Effectiveness of minocycline in acute white matter injury after intracerebral hemorrhage

Abstract

OBJECTIVE Intracerebral hemorrhage (ICH) is a fatal disease with high morbidity and mortality, which may be followed by white matter injury (WMI) due to the local oxidizing reaction induced by iron (Fe). In this study, the authors examined the effect of the tetracycline antibiotic minocycline on Fe-induced WMI and c-Jun N-terminal kinase (JNK) activation in rats. METHODS Thirty-six male Sprague-Dawley rats underwent an intracaudate injection of saline, Fe, or Fe + minocycline. Another 36 rats had an intracaudate injection of autologous blood and were treated with minocycline or vehicle (saline). Biomarkers of both WMI and JNK activation were examined. RESULTS In the Fe-injection group, minocycline suppressed WMI labeled by β-amyloid precursor protein (β-APP) and degraded myelin basic protein (dMBP)/MBP ratio. Protein levels of phosphorylated-JNK were increased after Fe injection, and could be suppressed by minocycline treatment. In the autologous blood-injection group, β-APP and dMBP/MBP levels increased in the ipsilateral site compared with the contralateral site, which could be suppressed by 7 days of minocycline intervention. CONCLUSIONS Iron plays a critical role in WMI after ICH, which can be suppressed by minocycline through reducing the damage induced by Fe.

White Matter Injury after Intracerebral Hemorrhage: Pathophysiology and Therapeutic Strategies

“…The authors found obvious demyelination and axonal damage at the edge of the hematoma within 3 days, and the axonal injury progressively extended to the surrounding parenchyma over time, but no dMBP or APP accumulation was detected outside of the hematoma at a later time point of 28 days. These results are consistent with studies by Moxon-Emre and Schlichter ( 2011 ) and Zou et al ( 2017 ) who discovered that APP nearly disappeared after 7 days using a blood infusion rat model. However, the demyelination detected using Luxol fast blue staining can persist for up to 2 months, suggesting that the WMI is long-lasting following ICH (Liu et al, 2010 ; Ni et al, 2015 ).…”

White Matter Injury and Recovery after Hypertensive Intracerebral Hemorrhage

“…Morphologic changes of myelin sheaths included swelling and damage at first, followed by demyelination and lastly oligodendrocyte apoptosis after ICH [30]. Accompanying this, a large number of pathological molecules were highly expressed or overactivated, such as TNF- α [31], RIPK1 [32], receptor for advanced glycation end-products (RAGE), HMGB1 [33], CD47 [34], SC1 [35], β -APP [36], and JNK signaling pathway [37]. These pathological molecules had aggravated the damage of myelin sheaths and then affected the morphology and function of the white matter.…”

“…Some drugs had been shown to reduce the damage of white matter in animal models of ICH, just as FPS-ZM1 (RAGE-specific antagonist) could relieve the damage of white matter via antagonism of ligand/receptor interaction [33]; SC51089 (EP1R antagonist) could decrease Src kinase phosphorylation and MMP-9 activity and then relieve the damage of the white matter [58]. Zinc protoporphyrin (ZnPP), as a heme oxygenase inhibitor, could also reduce white matter injury [29]; and minocycline was able to suppress Fe-induced white matter injury and c-JNK activation after hypertensive ICH in rats [36]. As a crucial component of the white matter, axon damage after ICH is relatively common.…”

“…And another animal experiment also found that cattle encephalon glycoside and ignotin (CEGI) treatment could effectively upregulate MBP/MAP-2 expression, ameliorate white matter fibers damage, and alleviate the neurobehavioral dysfunction after ICH [63]. Minocycline and deferoxamine were also demonstrated to be protective towards white matter injury after ICH, possible via iron clearance [32, 36, 37, 64]. And ZnPP reduced white matter injury via reducing heme degradation products after ICH [29].…”

“…Laboratory animals used for white matter injury studies after ICH include canines [69], pigs [11], cats [70], rabbits [71], rats [36], and mice [58]. Both rats and pigs were widely used in white matter injury research.…”