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Enhancing Endogenous Nitric Oxide by Whole Body Periodic Acceleration Elicits Neuroprotective Effects in Dystrophic Neurons

  • Jose R. Lopez
  • A. Uryash
  • J. Kolster
  • E. Estève
  • R. Zhang
  • J. A. Adams
Article

Abstract

We have previously shown that inadequate dystrophin in cortical neurons in mdx mice is associated with age-dependent dyshomeostasis of resting intracellular Ca2+ ([Ca2+]i) and Na+ ([Na+]i), elevated reactive oxygen species (ROS) production, increase in neuronal damage and cognitive deficit. In this study, we assessed the potential therapeutic properties of the whole body periodic acceleration (pGz) to ameliorate the pathology observed in cortical neurons from the mdx mouse. pGz adds small pulses to the circulation, thereby increasing pulsatile shear stress to the vascular endothelium, which in turn increases production of nitric oxide (NO). We found [Ca2+]i and [Na+]i overload along with reactive oxygen species (ROS) overproduction in mdx neurons and cognitive dysfunction. mdx neurons showed increased activity of superoxide dismutase, glutathione peroxidase, malondialdehyde, and calpain as well as decreased cell viability. mdx neurons were more susceptible to hypoxia-reoxygenation injury than WT. pGz ameliorated the [Ca2+]i, and [Na+]i elevation and ROS overproduction and further increased the activities of superoxide dismutase, glutathione peroxidase and reduced the malondialdehyde and calpains. pGz diminished cell damage and elevated [Ca2+]i during hypoxia-reoxygenation and improved cognitive function in mdx mice. Moreover, pGz upregulated the expression of utrophin, dystroglycan-β and CAPON, constitutive nitric oxide synthases, prosaposin, brain-derived neurotrophic, and glial cell line-derived neurotrophic factors. The present study demonstrated that pGz is an effective therapeutic approach to improve mdx neurons function, including cognitive functions.

Keywords

Duchenne muscular dystrophy Neurons Calcium Nitric oxide Whole body periodic acceleration Cognitive function 

Notes

Acknowledgments

We would like to thank Dr. Marvin Sackner and Dr. Angelo da Rosa for their careful reading of the manuscript and suggestions for further improvement.

Funding Information

This research was supported by the Florida Heart Research Institute (JAA).

Supplementary material

12035_2018_1018_MOESM1_ESM.pdf (3.1 mb)
Supplemental Figure 1 pGz treatment upregulates expression of superoxide dismutase. Whole brain homogenates were prepared from pGz-treated and untreated WT and mdx mice. Proteins were separated by SDS-PAGE, transferred onto PVDF membrane, and detected using Enhanced Chemifluorescence. pGz augmented the expression of superoxide dismutase (SOD) and no effect on CAT and GPX. Left panel: representative immunoblots showing the expression of CAT, GPX and SOD before and alter pGz treatment. Right panel: densitometry quantification of the signals. Values are expressed as mean ± SD, n = 5 per experimental condition, N = 5 mice per genotype. *p≤0.05 (one-way ANOVA with Tukey post test). (PDF 3149 kb)
12035_2018_1018_MOESM2_ESM.pdf (3.1 mb)
Supplemental Figure 2 pGz treatment upregulates expression of structural proteins within the dystrophin protein complex in whole mdx brains. Whole brain homogenates were prepared from pGz-treated and untreated WT and mdx mice. pGz significantly upregulated the expression of utrophin (UTR), dystroglycan-β (DGβ) and capon (CAPON). There was not increased expression of sarcoglycans-α (SGα), synthrophin (SYN) and sarcoglycan-β (SG β). Left panel: representative immunoblots showing the expression of UTR, SYN, SGα, SGβ, DGβ and CAPON before and alter pGz treatment. Right panel: densitometry quantification of the signals. Values are expressed as mean ± SD, n = 5 per experimental condition, N = 5 mice per genotype. **p≤0.01, (one-way ANOVA with Tukey post test). (PDF 3149 kb)
12035_2018_1018_MOESM3_ESM.pdf (3.1 mb)
Supplemental Figure 3 Expression of constitutive NOS isoforms in mdx brains is enhanced by pGz treatment. Whole brain homogenates were prepared from pGz-treated and untreated WT and mdx mice. pGz elicited an upregulation of endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) expression, with no significant effect on the expression of the inducible nitric oxide synthase (iNOS). Left panel: representative immunoblots showing the expression of iNOS, eNOS and nNOS before and after pGz treatment. Right panel: densitometry quantification of the signals. Values are expressed as mean ± SD, n = 5 per experimental condition, N = 5 mice per genotype. **p≤0.01, (one-way ANOVA with Tukey post test). (PDF 3148 kb)
12035_2018_1018_MOESM4_ESM.pdf (3.1 mb)
Supplemental Figure 4 pGz treatment stimulates upregulation of neuroprotective factors in whole mdx brains. Whole brain homogenates were prepared from pGz-treated and untreated WT and mdx mice. pGz enhances the expressions of prosaposin (Psap), glial cell line-derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF) significantly in brain homogenates from mdx treated mice. Left panel: representative immunoblots showing the expression of Psap, GDNF, and BDNF before and after pGz treatment. Right panel: densitometry quantification of the signals. Values are expressed as mean ± SD, n = 5 per experimental condition, N = 5 mice per genotype **p≤0.01, (one-way ANOVA with Tukey post test). (PDF 3148 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Jose R. Lopez
    • 1
    • 2
  • A. Uryash
    • 2
  • J. Kolster
    • 3
  • E. Estève
    • 4
  • R. Zhang
    • 1
  • J. A. Adams
    • 2
  1. 1.Department of Molecular BiosciencesUniversity of California DavisDavisUSA
  2. 2.Division of NeonatologyMount Sinai Medical CenterMiamiUSA
  3. 3.Centro de Investigaciones BiomédicasMéxico D.F.México
  4. 4.HP2 INSERM 1042 Institut Jean RogetUniversité Grenoble AlpesGrenoble CedexFrance

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