ANALGESIC POTENTIAL OF ALLOPREGNANOLONE IN MALE AND FEMALE MODELS OF BORTEZOMIB-INDUCED PERIPHERAL NEUROPATHY

Proteasome inhibitor bortezomib (BTZ) causes painful peripheral neuropathy (BIPN) that hinders patients’ quality of life. Currently, there has been little preclinical research investigating sexually dimorphic differences in BINP or response to therapeutics. Therefore, identifying novel compounds with favorable safety profiles is essential to develop effective strategies. Several reports suggested that similar paradigms can be ameliorated by concomitant use of neuroactive steroids, cholesterol derivatives with proven neuroprotective effects. Therefore, we tested the analgesic potential of allopregnanolone (ALLO) in rodent models of BIPN. Female and male Wistar rats were intravenously treated with BTZ (0.2 mg/kg, 3qw) for 4 weeks together with subcutaneous co-administrations of BTZ and ALLO (3mg/kg) every other day. We investigated the efficacy of ALLO using a battery of behavioral and neurophysiological tests, morphometrical analyses of myelinated nerves and intraepidermal small unmyelinated fibers densities, and macrophage infiltration assays. The development of BINP in these animals was not dependent on their sex, since BTZ led to the development of neuropathy and allodynia in both males and females, and was similarly alleviated by ALLO. Moreover, BTZ induced significant loss of both myelinated and unmyelinated fibers in the caudal nerves and skin, respectively. ALLO successfully protected unmyelinated fibers from degeneration in both sexes. Taken together, our results show that ALLO could represent a valuable tool to manage painful BIPN in the clinical setting for both sexes, paving the way for further testing of its therapeutic potential. This research is funded by EU in NextGenerationEU plan through “Bando Prin 2022D.D. 1409 del 14-09-2022”.