Meclizine Preconditioning Protects the Kidney Against Ischemia–Reperfusion Injury

• Pretreatment with meclizine protected mice from kidney ischemia–reperfusion injury.
• Meclizine reduced mitochondrial oxygen consumption and upregulated glycolysis.
• Meclizine caused accumulation of phosphoethanolamine, a mitochondrial respiration inhibitor.
• Phosphoethanolamine recapitulated meclizine's effects on metabolism and renal protection.Kishi et al. demonstrate that meclizine, an over-the-counter anti-nausea drug, protects mouse against kidney ischemia. Pretreatment with 100 mg/kg of meclizine, 17 or 24 h prior to ischemia showed kidney protection in mice. Meclizine reduced mitochondrial oxygen consumption by directly inhibiting the Kennedy pathway of phosphatidylethanolamine biosynthesis and up-regulated glycolysis.

Global or local ischemia contributes to the pathogenesis of acute kidney injury (AKI). Currently there are no specific therapies to prevent AKI. Potentiation of glycolytic metabolism and attenuation of mitochondrial respiration may decrease cell injury and reduce reactive oxygen species generation from the mitochondria. Meclizine, an over-the-counter anti-nausea and -dizziness drug, was identified in a ‘nutrient-sensitized’ chemical screen. Pretreatment with 100 mg/kg of meclizine, 17 h prior to ischemia protected mice from IRI. Serum creatinine levels at 24 h after IRI were 0.13 ± 0.06 mg/dl (sham, n = 3), 1.59 ± 0.10 mg/dl (vehicle, n = 8) and 0.89 ± 0.11 mg/dl (meclizine, n = 8). Kidney injury was significantly decreased in meclizine treated mice compared with vehicle group (p < 0.001). Protection was also seen when meclizine was administered 24 h prior to ischemia. Meclizine reduced inflammation, mitochondrial oxygen consumption, oxidative stress, mitochondrial fragmentation, and tubular injury. Meclizine preconditioned kidney tubular epithelial cells, exposed to blockade of glycolytic and oxidative metabolism with 2-deoxyglucose and NaCN, had reduced LDH and cytochrome c release. Meclizine upregulated glycolysis in glucose-containing media and reduced cellular ATP levels in galactose-containing media. Meclizine inhibited the Kennedy pathway and caused rapid accumulation of phosphoethanolamine. Phosphoethanolamine recapitulated meclizine-induced protection both in vitro and in vivo.

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