Dexmedetomidine Protects Against Neurological Dysfunction in a Mouse Intracerebral Hemorrhage Model by Inhibiting 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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Mechanisms of memory impairment in animal models of nontraumatic intracranial hemorrhage: A systematic review of the literature
2022, Brain HemorrhagesCitation Excerpt :After full text review of the 196 studies, 90 pre-clinical animal studies were able to be included in the final systematic review. Publication year, total animal number, species strain, and mechanism of memory decline after ICH were collected (Table 2).9–98 Plurality of studies were published in 2019 (Fig. 2).
Traditional Chinese medicine use in the pathophysiological processes of intracerebral hemorrhage and comparison with conventional therapy
2022, Pharmacological ResearchCitation Excerpt :They mainly can inhibit inflammatory cytokines including TLR4, NF-κB, TNF-α and IL-1β. They inhibit apoptosis by increasing Bcl-2/Bax ratio, and decreasing mTOR, caspase-3 expression [227,230], and inhibit OS by increasing PPARγ, Nrf2, glutathione peroxidase and superoxide dismutase levels and decreasing ROS, MDA, NO expression [231,234]. They also can increase ZO-1, claudin-5 expression to reduce the permeability of BBB [229,231,233].
Competing interests: The authors have declared that no competing interests exist.