MITOCHONDRIAL DYSFUNCTION IS A FEATURE OF PACLITAXEL AND OXALIPLATIN-PROMOTED CHEMOTHERAPY-INDUCED PERIPHERAL NEUROTOXICITY

Introduction: Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the dose-limiting side effects for several effective anticancer drugs. In case of severe neuropathy, chemotherapy dose reduction/withdrawal can occur, with possible negative effects on oncological prognosis. ncomplete knowledge of CIPN pathogenesis is the main reason why therapeutic strategies are not currently available. Herein we evaluated the onsequences of CIPN on oxidative stress and mitochondria dynamics using in vivo and in vitro models. Methods: Adult male Wistar rats were treated with chemotherapeutic agents (paclitaxel (PTX) 10 mg/kg 1 qw, i.v; oxaliplatin (OHP) 5mg/kg 2qw, i.v; 5 fluorouracil (5FU) 50 mg/kg 1 qw i.p, the latter used as non CIPN-promoting chemotherapeutic drug) or vehicle for 4 or 6 weeks and multimodal assessment of CIPN was performed (neurophysiology nd behavioral test). Oxidative stress, gene and protein expression were evaluated in dorsal root ganglia (DRG) of treated animals; moreover, in vitro nalyses of mitochondria motility were performed. Results: PTX-treated rats showed allodynia and neurophysiological alterations. Molecular analyses of RG isolated from PTX-treated rats indicated lack of oxidative stress; however, the expression of the key markers associated with mitochondrial dynamics was altered. Conversely, OHP- or 5FU-treated rats did not show similar mechanical allodynia, nor presented modifications in markers associated with mitochondrial dynamics. However, OHP selectively affected mitochondrial electron transport chain protein levels and induced oxidative stress. We measured mitochondria motility in cultured adult DRG neurons exposed to doses at which OHP induced axonal degeneration in vitro and found that OHP promoted mitochondrial motility prior to axonal degeneration. Conclusions: Altogether our data support the notion that allodynia specifically orrelates with perturbation of mitochondria dynamics and suggest that seemingly unrelated CIPN drugs may converge on induction of abnormal mitochondrial function in DRG neurons.