Minocycline reduces intracerebral hemorrhage-induced white matter injury in piglets.

Heng Yang,Jia‐Bin Su,Tong‐Zhou E,Yan‐Jiang Li,Wei Ni,Xin‐Jie Gao,Yu‐Xiang Gu,Xin Zhang

doi:10.1111/cns.13220

Abstract

AimsWhite matter (WM) injury after intracerebral hemorrhage (ICH) results in poor or even fatal outcomes. As an anti‐inflammatory drug, minocycline has been considered a promising choice to treat brain injury after ICH. However, whether minocycline can reduce WM injury after ICH is still controversial. In the present study, we investigate the effect and underlying mechanism of minocycline on WM injury after ICH.MethodsAn ICH model was induced by an injection of autologous blood into the right frontal lobe of piglets. First, transcriptional analysis was performed at day 1 or 3 to investigate the dynamic changes in neuroinflammatory gene expression in WM after ICH. Second, ICH piglets were treated either with minocycline or with vehicle alone. All piglets then underwent magnetic resonance imaging to measure brain swelling. Brain tissue was used for real‐time polymerase chain reaction (RT‐PCR), immunohistochemistry, Western blot, and electron microscopy.ResultsTranscriptional analysis demonstrated that transforming growth factor‐β (TGF‐β)/mitogen‐activated protein kinase (MAPK) signaling is associated with microglia/macrophage‐mediated inflammation activation after ICH and is then involved in WM injury after ICH in piglets. Minocycline treatment results in less ICH‐induced brain swelling, fewer neurological deficits, and less WM injury in comparison with the vehicle alone. In addition, minocycline reduces microglial activation and alleviates demyelination in white matter after ICH. Finally, we found that minocycline attenuates WM injury by increasing the expression of TGF‐β and suppressing MAPK activation after ICH.ConclusionThese results indicate that TGF‐β–mediated MAPK signaling contributes to WM injury after ICH, which can be altered by minocycline treatment.

Highlights

Intracerebral hemorrhage (ICH) often results in brain injury, which contributes to the high morbidity and mortality of this subtype of stroke.[1,2,3] The complex tissue pathology resulting from ICH involves both gray matter and white matter (WM)
To analyze the pathway minocycline affects during ICH‐induced WM injury, we examined the activation of extracellular signal‐regulated kinase1/2 (ERK1/2), P38, and JNK in WM after ICH
We show that: (a) WM injury occurred after ICH and was associated with inflammation regulated by the transforming growth factor‐β (TGF‐β)/mitogen‐activated protein kinase (MAPK) signaling pathway; (b) systemic treatment with minocycline alleviated ICH‐induced brain swelling and neurological deficits; (c) minocycline treatment caused less microglial activation, but more TGF‐β upregulation in alternatively activated microglia/ macrophages in WM after ICH; and (d) minocycline treatment

Summary

| BACKGROUND

Intracerebral hemorrhage (ICH) often results in brain injury, which contributes to the high morbidity and mortality of this subtype of stroke.[1,2,3] The complex tissue pathology resulting from ICH involves both gray matter and white matter (WM). Transforming growth factor‐β (TGF‐β) is a ubiquitous anti‐inflammatory cytokine that is active in a variety of cell types It is minimally expressed with latent isoforms in normal brain, but its expression increases strongly after several types of brain insult, including ischemia, trauma, and hemorrhage. Minocycline shows anti‐inflammatory and neuroprotective effects in a rodent model of ICH and cerebral ischemia.[12,13] Our previous studies have demonstrated that minocycline is able to inhibit the inflammatory response to brain injury and reduce neuronal apoptosis, brain edema, and BBB disruption by iron chelation.[14,15] ongoing clinical trials suggest that minocycline may be a neurovascular protective agent in humans, the underlying mechanisms remain to be elucidated.[16,17] Previous studies have indicated that minocycline significantly reduces neuroinflammatory WM injury induced by hypoxia and alleviates WM‐ related cognitive impairment after chronic hypoperfusion through its robust effects on oligodendrocyte progenitor cells.[18,19] We hypothesize that minocycline can reduce neuroinflammation and alleviate WM injury and improve behavioral impairment after ICH. We chose the piglet as it is a large mammal exhibiting close similarity to humans with a higher WM concentration in piglets' brains compared to other potential model species.[21,22]

| METHODS

| DISCUSSION

Findings

FUNDING INFORMATION