Postgraduate Program in Biological Sciences/Center of Biosciences, Federal University of Pernambuco (UFPE), Recife, PE, Brazil; Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), PE, Brazil.
Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), PE, Brazil; Postgraduate Program in Biosciences and Biotechnology for Health (PPGBBS), Oswaldo Cruz Foundation (FIOCRUZ-PE)/Aggeu Magalhães Institute (IAM), Recife, PE, Brazil.
Int Immunopharmacol. 2020 Aug;85:106581. doi: 10.1016/j.intimp.2020.106581. Epub 2020 May 19.
Multiple sclerosis (MS) is a chronic immuno-inflammatory disease of the central nervous system characterized by demyelination and axonal damage. Cognitive changes are common in individuals with MS since inflammatory molecules secreted by microglia interfere with the physiological mechanisms of synaptic plasticity. According to previous data, inhibition of PDE5 promotes the accumulation of cGMP, which inhibits neuroinflammation and seems to improve synaptic plasticity and memory. The present study aimed to evaluate the effect of sildenafil on the signaling pathways of neuroinflammation and synaptic plasticity in experimental autoimmune encephalomyelitis (EAE). C57BL/6 mice were divided into three experimental groups (n = 10/group): (a) Control; (b) EAE; (c) EAE + sild (25 mg/kg/21 days). Sildenafil was able to delay the onset and attenuate the severity of the clinical symptoms of EAE. The drug also reduced the infiltration of CD4+ T lymphocytes and their respective IL-17 and TNF-α cytokines. Moreover, sildenafil reduced neuroinflammation in the hippocampus (assessed by the reduction of inflammatory markers IL-1β, pIKBα and pNFkB and reactive gliosis, as well as elevating the inhibitory cytokines TGF-β and IL-10). Moreover, sildenafil induced increased levels of NeuN, BDNF and pCREB, protein kinases (PKA, PKG, and pERK) and synaptophysin, and modulated the expression of the glutamate receptors AMPA and NMDA. The present findings demonstrated that sildenafil has therapeutic potential for cognitive deficit associated with multiple sclerosis.
多发性硬化症（MS）是一种中枢神经系统的慢性免疫炎症性疾病，其特征是脱髓鞘和轴突损伤。由于小胶质细胞分泌的炎症分子干扰了突触可塑性的生理机制，因此 MS 患者常出现认知变化。根据先前的数据，PDE5 的抑制可促进 cGMP 的积累，从而抑制神经炎症，并似乎改善突触可塑性和记忆。本研究旨在评估西地那非对实验性自身免疫性脑脊髓炎（EAE）中神经炎症和突触可塑性信号通路的影响。C57BL/6 小鼠分为三组（每组 n=10）：（a）对照组；（b）EAE 组；（c）EAE+sild（25mg/kg/21 天）。西地那非能够延迟 EAE 的发病并减轻其临床症状的严重程度。该药物还减少了 CD4+T 淋巴细胞及其各自的 IL-17 和 TNF-α细胞因子的浸润。此外，西地那非减少了海马体中的神经炎症（通过降低炎症标志物 IL-1β、pIKBα和 pNFkB以及反应性神经胶质增生，以及提高抑制性细胞因子 TGF-β和 IL-10 来评估）。此外，西地那非诱导了 NeuN、BDNF 和 pCREB 蛋白激酶（PKA、PKG 和 pERK）和突触小体蛋白水平的升高，并调节了谷氨酸受体 AMPA 和 NMDA 的表达。本研究结果表明，西地那非对多发性硬化症相关认知障碍具有治疗潜力。
