）诱导的小鼠认知障碍的神经保护作用。将40只雄性白化小鼠分为五组：正常对照组、SCOP对照组、CGA + SCOP组、CILO + SCOP组和CILO + CGA + SCOP组。行为学评估，包括Y迷宫和爬杆试验，表明SCOP显著损害认知功能，而CILO和CGA治疗可逆转这些缺陷，联合用药组改善最为明显。组织病理学分析显示，CILO和CGA减少了神经元损伤和β淀粉样蛋白（Aβ）积累。免疫组织化学和生化评估证实神经炎症标志物减少，包括肿瘤坏死因子-α（TNF-α）和核因子κB（NF-κB）。分子分析表明，CILO恢复了环磷酸腺苷（cAMP）水平，导致蛋白激酶A（PKA）、cAMP反应元件结合蛋白（CREB）和脑源性神经营养因子（BDNF）激活，这些是神经元可塑性和存活的关键调节因子。CGA通过进一步抑制PDE4增强了这些作用，放大了神经保护反应。这些发现表明，PDE4抑制剂，特别是与CGA联合使用时，可能是治疗AD相关认知障碍的有前景的治疗策略。
