Mitochondrial Dysfunction in Chemotherapy-Induced Peripheral Neuropathy (CIPN)

Abstract

The mitochondrial dysfunction has a critical role in several disorders including chemotherapy-induced peripheral neuropathies (CIPN). This is due to a related dysregulation of pathways involving calcium signalling, reactive oxygen species and apoptosis. Vincristine is able to affect calcium movement through the Dorsal Root Ganglia (DRG) neuronal mitochondrial membrane, altering its homeostasis and leading to abnormal neuronal excitability. Paclitaxel induces the opening of the mitochondrial permeability transition pore in axons followed by mitochondrial membrane potential loss, increased reactive oxygen species generation, ATP level reduction, calcium release and mitochondrial swelling. Cisplatin and oxaliplatin form adducts with mitochondrial DNA producing inhibition of replication, disruption of transcription and morphological abnormalities within mitochondria in DRG neurons, leading to a gradual energy failure. Bortezomib is able to modify mitochondrial calcium homeostasis and mitochondrial respiratory chain. Moreover, the expression of a certain number of genes, including those controlling mitochondrial functions, was altered in patients with bortezomib-induced peripheral neuropathy.

The Possible Role of Propolis in Ameliorating Paclitaxel-Induced Peripheral Neuropathy in Sciatic Nerve of Adult Male Albino Rats

“…Microtubule stability affects axonal transport of growth factors leading to abnormal nerve physiology and loss of axonal integrity [7] . In addition, paclitaxel can evoke apoptotic cascade by stimulation of cytochrome C release which activates caspase signaling pathway and also by binding to mitochondrial anti-apoptotic Bcl2 resulting in its inactivation [10,35] .…”

“…Stimulation of mPTP opening by paclitaxel leads to mitochondrial depolarization and Ca++ release. Increase Ca++ mediated neuronal excitability results in mitochondrial structural changes [10] . Another explanation for mitochondrial swelling in paclitaxel-treated animals is that paclitaxel binds to β-tubulin moiety which is associated with VDAC.…”

“…Patients may also suffer from intermitting sharp, shooting leg pain [10] . Most cases may develop myalgias or arthralgias [2] .…”

“…The pathogenesis of CIPN is attributed to the development of axonopathy and myelinopathy [4][5][6][7][8][9][10] . Paclitaxel was found to be concentrated in dorsal root ganglia then in sciatic nerve and spinal cord due to paclitaxel transport along centrifugal and centripetal branches of the dorsal root ganglia neuron axon [12] .…”

“…This leads to disruption of peripheral nerve signaling causing sensory, motor, or autonomic peripheral neuropathy influencing the patient routine daily activities or even causes significant disability [8][9][10][11] .…”