Minocycline plus N-acteylcysteine induces remyelination, synergistically protects oligodendrocytes and modifies neuroinflammation in a rat model of mild traumatic brain injury

Abstract

Mild traumatic brain injury afflicts over 2 million people annually and little can be done for the underlying injury. The Food and Drug Administration-approved drugs Minocycline plus N-acetylcysteine (MINO plus NAC) synergistically improved cognition and memory in a rat mild controlled cortical impact (mCCI) model of traumatic brain injury. The underlying cellular and molecular mechanisms of the drug combination are unknown. This study addressed the effect of the drug combination on white matter damage and neuroinflammation after mCCI. Brain tissue from mCCI rats given either sham-injury, saline, MINO alone, NAC alone, or MINO plus NAC was investigated via histology and qPCR at four time points (2, 4, 7, and 14 days post-injury) for markers of white matter damage and neuroinflammation. MINO plus NAC synergistically protected resident oligodendrocytes and decreased the number of oligodendrocyte precursor cells. Activation of microglia/macrophages (MP/MG) was synergistically increased in white matter two days post-injury after MINO plus NAC treatment. Patterns of M1 and M2 MP/MG were also altered after treatment. The modulation of neuroinflammation is a potential mechanism to promote remyelination and improve cognition and memory. These data also provide new and important insights into how drug treatments can induce repair after traumatic brain injury.

Heterogeneity of microglia and their differential roles in white matter pathology

“…Treatment of dimethyl fumarate, a drug known to suppress microglial inflammation, to mice with severe brain hypoperfusion resulted in modest decrease in the number of inflammatory microglia and macrophages and improved functional impairment in the white matter . Moreover, in rat TBI model, rats co‐treated with minocycline and N‐acetylcysteine showed altered ratio of pro‐inflammatory vs immuno‐regulatory population of microglia along with increased remyelination and improved cognition and memory . Overall, these studies support the idea that directly targeting and converting microglial subtypes could be a novel and efficient therapy for various white matter diseases.…”

“…101 Moreover, in rat TBI model, rats co-treated with minocycline and N-acetylcysteine showed altered ratio of pro-inflammatory vs immuno-regulatory population of microglia along with increased remyelination and improved cognition and memory. 14 Overall, these studies support the idea that directly targeting and converting microglial subtypes could be a novel and efficient therapy for various white matter diseases.…”

“…Filling in nearly half of the human brain, 1 growing evidence shows that appropriate myelination in the white matter is required for the development of cognition, memory, motor function, and complex skills. [2][3][4][5][6] Thus damage or abnormalities in white matter can result in various neuronal diseases, such as multiple sclerosis (MS), [7][8][9] Alzheimer's disease (AD), [10][11][12] traumatic brain injury (TBI) [13][14][15] and vascular cognitive impairment and dementia (VCID) including subcortical ischemic vascular dementia (SIVD). 12,16,17 Moreover, structural changes in white matter or abnormalities in myelin genes are reported to be the risk factors of psychiatric disorders such as depression, [18][19][20] schizophrenia, [21][22][23] and obsessive-compulsive disorder.…”

Effect of pretreatment with intracerebroventricular injection of minocycline on morphine‐induced memory impairment in passive avoidance test: Role of P‐CREB and c‐Fos expression in the dorsal hippocampus and basolateral amygdala regions

“…Beneficial effects of the drug have been shown in animal models of neuropathic pain, drug addiction, major depression, schizophrenia, cerebral ischaemia and also prevention of neurodegenerative disorders . In addition, a great deal of literature has shown that minocycline improves memory and cognition in animal models of sleep deprivation, transient ishchaemic reperfusion injury, alzheimer, brain injury, drug‐induced memory impairment, aging and also in human beings . Minocycline has been shown to be beneficial in decline of morphine tolerance and also morphine‐induced microglial activation by a suppression of microglial morphine‐induced p38 MAP kinase activation .…”

“…in the presence or absence of ICV injection of minocycline (50 μg/rat) on locomotor activity (total distance traveled) (A), mobility counts (B) and velocity (C). Statistical analysis revealed that morphine could not change locomotor activity, mobility counts and velocity significantly compared to saline control group [One-way ANOVA: F(5,35) = 0.41, 0.47 and 0.1, respectively; P > 0.05]. Moreover, two-way ANOVA showed that ICV injection of minocycline (50 μg/rat) prior to morphine did not change the effect of morphine on locomotor activity, mobility counts and velocity [Two-way ANOVA: F (5,72) = 0.17, 0.98 and 0.27, respectively; P > 0.05].…”