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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)

Bottom Line: Potentiation of glycolytic metabolism and attenuation of mitochondrial respiration may decrease cell injury and reduce reactive oxygen species generation from the mitochondria.Kidney injury was significantly decreased in meclizine treated mice compared with vehicle group (p < 0.001).Meclizine upregulated glycolysis in glucose-containing media and reduced cellular ATP levels in galactose-containing media.

View Article: PubMed Central - PubMed

Affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Meclizine is not protective if given after IRI or in two toxicity models of AKI. (A) Serum creatinine levels at 24 h after ischemia in mice treated with two injections of meclizine (100 mg/kg; given right after reperfusion and 8 h after reperfusion). (B) Representative images of H&E staining at 48 h after ischemia. Scale bar = 100 μm. (C) Tubular necrosis was semiquantified by scoring H&E stained slides. (D) KIM-1 mRNA (Havcr1) expression at 48 h after IRI relative to revels in sham kidneys. (E) Ccl2, Tnf, and Il1b mRNAs expression at 48 h after ischemia relative to revels in sham kidneys. n = 3 sham, n = 3 to 4 IRI + Veh and IRI + meclizine.(F) Serum creatinine and (G) urinary KIM-1 levels at 5 days following aristolochic acid (AA) injection in mice pretreated with or without meclizine (Mec) 17 h or 1 h before injection. n = 2 sham, n = 5 AA + Veh and AA + meclizine. (H) Serum creatinine and (I) urinary KIM-1 levels at 3 days following cisplatin (Cis) injection in mice pretreated with or without meclizine. sham (n = 2), Cis + Veh and Cis + meclizine (n = 3); ns = not significant. Statistical significance was determined using one-way ANOVA followed by Tukey's post-hoc test. The columns and error bars are the mean ± SEM. Scale bar = 100 μm.
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f0025: Meclizine is not protective if given after IRI or in two toxicity models of AKI. (A) Serum creatinine levels at 24 h after ischemia in mice treated with two injections of meclizine (100 mg/kg; given right after reperfusion and 8 h after reperfusion). (B) Representative images of H&E staining at 48 h after ischemia. Scale bar = 100 μm. (C) Tubular necrosis was semiquantified by scoring H&E stained slides. (D) KIM-1 mRNA (Havcr1) expression at 48 h after IRI relative to revels in sham kidneys. (E) Ccl2, Tnf, and Il1b mRNAs expression at 48 h after ischemia relative to revels in sham kidneys. n = 3 sham, n = 3 to 4 IRI + Veh and IRI + meclizine.(F) Serum creatinine and (G) urinary KIM-1 levels at 5 days following aristolochic acid (AA) injection in mice pretreated with or without meclizine (Mec) 17 h or 1 h before injection. n = 2 sham, n = 5 AA + Veh and AA + meclizine. (H) Serum creatinine and (I) urinary KIM-1 levels at 3 days following cisplatin (Cis) injection in mice pretreated with or without meclizine. sham (n = 2), Cis + Veh and Cis + meclizine (n = 3); ns = not significant. Statistical significance was determined using one-way ANOVA followed by Tukey's post-hoc test. The columns and error bars are the mean ± SEM. Scale bar = 100 μm.

Mentions: To evaluate whether meclizine would also be protective when given after the injury had been already established, we treated mice with 100 mg/kg of meclizine twice, one injection right after reperfusion and a second injection 8 h after IRI. No significant differences were measured in serum creatinine levels, tubular necrosis score or kidney KIM-1 mRNA (Havcr1) expression between the vehicle and meclizine-treated group after IRI (Fig. 4A–D). There was also no difference in the tissue mRNA expression of inflammatory mediators (Fig. 4E). Thus protection by meclizine was limited to preconditioning.


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)

Meclizine is not protective if given after IRI or in two toxicity models of AKI. (A) Serum creatinine levels at 24 h after ischemia in mice treated with two injections of meclizine (100 mg/kg; given right after reperfusion and 8 h after reperfusion). (B) Representative images of H&E staining at 48 h after ischemia. Scale bar = 100 μm. (C) Tubular necrosis was semiquantified by scoring H&E stained slides. (D) KIM-1 mRNA (Havcr1) expression at 48 h after IRI relative to revels in sham kidneys. (E) Ccl2, Tnf, and Il1b mRNAs expression at 48 h after ischemia relative to revels in sham kidneys. n = 3 sham, n = 3 to 4 IRI + Veh and IRI + meclizine.(F) Serum creatinine and (G) urinary KIM-1 levels at 5 days following aristolochic acid (AA) injection in mice pretreated with or without meclizine (Mec) 17 h or 1 h before injection. n = 2 sham, n = 5 AA + Veh and AA + meclizine. (H) Serum creatinine and (I) urinary KIM-1 levels at 3 days following cisplatin (Cis) injection in mice pretreated with or without meclizine. sham (n = 2), Cis + Veh and Cis + meclizine (n = 3); ns = not significant. Statistical significance was determined using one-way ANOVA followed by Tukey's post-hoc test. The columns and error bars are the mean ± SEM. Scale bar = 100 μm.
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f0025: Meclizine is not protective if given after IRI or in two toxicity models of AKI. (A) Serum creatinine levels at 24 h after ischemia in mice treated with two injections of meclizine (100 mg/kg; given right after reperfusion and 8 h after reperfusion). (B) Representative images of H&E staining at 48 h after ischemia. Scale bar = 100 μm. (C) Tubular necrosis was semiquantified by scoring H&E stained slides. (D) KIM-1 mRNA (Havcr1) expression at 48 h after IRI relative to revels in sham kidneys. (E) Ccl2, Tnf, and Il1b mRNAs expression at 48 h after ischemia relative to revels in sham kidneys. n = 3 sham, n = 3 to 4 IRI + Veh and IRI + meclizine.(F) Serum creatinine and (G) urinary KIM-1 levels at 5 days following aristolochic acid (AA) injection in mice pretreated with or without meclizine (Mec) 17 h or 1 h before injection. n = 2 sham, n = 5 AA + Veh and AA + meclizine. (H) Serum creatinine and (I) urinary KIM-1 levels at 3 days following cisplatin (Cis) injection in mice pretreated with or without meclizine. sham (n = 2), Cis + Veh and Cis + meclizine (n = 3); ns = not significant. Statistical significance was determined using one-way ANOVA followed by Tukey's post-hoc test. The columns and error bars are the mean ± SEM. Scale bar = 100 μm.
Mentions: To evaluate whether meclizine would also be protective when given after the injury had been already established, we treated mice with 100 mg/kg of meclizine twice, one injection right after reperfusion and a second injection 8 h after IRI. No significant differences were measured in serum creatinine levels, tubular necrosis score or kidney KIM-1 mRNA (Havcr1) expression between the vehicle and meclizine-treated group after IRI (Fig. 4A–D). There was also no difference in the tissue mRNA expression of inflammatory mediators (Fig. 4E). Thus protection by meclizine was limited to preconditioning.

Bottom Line: Potentiation of glycolytic metabolism and attenuation of mitochondrial respiration may decrease cell injury and reduce reactive oxygen species generation from the mitochondria.Kidney injury was significantly decreased in meclizine treated mice compared with vehicle group (p < 0.001).Meclizine upregulated glycolysis in glucose-containing media and reduced cellular ATP levels in galactose-containing media.

View Article: PubMed Central - PubMed

Affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus