Early treatment of minocycline alleviates white matter and cognitive impairments after chronic cerebral hypoperfusion.

Jing Ma,Li San Zhang,Zhong Chen,Zhe Wang,Ru Jia Liao,Jing Zhang,Wei Wei Hou,Xiao Hua Wu,Wei Wei Hu,Ying Chen,Xiang Nan Zhang,Yu Dong Zhou

doi:10.1038/srep12079

Abstract

Subcortical ischemic vascular dementia (SIVD) caused by chronic cerebral hypoperfusion develops with progressive white matter and cognitive impairments, yet no effective therapy is available. We investigated the temporal effects of minocycline on an experimental SIVD exerted by right unilateral common carotid arteries occlusion (rUCCAO). Minocycline treated at the early stage (day 0–3), but not the late stage after rUCCAO (day 4–32) alleviated the white matter and cognitive impairments, and promoted remyelination. The actions of minocycline may not involve the inhibition of microglia activation, based on the effects after the application of a microglial activation inhibitor, macrophage migration inhibitory factor, and co-treatment with lipopolysaccharides. Furthermore, minocycline treatment at the early stage promoted the proliferation of oligodendrocyte progenitor cells (OPCs) in subventricular zone, increased OPC number and alleviated apoptosis of mature oligodendrocytes in white matter. In vitro, minocycline promoted OPC proliferation and increased the percentage of OPCs in S and G2/M phases. We provided direct evidence that early treatment is critical for minocycline to alleviate white matter and cognitive impairments after chronic cerebral hypoperfusion, which may be due to its robust effects on OPC proliferation and mature oligodendrocyte loss. So, early therapeutic time window may be crucial for its application in SIVD.

Highlights

Minocycline is a semisynthetic second-generation tetracycline and has been used to treat a variety of infectious diseases with relatively few adverse effects[6]
We demonstrated the protective effects of minocycline under the chronic cerebral hypoperfusion induced by right unilateral common carotid arteries occlusion (rUCCAO), which well mimics the white matter and cognitive impairments of SIVD23,24
We found that early treatment of minocycline remarkably ameliorated the cognitive impairment, white matter rarefaction, axonal damage and demyelination, but improved remyelination in the corpus callosum after rUCCAO

Summary

Introduction

Minocycline is a semisynthetic second-generation tetracycline and has been used to treat a variety of infectious diseases with relatively few adverse effects[6]. Minocycline has been shown to improves neurobehavioral performance, attenuates the hypoxia-induced loss of oligodendrocytes and hypomyelination in the white matter of neonatal rats, possibly by suppressing microglial activation[16,17]. Minocycline protects against white matter damage by inhibiting microglial activation in rats, which were subjected to bilateral permanent occlusion of the common carotid arteries[18]. The action of minocycline on OPCs and mature oligodendrocytes was investigated in a mouse model of chronic cerebral hypoperfusion established by right unilateral common carotid arteries occlusion (rUCCAO). This model well simulates the behavioral and pathological impairments of SIVD23,24. The protection of minocycline may be due to the robust effects of minocycline on OPC proliferation and mature oligodendrocyte loss at the early stage, but not the inhibition of microglia activation

Methods

Results

Conclusion