Proton-Mediated PIEZO2 Channelopathy: Linking Oxaliplatin Treatment to Impaired Proprioception and Cognitive Deficits

Oxaliplatin induces acute neuropathy within a few hours post-treatment, with symptoms persisting for several days. Delayed onset muscle soreness also causes the delayed onset of mechanical pain sensation starting at about 6-8 h and lasting up to a week after exercise. Both conditions come with impaired proprioception and could be chronic if these bouts are repeated frequently. The involvement of PIEZO2 ion channels, as the principal mechanosensory channels responsible for proprioception, is theorized in both conditions as well. The current opinion manuscript is meant to explain how the minor stretch-related microdamage of PIEZO2 on Type Ia proprioceptive terminals could explain the aforementioned symptoms of impaired proprioception. This includes a platinum-induced proton affinity 'switch' on these proprioceptive endings with PIEZO2 content, resulting in this being the likely initiating cause. Furthermore, it postulates how the proton-based ultrafast long-range oscillatory synchronization to the hippocampus could be impaired due to this microdamage on Type Ia proprioceptive terminals. Finally, the manuscript provides insight into how the impairment of the PIEZO2-initiated ultrafast muscle-brain axis may contribute to chemobrain and its associated cognitive and memory deficits.