Overexpression of human Hsp27 (hHsp27) protects against Paclitaxel-induced peripheral neuropathy in mice

Paclitaxel (Taxol®) is widely used to treat breast, ovarian and lung cancer. It binds to β-subunit of microtubules and causes its excessive polymerisation. This leads to dynamic instability of microtubule and results in cancer cell death. Our recent studies revealed that Paclitaxel disrupt microtubule organization in mouse primary dorsal root ganglion neuron measured by atomic force microscopy and confocal imaging. Paclitaxel was also reported to cause oxidative stress and mitochondrial damage in peripheral neurons. Oxidative stress and mitochondrial damage triggers cytochrome-c mediated caspase dependent apoptosis while microtubule disruption results in p53 and poly (ADP-ribose) polymerase activated cell death in peripheral neurons. Subsequently neuronal damage and neuroinflammation occur, resulting in hypersensitivity and hyperxcitability of peripheral nociceptors. Development of mechanical and thermal allodynia with decreased sensory nerve conduction velocity due to mitochondrial dysfunction and intra-epidermal nerve fiber (IENF) loss has been reported as a distinct pathobiological feature of Paclitaxel induced peripheral neuropathy in animal models. Heat shock protein 27 (Hsp27) is a molecular chaperone which acts as an anti-apoptotic and anti-oxidant. It has been shown that Hsp27 prevents both the caspase dependent and p53 activated apoptosis. Our studies showed that hHsp27 overexpression accelerated the axonal regeneration with better functional recovery after peripheral nerve injury. Paclitaxel was injected intraperitoneally to transgenic (TG) hHsp27 and their littermate (LM) controls to induce peripheral neuropathy. Cremophore EL/Ethanol was injected as vehicle (VH) controls. Development of mechanical and cold allodynia was observed only in LM group as compared to both TG and VH groups. Furthermore, nerve conduction velocity and compound muscle action potential values were significantly lower in LM mice as compared with TG and VH groups. Histology studies showed significant reduction in IENF density, axon numbers and neuromuscular junctions in LM group when compared with TG and VH groups. In summary, our data suggest that Hsp27 could be a potential therapeutic target for chemotherapy induced peripheral neuropathy.