THERAPEUTIC VERSUS PREVENTIVE ADMINISTRATION OF NEUROACTIVE STEROIDS TO TREAT BORTEZOMIB-INDUCED PAINFUL NEUROPATHY

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling condition resulting from antineoplastic treatment. The proteasome inhibitor bortezomib (BTZ) can cause painful peripheral neuropathy (BIPN) with a negative impact on cancer survivors’ quality of life. Although reducing pain is often a main focus of BIPN treatment, remarkably few analgesics have been tested. A growing number of reports suggest that CIPN can be attenuated by the concomitant use of neuroactive steroids (NAS), cholesterol derivatives with proven neuroprotective effects in several in vivo models of peripheral neuropathy. However, an important factor in the development of neuroprotective intervention is whether to adopt a therapeutic or a preventive approach. Therefore, we tested the analgesic effect of two NAS, allopregnanolone (ALLO) and pregnenolone (PREG), in two rodent models of BIPN. Female Wistar rats were intravenously treated with BTZ (0.2 mg/kg, 3qw) for 4 weeks. To study the therapeutic effect, co-administrations of BTZ and ALLO (3 mg/kg/every 2 days) or PREG (6 mg/kg/every 2 days) were performed subcutaneously for another 4 weeks. Instead, in the preventive schedule, ALLO or PREG were coadministered for 4 weeks with BTZ from the beginning of the study. Here, we tested the protective effects of the two NAS using a battery of behavioral and neurophysiological tests as well as morphological and morphometrical analyses of myelinated nerves and intraepidermal small unmyelinated fibers (IENF) densities. Treatment with BTZ induced significant mechanical allodynia and thermal hyperalgesia, as well as a reduction of sensory action potential amplitude in peripheral nerves already at 4 weeks, with severe neuropathic symptoms at 8 weeks. NAS administration alleviated BTZ-induced behavioral alterations and partially prevented neurophysiological symptoms. In addition, BTZ treatment induced a significant loss of both myelinated and unmyelinated fibers in the caudal nerves and skin, respectively. A protective effect was observed after NAS treatment on IENF. Taken together, our results suggest that since NAS counteracted painful symptoms induced by BTZ, they could be used to alleviate BIPN neurotoxic manifestations. Moreover, having knowledge of the precise timing of therapeutic intervention is paramount to boost any neuroprotective treatment efficacy. This research has received funding from EU in NextGenerationEU plan through the Italian “Bando Prin 2022D.D. 1409 del 14-09-2022”.