Olesoxime (cholest-4-en-3-one, oxime): analgesic and neuroprotective effects in a rat model of painful peripheral neuropathy produced by the chemotherapeutic agent, paclitaxel.
Olesoxime is a small cholesterol-like molecule that was discovered in a screening program aimed at finding treatment for amyotrophic lateral sclerosis and other diseases where motor neurons degenerate. In addition to its neuroprotective and pro-regenerative effects on motor neurons in vitro and in vivo, it has been shown to have analgesic effects in rat models of painful peripheral neuropathy due to vincristine and diabetes. We used a rat model of painful peripheral neuropathy produced by the chemotherapeutic agent, paclitaxel, to determine whether olesoxime could reverse established neuropathic pain. In addition, we determined whether giving olesoxime during the exposure to paclitaxel could prevent the development of the neuropathic pain syndrome and the accompanying degeneration of the terminal arbors of sensory fibers in the epidermis. Olesoxime significantly reduced established mechano-allodynia and mechano-hyperalgesia. There was no indication of tolerance to the effect during five days of dosing and the analgesia persisted for 5-10 days after the last injection. Giving olesoxime during the exposure to paclitaxel significantly and permanently reduced the severity of mechano-allodynia and mechano-hyperalgesia and significantly reduced the amount of sensory terminal arbor degeneration. Olesoxime targets mitochondrial proteins and its effects are consistent with the mitotoxicity hypothesis for paclitaxel-evoked painful peripheral neuropathy. We conclude that olesoxime may be useful clinically for both the prevention and treatment of paclitaxel-evoked painful peripheral neuropathy.
Xiao
Wen Hua
WH
Department of Anesthesia, McGill University, Montreal, Que., Canada. wenhua.xiao@mcgill.ca
Zheng
Felix Y
FY
Bennett
Gary J
GJ
Bordet
Thierry
T
Pruss
Rebecca M
RM
D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D002783:Cholestenones / Q000008:administration & dosage* / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005071:Evoked Potentials / Q000187:drug effects; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D009412:Nerve Fibers / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D009437:Neuralgia / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000097:blood; D017239:Paclitaxel / Q000009:adverse effects / Q000031:analogs & derivatives*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D043222:Ubiquitin Thiolesterase / Q000378:metabolism
D002783:Cholestenones; D018696:Neuroprotective Agents; C495179:Pacliex; C522838:olesoxime; C489034:UCHL1 protein, rat; D043222:Ubiquitin Thiolesterase; D017239:Paclitaxel