Abstract
Global cerebral ischemia (GCI) commonly occurs in the elderly. Subcortical white matter lesions and oligodendrocyte (OLG) loss caused by cerebral ischemia have been implicated in the development of post-ischemic depression and cognitive impairment. OLGs are necessary for axonal myelination; the disrupted differentiation of OLG progenitor cells (OPCs) is associated with impaired remyelination. Evidence has indicated that increased levels of inflammatory cytokines released from activated microglia induce depression-like behaviors by affecting neurotransmitter pathways, but the mechanisms remain elusive. We explored the potential mechanisms that link microglia activation with GCI-induced depression and cognitive dysfunction by studying effects of minocycline on white matter damage, cytokine levels, and the monoaminergic neurotransmitters. An acute GCI animal model was generated through bilateral common carotid artery occlusion to induce ischemic inflammation and subcortical white matter damage. Minocycline, an inhibitor of microglia activation, was intraperitoneally administrated immediately after surgery and continued daily for additional six days. Minocycline shortened the immobile duration in tail suspension test and forced swimming test, while no improvement was found in Morris water maze test. The plasma levels of IL-1β, IL-6, TNF-α, HMGB1, and netrin-1 were significantly reduced with the treatment of minocycline. Minocycline treatment substantially reversed demyelination in corpus callosum and hippocampus, alleviated hippocampal microglia activation, and promoted OPCs maturation, while no effect was found on hippocampal neurodegeneration. Besides, the content of dopamine (DA) in the hippocampus was upregulated by minocycline treatment after GCI. Collectively, our data demonstrated that minocycline exerts an anti-depressant effect by inhibiting microglia activation, promoting OPCs maturation and remyelination. Increased DA in hippocampus may also play a role in ameliorating depressive behavior with minocycline treatment.
Highlights
Cerebral ischemia is a leading cause of neurological disability and mortality in the elderly (Feigin et al, 2014; Mori et al, 2017)
Administration of MIN decreased the immobile time in Global cerebral ischemia (GCI)+MIN mice in both tests (TST: p = 0.014, Forced swimming test (FST): p = 0.023), demonstrating that MIN ameliorated the depression-like behaviors in mice caused by GCI
On the 4th day, a significant model-by-treatment interaction (F = 3.743, P = 0.037) was seen with the GCI+normal saline (NS) group showing noticeable longer latency compared to the sham+NS group (Figure 3B, p = 0.011), indicating reduced learning and memory ability occurred in GCI
Summary
Cerebral ischemia is a leading cause of neurological disability and mortality in the elderly (Feigin et al, 2014; Mori et al, 2017). M1 microglia are considered to be pro-inflammatory and the primary source of IL-1β, IL-6, and TNF-α (Gregersen et al, 2000; Ceulemans et al, 2010), which contribute to demyelination and neurodegeneration caused by stroke (Becker et al, 2011). Increased levels of these cytokines could induce depressionlike behavior by affecting neurotransmitter pathways (Miller, 2009; O’Connor et al, 2009). M2 microglia are considered to be anti-inflammatory and ameliorate inflammation-induced demyelination and neurodegeneration (Yu et al, 2015)
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