Behavioral and electromyographic assessment of oxaliplatin-induced motor dysfunctions: Evidence for a therapeutic effect of allopregnanolone

Abstract

The antineoplastic oxaliplatin (OXAL) is pivotal for metastatic cancer treatments. However, OXAL evokes sensory and motor side-effects including pain, muscle weakness, motor nerve fiber dysfunctions/neuropathies that significantly impact patients' lives. Therefore, preclinical investigations are struggling to characterize effective analgesics against OXAL-induced painful/sensory symptoms but surprisingly, OXAL-evoked motor dysfunctions received little attention although these neurological symptoms are also disabling for patients. Here, we validated a rat model of OXAL-induced motor neuropathy by using (i) behavioral methods as the wire suspension and balance beam tests to assess muscle weakness and (ii) electrophysiological techniques to record the gastrocnemius electromyography (EMG). The conductance velocity of motor fibers was reduced and compound muscle action potential (CMAP) duration increased in OXAL-treated rats, leading to CMAP dispersion with no modification of the area under the curve, reflecting a heterogeneous demyelination of motor fibers. Functional motor unit analysis revealed a 50 % decrease of their estimated number which was compensated by a motor unit size increase. OXAL-induced motor weakness appeared as a combined consequence of motor fiber demyelination and motor axonopathy. Because we previously observed that allopregnanolone (AP) counteracted OXAL-evoked painful/sensory symptoms, we evaluated its action against OXAL-induced motor neurological dysfunctions. AP treatment successfully corrected motor behaviors, conductance velocity, CMAP duration, motor unit number (MUN) and motor unit size altered by OXAL-chemotherapy. These results, which are the first to show that AP efficiently rescues OXAL-induced motor neuropathy, consolidate the idea that AP-based therapy may be relevant for the treatment of both sensory and motor peripheral neuropathies.

Keywords: Motor disorders; Nerve fiber dysfunction; Neuroprotection; Neurosteroid; Peripheral neuropathy.