Protective effect of hHsp27 on chemotherapy induced peripheral neuropathy in mice.

Paclitaxel and vincristine are commonly used antineoplastic drugs. Cancer patients withdraw their lifesaving chemotherapy because of adverse effect associated with chemotherapy induced peripheral neuropathy (CIPN). Development of mechanical and thermal allodynia is observed in CIPN as a major clinical symptom. The mechanism of CIPN has not fully elucidated which can enables its effective treatment or prevention. Paclitaxel excessively polymerize microtubules while vincristine depolymerize microtubule resulting in disruption of microtubule dynamics. This disruption results in inefficient axonal transport and thereby causing peripheral nerve degeneration. Our previous studies already reported the reduced axonal regeneration and alteration in cytoskeleton of dorsal root ganglia (DRG) neurons after vincristine and paclitaxel treatment. DRG sensory neurons play critical role in transducing pain signals. Alteration in intrinsic membrane properties of DRG neuron after peripheral nerve injury or inflammation was reported to cause the development of hyperalgesia and allodynia. Heat shock proteins (HSPs) are inducible molecular chaperons which protects sensory neurons from neurotoxicity. Hsp27 was one of the first injury-induced genes identified in DRG neurons. Also in cultured DRG neurons expression of Hsp27 enhances neurite growth may be because of its promoting action in actin polymerization. Also binding of Hsp27 with tubulin and microtubule has been shown to increase stability of microtubule network in DRG neurons. Overexpression of hHsp27 has already shown to acceralate axonal regeneration with complete motor and sensory recovery in peripheral nerve injury mice model. Therefore we intend to examine the protective effect of hHsp27 on CIPN mouse model. We have generated hHsp27 transgenic (Tg) mouse lines which highly express hHsp27 in both sensory and motor neurons. Intraperitoneal injections of Paclitaxel and Vincristine will be used to induce CIPN in hHsp27 Tg mice and their wild type littermates. Assessment of mechanical allodynia is performed using von Frey assay and cold allodynia by acetone drop test for 28 days. Quantification of intra-epidermal nerve fiber density of bilateral hind paw skin in these animals is being determined by immunohistochemistry. Our preliminary studies showed protective effect of hHsp27 on CIPN in both mechanical and cold allodynia but further studies will be required.