Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Survivors of a traumatic brain injury can deteriorate years later, developing brain atrophy and dementia. Traumatic brain injury triggers chronic microglial activation, but it is unclear whether this is harmful or beneficial. A successful chronic-phase treatment for traumatic brain injury might be to target microglia. In experimental models, the antibiotic minocycline inhibits microglial activation. We investigated the effect of minocycline on microglial activation and neurodegeneration using PET, MRI, and measurement of the axonal protein neurofilament light in plasma. Microglial activation was assessed using 11C-PBR28 PET. The relationships of microglial activation to measures of brain injury, and the effects of minocycline on disease progression, were assessed using structural and diffusion MRI, plasma neurofilament light, and cognitive assessment. Fifteen patients at least 6 months after a moderate-to-severe traumatic brain injury received either minocycline 100 mg orally twice daily or no drug, for 12 weeks. At baseline, 11C-PBR28 binding in patients was increased compared to controls in cerebral white matter and thalamus, and plasma neurofilament light levels were elevated. MRI measures of white matter damage were highest in areas of greater 11C-PBR28 binding. Minocycline reduced 11C-PBR28 binding (mean Δwhite matter binding = −23.30%, 95% confidence interval −40.9 to −5.64%, P = 0.018), but increased plasma neurofilament light levels. Faster rates of brain atrophy were found in patients with higher baseline neurofilament light levels. In this experimental medicine study, minocycline after traumatic brain injury reduced chronic microglial activation while increasing a marker of neurodegeneration. These findings suggest that microglial activation has a reparative effect in the chronic phase of traumatic brain injury.
Date Issued
2017-12-19
Date Acceptance
2017-11-22
Citation
Brain, 2017, 141 (2), pp.459-471
ISSN
1460-2156
Publisher
Oxford University Press (OUP)
Start Page
459
End Page
471
Journal / Book Title
Brain
Volume
141
Issue
2
Copyright Statement
© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits
non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits
non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
License URL
Sponsor
GlaxoSmithKline Services Unlimited
National Institute for Health Research
Medical Research Council (MRC)
Medical Research Council (MRC)
Grant Number
COL011953
NIHR-RP-011-048
MR/N008219/1
MR/N026934/1
Subjects
microglia
minocycline
neurodegeneration
positron emission tomography
traumatic brain injury
11 Medical And Health Sciences
17 Psychology And Cognitive Sciences
Neurology & Neurosurgery
Publication Status
Published online