Specific antinociceptive activity of cholest-4-en-3-one, oxime (TRO19622) in experimental models of painful diabetic and chemotherapy-induced neuropathy.
Diabetes and cancer chemotherapies are often associated with painful neuropathy. The mechanisms underlying neuropathic pain remain poorly understood, and the current therapies have limited efficacy and are associated with dose-limiting side effects. We recently described the pharmacological characterization of cholest-4-en-3-one, oxime (TRO19622), a cholesterol-like compound, that significantly reduced axonal degeneration and accelerated recovery of motor nerve conduction in a model of peripheral neuropathy induced by crushing the sciatic nerve. These results triggered investigation of efficacy in other preclinical models of peripheral neuropathy. Here, we report evidence that daily oral administration of TRO19622, while similarly improving motor nerve conduction impaired in streptozotocin-induced diabetic rats, also reversed neuropathic pain behavior as early as the first administration. Further exploration of these acute antinociceptive effects demonstrated that TRO19622 was also able to reverse tactile allodynia in vincristine-treated rats, a model of chemotherapy-induced neuropathic pain. It is interesting to note that TRO19622 did not have analgesic activity in animal models of pain produced by formalin injection, noxious thermal or mechanical stimulation, or chronic constriction injury of the sciatic nerve, indicating that painful diabetic or chemotherapy-induced neuropathies share a common mechanism that is distinct from acute, inflammationdriven, or lesion-induced neuropathic pain. These results support the potential use of TRO19622 to treat painful diabetic and chemotherapy-induced neuropathies.
Bordet
Thierry
T
Trophos, Parc Scientifique de Luminy, Luminy Biotech Entreprises, Case 931, 13288 Marseille Cedex 9, France.
Buisson
Bruno
B
Michaud
Magali
M
Abitbol
Jean-Louis
JL
Marchand
Fabien
F
Grist
John
J
Andriambeloson
Emile
E
Malcangio
Marzia
M
Pruss
Rebecca M
RM
D000700:Analgesics / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects; D001522:Behavior, Animal / Q000187:drug effects*; D002783:Cholestenones / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D008297:Male; D009431:Neural Conduction / Q000187:drug effects; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D010147:Pain Measurement / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D013311:Streptozocin; D014750:Vincristine / Q000009:adverse effects
D000700:Analgesics; D000972:Antineoplastic Agents, Phytogenic; D002783:Cholestenones; D014750:Vincristine; D013311:Streptozocin; C522838:olesoxime