Journal of Neuroimmune Pharmacology

, Volume 9, Issue 2, pp 218–232 | Cite as

Protection of Dopaminergic Neurons in a Mouse Model of Parkinson’s Disease by a Physically-Modified Saline Containing Charge-Stabilized Nanobubbles

  • Saurabh Khasnavis
  • Avik Roy
  • Supurna Ghosh
  • Richard Watson
  • Kalipada Pahan
ORIGINAL ARTICLE

Abstract

Neuroinflammation underlies the pathogenesis of various neurodegenerative disorders including Parkinson’s disease (PD). Despite intense investigations, no effective therapy is available to stop its onset or halt its progression. RNS60 is a novel therapeutic containing charge-stabilized nanobubbles in saline, generated by subjecting normal saline to Taylor-Couette-Poiseuille flow under elevated oxygen pressure. Recently, we have delineated that RNS60 inhibits the expression of proinflammatory molecules in glial cells via type 1A phosphatidylinositol-3 kinase (PI3K)-mediated upregulation of IκBα. In this study, we demonstrate that RNS60 inhibited the expression of proinflammatory molecules in cultured microglial cells stimulated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridium ion (MPP+) and in vivo in the nigra of MPTP-intoxicated mice. While investigating the underlying mechanisms, we found that MPTP intoxication rapidly stimulated the activation of type IB PI3K p110γ in the nigra, while suppressing the activation of type IA PI3K p110α/β. Interestingly, RNS60 treatment suppressed the activation of p110γ PI3K, while inducing the activation of p110α/β PI3K in the nigra of MPTP-intoxicated mice. Accordingly, RNS60 treatment increased the level of IκBα and inhibited the activation of NF-κB in the SNpc of MPTP-intoxicated mice. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions in MPTP-intoxicated mice. These results strongly suggest a promising therapeutic role of this simple modified saline in PD and other neuroinflammatory disorders.

Keywords

Modified saline Nanobubbles MPTP/MPP+ NF-κB Anti-inflammation Neuroprotection 

Supplementary material

11481_2013_9503_MOESM1_ESM.doc (1.5 mb)
ESM 1(DOC 1582 kb)

References

  1. Baeuerle PA, Baltimore D (1988) I kappa B: a specific inhibitor of the NF-kappa B transcription factor. Science 242:540–546PubMedCrossRefGoogle Scholar
  2. Barnum CJ, Tansey MG (2010) Modeling neuroinflammatory pathogenesis of Parkinson’s disease. Prog Brain Res 184:113–132PubMedCrossRefGoogle Scholar
  3. Benner EJ, Mosley RL, Destache CJ, Lewis TB, Jackson-Lewis V, Gorantla S, Nemachek C, Green SR, Przedborski S, Gendelman HE (2004) Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson’s disease. Proc Natl Acad Sci U S A 101:9435–9440PubMedCentralPubMedCrossRefGoogle Scholar
  4. Brahmachari S, Jana A, Pahan K (2009) Sodium benzoate, a metabolite of cinnamon and a food additive, reduces microglial and astroglial inflammatory responses. J Immunol 183:5917–5927PubMedCentralPubMedCrossRefGoogle Scholar
  5. Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39:889–909PubMedCrossRefGoogle Scholar
  6. Dehmer T, Lindenau J, Haid S, Dichgans J, Schulz JB (2000) Deficiency of inducible nitric oxide synthase protects against MPTP toxicity in vivo. J Neurochem 74:2213–2216PubMedCrossRefGoogle Scholar
  7. Fahn S (2010) Parkinson’s disease: 10 years of progress, 1997–2007. Mov Disord 25(Suppl 1):S2–S14PubMedCrossRefGoogle Scholar
  8. Gao HM, Liu B, Zhang W, Hong JS (2003) Novel anti-inflammatory therapy for Parkinson’s disease. Trends Pharmacol Sci 24:395–401PubMedCrossRefGoogle Scholar
  9. Ghosh A, Roy A, Liu X, Kordower JH, Mufson EJ, Hartley DM, Ghosh S, Mosley RL, Gendelman HE, Pahan K (2007) Selective inhibition of NF-kappaB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson’s disease. Proc Natl Acad Sci U S A 104:18754–18759PubMedCentralPubMedCrossRefGoogle Scholar
  10. Ghosh A, Roy A, Matras J, Brahmachari S, Gendelman HE, Pahan K (2009) Simvastatin inhibits the activation of p21ras and prevents the loss of dopaminergic neurons in a mouse model of Parkinson’s disease. J Neurosci 29:13543–13556PubMedCentralPubMedCrossRefGoogle Scholar
  11. Hayden MS, Ghosh S (2008) Shared principles in NF-kappaB signaling. Cell 132:344–362PubMedCrossRefGoogle Scholar
  12. Hunot S, Boissiere F, Faucheux B, Brugg B, Mouatt-Prigent A, Agid Y, Hirsch EC (1996) Nitric oxide synthase and neuronal vulnerability in Parkinson’s disease. Neuroscience 72:355–363PubMedCrossRefGoogle Scholar
  13. Jana M, Liu X, Koka S, Ghosh S, Petro TM, Pahan K (2001) Ligation of CD40 stimulates the induction of nitric-oxide synthase in microglial cells. J Biol Chem 276:44527–44533PubMedCentralPubMedCrossRefGoogle Scholar
  14. Jana M, Jana A, Liu X, Ghosh S, Pahan K (2007) Involvement of phosphatidylinositol 3-kinase-mediated up-regulation of I kappa B alpha in anti-inflammatory effect of gemfibrozil in microglia. J Immunol 179:4142–4152PubMedCentralPubMedGoogle Scholar
  15. Khasnavis S, Pahan K (2012) Sodium benzoate, a metabolite of cinnamon and a food additive, upregulates neuroprotective parkinson disease protein DJ-1 in astrocytes and neurons. J Neuroimmune Pharmacol 7:424–435Google Scholar
  16. Khasnavis S, Jana A, Roy A, Mazumder M, Bhushan B, Wood T, Ghosh S, Watson R, Pahan K (2012) Suppression of nuclear factor-kappaB activation and inflammation in microglia by physically modified saline. J Biol Chem 287:29529–29542PubMedCentralPubMedCrossRefGoogle Scholar
  17. Mondal S, Martinson JA, Ghosh S, Watson R, Pahan K (2012a) Protection of tregs, suppression of Th1 and Th17 cells, and amelioration of experimental allergic encephalomyelitis by a physically-modified saline. PLoS One 7:e51869PubMedCentralPubMedCrossRefGoogle Scholar
  18. Mondal S, Roy A, Jana A, Ghosh S, Kordower JH, Pahan K (2012b) Testing NF-kappaB-based therapy in hemiparkinsonian monkeys. J Neuroimmune Pharmacol 7:544–556PubMedCentralPubMedCrossRefGoogle Scholar
  19. Morley JF, Hurtig HI (2010) Current understanding and management of Parkinson disease: five new things. Neurology 75:S9–S15Google Scholar
  20. Nagatsu T, Mogi M, Ichinose H, Togari A (2000) Changes in cytokines and neurotrophins in Parkinson’s disease. J Neural Transm Suppl 60:277–290Google Scholar
  21. Olanow CW, Tatton WG (1999) Etiology and pathogenesis of Parkinson’s disease. Annu Rev Neurosci 22:123–144PubMedCrossRefGoogle Scholar
  22. Pahan K, Sheikh FG, Namboodiri AM, Singh I (1997) Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages. J Clin Invest 100:2671–2679PubMedCentralPubMedCrossRefGoogle Scholar
  23. Qureshi GA, Baig S, Bednar I, Sodersten P, Forsberg G, Siden A (1995) Increased cerebrospinal fluid concentration of nitrite in Parkinson’s disease. Neuroreport 6:1642–1644PubMedCrossRefGoogle Scholar
  24. Roy A, Pahan K (2011) Prospects of statins in Parkinson disease. Neuroscientist 17:244–255PubMedCentralPubMedCrossRefGoogle Scholar
  25. Roy A, Fung YK, Liu X, Pahan K (2006) Up-regulation of microglial CD11b expression by nitric oxide. J Biol Chem 281:14971–14980PubMedCentralPubMedCrossRefGoogle Scholar
  26. Roy A, Ghosh A, Jana A, Liu X, Brahmachari S, Gendelman HE, Pahan K (2012) Sodium phenylbutyrate controls neuroinflammatory and antioxidant activities and protects dopaminergic neurons in mouse models of Parkinson’s disease. PLoS One 7:e38113PubMedCentralPubMedCrossRefGoogle Scholar
  27. Saha RN, Pahan K (2006) Signals for the induction of nitric oxide synthase in astrocytes. Neurochem Int 49:154–163PubMedCentralPubMedCrossRefGoogle Scholar
  28. Saha RN, Liu X, Pahan K (2006) Up-regulation of BDNF in astrocytes by TNF-alpha: a case for the neuroprotective role of cytokine. J Neuroimmune Pharmacol 1:212–222PubMedCentralPubMedCrossRefGoogle Scholar
  29. Saha RN, Jana M, Pahan K (2007) MAPK p38 regulates transcriptional activity of NF-kappaB in primary human astrocytes via acetylation of p65. J Immunol 179:7101–7109PubMedCentralPubMedGoogle Scholar
  30. Tieu K, Perier C, Caspersen C, Teismann P, Wu DC, Yan SD, Naini A, Vila M, Jackson-Lewis V, Ramasamy R, Przedborski S (2003) D-beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease. J Clin Invest 112:892–901PubMedCentralPubMedCrossRefGoogle Scholar
  31. Wymann MP, Bjorklof K, Calvez R, Finan P, Thomast M, Trifilieff A, Barbier M, Altruda F, Hirsch E, Laffargue M (2003) Phosphoinositide 3-kinase gamma: a key modulator in inflammation and allergy. Biochem Soc Trans 31:275–280PubMedCrossRefGoogle Scholar
  32. Xie QW, Kashiwabara Y, Nathan C (1994) Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase. J Biol Chem 269:4705–4708PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Saurabh Khasnavis
    • 1
  • Avik Roy
    • 1
  • Supurna Ghosh
    • 2
  • Richard Watson
    • 2
  • Kalipada Pahan
    • 1
  1. 1.Department of Neurological SciencesRush University Medical CenterChicagoUSA
  2. 2.Revalesio CorporationTacomaUSA

Personalised recommendations