Антигіпералгезивна активність пропоксазепаму при холодовій алодинії, індукованій оксаліплатином, у щурів

Background. Oxaliplatin (OXP), a third-generation chemotherapeutic platinum compound, is widely used in treating metastatic colorectal cancer. However, its clinical utility is limited by oxaliplatin-induced peripheral neuropathy (OIPN), a dose-dependent and often persistent adverse effect characterized by sensory dysfunction such as cold allodynia. Current pharmacological options for OIPN management are limited, with duloxetine being the only drug recommended with moderate confidence by clinical guidelines. Novel analgesics with alternative mechanisms of action are urgently needed. Objective. This study aimed to evaluate the antihyperalgesic (analgesic) effect of propoxazepam, a novel benzo­diazepine derivative with known GABAergic and glycinergic activity, in a rat model of OXP-induced peripheral neuropathy. Methods. Chronic peripheral neuropathy was induced in male Sprague–Dawley rats via repeated intraperitoneal injections of OXP (4 mg/kg, twice weekly for 3 weeks). Cold allodynia was assessed using the paw immersion test at 10 °C. Rats received a single oral dose of propoxazepam (0.5–8 mg/kg) or duloxetine (100 mg/kg) on days 4, 11, and 18, with paw withdrawal latency (PWL) measured at 60, 120, and 180 minutes post-administration. Data were analyzed using Student's t-test with p £ 0.05 as the threshold for statistical significance. Results. OXP administration significantly reduced PWL, indicating development of cold allodynia. Propoxazepam demonstrated a dose-dependent analgesic effect starting as early as Day 4. Significant increases in PWL were observed at doses of 4 and 8 mg/kg, with maximal effects on Day 11 (up to 62% relative to the control). While duloxetine induced a stronger initial effect (~70–75%), it diminished rapidly to 19% by 180 minutes. Lower doses (0.5–2 mg/kg) of propoxazepam did not show statistically significant effects. The analgesic effect of propoxazepam peaked at 120 minutes post-administration and declined by 180 minutes. Conclusions. Propoxazepam effectively reduces cold allodynia in a rat model of OIPN in a dose- and time-dependent manner. Its analgesic efficacy, mediated through GABAergic and glycinergic modulation and supported by anti-inflammatory properties, positions it as a promising candidate for treating chemotherapy-induced neuropathic pain. Given its favorable safety profile and novel mechanism, propoxazepam warrants further investigation in clinical trials. Objective. This study aimed to evaluate the antihyperalgesic (analgesic) effect of propoxazepam, a novel benzodiazepine derivative with known GABAergic and glycinergic activity, in a rat model of OXP-induced peripheral neuropathy. Methods: Chronic peripheral neuropathy was induced in male Sprague-Dawley rats via repeated intraperitoneal injections of OXP (4 mg/kg, twice weekly for 3 weeks). Cold allodynia was assessed using the paw immersion test at 10°C. Rats received a single oral dose of propoxazepam (0.5–8 mg/kg) or duloxetine (100 mg/kg) on days 4, 11, and 18, with paw withdrawal latency (PWL) measured at 60, 120, and 180 minutes post-administration. Data were analyzed using Student's t-test with p ≤ 0.05 as the threshold for statistical significance. Results. OXP administration significantly reduced PWL, indicating development of cold allodynia. Propoxazepam demonstrated a dose-dependent analgesic effect starting as early as Day 4. Significant increases in PWL were observed at doses of 4 and 8 mg/kg, with maximal effects on Day 11 (up to 62% relative to the control). While duloxetine induced a stronger initial effect (~70–75%), it diminished rapidly to 19% by 180 minutes. Lower doses (0.5–2 mg/kg) of propoxazepam did not show statistically significant effects. The analgesic effect of propoxazepam peaked at 120 minutes post-administration and declined by 180 minutes. Conclusion. Propoxazepam effectively reduces cold allodynia in a rat model of OIPN in a dose- and time-dependent manner. Its analgesic efficacy, mediated through GABAergic and glycinergic modulation and supported by anti-inflammatory properties, positions it as a promising candidate for treating chemotherapy-induced neuropathic pain. Given its favorable safety profile and novel mechanism, propoxazepam warrants further investigation in clinical trials.