Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, 5790, CEP 87020-900, Maringá, Paraná, Brazil.
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands; Department of Immunology and Biochemistry, Biomedical Research Institute, Hasselt University, Hasselt, Belgium.
Neuropharmacology. 2018 Aug;138:360-370. doi: 10.1016/j.neuropharm.2018.06.019. Epub 2018 Jun 19.
Chronic cerebral hypoperfusion (CCH) has been associated with aging-related vascular dementia, including Alzheimer's disease. It can be induced by the four-vessel occlusion/internal carotid artery (4VO/ICA) model in aged rats, resulting in persistent memory deficits, white matter injury, and significant neuronal loss in the hippocampus and cerebral cortex. The phosphodiesterase type 4 inhibitor (PDE4-I) roflumilast has been reported to have pro-cognitive effects in several behavioral paradigms. The present study evaluated the effects of repeated roflumilast treatment in aged rats that were subjected to CCH. After surgery, roflumilast (0.003 and 0.01 mg/kg) was administered intraperitoneally once per day for 29 days. Memory performance was assessed in the aversive radial maze (AvRM) 7, 14, and 21 days after CCH. The effects of roflumilast on hippocampal neurodegeneration and white matter injury were investigated using Nissl and Kluver-Barrera staining, respectively. Western blot and RT-qPCR were used to explore microglial polarization using M1 (Iba-1 and iNOS) and M2 (Arginase-1) markers. Chronic cerebral hypoperfusion caused persistent memory deficits, hippocampal neurodegeneration, and vacuolization and fiber disarrangement in white matter. Repeated roflumilast treatment restored CCH-induced cognitive impairments in aged rats but in the absence of the rescue of hippocampal neurons. Attenuation of white matter injury was detected in the optic tract in aged CCH rats that were treated with roflumilast. In vitro, roflumilast increased Arg-1 gene expression in myelin-laden primary microglia. The present data suggest that roflumilast might be useful for the treatment of cognitive sequelae associated with CCH.
慢性脑灌注不足（CCH）与衰老相关的血管性痴呆有关，包括阿尔茨海默病。它可以通过老龄大鼠的四血管闭塞/颈内动脉（4VO/ICA）模型诱导，导致持续的记忆缺陷、白质损伤和海马和大脑皮层的显著神经元丢失。磷酸二酯酶 4 抑制剂（PDE4-I）罗氟司特已被报道在几种行为范式中具有认知促进作用。本研究评估了反复给予罗氟司特治疗经历 CCH 的老龄大鼠的效果。手术后，罗氟司特（0.003 和 0.01mg/kg）每天腹膜内给药一次，共 29 天。在 CCH 后 7、14 和 21 天，使用厌恶性放射状迷宫（AvRM）评估记忆表现。使用尼氏染色和 Kluver-Barrera 染色分别评估罗氟司特对海马神经退行性变和白质损伤的影响。使用 M1（Iba-1 和 iNOS）和 M2（精氨酸酶-1）标志物的 Western blot 和 RT-qPCR 来探索小胶质细胞极化。慢性脑灌注不足导致持续的记忆缺陷、海马神经退行性变以及白质中的空泡化和纤维排列紊乱。反复给予罗氟司特可恢复老龄大鼠 CCH 诱导的认知障碍，但不能挽救海马神经元。在接受罗氟司特治疗的老龄 CCH 大鼠的视神经束中检测到白质损伤的减轻。在体外，罗氟司特增加了富含髓鞘的原代小胶质细胞中 Arg-1 基因的表达。本数据表明，罗氟司特可能对治疗与 CCH 相关的认知后遗症有用。
