Development of Novel Combinatorial Treatment to Prevent Chemotherapeutic Resistance and Enhance Efficacy of Riluzole in a Rodent Model of SCI
Technical Report,30 Sep 2015,29 Sep 2016
University of Mississippi Medical Center Jackson United States
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Overall goal of this proposal is to use a pharmacological approach to prevent or significantly reduce the onset of chemotherapeutic resistance that we have recently observeddescribed following spinal cord injury SCI. In our initial, published report, we found that SCI produced a sustained upregulation of P-glycoprotein Pgpwithin the spinal cord that prevented access of systemically intraperitoneally administered riluzole. This chemotherapeutic resistance was found to be permanent within the spinal cord as we continued to detect elevated Pgp at the lesion site as well as in the cervical and lumbar cords out to at least 10 months post-injury. While our rodent study was ongoing, a multi-center clinical trial was performed assessing riluzole as an acute treatment for SCI. While showing a trend toward improved function, the results were not statistically significant. Pharmacokinetic assessment of orally-riluzole bioavailability, however, showed a dramatic reduction of plasma concentrations of riluzole between 3 and 14 days of treatment. Based on our rodent spinal cord data, we asked whether this could suggest a Pgp-dependent reduction of orally-administered riluzole. We subsequently showed in preliminary data for this project that SCI produced a rapid induction of Pgp protein expression in the gastrointestinal tract of rats. This lead us to hypothesize that 1 SCI produces systemic chemotherapeutic resistance, 2 that targeting the inflammatory pathways that promote Pgp induction will prevent onset of chemotherapeutic resistance, 3 that co-administration of riluzole with the anti-inflammatory treatment will both suppress GI Pgp and enhance plasma concentrations of riluzole, and 4 that this combinatorial treatment will lead to a preservation of motor function and an attenuation in long-term pathologies like neuropathic pain in rats following an acute therapeutic intervention.
- Medicine and Medical Research