Targeting retinoid acid metabolic pathway to enhance neuroprotection and regeneration after SCI

Traumatic injury to the spinal cord (SCI) results in permanent motor impairment and sensory dysfunction including chronic pain, which affect every aspect of SCI survivors’ life. Several pharmacological interventions have been proposed for SCI treatment; however, none have been shown to be widely effective without serious side effects. In most cases, initial traumatic injury fails to completely sever the spinal cord. Preservation of even 5-10% of the neuronal fibers cross the injured site could enable significant recovery of locomotor and sensory function. Unfortunately, many of the fibers that survive from the initial injury later degenerate. Much of this later loss of neurons and fibers is driven by inflammation. Neuroinflammation is also critical for the development of SCI-induced chronic pain. Reducing inflammation and enhancing neuronal regrowth may thus decrease SCI-induced chronic pain and promote the survival of spinal tissue needed to preserve and restore function. Retinoic acid (RA), an active derivative of vitamin A, is critical for neuroinflammation and neuronal regeneration under pathological conditions. In this proposal, we will target the RA metabolism pathway to reduce neuroinflammation after SCI. DX308, a patented compound to specifically inhibit RA degradation, is used to get more endogenous RA to reduce euroinflammation and enhance regeneration. DX308 will be systematically applied for 14 days after contusion to see if it reduces inflammatory activity, as well as promoting locomotor and sensory function. Sensitive methods will assess the pathological consequence of the injury, and the protective effects of DX308 treatment. If successful, it should provide a novel therapeutic target and strategy for SCI treatment. In the long term, these studies will provide a scientific rationale for further clinical trials of DX308 for the treatment of SCI, leading to a new treatment strategy that could benefit SCI patients and their families.