Abstract
Aging is associated with molecular and functional declines in multiple physiologic systems. We have previously reported age-related changes in spinal cord that included a decline in α-motor neuron numbers, axonal loss, and demyelination associated with increased inflammation and blood-spinal cord barrier (BSCB) permeability. These changes may influence other pathologies associated with aging, in particular loss of muscle mass and function (sarcopenia), which we and others have shown is accompanied by neuromuscular junction disruption and loss of innervation. Interventions to protect and maintain motor neuron viability and function in aging are currently lacking and could have a significant impact on improving healthspan. Here we tested a promising compound, OKN-007, that has known antioxidant, anti-inflammatory and neuroprotective properties, as a potential intervention in age-related changes in the spinal cord. OKN-007 is a low molecular weight disulfonyl derivative of (N-tert Butyl-α-phenylnitrone) (PBN) that can easily cross the blood-brain barrier. We treated middle age (16 month) wild-type male mice with OKN-007 in drinking water at a dose of 150 mg/kg/day until 25 months of age. OKN-007 treatment exerted a number of beneficial effects in the aging spinal cord, including a 35% increase in the number of lumbar α-motor neurons in OKN-treated old mice compared to age-matched controls. Brain spinal cord barrier permeability, which is increased in aging spinal cord, was also blunted by OKN-007 treatment. Age-related changes in microglia proliferation and activation are blunted by OKN-007, while we found no effect on astrocyte proliferation. Transcriptome analysis identified expression changes in a number of genes that are involved in neuronal structure and function and revealed a subset of genes whose changes in response to aging are reversed by OKN-007 treatment. Overall, our findings suggest that OKN-007 exerts neuroprotective and anti-inflammatory effects on the aging spinal cord and support OKN-007 as a potential therapeutic to improve α-motor neuron health.