Basmadjian Osvaldo M, Occhieppo Victoria B, Marchese Natalia A, Silvero C M Jazmin, Becerra María Cecilia, Baiardi Gustavo, Bregonzio Claudia
Departamento de Farmacología, Facultad de Ciencias Químicas, Instituto de Farmacología Experimental Córdoba (IFEC-CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina.
Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC), CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
Front Pharmacol. 2021 May 3;12:647747. doi: 10.3389/fphar.2021.647747. eCollection 2021.
Amphetamine (AMPH) alters neurons, glia and microvessels, which affects neurovascular unit coupling, leading to disruption in brain functions such as attention and working memory. Oxidative stress plays a crucial role in these alterations. The angiotensin type I receptors (AT-R) mediate deleterious effects, such as oxidative/inflammatory responses, endothelial dysfunction, neuronal oxidative damage, alterations that overlap with those observed from AMPH exposure. The aim of this study was to evaluate the AT-R role in AMPH-induced oxidative stress and glial and vascular alterations in the prefrontal cortex (PFC). Furthermore, we aimed to evaluate the involvement of AT-R in the AMPH-induced short-term memory and working memory deficit. Male Wistar rats were repeatedly administered with the AT-R blocker candesartan (CAND) and AMPH. Acute oxidative stress in the PFC was evaluated immediately after the last AMPH administration by determining lipid and protein peroxidation. After 21 off-drug days, long-lasting alterations in the glia, microvessel architecture and to cognitive tasks were evaluated by GFAP, CD11b and von Willebrand immunostaining and by short-term and working memory assessment. AMPH induced acute oxidative stress, long-lasting glial reactivity in the PFC and a working memory deficit that were prevented by AT-R blockade pretreatment. Moreover, AMPH induces transient angiogenesis in PFC via AT-R. AMPH did not affect short-term memory. Our results support the protective role of AT-R blockade in AMPH-induced oxidative stress, transient angiogenesis and long-lasting glial activation, preserving working memory performance.
苯丙胺（AMPH）会改变神经元、神经胶质细胞和微血管，进而影响神经血管单元耦合，导致注意力和工作记忆等脑功能紊乱。氧化应激在这些改变中起关键作用。血管紧张素I型受体（AT-R）介导有害作用，如氧化/炎症反应、内皮功能障碍、神经元氧化损伤，这些改变与AMPH暴露所观察到的改变重叠。本研究的目的是评估AT-R在AMPH诱导的前额叶皮质（PFC）氧化应激以及神经胶质和血管改变中的作用。此外，我们旨在评估AT-R在AMPH诱导的短期记忆和工作记忆缺陷中的作用。雄性Wistar大鼠反复接受AT-R阻滞剂坎地沙坦（CAND）和AMPH处理。在最后一次给予AMPH后，通过测定脂质和蛋白质过氧化作用，立即评估PFC中的急性氧化应激。在停药21天后，通过胶质纤维酸性蛋白（GFAP）、CD11b和血管性血友病因子免疫染色以及短期和工作记忆评估，评估神经胶质、微血管结构的长期改变以及对认知任务的影响。AMPH诱导急性氧化应激、PFC中持久的神经胶质反应以及工作记忆缺陷，而AT-R阻断预处理可预防这些情况。此外，AMPH通过AT-R诱导PFC中的短暂血管生成。AMPH不影响短期记忆。我们的结果支持AT-R阻断在AMPH诱导的氧化应激、短暂血管生成和持久神经胶质激活中的保护作用，从而保留工作记忆表现。
