Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Hubert Burden (Creator)

Russell Burgess (Creator)

Sarah E. James (Creator)

Frank M. Longo (Creator)

Qun Lu (Creator)

Stephen M. Massa (Creator)

Tao Tang (Creator)

Youmei Xie (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Many chemotherapy drugs are known to cause significant clinical neurotoxicity which can result in the early cessation of treatment. To identify and develop more effective means of neuroprotection it is important to understand the toxicity of these drugs at the molecular and cellular levels. In the present study we examine the effects of paclitaxel (taxol) cisplatin and methotrexate on primary rat neurons including hippocampal cortical and dorsal horn/dorsal root ganglion neuronal cultures. We found that all of these anti-cancer drugs induce substantial neurotoxicity evidenced by neurite degeneration. The neurons are capable of recovering after treatment withdrawal but taxol exerts a biphasic effect that results in the collapse of processes days after treatment is withdrawn. After cisplatin and methotrexate treatment we observed the degeneration of neuronal processes including the reduction of dendritic branching length and altered growth cone formation indicating an abnormal arrangement of the actin cytoskeleton consistent with the involvement of Rho family small GTPases. Inhibiting RhoA downstream effector p160ROCK/Rho kinase using Y-27632 or activating p75 neurotrophin receptor (p75NTR) using non-peptide mimetic LM11A-31 were able to reverse the degeneration caused by cisplatin and methotrexate. Therefore the neurotoxicity resulting from exposure to the anti-cancer drugs cisplatin and methotrexate can be alleviated by inhibiting Rho signaling pathway. Originally published Neurotoxicology Vol. 29 No. 4 July 2008

Additional Information

Publication

Other

Neurotoxicology. 29:4(July 2008) p. 605-612.

Language: English

Date: 2011

Keywords

cancer drug, neurotoxicity, neuroprotectant, cisplatin, methotrexate, Rho GTPases

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