Minocycline treatment prevents depression and anxiety-like behaviors and promotes neuroprotection after experimental ischemic stroke

Abstract

Depression and anxiety have been reported as the major neuropsychiatric consequences following stroke. Minocycline, a neuroprotective drug has minimized depressive symptoms in patients with major depressive disorders and anxiety-like symptoms. In addition, minocycline demonstrated efficacy and seemed a promising neuroprotective agent in acute stroke patients. The present studied evaluated the effects of minocycline treatment on the depression and anxiety-like behaviors, brain damage and expression of inflammatory and neuroprotective mediators after transient global cerebral ischemia in C57BL/6 mice. Brain ischemia was induced by bilateral occlusion of the common carotids (BCCAo) for 25 min and subsequent reperfusion. Sham and BCCAo animals received minocycline at a dose of 30 mg/kg by intraperitoneal injection during 14 days. The locomotor activity, depression and anxiety-like behaviors were assessed by open field, forced swim and elevated plus maze tests, respectively. Then, the brains were removed and processed to evaluate brain damage by histological and morphometric analysis, hippocampal neurodegeneration using Fluoro-Jade C histochemistry, microglial activity using iba-1 immunohistochemistry, brain levels of TNF, IFN-γ, IL-6, IL-10, IL-12p70 and CCL2 by CBA, CX3CL1 and BDNF by ELISA assays. The animals developed depression and anxiety-like behaviors post-stroke and minocycline treatment prevented those neurobehavioral changes. Moreover, minocycline-treated BCCAo animals showed less intense brain damage in the cerebral cortex, brainstem and cerebellum as well as significantly reduced hippocampal neurodegeneration. BCCAo groups exhibited up-regulation of some cytokines at day 14 after ischemia and brain levels of CX3CL1 and BDNF remained unaltered. Our data indicate that the depression and anxiety-like behavioral improvements promoted by minocycline treatment might be related to its neuroprotective effect after brain ischemia in mice.

Keywords: Anxiety; Depression; Inflammation; Ischemia; Mice; Minocycline; Neuropathology; Neurotrophic factors.