Craig brooks
Faculty Member
Last active: 3/14/2019

Meclizine Preconditioning Protects the Kidney Against Ischemia-Reperfusion Injury.

Kishi S, Campanholle G, Gohil VM, Perocchi F, Brooks CR, Morizane R, Sabbisetti V, Ichimura T, Mootha VK, Bonventre JV
EBioMedicine. 2015 2 (9): 1090-101

PMID: 26501107 · PMCID: PMC4588407 · DOI:10.1016/j.ebiom.2015.07.035

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.

MeSH Terms (27)

Acute Kidney Injury Adenosine Triphosphate Animals Cell Respiration Cytochromes c Deoxyglucose Disease Models, Animal Epithelial Cells Ethanolamines Galactose Glycolysis Humans Inflammation Ischemic Preconditioning Kidney Kidney Tubules L-Lactate Dehydrogenase LLC-PK1 Cells Male Meclizine Mice, Inbred C57BL Mitochondria Protective Agents Reperfusion Injury Sodium Cyanide Swine Up-Regulation

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