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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

Inflammation after IRI is reduced with meclizine (100mg/kg) pretreatment 17 h prior to ischemia.(A) Representative images of GR1 + (neutrophils) and F4/80 (macrophages) stained kidneys from sham, vehicle and meclizine pretreated mice at 48 h after IRI. Original magnification 400 ×, scale bar = 20 μm. (B and C) Quantification of GR1 + positive cells and F4/80 positive area. (D–G) Real-time PCR analysis of Il1b, Ccl2, Tnf and Il6 mRNA in sham, vehicle and meclizine pretreated mice at 48 h after IRI. Sham (n = 3), IRI + Veh and IRI + meclizine (n = 4 to 6). ***p < 0.001; **p < 0.01 and *p < 0.05. Statistical significance was determined using one-way ANOVA followed by Tukey's post-hoc test. The columns and error bars are the mean ± SEM.
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f0015: Inflammation after IRI is reduced with meclizine (100mg/kg) pretreatment 17 h prior to ischemia.(A) Representative images of GR1 + (neutrophils) and F4/80 (macrophages) stained kidneys from sham, vehicle and meclizine pretreated mice at 48 h after IRI. Original magnification 400 ×, scale bar = 20 μm. (B and C) Quantification of GR1 + positive cells and F4/80 positive area. (D–G) Real-time PCR analysis of Il1b, Ccl2, Tnf and Il6 mRNA in sham, vehicle and meclizine pretreated mice at 48 h after IRI. Sham (n = 3), IRI + Veh and IRI + meclizine (n = 4 to 6). ***p < 0.001; **p < 0.01 and *p < 0.05. Statistical significance was determined using one-way ANOVA followed by Tukey's post-hoc test. The columns and error bars are the mean ± SEM.

Mentions: Because inflammation contributes to IRI, we analyzed inflammatory cell infiltration and cytokine production 48 h after IRI in animals pretreated with meclizine or vehicle. As expected, there was an increase in GR-1 + neutrophils and F4/80 + macrophage infiltration in the kidney subjected to IRI, as well as an increase in tissue mRNA levels of inflammatory mediators: Il1b, Tnf, Il6 and Ccl2 when compared to vehicle-treated sham non-ischemic animal kidneys (Fig. 2). In meclizine pre-treated animals there were fewer infiltrating neutrophils 48 h after ischemia (1.5 ± 0.1 vs 3.6 ± 0.8 cells per high power field, p < 0.05) (Fig. 2A and B). There was also a trend toward reduced numbers of infiltrating F4/80 + macrophages (Fig. 2C). Meclizine pretreatment resulted in reduced fold-increases in mRNA expression of inflammatory cytokines Il1b (4.38 ± 0.96 vs 7.80 ± 0.83 (vehicle-treated) p < 0.05), Tnf (1.89 ± 0.65 vs 8.47 ± 2.00, p < 0.01), Il6 (40 ± 16 vs 164 ± 39, p < 0.05) and the chemokine Ccl2 (5.6 ± 1.0 vs 12.8 ± 2.2, p < 0.05) (Fig. 2D–G). Thus the protection afforded by pretreatment with meclizine reduced inflammation after IRI.


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)

Inflammation after IRI is reduced with meclizine (100mg/kg) pretreatment 17 h prior to ischemia.(A) Representative images of GR1 + (neutrophils) and F4/80 (macrophages) stained kidneys from sham, vehicle and meclizine pretreated mice at 48 h after IRI. Original magnification 400 ×, scale bar = 20 μm. (B and C) Quantification of GR1 + positive cells and F4/80 positive area. (D–G) Real-time PCR analysis of Il1b, Ccl2, Tnf and Il6 mRNA in sham, vehicle and meclizine pretreated mice at 48 h after IRI. Sham (n = 3), IRI + Veh and IRI + meclizine (n = 4 to 6). ***p < 0.001; **p < 0.01 and *p < 0.05. Statistical significance was determined using one-way ANOVA followed by Tukey's post-hoc test. The columns and error bars are the mean ± SEM.
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f0015: Inflammation after IRI is reduced with meclizine (100mg/kg) pretreatment 17 h prior to ischemia.(A) Representative images of GR1 + (neutrophils) and F4/80 (macrophages) stained kidneys from sham, vehicle and meclizine pretreated mice at 48 h after IRI. Original magnification 400 ×, scale bar = 20 μm. (B and C) Quantification of GR1 + positive cells and F4/80 positive area. (D–G) Real-time PCR analysis of Il1b, Ccl2, Tnf and Il6 mRNA in sham, vehicle and meclizine pretreated mice at 48 h after IRI. Sham (n = 3), IRI + Veh and IRI + meclizine (n = 4 to 6). ***p < 0.001; **p < 0.01 and *p < 0.05. Statistical significance was determined using one-way ANOVA followed by Tukey's post-hoc test. The columns and error bars are the mean ± SEM.
Mentions: Because inflammation contributes to IRI, we analyzed inflammatory cell infiltration and cytokine production 48 h after IRI in animals pretreated with meclizine or vehicle. As expected, there was an increase in GR-1 + neutrophils and F4/80 + macrophage infiltration in the kidney subjected to IRI, as well as an increase in tissue mRNA levels of inflammatory mediators: Il1b, Tnf, Il6 and Ccl2 when compared to vehicle-treated sham non-ischemic animal kidneys (Fig. 2). In meclizine pre-treated animals there were fewer infiltrating neutrophils 48 h after ischemia (1.5 ± 0.1 vs 3.6 ± 0.8 cells per high power field, p < 0.05) (Fig. 2A and B). There was also a trend toward reduced numbers of infiltrating F4/80 + macrophages (Fig. 2C). Meclizine pretreatment resulted in reduced fold-increases in mRNA expression of inflammatory cytokines Il1b (4.38 ± 0.96 vs 7.80 ± 0.83 (vehicle-treated) p < 0.05), Tnf (1.89 ± 0.65 vs 8.47 ± 2.00, p < 0.01), Il6 (40 ± 16 vs 164 ± 39, p < 0.05) and the chemokine Ccl2 (5.6 ± 1.0 vs 12.8 ± 2.2, p < 0.05) (Fig. 2D–G). Thus the protection afforded by pretreatment with meclizine reduced inflammation after IRI.

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