| Subcortical ischemic vascular dementia (SIVD) induced by chronic hypoperfusion due to small-artery disease is a common cause of vascular dementia (VaD), which is recognized as the second most prevalent type of dementia. SIVD, including Binswanger’s disease, is often observed in patients with hypertension or atherosclerosis, as well as in the aging population. Its characteristic damage involves progressive demyelination, white matter rarefaction and cognitive impairment. However, pathogenetic mechanisms are far from understood, with currently no effective agents to prevent or reverse its progression. In the clinic, acetylcholinesterase inhibitors and vasodilators are used to treat SIVD with limited benefits. Therefore, it’s necessary to develop new agents for treatment or prevention of SIVD.Minocycline is a semisynthetic second-generation tetracycline and has been used to treat a variety of infectious diseases with relatively few adverse effects. Its original antimicrobial action is based on the characteristics that tetracyclines inhibit protein synthesis by acting at the ribosome. However, its clinical application is limited, because of its bacterial resistance and the development of more effective antibiotics. Recently, the new functions of minocycline were observed, including anti-inflammatory, glutamate antagonistic, and antiapoptotic actions. It also showed an easy penetration of the blood-brain barrier due to its high lipophilicity, suggesting an ideal candidate for central nervous system diseases. Overall, the pharmacological effects of minocycline on several neurological diseases, such as multiple sclerosis, Alzheimer’s disease and brain injury, have been studied.Recently, minocycline has been shown to protect against acute cerebral ischemic injury in a middle cerebral artery occlusion (MCAO) model with improved neurologic score, motor coordination, and decreased neuronal apoptosis. Minocycline also improves neurobehavioral performance, attenuates the loss of oligodendrocytes and hypomyelination in white matter of neonatal rat after hypoxia possibly by suppressing microglia activation and nitrosative stress. Similarly, acute white matter damage was reduced in N-methyl-D-aspartate striatum injected rats that were treated with minocycline. Based on all of above, we proposed that minocycline may be effective to prevent SIVD.However, Tsuji et al. reported that in neonatal mice minocycline displays detrimental effect in white matter after hypoxic-ischemic insult. In a demyelination model induced by injection of ethidium bromide, minocycline inhibits the remyelination by suppressing oligodendrocyte progenitor cells (OPCs) producing at the lesion area after demyelination. Therefore, the effects of minocycline on SIVD as well as its actions on OPCs and mature oligodendrocytes need to be explored. Also, due to the progressive damage of cerebral white matter in SIVD, different therapeutic approaches were investigated according to the stage of damage progression in a SIVD mouse model induced by permanent occlusion of the right unilateral common carotid arteries (rUCCAO).The new therapeutic approaches of minocycline in SIVD as well as its effect on oligodendrocytes were investigated following right unilateral common carotid arteries occlusion (rUCCAO). Minocycline (25mg/kg) treated at day0-32, day0-3(early stage), day15-32(late stage), or day0-3&15-32after rUCCAO recovered the depletion of myelin basic protein (MBP) expression and alleviated cognitive impairment in object recognition and Morris water maze tests induced by rUCCAO. In contrast, minocycline at day4-7or day4-14(middle stage) aggravated both the reduction of MBP expression and the cognitive impairment. Minocycline alleviated the loss of mature oligodendrocytes, both in the early and late stages of SIVD but not in the middle stage. For the oligodendrocyte progenitor cells (OPCs), minocycline markedly increased the number of OPCs during the early and late stages of SIVD, but decreased the number of OPCs at the middle stage. The actions of minocycline at the middle and late stages, but not the early stage, were similar as that of a microglia activation inhibitor. Minocycline promoted the proliferation of OPCs at subventricular area and rescued the decrease of Cdk2and cyclin A expression at the early stage after rUCCAO. In cultured OPCs, minocycline promoted OPCs proliferation and increased the percentage of OPCs in S and G2/M phases. Taken together, these results suggest that minocycline has protective effect on SIVD. Based on its complicated actions on OPCs and mature oligodendrocytes, a stage dependent therapeutic strategy is proposed to treat SIVD.In conclusion, we demonstrated that minocycline showed the protective effect on white matter lesions and cognitive impairment in SIVD. Based on its complicated actions on OPCs and oligodendrocytes, a stage dependent therapeutic strategy was proposed to treat SIVD, which provides a rational future clinical guide. |
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