A Novel PPAR Gamma Agonist ELB00824 Suppresses Oxaliplatin-induced Pain, Neuronal Hypersensitivity, and Oxidative Stress

Chemotherapy-induced neuropathic pain (CINP) is a debilitating and difficult-to-treat side effect of chemotherapeutic drugs (e.g., oxaliplatin). CINP is marked with oxidative stress and neuronal hypersensitivities. The peroxisome proliferator-activated receptor gamma (PPARϒ) is a transcription factor that regulates genes involved in oxidative stress and inflammation. We hypothesize that PPARϒ agonists are protective against CIPN by reducing oxidative stress and inhibiting neuronal hypersensitivities. To test our hypothesis, we used a novel BBB (blood-brain barrier) penetrable PPARϒ agonist ELB00824 we characterized previously and a low BBB permeable PPARϒ agonist pioglitazone. CIPN was introduced in BALB/c mice (8-12 week old female) with two established treatment schedules of oxaliplatin injection (a short-lasting model with daily intraperitoneal (IP, 3 mg/kg) injection for 5 consecutive days and a long-lasting model with intravenous (IV, 5 mg/kg) injection twice per week for 4 weeks). 3, 10, or 30 mg/kg ELB00824 or pioglitazone was IP injected 5 min before each oxaliplatin treatment, and 30% DMSO, 15% [email protected] in PBS buffer was used as a vehicle control. Cold allodynia, mechanical allodynia, motor coordination, sedation and addiction were measured with dry ice, von Frey filaments, beam-walking tests, and conditioned place preference, respectively. Oxidative stress was accessed by measuring spinal carbonyl groups, thiobarbituric acid reactive substance (TBARS), and nitrotyrosine levels. Neuronal hypersensitivities were measured using whole-cell current clamp recordings in isolated dorsal root ganglion neurons. In both models ELB00824, but not pioglitazone, reduced oxaliplatin-induced cold and mechanical allodynia and spinal oxidative stress. ELB0824 suppressed oxaliplatin-induced firing in IB4- neurons. ELB00824 did not cause motor discoordination or sedation/addiction or reduce the antineoplastic activity of oxaliplatin (measured with an MTS-based cell proliferation assay) in a human colon cancer cell line (HCT116) and a human oral cancer cell line (HSC-3). Our results demonstrated that ELB00824 prevents oxaliplatin-induced pain, likely via inhibiting neuronal hypersensitivities and oxidative stress. Grant support from NIH grants R01DE029493 (Y. Ye). Chemotherapy-induced neuropathic pain (CINP) is a debilitating and difficult-to-treat side effect of chemotherapeutic drugs (e.g., oxaliplatin). CINP is marked with oxidative stress and neuronal hypersensitivities. The peroxisome proliferator-activated receptor gamma (PPARϒ) is a transcription factor that regulates genes involved in oxidative stress and inflammation. We hypothesize that PPARϒ agonists are protective against CIPN by reducing oxidative stress and inhibiting neuronal hypersensitivities. To test our hypothesis, we used a novel BBB (blood-brain barrier) penetrable PPARϒ agonist ELB00824 we characterized previously and a low BBB permeable PPARϒ agonist pioglitazone. CIPN was introduced in BALB/c mice (8-12 week old female) with two established treatment schedules of oxaliplatin injection (a short-lasting model with daily intraperitoneal (IP, 3 mg/kg) injection for 5 consecutive days and a long-lasting model with intravenous (IV, 5 mg/kg) injection twice per week for 4 weeks). 3, 10, or 30 mg/kg ELB00824 or pioglitazone was IP injected 5 min before each oxaliplatin treatment, and 30% DMSO, 15% [email protected] in PBS buffer was used as a vehicle control. Cold allodynia, mechanical allodynia, motor coordination, sedation and addiction were measured with dry ice, von Frey filaments, beam-walking tests, and conditioned place preference, respectively. Oxidative stress was accessed by measuring spinal carbonyl groups, thiobarbituric acid reactive substance (TBARS), and nitrotyrosine levels. Neuronal hypersensitivities were measured using whole-cell current clamp recordings in isolated dorsal root ganglion neurons. In both models ELB00824, but not pioglitazone, reduced oxaliplatin-induced cold and mechanical allodynia and spinal oxidative stress. ELB0824 suppressed oxaliplatin-induced firing in IB4- neurons. ELB00824 did not cause motor discoordination or sedation/addiction or reduce the antineoplastic activity of oxaliplatin (measured with an MTS-based cell proliferation assay) in a human colon cancer cell line (HCT116) and a human oral cancer cell line (HSC-3). Our results demonstrated that ELB00824 prevents oxaliplatin-induced pain, likely via inhibiting neuronal hypersensitivities and oxidative stress. Grant support from NIH grants R01DE029493 (Y. Ye).