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Research ArticleBEHAVIORAL PHARMACOLOGY

Specific Antinociceptive Activity of Cholest-4-en-3-one, Oxime (TRO19622) in Experimental Models of Painful Diabetic and Chemotherapy-Induced Neuropathy

Thierry Bordet, Bruno Buisson, Magali Michaud, Jean-Louis Abitbol, Fabien Marchand, John Grist, Emile Andriambeloson, Marzia Malcangio and Rebecca M. Pruss
Journal of Pharmacology and Experimental Therapeutics August 2008, 326 (2) 623-632; DOI: https://doi.org/10.1124/jpet.108.139410
Thierry Bordet
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Bruno Buisson
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Magali Michaud
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Jean-Louis Abitbol
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Fabien Marchand
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John Grist
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Emile Andriambeloson
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Marzia Malcangio
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Rebecca M. Pruss
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Abstract

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.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.108.139410.

  • ABBREVIATIONS: TRO19622, cholest-4-en-3-one, oxime; STZ, streptozotocin; CCI, chronic constriction injury; 4-MC, 4-methylcatechol; SNCV, sensory nerve conduction velocity; CMAP, compound muscle action potential; NGF, nerve growth factor; mPTP, mitochondrial permeability transition pore; ALCAR, acetyl-l-carnitine.

  • ↵ Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ↵1 Current affiliation: NEUROSERVICE, Marseille, France.

  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 326 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 326, Issue 2
1 Aug 2008
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Research ArticleBEHAVIORAL PHARMACOLOGY

Specific Antinociceptive Activity of Cholest-4-en-3-one, Oxime (TRO19622) in Experimental Models of Painful Diabetic and Chemotherapy-Induced Neuropathy

Thierry Bordet, Bruno Buisson, Magali Michaud, Jean-Louis Abitbol, Fabien Marchand, John Grist, Emile Andriambeloson, Marzia Malcangio and Rebecca M. Pruss
Journal of Pharmacology and Experimental Therapeutics August 1, 2008, 326 (2) 623-632; DOI: https://doi.org/10.1124/jpet.108.139410

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Research ArticleBEHAVIORAL PHARMACOLOGY

Specific Antinociceptive Activity of Cholest-4-en-3-one, Oxime (TRO19622) in Experimental Models of Painful Diabetic and Chemotherapy-Induced Neuropathy

Thierry Bordet, Bruno Buisson, Magali Michaud, Jean-Louis Abitbol, Fabien Marchand, John Grist, Emile Andriambeloson, Marzia Malcangio and Rebecca M. Pruss
Journal of Pharmacology and Experimental Therapeutics August 1, 2008, 326 (2) 623-632; DOI: https://doi.org/10.1124/jpet.108.139410
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