Dexmedetomidine Protects Against Neurological Dysfunction in a Mouse Intracerebral Hemorrhage Model by Inhibiting Mitochondrial Dysfunction-Derived Oxidative Stress

https://doi.org/10.1016/j.jstrokecerebrovasdis.2019.01.016Get rights and content

Abstract

Background

Intracerebral hemorrhage (ICH) is a subtype of stroke with high disability and mortality. Dexmedetomidine (Dex) has been shown to provide neuroprotection in several neurological diseases. The aim of present study was to investigate the effects of Dex on ICH-induced neurological deficits and brain injury and the underlying mechanisms.

Methods

ICH mouse model was established by intracerebral injection of autologous blood, followed by Dex or vehicle treatment. Neurological function, brain water content, neuronal activity, and oxidative parameters were determined. The protein expressions of peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), uncoupling protein 2, and manganese-dependent superoxide dismutase were examined by western blotting.

Results

Dex administration significantly inhibited ICH-induced the memory impairment, dyskinesia, brain edema, and neuron loss. In addition, ICH-induced the increase in brain oxidative stress level was markedly attenuated after Dex treatment, as evidenced by increased glutathione peroxidase and superoxide dismutase levels and reduced malondialdehyde and nitric oxide levels. Compared with vehicle-treated ICH mice, Dex-treated ICH mice showed significantly decreased intracellular reactive oxygen species (ROS) and mitochondrial ROS (mROS) production in brain, but had no effects on the increased nicotinamide-adenine dinucleotide phosphate oxidase activity. However, stimulation of mROS abrogated the inhibitory effects of Dex on neurological deficits and oxidative stress. The decrease in production of adenosine triphosphate and the expressions of PGC-1α, uncoupling protein 2, and manganese-dependent superoxide dismutase induced by ICH was restored by Dex treatment.

Conclusions

Our results reveal that Dex improves ICH-induced neurological deficits and brain injury by inhibiting PGC-1α pathway inactivation and mitochondrial dysfunction-derived oxidative stress.

Introduction

Intracerebral hemorrhage (ICH) is a severe subtype of stroke, which takes up for 8%-15% of all strokes in Western countries and 20%-30% in the Asian area.1 It causes much higher mortality and disability rate than ischemia stroke.2 Despite the remarkable progress in the understanding of ICH pathogenesis, effective treatment options are still lacking.

Increasing evidences indicate that oxidative stress that being triggered in the early period after ICH challenge is a critical factor exacerbating ICH-induced the secondary brain injury.3, 4 Oxidative stress induces damages of macromolecules, disruption of cellular signaling, and loss of neuronal activity that known to lead to neurological dysfunction.5, 6 Mitochondrial dysfunction is implicated in oxidative stress linked to the pathogenesis of neurological diseases.3 The dysfunction of mitochondria impairs adenosine triphosphate (ATP) synthesis and induces excessive reactive oxygen species (ROS) production, which in turn aggravates brain injury.5, 7

Dexmedetomidine (Dex) is a highly selective agonist of α2-adrenergic receptors with anxiolytic, analgesic, and sedative effects.8 The neuroprotective effects of dexmedetomidine have been reported in clinical practice and basic studies. A previous study showed that Dex is a safe and effective sedation for hypertensive cerebral hemorrhage patients who received craniotomy, because it can reduce blood pressure, alleviate the cardiovascular responses, and prevent respiratory depression.9 In addition, a pilot study also revealed that Dex appears effective in sedating severely brain-injured patients without adverse physiological effects.10 In a mouse model of ICH, Dex attenuates memory impairment by reducing neuronal cell apoptosis.11 Moreover, Wang et al reported that post-treatment with Dex ameliorates subarachnoid hemorrhage-induced brain injury via activation of extracellular signal-regulated kinase.12 However, the mechanisms by which Dex prevents ICH-induced brain injury and neurological dysfunction remain to be further explored. In this study, we uncover a novel mechanism of the neuroprotective effects of Dex and provide solid theoretical evidence for the clinical use of Dex for ICH treatment.

Section snippets

Materials and Reagents

2′,7′-Dichlorofluorescin diacetate, MitoSOX Red, nicotinamide-adenine dinucleotide phosphate (NADPH) Assay Kit and Fluoro-Jade B (FJB) were purchased from Sigma Chemical Co. (MO). Male C57/BL6 mice (8-10 weeks) were purchased from the Chinese Academy of Sciences (Shanghai, China). All animal experiments were performed in accordance with China Animal Welfare Legislation and approved by the Institutional Animal Care and Use Committee of Nanjing Medical University.

ICH Model Construction

ICH model was established as

Dex Ameliorates ICH-Induced the Neurological Deficits

To investigate the effects of Dex on neurobehavioral outcomes in ICH mice, several kinds of behavior tests were performed. Morriz water maze test showed that Dex administration had no effect on the ability of mice to find the platform under sham conditions. After ICH surgery, mice took significantly longer time to reach the platform in vehicle-treated group, but not in Dex-treated group (Fig 1, A). The rota-rod test revealed that ICH significantly impaired the performance, which was attenuated

Discussion

The protective role of Dex has been well characterized in preclinical studies in a wide range of organ system.10, 11, 12,15 In this study, we utilized autologous blood injection model to investigate the effects of Dex on ICH in mouse. Our results showed that Dex improves the neurological outcome after ICH, and also ameliorates brain injury. This is the first report to demonstrate that the Dex-induced neuroprotection may be associated with inhibition of mitochondrial dysfunction-mediated

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    Competing interests: The authors have declared that no competing interests exist.

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