Instituto de Farmacología Experimental Córdoba (IFEC-CONICET) Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
Instituto Multidisciplinario de Biología Vegetal (IMBIV-CONICET) Departamento de Ciencias Farmacéuticas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
Eur J Neurosci. 2021 Sep;54(5):5705-5716. doi: 10.1111/ejn.14756. Epub 2020 May 18.
Astrocytes play an essential role in the genesis, maturation and regulation of the neurovascular unit. Multiple evidence support that astrocyte reactivity has a close relationship to neurovascular unit dysfunction, oxidative stress and inflammation, providing a suitable scenario for the development of mental disorders. Ketamine has been proposed as a single-use antidepressant treatment in major depression, and its antidepressant effects have been associated with anti-inflammatory properties. However, Ketamine long-lasting effects over the neurovascular unit components remain unclear. Angiotensin II AT receptor (AT -R) blockers have anti-inflammatory, antioxidant and neuroprotective effects. The present work aims to distinguish the acute and long-term Ketamine effects over astrocytes response extended to other neurovascular unit components, and the involvement of AT -R, in prefrontal cortex and ventral tegmental area. Male Wistar rats were administered with AT -R antagonist Candesartan/Vehicle (days 1-10) and Ketamine/Saline (days 6-10). After 14 days drug-free, at basal conditions or after Ketamine Challenge, the brains were processed for oxidative stress analysis, cresyl violet staining and immunohistochemistry for glial, neuronal activation and vascular markers. Repeated Ketamine administration induced long-lasting region-dependent astrocyte reactivity and morphological alterations, and neuroadaptative changes observed as exacerbated oxidative stress and neuronal activation, prevented by the AT -R blockade. Ketamine Challenge decreased microglial and astrocyte reactivity and augmented cellular apoptosis, independently of previous treatment. Overall, AT -R is involved in the development of neuroadaptative changes induced by repeated Ketamine administration but does not interfere with the acute effects supporting the potential use of AT -R blockers as a Ketamine complementary therapy in mental disorders.
星形胶质细胞在神经血管单元的发生、成熟和调节中起着至关重要的作用。有多项证据表明，星形胶质细胞反应与神经血管单元功能障碍、氧化应激和炎症密切相关，为精神疾病的发展提供了合适的场景。氯胺酮已被提议作为一种治疗重度抑郁症的即用型抗抑郁药物，其抗抑郁作用与抗炎特性有关。然而，氯胺酮对神经血管单元成分的长期影响仍不清楚。血管紧张素 II AT 受体 (AT -R) 阻滞剂具有抗炎、抗氧化和神经保护作用。本研究旨在区分氯胺酮对星形胶质细胞反应的急性和长期影响，以及 AT -R 对前额叶皮层和腹侧被盖区其他神经血管单元成分的影响。雄性 Wistar 大鼠给予 AT -R 拮抗剂坎地沙坦/载体（第 1-10 天）和氯胺酮/盐水（第 6-10 天）。在 14 天无药物治疗后，在基础条件下或在氯胺酮挑战后，对大脑进行氧化应激分析、甲苯胺蓝染色和胶质、神经元激活和血管标志物的免疫组织化学分析。重复给予氯胺酮诱导了持续的区域依赖性星形胶质细胞反应和形态改变，以及神经适应性变化，表现为氧化应激和神经元激活加剧，这一现象被 AT -R 阻断所阻止。氯胺酮挑战降低了小胶质细胞和星形胶质细胞的反应性，并增加了细胞凋亡，与之前的治疗无关。总的来说，AT -R 参与了重复给予氯胺酮引起的神经适应性变化的发展，但不干扰急性作用，支持 AT -R 阻滞剂作为精神疾病氯胺酮补充治疗的潜在用途。
