Department of Pharmacology and Therapeutics, State University of Maringá, Paraná, Brazil.
Neuroimmune Connect and Repair Lab., Biomedical Research Institute, Hasselt University, Hasselt, Belgium.
Behav Pharmacol. 2021 Sep 1;32(6):459-471. doi: 10.1097/FBP.0000000000000640.
Inhibition of phosphodiesterase 4 (PDE4) is a promising pharmacological strategy for the treatment of cerebral ischemic conditions. To increase the relevance and increase the translational value of preclinical studies, it is important to conduct experiments using different animal species and strains, different animal models, and to evaluate long-term functional outcomes after cerebral ischemia. In the present study, the effects of the selective PDE4 inhibitor roflumilast were evaluated in vivo and in vitro. Balb/c mice were subjected to bilateral common carotid artery occlusion (BCCAO) and tested during 21 days in multiple behavioral tasks to investigate the long-term effects of roflumilast on functional recovery. The effects of roflumilast were also investigated on hippocampal cell loss, white matter injury, and expression of neuroinflammatory markers. Roflumilast prevented cognitive and emotional deficits induced by BCCAO in mice. Roflumilast also prevented neurodegeneration and reduced the white matter damage in the brain of ischemic animals. Besides, roflumilast decreased Iba-1 (microglia marker) levels and increased Arginase-1 (Arg-1; microglia M2 phenotype marker) levels in the hippocampus of these mice. Likewise, roflumilast suppressed inducible nitric oxide synthase (microglia M1 phenotype marker) expression and increased Arg-1 levels in a primary mouse microglia culture. These findings support evidence that PDE4 inhibition by roflumilast might be beneficial in cerebral ischemic conditions. The neuroprotective effects of roflumilast appear to be mediated by a decrease in neuroinflammation.
抑制磷酸二酯酶 4（PDE4）是治疗脑缺血的一种很有前途的药理学策略。为了提高临床前研究的相关性和转化价值，使用不同的动物物种和品系、不同的动物模型进行实验，并评估脑缺血后的长期功能结果非常重要。在本研究中，评估了选择性 PDE4 抑制剂罗氟司特的体内和体外作用。Balb/c 小鼠接受双侧颈总动脉闭塞（BCCAO），并在多个行为任务中测试 21 天，以研究罗氟司特对功能恢复的长期影响。还研究了罗氟司特对海马细胞丢失、白质损伤和神经炎症标志物表达的影响。罗氟司特可预防 BCCAO 诱导的小鼠认知和情感缺陷。罗氟司特还可预防缺血动物的神经退行性变并减少大脑中的白质损伤。此外，罗氟司特降低了这些小鼠海马中的 Iba-1（小胶质细胞标志物）水平，并增加了精氨酸酶-1（Arg-1；小胶质细胞 M2 表型标志物）水平。同样，罗氟司特在原代小鼠小胶质细胞培养物中抑制诱导型一氧化氮合酶（小胶质细胞 M1 表型标志物）的表达并增加 Arg-1 水平。这些发现支持了罗氟司特抑制 PDE4 可能有益于脑缺血的证据。罗氟司特的神经保护作用似乎是通过减少神经炎症介导的。
