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

Ma, Jing; Zhang, Jing; Hou, Wanwan; Xiao, Wei; Liao, Rujia; Chen, Ying; Wang, Zhe; Zhang, Xiang Nan; Zhang, Li san; Zhou, Yu; Chen, Zhong; Hu, Wei

doi:10.1038/srep12079

Cited by 38 publications

(39 citation statements)

References 49 publications

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“…Treatment with minocycline, reduced microgliosis and nodal/paranodal disruption albeit no functional alterations were investigated (Howell et al, ). Minocycline has also been effectively used in models of hypoxia‐ischemia insult (Cho, La, Cho, Sung, & Kim, ; Jalal et al, ; Ma et al, ; Yang et al, ), hyperoxia (Schmitz et al, ), demyelination (Skripuletz et al, ) and intracerebral haemorrhage (Power et al, ; Yan et al, ). In these studies, minocycline significantly reduced microgliosis and promoted neuroprotection as evidenced by the attenuation of white matter damage (Cho et al, ; Jalal et al, ; Ma et al, ; Schmitz et al, ; Skripuletz et al, ; Yang et al, ) but a direct functional on white matter was not investigated.…”

Section: Discussionmentioning

confidence: 99%

Minocycline reduces microgliosis and improves subcortical white matter function in a model of cerebral vascular disease

Manso

Holland

Kitamura

et al. 2017

Glia

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Chronic cerebral hypoperfusion is a key mechanism associated with white matter disruption in cerebral vascular disease and dementia. In a mouse model relevant to studying cerebral vascular disease, we have previously shown that cerebral hypoperfusion disrupts axon-glial integrity and the distribution of key paranodal and internodal proteins in subcortical myelinated axons. This disruption of myelinated axons is accompanied by increased microglia and cognitive decline. The aim of the present study was to investigate whether hypoperfusion impairs the functional integrity of white matter, its relation with axon-glial integrity and microglial number, and whether by targeting microglia these effects can be improved. We show that in response to increasing durations of hypoperfusion, the conduction velocity of myelinated fibres in the corpus callosum is progressively reduced and that paranodal and internodal axon-glial integrity is disrupted. The number of microglial cells increases in response to hypoperfusion and correlates with disrupted paranodal and internodal integrity and reduced conduction velocities. Further minocycline, a proposed antiinflammatory and microglia inhibitor, restores white matter function related to a reduction in the number of microglia. The study suggests that microglial activation contributes to the structural and functional alterations of myelinated axons induced by cerebral hypoperfusion and that dampening microglia numbers/proliferation should be further investigated as potential therapeutic benefit in cerebral vascular disease. K E Y W O R D Sblood flow, conduction velocity, microglia, minocycline, white matter integrity

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Section: Discussionmentioning

confidence: 99%

Minocycline reduces microgliosis and improves subcortical white matter function in a model of cerebral vascular disease

Manso

Holland

Kitamura

et al. 2017

Glia

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“…Therefore, targeting astrocytes with agents that return them to a quiescent phenotype (Choudhury and Ding 2016) could be protective for the WM. Similarly, identifying molecular targets (Wang et al 2013) of microglial activation and microglial suppressant agents similar to minocycline (Cai et al 2006;Ma et al 2015), ethyl pyruvate (Shen et al 2010), edaravone (Miyamoto et al 2013a and autophagy inhibitors, such as 3-methyladenine, could attenuate microglial activation (Yang et al 2014) and protect against the WM from further damage. The overproduction of reactive oxygen species, pro-inflammatory cytokines and matrix metalloproteinases (e.g.…”

Section: Contribution Of Laboratory Animal Studiesmentioning

confidence: 99%

White matter degeneration in vascular and other ageing‐related dementias

Hase

Horsburgh

Ihara

et al. 2018

Journal of Neurochemistry

168

152

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Advances in neuroimaging have enabled greater understanding of the progression of cerebral degenerative processes associated with ageing-related dementias. Leukoaraiosis or rarefied white matter (WM) originally described on computed tomography is one of the most prominent changes which occurs in older age. White matter hyperintensities (WMH) evident on magnetic resonance imaging have become commonplace to describe WM changes in relation to cognitive dysfunction, types of stroke injury, cerebral small vessel disease and neurodegenerative disorders including Alzheimer's disease. Substrates of WM degeneration collectively include myelin loss, axonal abnormalities, arteriolosclerosis and parenchymal changes resulting from lacunar infarcts, microinfarcts, microbleeds and perivascular spacing. WM cells incorporating astrocytes, oligodendrocytes, pericytes and microglia are recognized as key cellular components of the gliovascular unit. They respond to ongoing pathological processes in different ways leading to disruption of the gliovascular unit. The most robust alterations involve oligodendrocyte loss and astrocytic clasmatodendrosis with displacement of the water channel protein, aquaporin 4. These modifications likely precede arteriolosclerosis and capillary degeneration and involve tissue oedema, breach of the blood-brain barrier and induction of a chronic hypoxic state in the deep WM. Several pathophysiological mechanisms are proposed to explain how WM changes commencing with haemodynamic changes within the vascular system impact on cognitive dysfunction. Animal models simulating cerebral hypoperfusion in man have paved the way for several translational opportunities. Various compounds with variable efficacies have been tested to reduce oxidative stress, inflammation and blood-brain barrier damage in the WM. Our review demonstrates that WM degeneration encompasses multiple substrates and therefore more than one pharmacological approach is necessary to preserve axonal function and prevent cognitive impairment. Keywords: astrocytes, blood-brain barrier, post-stroke dementia, stroke, vascular dementia, white matter. Ageing-related cognitive impairment involves multiple substrates affecting brain structure and function. Neuroimaging evidence shows that white matter (WM) changes are associated with various clinical, sensorimotor, lifestyle, behavioural and cognitive abnormalities, particularly related to the small vessel disease (SVD) syndrome (Pantoni 2010).

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“…In addition, activated microglia and astrocytes are present in WM lesions, which might exacerbate oxidative stress (Simpson et al, 2007). Therapeutic scavenging of ROS and anti-inflammatory approaches have been used to suppress inflammation and attenuate WM injuries in rodent models (Ma et al, 2015; Ueno et al, 2009; Wakita et al, 2008). …”

Section: Vascular Pathophysiology Underlying Vcid—how Does Vasculamentioning

confidence: 99%

“…Two-vessel occlusion (2VO), also known as bilateral common carotid artery occlusion (BCCAO): 2 VO is induced by permanently occluding both CCAs, and is the most frequently used model of VCID (Liu and Zhang, 2012; Ma et al, 2015; Ni et al, 1995; Shibata et al, 2004; Soria et al, 2013; Wakita et al, 2002; Zhao et al, 2014). Mice cannot tolerate sudden occlusion of both CCAs.…”

Section: Animal Models Of Vcidmentioning

confidence: 99%

The impact of cerebrovascular aging on vascular cognitive impairment and dementia

Yang

Sun

et al. 2017

Ageing Research Reviews

158

128

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As human life expectancy rises, the aged population will increase. Aging is accompanied by changes in tissue structure, often resulting in functional decline. For example, aging within blood vessels contributes to a decrease in blood flow to important organs, potentially leading to organ atrophy and loss of function. In the central nervous system, cerebral vascular aging can lead to loss of the integrity of the blood-brain barrier, eventually resulting in cognitive and sensorimotor decline. One of the major of types of cognitive dysfunction due to chronic cerebral hypoperfusion is vascular cognitive impairment and dementia (VCID). In spite of recent progress in clinical and experimental VCID research, our understanding of vascular contributions to the pathogenesis of VCID is still very limited. In this review, we summarize recent findings on VCID, with a focus on vascular age-related pathologies and their contribution to the development of this condition.

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

Cited by 38 publications

References 49 publications

Minocycline reduces microgliosis and improves subcortical white matter function in a model of cerebral vascular disease

Minocycline reduces microgliosis and improves subcortical white matter function in a model of cerebral vascular disease

White matter degeneration in vascular and other ageing‐related dementias

The impact of cerebrovascular aging on vascular cognitive impairment and dementia

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