Dantrolene prevents hepatic steatosis by reducing cytoplasmic Ca2+ level and ER stress

Tamitani, Masaki; Yamamoto, Takakazu; Yamamoto, Naoki; Fujisawa, Koichi; Tanaka, Shinji; Nakamura, Yoshihide; Uchinoumi, Hitoshi; Oda, Tatsuya; Okuda, Shinichi; Takami, Taro; Kobayashi, Shigeki; Sakaida, Isao; Yano, Masafumi

doi:10.1016/j.bbrep.2020.100787

Cited by 4 publications

(2 citation statements)

References 23 publications

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“…Recent experiments in high-fat-diet-fed mice suggest that appropriate oral dantrolene dosage may prevent liver steatosis by reducing endoplasmic reticulum stress. 24 Nevertheless, reports of severe liver injury with oral dantrolene should prompt close monitoring of liver enzymes. Responders received a lower median daily dose of dantrolene compared to nonresponders (50 mg vs 200 mg, respectively), suggesting that dose increases may not be beneficial in patients who do not respond to the initial dose adjustments.…”

Section: Discussionmentioning

confidence: 99%

Oral Dantrolene for Myopathic Symptoms in Malignant Hyperthermia–Susceptible Patients: A 25-Year Retrospective Cohort Study of Adverse Effects and Tolerability

Moreno

Kraeva

Zvaritch

et al. 2022

Anesthesia &Amp; Analgesia

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BACKGROUND: Patients susceptible to malignant hyperthermia (MH) may experience disabling manifestations of an unspecified myopathy outside the context of anesthesia, including myalgia, fatigue, or episodic rhabdomyolysis. Clinical observations suggest that oral dantrolene may relief myopathic symptoms in MH-susceptible (MHS) patients. However, high-dose oral dantrolene has been associated with severe hepatotoxicity. METHODS: In a retrospective database review (1994–2018), we investigated a cohort of patients who were diagnosed as MHS by a positive caffeine-halothane contracture test (CHCT), had myopathic manifestations, and received oral dantrolene. Our aim was to investigate the occurrence of serious adverse effects and the adherence to oral dantrolene therapy. We also explored factors associated with self-reported clinical improvement, considering as nonresponders patients with intolerable adverse effects or who reported no improvement 8 weeks after starting treatment. RESULTS: Among 476 MHS patients with positive CHCT, 193 had muscle symptoms, 164 started oral dantrolene, 27 refused treatment, and 2 were excluded due to abnormal liver function before starting therapy. There were no serious adverse effects reported. Forty-six of 164 patients (28%; 95% confidence interval [CI], 22%–35%) experienced mild to moderate adverse effects. Twenty-two patients (22/164, 13%; 95% CI, 9%–19%) discontinued treatment, among which 16 due to adverse effects and 6 due to lack of improvement. One hundred forty-two patients (87%; 95% CI, 80%–90%) adhered to therapy and reported improvement of myalgia (n = 78), fatigue (n = 32), or rhabdomyolysis/hiperCKemia (n = 32). The proportion of responders was larger among patients with MH history than among those referred due to a clinical myopathy with nonpertinent anesthetic history (97% vs 79%, respectively; 95% CI of the difference, 8.5–28; P < .001). Patients with a sarcoplasmic reticulum Ca2+ release channel ryanodine receptor gene (RYR1) variant had higher odds of responding to dantrolene treatment (OR, 6.4; 95% CI, 1.3–30.9; P = .013). Dantrolene median dose was 50 (25–400) and 200 (25–400) mg·day–1 in responders and nonresponders, respectively. CONCLUSIONS: We found that oral dantrolene produced no serious adverse effects within the reported dose range, and was well tolerated by most MH-susceptible patients presenting myopathic symptoms. Our study provides dosing and adverse effect data as a basis for further randomized controlled clinical trials to determine the efficacy of oral dantrolene for symptomatic relief in MHS-related myopathies.

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Section: Discussionmentioning

confidence: 99%

Oral Dantrolene for Myopathic Symptoms in Malignant Hyperthermia–Susceptible Patients: A 25-Year Retrospective Cohort Study of Adverse Effects and Tolerability

Moreno

Kraeva

Zvaritch

et al. 2022

Anesthesia &Amp; Analgesia

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“…Ryanodine receptor (RyR) and IP3R mediate calcium release from ER to cytosol or mitochondria. Inhibition of RyR by dantrolene or IP3R by xestospongin C has been shown to restore thapsigargin-induced ER stress in hepatocytes ( 174 ) or islet cells ( 175 ) ( Figure 7 ). Although there are no animal colitis studies or clinical trials conducted to date, the applications of these inhibitors for colitis might be worth a try.…”

Section: Targeting T Cell Mitochondria For Treating Colitismentioning

confidence: 99%

Mitochondrial dysfunctions in T cells: focus on inflammatory bowel disease

Lee,

Jeon,

Kim

2023

Front. Immunol.

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Mitochondria has emerged as a critical ruler of metabolic reprogramming in immune responses and inflammation. In the context of colitogenic T cells and IBD, there has been increasing research interest in the metabolic pathways of glycolysis, pyruvate oxidation, and glutaminolysis. These pathways have been shown to play a crucial role in the metabolic reprogramming of colitogenic T cells, leading to increased inflammatory cytokine production and tissue damage. In addition to metabolic reprogramming, mitochondrial dysfunction has also been implicated in the pathogenesis of IBD. Studies have shown that colitogenic T cells exhibit impaired mitochondrial respiration, elevated levels of mROS, alterations in calcium homeostasis, impaired mitochondrial biogenesis, and aberrant mitochondria-associated membrane formation. Here, we discuss our current knowledge of the metabolic reprogramming and mitochondrial dysfunctions in colitogenic T cells, as well as the potential therapeutic applications for treating IBD with evidence from animal experiments.

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Dimethyl fumarate restores Ca2+ dyshomeostasis through activation of the SIRT1 signal to treat nonalcoholic fatty liver disease

Zhang,

Cui

et al. 2024

Life Sciences

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Dantrolene prevents hepatic steatosis by reducing cytoplasmic Ca2+ level and ER stress

Cited by 4 publications

References 23 publications

Oral Dantrolene for Myopathic Symptoms in Malignant Hyperthermia–Susceptible Patients: A 25-Year Retrospective Cohort Study of Adverse Effects and Tolerability

Oral Dantrolene for Myopathic Symptoms in Malignant Hyperthermia–Susceptible Patients: A 25-Year Retrospective Cohort Study of Adverse Effects and Tolerability

Mitochondrial dysfunctions in T cells: focus on inflammatory bowel disease

Dimethyl fumarate restores Ca2+ dyshomeostasis through activation of the SIRT1 signal to treat nonalcoholic fatty liver disease

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