2011 AAN MS Abstract

Abstract from poster presentation at
2011 American Academy of Neurology (AAN) Conference

Isotonic Saline Subjected to Taylor-Couette-Poiseuille Flow Demonstrates Anti-Inflammatory Activity in Rodent Models of Multiple Sclerosis

Supurna Ghosh, Linda Burke, Tacoma, WA, Susanta Mondal, Chicago, IL, Richard Watson, Tacoma, WA, Kalipada Pahan, Chicago, IL

OBJECTIVE: Nanobubble-based structures have received attention for their potential use in biomedical imaging and drug delivery,
but have not been reported to elicit direct biological or therapeutic effects. The current study examines direct therapeutic effects of
a charge-stabilized nanostructure (CSN)-containing fluid, RNS60.
BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune demyelenating disease of the central nervous system. Existing therapies are limited and present significant side effects. Since RNS60 has demonstrated broad-spectrum anti-inflammatory efficacy with extraordinarily low toxicty in multiple in vitro and in vivo models, we tested its efficacy in experimental allergic encepahalomyelitis (EAE) models.
DESIGN/METHODS: We generated RNS60 by subjecting normal saline to Taylor-Couette-Poiseuille (TCP) flow under high oxygen pressure. Intravenous/intraperitoneal RNS60 treatment was tested in a) myelin basic protein (MBP)-induced EAE in rats, b) myelin ligodendrocyte glycoprotein (MOG)-induced chronic EAE in mice, and c) adoptive T cell-transfer induced relapsing-remitting EAE in mice.
RESULTS: Therapeutic dosing of RNS60 was effective in reducing clinical scores in all three models. In the MOG-induced
model, RNS60 therapeutic treatment, starting at the first sign of clinical symptoms, significantly reduced the clinical score on study
days 29 to 35 compared to the control group (n=10/group, P<0.1) and lowered the circulating levels of the proinflammatory
cytokines IL-6 and IL-17. Similarly, RNS60 attenuated clinical symptoms of adoptively-transferred relapsing-remitting EAE in
female SJL/J mice from 13 to 40 days post transfer (n=5/group, P<0.1).
CONCLUSIONS: These results demonstrate that physical processing of saline can generate a fluid with significant efficacy in multiple EAE models. We propose that this activity is based on the presence of CSNs generated during the processing of RNS60. The ability to influence disease parameters by a chemically unaltered fluid opens possibilities for the generation of low risk therapeutics for MS. Supported by: Revalesio Corporation, Tacoma, WA, has supported this study.

2011 ASN Abstract In Vivo

Abstract from poster presentation at
2011 American Society for Neurochemistry (ASN) Conference

MODIFIED SALINE CONTAINING CHARGE-STABILIZED NANOSTRUCTURES PROTECTS NEURONS IN THE MPTP MOUSE MODEL OF PARKINSON’S DISEASE

Khasnavis, S.1, Ghosh, S.2, Watson, R.2, Pahan, K.1

1 Rush University Medical Center, Department of Neurological Sciences, Chicago, USA
2 Revalesio Corporation, Tacoma, USA

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. Despite intense investigations, no effective therapy is available to stop its onset or halt its progression. RNS60 is generated by subjecting normal saline to Taylor-Couette-Poiseuille flow under high oxygen pressure. It contains chargestabilized nanostructures and has broad anti-inflammatory activities. The present study evaluates the ability of RNS60 to prevent nigrostriatal degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and establish a therapeutic role for RIS60 in human parkinsonism. Glial inflammation is a critical component of PD pathogenesis, that is mirrored in the MPTP mouse model. The neurotoxic effect of MPTP depends on its conversion into MPP+, which activates glial cells. Therefore, as expected, MPP+ induced the expression of inducible nitric oxide synthase (iNOS) and interleukin-1b (IL-1b) in microglial cells. RNS60, but not NS (control saline), suppressed MPP+-induced microglial expression of iNOS and IL-1b highlighting antiinflammatory effect of RNS60. In vivo, MPTP intoxication led to loss of tyrosine hydroxylase (TH)-positive neurons, decrease in striatal dopamine and impairment of locomotor activities. RNS60 protected TH-positive neurons in the substantia nigra pars compacta (SNpc), defended dopamine in the striatum and improved motor functions (rotorod, horizontal activity, total distance travelled, number of movement, stereotypy count, vertical activity, movement time) in MPTP-intoxicated mice. Since RNS60 is unique in its mode of action, these results demonstrate a novel mechanism of suppressing disease parameters in the MPTP-induced PD model, and suggest that RNS60 may be of therapeutic benefit for PD patients. This study has been supported by Revalesio Corporation, Tacoma, WA.

2011 ASN Abstract In Vitro

Abstract from poster presentation at
2011 American Society for Neurochemistry (ASN) Conference

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2011 AAN Abstract In Vitro

Abstract from poster presentation at
2011 American Academy of Neurology (AAN) Conference

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2011 AAAAI Abstract In Vivo

Abstract from poster presentation at 2011 American Academy of Allergy, Asthma & Immunology (AAAAI) Conference

Isotonic Saline Subjected to Taylor-Couette-Poiseuille Flow Demonstrates Anti-Inflammatory Activity in a Rat Model of Allergic Asthma

S. Ghosh, T. L. Mega, S. German, L. M. Burke, M. L. Diegel, A. B.Wood, R. L. Watson; Revalesio Corporation, Tacoma, WA.

RATIONALE: Nanobubble-based structures have received attention for their potential use in biomedical imaging and drug delivery, but have not been reported to elicit direct biological or therapeutic effects. Asthma is a chronic inflammatory disease of the airways affecting more than 300 million people worldwide. Since we have demonstrated that RNS60, a solution containing charge-stabilized nanostructures, has anti-inflammatory effects on airway epithelial and peripheral blood mononuclear cells in vitro, we tested its efficacy in treating allergic asthma in a rodent model.
METHODS: We generated RNS60 by subjecting normal saline to Taylor-Couette-Poiseuille (TCP) flow under high oxygen pressure. We compared the efficacy of RNS60 with that of budesonide, an FDA-approved corticosteroid, in the Brown Norway rat ovalbumin challenge model. Study endpoints included the key respiratory parameters tidal volume and PenH. In addition, we used Luminex technology to measure multiple inflammatory proteins in serum and bronchoalveolar lavage fluid (BAL).
RESULTS: RNS60 caused a significant improvement in tidal volume and PenH. Moreover, RNS60 reduced blood and BAL levels of several key proinflammatory proteins (including IL-4, IL-6, Eotaxin, and TNF-a) at 6 and 24 hours post ovalbumin challenge (n514/group).
CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that physical processing of saline under the conditions employed here can generate a fluid with significant efficacy in a rodent model of allergic asthma.We propose that this activity is based on the presence of charge-stabilized nanostructures generated during the processing of RNS60. The ability to influence physiological parameters associated with asthma by a chemically unaltered fluid opens possibilities for the generation of lowrisk therapeutics.

2011 AAAAI InVitro Abstracts

Abstract from poster presentation at 2011 American Academy of Allergy, Asthma & Immunology (AAAAI) Conference

Isotonic Saline Subjected to Taylor-Couette-Poiseuille Flow Demonstrates Anti-Inflammatory Activity In Vitro

S. German, S. Ghosh, T. L. Mega, L. M. Burke, M. L. Diegel, A. B. Wood, R. L. Watson; Revalesio Corporation, Tacoma, WA.

RATIONALE: Unlike nanoparticles, nanobubbles have not been demonstrated to elicit direct biological effects. Evidence suggests that nanobubble-based nanostructures have diverse size and charge properties similar to nanoparticles, and thus may have direct biological effects. Here, we investigated whether RNS60, a solution containing charge-stabilized nanostructures, has anti-inflammatory activity in vitro.
METHODS: We generated RNS60 by subjecting saline to Taylor-Couette-Poiseuille (TCP) flow in the presence of high oxygen pressure, and confirmed the presence of nanostructures using atomic force microscopy and a particle size analyzer. We employed whole cell voltage clamp to measure electrophysiological effects of RNS60 in airway epithelial cells.We also measured the effect of RNS60 on expression of CCR3 by peripheral blood mononuclear cells (PBMCs) and expression of interleukin-8 (IL-8) by airway epithelial cells using flow cytometry and ELISA, respectively.
RESULTS: RNS60 increased whole cell conductance in airway epithelial cells through multiple ion channels including inwardly rectifying and cAMP-activated channels. In addition, RNS60 decreased CCR3 levels on PBMCs stimulated with phytohemaglutinin and IL-8 expression by airway epithelial cells challenged with TNF-a or Diesel exhaust particles.
CONCLUSIONS/SIGNIFICANCE: Our data demonstrate that processing of saline by regulated TCP flow can generate a fluid with the ability to modulate the electrophysiology of airway epithelial cells and to downregulate key cellular mediators of inflammation.We propose that this activity is based on the presence of charge-stabilized nanostructures generated during the processing of RNS60. The ability to influence cells with a fluid devoid of added pharmaceutical ingredients opens possibilities for the generation of low risk therapeutics.

Xconomy Editorial: Hitting the Target, Missing the Mark: How Targeted Therapies Have Left Patients Wanting

Date: April 14, 2011

Read article by Dr. Richard Watson on Xconomy.com

Revalesio Presents Multiple Sclerosis and Alzheimer’s Disease Research at National Neurology Conference

Date: April 4, 2011

Revalesio Corporation, a pioneering biotechnology company, and Rush University will present research on the use of RNS60 in Multiple Sclerosis and Alzheimer’s disease at the American Academy of Neurology (AAN) meeting April 9-16 in Honolulu, Hawaii.

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