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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- 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
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
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