Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt.
Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt.
Eur J Pharmacol. 2022 Apr 15;921:174873. doi: 10.1016/j.ejphar.2022.174873. Epub 2022 Mar 10.
Several studies have suggested that phosphodiesterase (PDE) inhibitors may be a disease-modifying for Alzheimer's disease (AD). Cilostazol (CSZ) has been shown to be a new treatment for cognitive impairment with limited efficacy. Our aim was to investigate the effect of caffeine on the efficacy of CSZ against STZ-induced type 2 diabetes (T2D)-related cognitive impairment in high fat/high fructose fed rats. The efficacy of low doses of caffeine, CSZ, and CSZ plus caffeine against abnormal behavioral, biochemical, histological, or genetic changes of animal models of AD was examined. Eight weeks treatment with CSZ plus caffeine was more effective than CSZ or caffeine in improving impaired behavioral tests for cognition and memory. Histological examination exhibited a significant augmentation in the efficacy of CSZ by caffeine in protecting neurons from damage in T2D rats. Importantly, CSZ and caffeine normalized the accumulation of Amyloid beta (Aβ-42) and phosphorylated tau protein (p-tau) positive cells in the brain of T2D rats. CSZ or CSZ plus caffeine reversed low glutamate gene expression, elevated cholinesterase level, and elevated caspase-3 activity in T2D rats. Furthermore, CSZ plus caffeine was significantly more effective than CSZ or caffeine in inhibiting the increase in malondialdehyde (MDA) level, total oxidative stress, pro-inflammatory cytokines and glucogen synthase kinase-3 beta (GSK-3β) in the hippocampus of T2D rats. Also, CSZ plus caffeine was more effective than CSZ or caffeine in alleviating insulin resistance and hypercholesterolemia in T2D rats. Our findings suggest the possibility of effective treatment of AD by enhancing the therapeutic potential of CSZ through combined treatment with lower doses of caffeine. The enhancement of CSZ effect by caffeine is attributed to the increased inhibitory effect of CSZ on insulin resistance, GSK-3β activity, hypercholesterolemia, oxidative stress and pro-inflammatory cytokines.
几项研究表明，磷酸二酯酶（PDE）抑制剂可能是阿尔茨海默病（AD）的一种疾病修饰物。西洛他唑（CSZ）已被证明是治疗认知障碍的一种新方法，但疗效有限。我们的目的是研究咖啡因对 CSZ 治疗高脂肪/高果糖喂养大鼠 2 型糖尿病（T2D）相关认知障碍的疗效的影响。研究了低剂量咖啡因、CSZ 和 CSZ 加咖啡因对 AD 动物模型异常行为、生化、组织学或遗传变化的疗效。与 CSZ 或咖啡因相比，CSZ 加咖啡因 8 周治疗更能改善认知和记忆受损的行为测试。组织学检查显示，咖啡因显著增强了 CSZ 对 T2D 大鼠神经元损伤的保护作用。重要的是，CSZ 和咖啡因使 T2D 大鼠大脑中淀粉样β（Aβ-42）和磷酸化 tau 蛋白（p-tau）阳性细胞的积累正常化。CSZ 或 CSZ 加咖啡因逆转了 T2D 大鼠低谷氨酸基因表达、乙酰胆碱酯酶水平升高和半胱天冬酶-3 活性升高。此外，CSZ 加咖啡因在抑制 T2D 大鼠海马丙二醛（MDA）水平、总氧化应激、促炎细胞因子和糖原合酶激酶-3β（GSK-3β）升高方面比 CSZ 或咖啡因更有效。此外，CSZ 加咖啡因在缓解 T2D 大鼠胰岛素抵抗和高胆固醇血症方面比 CSZ 或咖啡因更有效。我们的研究结果表明，通过联合使用低剂量咖啡因增强 CSZ 的治疗潜力，有可能有效治疗 AD。咖啡因增强 CSZ 作用的原因在于 CSZ 对胰岛素抵抗、GSK-3β活性、高胆固醇血症、氧化应激和促炎细胞因子的抑制作用增强。
