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ORIGINAL RESEARCH article

Front. Neurosci.
Sec. Neurodegeneration
Volume 18 - 2024 | doi: 10.3389/fnins.2024.1505369

The nitrone compound OKN-007 delays motor neuron loss and disease progression in the G93A mouse model of Amyotrophic Lateral Sclerosis

Provisionally accepted
Shylesh Bhaskaran Shylesh Bhaskaran 1*Katarzyna M. Piekarz Katarzyna M. Piekarz 1Jacob Brown Jacob Brown 1*Brian Yang Brian Yang 1*Sarah R. Ocañas Sarah R. Ocañas 1*Jonathan D. Wren Jonathan D. Wren 1Constantin Georgescu Constantin Georgescu 1*Christopher Bottoms Christopher Bottoms 1Ashley Murphy Ashley Murphy 1*Jessica Thomson Jessica Thomson 1*Debra Saunders Debra Saunders 1*Nataliya Smith Nataliya Smith 2*Rheal Towner Rheal Towner 3*Holly Van Remmen Holly Van Remmen 1*
  • 1 Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States
  • 2 University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • 3 University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada

The final, formatted version of the article will be published soon.

    Our study investigated the therapeutic potential of OKN-007 in the SOD1 G93A mouse model of amyotrophic lateral sclerosis (ALS). The impact of OKN-007, known for its antioxidant, anti-inflammatory, and neuroprotective properties, was tested at two doses (150 mg/kg and 300 mg/kg) at onset and latestage disease. Results demonstrated a significant delay in disease progression at both doses, with treated mice showing a slower advance to early disease stages compared to untreated controls. Motor neuron counts in the lumbar spinal cord were notably higher in OKN-007 treated mice at the time of disease onset, suggesting neuroprotection. Additionally, OKN-007 reduced microglial activation and preserved reduced neuromuscular junction fragmentation, although it did not significantly alter the increase in astrocyte number or the decline in hindlimb muscle mass. MR spectroscopy (MRS) revealed improved spinal cord perfusion and normalized myo-inositol levels in treated mice, supporting reduced neuroinflammation. While the expression of several proteins associated with inflammation is increased in spinal cord extracts from G93A mice, OKN-007 dampened the expression of IL-1β, IL-1ra and IL-1α. Despite its promising effects on early-stage disease progression, in general, the beneficial effects of OKN-007 diminished over longer treatment durations. Further, we found no improvement in muscle atrophy or weakness phenotypes in OKN-007 treated G93A mice, and no effect on mitochondrial function or lifespan. Overall, our findings suggest that OKN-007 holds potential as a disease-modifying treatment for ALS, although further research is needed to optimize dosing regimens and understand its long-term effects.

    Keywords: Amyotrophic lateral sclerosis (ALS), OKN-007, Spinal Cord, disease progression, Cytokine - immunological terms

    Received: 02 Oct 2024; Accepted: 28 Oct 2024.

    Copyright: © 2024 Bhaskaran, Piekarz, Brown, Yang, Ocañas, Wren, Georgescu, Bottoms, Murphy, Thomson, Saunders, Smith, Towner and Van Remmen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Shylesh Bhaskaran, Oklahoma Medical Research Foundation, Oklahoma City, 73104, Oklahoma, United States
    Jacob Brown, Oklahoma Medical Research Foundation, Oklahoma City, 73104, Oklahoma, United States
    Brian Yang, Oklahoma Medical Research Foundation, Oklahoma City, 73104, Oklahoma, United States
    Sarah R. Ocañas, Oklahoma Medical Research Foundation, Oklahoma City, 73104, Oklahoma, United States
    Constantin Georgescu, Oklahoma Medical Research Foundation, Oklahoma City, 73104, Oklahoma, United States
    Ashley Murphy, Oklahoma Medical Research Foundation, Oklahoma City, 73104, Oklahoma, United States
    Jessica Thomson, Oklahoma Medical Research Foundation, Oklahoma City, 73104, Oklahoma, United States
    Debra Saunders, Oklahoma Medical Research Foundation, Oklahoma City, 73104, Oklahoma, United States
    Nataliya Smith, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, Oklahoma, United States
    Rheal Towner, University of Prince Edward Island, Charlottetown, C1A 4P3, Prince Edward Island, Canada
    Holly Van Remmen, Oklahoma Medical Research Foundation, Oklahoma City, 73104, Oklahoma, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.