The neuroprotective effect of diazoxide is mediated by mitochondrial ATP-dependent potassium channels in a rat model of acute subdural hematoma

Nakagawa, Ichiro; Wajima, Daisuke; Tamura, Kentaro; Nishimura, Fusanori; Park, Young-Su; Nakase, Hiroyuki

doi:10.1016/j.jocn.2012.03.027

Cited by 15 publications

(11 citation statements)

References 25 publications

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“…Interestingly, these results showed that only low concentrations of diazoxide were neuroprotective [51]. Several studies confirmed that the protection towards neurons conferred by diazoxide is mainly mediated by mito-K ATP [52]–[54], but, unfortunately, the exact mechanism and structure of mito-K ATP itself is still controversial [55], [56]. In this way, our results suggest that diazoxide has a direct effect on neurons and, as this is produced at low doses, this effect could be through activation of mito-K ATP channels.…”

Section: Discussionmentioning

confidence: 92%

KATP Channel Opener Diazoxide Prevents Neurodegeneration: A New Mechanism of Action via Antioxidative Pathway Activation

Virgili¹,

Mancera²,

Wappenhans³

et al. 2013

PLoS ONE

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Pharmacological modulation of ATP-sensitive potassium channels has become a promising new therapeutic approach for the treatment of neurodegenerative diseases due to their role in mitochondrial and cellular protection. For instance, diazoxide, a well-known ATP-sensitive potassium channel activator with high affinity for mitochondrial component of the channel has been proved to be effective in animal models for different diseases such as Alzheimer’s disease, stroke or multiple sclerosis. Here, we analyzed the ability of diazoxide for protecting neurons front different neurotoxic insults in vitro and ex vivo. Results showed that diazoxide effectively protects NSC-34 motoneurons from glutamatergic, oxidative and inflammatory damage. Moreover, diazoxide decreased neuronal death in organotypic hippocampal slice cultures after exicitotoxicity and preserved myelin sheath in organotypic cerebellar cultures exposed to pro-inflammatory demyelinating damage. In addition, we demonstrated that one of the mechanisms of actions implied in the neuroprotective role of diazoxide is mediated by the activation of Nrf2 expression and nuclear translocation. Nrf2 expression was increased in NSC-34 neurons in vitro as well as in the spinal cord of experimental autoimmune encephalomyelitis animals orally administered with diazoxide. Thus, diazoxide is a neuroprotective agent against oxidative stress-induced damage and cellular dysfunction that can be beneficial for diseases such as multiple sclerosis.

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Section: Discussionmentioning

confidence: 92%

KATP Channel Opener Diazoxide Prevents Neurodegeneration: A New Mechanism of Action via Antioxidative Pathway Activation

Virgili¹,

Mancera²,

Wappenhans³

et al. 2013

PLoS ONE

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“…Administration of 20 or 40 mg/kg diazoxide, i.p., for 3 days prior to global cerebral ischemia conferred partial protection against brain edema in rats (Lenzser et al , 2005). In addition, rapid preconditioning (15–30 minutes prior to injury) was achieved with diazoxide in a model of subdural hematoma (Nakagawa et al , 2013), a model of photochemical thrombotic venous ischemia (Nakagawa et al , 2005) and global cerebral ischemia in gerbils (Wang et al , 2011b). An inhibitor of the mtK+ATP channel abolished the preconditioning effect in both of these models.…”

Section: 0 Preconditioning Stimulimentioning

confidence: 99%

Preconditioning provides neuroprotection in models of CNS disease: Paradigms and clinical significance

Stetler

Leak

Gan

et al. 2014

Progress in Neurobiology

171

140

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Preconditioning is a phenomenon in which brief episodes of a sublethal insult induce robust protection against subsequent lethal injuries. Preconditioning has been observed in multiple organisms and can occur in the brain as well as other tissues. Extensive animal studies suggest that the brain can be preconditioned to resist acute injuries, such as ischemic stroke, neonatal hypoxia/ischemia, trauma, and agents that are used in models of neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease. Effective preconditioning stimuli are numerous and diverse, ranging from transient ischemia, hypoxia, hyperbaric oxygen, hypothermia and hyperthermia, to exposure to neurotoxins and pharmacological agents. The phenomenon of “cross-tolerance,” in which a sublethal stress protects against a different type of injury, suggests that different preconditioning stimuli may confer protection against a wide range of injuries. Research conducted over the past few decades indicates that brain preconditioning is complex, involving multiple effectors such as metabolic inhibition, activation of extra- and intracellular defense mechanisms, a shift in the neuronal excitatory/inhibitory balance, and reduction in inflammatory sequelae. An improved understanding of brain preconditioning should help us identify innovative therapeutic strategies that prevent or at least reduce neuronal damage in susceptible patients. In this review, we focus on the experimental evidence of preconditioning in the brain and systematically survey the models used to develop paradigms for neuroprotection, and then discuss the clinical potential of brain preconditioning. In a subsequent components of this two-part series, we will discuss the cellular and molecular events that are likely to underlie these phenomena.

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“… 13 – 17 These studies also suggest that diazoxide could produce neuroprotection through different mechanisms depending on the drug concentration and due to its selective activation of mito-KATP channels. 5 , 18 – 20 Multiple mechanisms could contribute to demyelination and neuroaxonal injury in MS. 21 , 22 It has been postulated that chronic microglial activation is partially responsible for the damage to the CNS during attacks, as well as between attacks, contributing to disease progression. 23 , 24 For this reason, downmodulating chronic microglia activation may prevent CNS damage during acute MS relapses, as well as in the progressive phases.…”

Section: Discussionmentioning

confidence: 99%

Effects of diazoxide in multiple sclerosis

Villoslada

Montalbán

Arroyo

et al. 2015

Neurol Neuroimmunol Neuroinflamm

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Objective:The aim of this study was to test the safety of diazoxide and to search for signs of efficacy in patients with relapsing-remitting multiple sclerosis (RRMS).Methods:In this multicenter, randomized, placebo-controlled, double-blind trial (treatment allocation was concealed), 102 patients with RRMS were randomized to receive a daily oral dose of diazoxide (0.3 and 4 mg/d) or placebo for 24 weeks (NCT01428726). The primary endpoint was the cumulative number of new T1 gadolinium-enhancing lesions per patient, recorded every 4 weeks from week 4 to week 24. Secondary endpoints included brain MRI variables such as the number of new/enlarging T2 lesions and the percentage brain volume change (PBVC); clinical variables such as the percentage of relapse-free patients, relapse rate, and change in the Expanded Disability Status Scale score; and safety and tolerability.Results:Diazoxide was well-tolerated and it produced no serious adverse events other than 1 case of Hashimoto disease. At the 2 doses tested, diazoxide did not improve the primary endpoint or the MRI and clinical variables related to the presence of new lesions or relapses. Patients treated with diazoxide showed reduced PBVC compared with the placebo group, although such changes could be confounded by the higher disease activity of the treated group and the vascular effects of diazoxide.Conclusion:At the doses tested, oral diazoxide did not decrease the appearance of new lesions evident by MRI. The effects in slowing the progression of brain atrophy require further validation.Classification of evidence:This study provides Class I evidence that for patients with RRMS, diazoxide (0.3 and 4 mg/d) does not significantly change the number of new MRI T1 gadolinium-enhancing lesions.

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The neuroprotective effect of diazoxide is mediated by mitochondrial ATP-dependent potassium channels in a rat model of acute subdural hematoma

Cited by 15 publications

References 25 publications

KATP Channel Opener Diazoxide Prevents Neurodegeneration: A New Mechanism of Action via Antioxidative Pathway Activation

KATP Channel Opener Diazoxide Prevents Neurodegeneration: A New Mechanism of Action via Antioxidative Pathway Activation

Preconditioning provides neuroprotection in models of CNS disease: Paradigms and clinical significance

Effects of diazoxide in multiple sclerosis

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