Development of Novel Combinatorial Treatment to Prevent Chemotherapeutic Resistance and Enhance Efficacy of Riluzole in a Rodent Model of SCI
Abstract
Riluzole is a Food and Drug Administration-approved drug used in the treatment of amyotrophic lateral sclerosis (ALS). In addition, riluzole has exhibited potent neuroprotective characteristics when tested in animal models of spinal cord injury (SCI). Based on riluzole s safety in ALS as well as its preclinical efficacy in SCI models, riluzole was recently tested in a Phase I clinical trial through the North American Clinical Trials Network (NACTN). Riluzole was delivered to patients orally and was shown to be both safe and efficacious for those who experienced a cervical level SCI. Interestingly, an analysis of riluzole pharmacokinetics indicated that the plasma concentration of riluzole decreased in patients when measured between days 3 and 14 post-injury/initiation of treatment, suggesting a time-dependent reduction in riluzole bioavailability following SCI. Our laboratory recently identified a novel mechanism through which the injured spinal cord develops resistance to pharmacological treatment in a manner analogous to what has been reported to occur in many forms of cancer. Blood vessels that feed tumors will often express high concentrations of molecular pumps on the walls of these blood vessels that bind up circulating levels of chemotherapeutic drugs and prevent them from gaining access to the tumor. We have found that the injured spinal cord also undergoes an increased expression of one of these molecular pumps, P-glycoprotein (Pgp), shortly after injury. Pgp exhibits an extremely broad range of selectivity for substances produced within the body or delivered to the body. Riluzole was recently shown to be a substrate for Pgp, leading us to test and subsequently demonstrate in a clinically relevant rat model of SCI that systemically delivered riluzole exhibited a reduced ability to enter the spinal cord following injury. These results led us to hypothesize that the reduced plasma bioavailability of riluzole reported in the NACTN trial might be influenced by Pgp expression. As riluzole was administered orally to patients in the NACTN trial, we hypothesized that Pgp expression may be elevated within the gastrointestinal tract (GI) following SCI, resulting in lowered passage through the GI tract and subsequent reduced plasma bioavailability. Preliminary studies performed in our lab indicate that GI tissues do experience an increase in Pgp shortly following SCI in the rat. The overall goals of this proposal are to: (1) determine whether a clinically relevant rat model will exhibit plasma and spinal tissue riluzole bioavailability when delivered early and over a 14-day period following a spinal contusion injury, and (2) whether the co-oral administration of licofelone, a new generation dual inhibitor of prostaglandin and leukotriene production, can suppress Pgp expression and enhance GI uptake and efficacy of riluzole. Outcome measures will include the biochemical assessment of GI Pgp expression and riluzole bioavailability within the injured brain and spinal cord. We will also determine whether this novel combination results in a successful reduction in SCI-induced chemotherapeutic resistance by determining whether the combination improves motor and neurosensory outcome. If we are successful, our subsequent goal will be to determine whether our findings could lead to an evaluation of licofelone and riluzole as a novel combination therapy to suppress chemotherapeutic resistance and improve functional outcome for patients that have received an SCI.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510668
Entities
People
- Raymond Grill
Organizations
- United States Army
- University of Mississippi