Targeting Axon Integrity to Prevent Chemotherapy-Induced Peripheral Neuropathy

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is an irreversible off-target adverse effect of many chemotherapeutic agents such as paclitaxel, yet its mechanism is poorly understood and no preventative measure is available. CIPN is characterized by peripheral nerve damages resulting in permanent sensory function deficits. Our recent unbiased genome-wide analysis revealed that heat shock protein (Hsp) 27 is part of a transcriptional network induced by axonal injury and highly enriched for genes involved in adaptive neuronal responses, particularly axonal regeneration. To examine if Hsp27 could prevent the occurrence of CIPN, we first demonstrated that paclitaxel-induced allodynia was associated directly with axonal degeneration in sensory neurons in a mouse model of CIPN. We therefore hypothesize that by preventing axonal degeneration could prevent the development of CIPN. We drove expression of human Hsp27 (hHsp27) specifically in neurons. Development of mechanical and thermal allodynia was prevented completely in paclitaxel-treated hHsp27 transgenic mice. Strikingly, hHsp27 protected against paclitaxel-induced neurotoxicity in vivo including degeneration of afferent nerve fibers, demyelination, mitochondrial swelling, apoptosis, and restored sensory nerve action potential. Finally, we delineated signaling cascades that link CIPN development to caspase 3 and RhoA/cofilin activation in sensory neurons and peripheral nerves. hHsp27 exerted anti-apoptotic effect and maintained axon integrity by restoring caspase 3 and RhoA expression to basal levels. Taken together, our data suggest that by preventing axonal degeneration might prove beneficial as anti-CIPN drugs, which represents an emerging research area for therapeutic development.

Chemotherapy-induced peripheral neuropathy: part 1—current state of knowledge and perspectives for pharmacotherapy

“…Oxidative stress increases the production of proinflammatory mediators, which further destroy mitochondria, enhance the production of reactive oxygen species and contribute to various pathological processes resulting from oxidative stress. These phenomena might also cause demyelination and disruption of the cytoskeleton of peripheral nerves [51].…”

“…In addition, vincristine dysregulates neuronal mitochondria, which leads to altered neuronal excitability and glial cell dysfunction. The influence of vincristine on mitochondria is thought to involve altered mitochondrial calcium signaling, and the maintenance of intracellular calcium homeostasis is beneficial for preventing CIPN [51,52]. Paclitaxel does not directly affect mitochondrial DNA but induces swollen and vacuolated mitochondria in both myelinated and unmyelinated sensory axons, and these changes are accompanied by increased production of reactive oxygen species in the nervous system [20,[53][54][55].…”

Chemotherapy-Induced Peripheral Neuropathy and Changes in Cytoskeleton

“…Here, MTs have the minus-end facing the cellular body and the plus-end facing the synapses. Alteration in this organization could lead to impaired axonal transport and consequently, axon degeneration and a decrease in conduction velocity [102,119,120]. In fact, Shemesh et al have demonstrated that paclitaxel induces the reconfiguration of the MT from a highly polar oriented MT to a chaotic distribution [121].…”

“…Heat shock protein 27 (Hsp27) is involved in the reduction of reactive oxygen species during oxidative stress, anti-apoptotic activity under condition of chemical stress, and protein folding, but also interacts with actin and the MT [119]. The interaction with the MT is still poorly understood, but Hsp27 participates in the stabilization of the MT [149,150].…”

“…A research group demonstrated that the overexpression of Hsp27 protects from paclitaxel-induced neuropathy. They proposed a different hypothesis, where a possible Hsp27 direct effect on the MT exists [119].…”