Glutamatergic system modulators as agents in prevention and management of chemotherapy- induced polyneuropathy

Polyneuropathy is a common and important chemotherapy-induced adverse effect which often leads to dose modifications and impact on patients’ quality of life. Limited treatment options for prevention and management of this neuropathology stimulate further research on the topic. Recent attention has been focused on downregulation of glial glutamate transporter expression observed in spinal region of rodents treated with cancer chemotherapy drugs. Consequent extrasynaptic glutamate overflow could be considered a key element in neuropathic pathogenesis resulting in excessive activation of glutamate receptors and neuronal hyper-excitability, finally contributing to develop neuropathic condition. Recently, the onset of neuropathy in bortezomib treated rats could be prevented by preemptive administration of drugs promoting glial glutamate transporter expression and antagonism at mGlur5, a metabotropic receptor which reinforces glutamatergic transmission in presence of high extracellular glutamate concentrations. These findings point to glial-glutamate system dysregulation as a main mechanism in the pathogenesis of anticancer chemotherapy induced neuropathy.