Allopregnanolone prevents and suppresses oxaliplatin-evoked painful neuropathy: multi-parametric assessment and direct evidence.
Oxaliplatin (OXAL) is a platinum-based drug used for the treatment of colorectal, lung, breast and ovarian cancers. OXAL does not cause renal or hematologic toxicity. However, OXAL induces neuropathic pain which hampers the chemotherapy success. Attempts with neuroprotective agents including anticonvulsivants and antidepressants were made to prevent OXAL-induced painful neuropathy but the clinical data are controversial and the tested neuroprotectors are able to evoke themselves undesirable effects. Here, we demonstrated that the natural neurosteroid allopregnanolone (3α,5α-THP), known to be devoid of toxic side-effects in humans and experimental models, prevented and suppressed OXAL-induced painful neuropathic symptoms. Indeed, 3α,5α-THP repaired OXAL-evoked neurochemical and functional alterations in peripheral nerves and intra-epidermal nerve fibers (IENF). Behavioral analyses showed that prophylactic or corrective 3α,5α-THP treatment (4mg/kg/2days) respectively prevented or abolished OXAL-induced cold allodynia, mechanical allodynia and hyperalgesia by reversing to normal decreased thermal and mechanical pain thresholds of OXAL-treated rats. Electrophysiological investigations revealed that 3α,5α-THP restored control values of sciatic nerve conduction velocity and action potential peak amplitude drastically reduced by OXAL-treatment. Furthermore, immunohistochemistry and confocal microscopic quantifications demonstrated that 3α,5α-THP repaired OXAL-induced neurochemical/cellular alterations by restoring IENF control density and normal level of neurofilament 200kDa that was strongly repressed by OXAL in dorsal root ganglion neurons and sciatic nerve axons. OXAL showed no toxicity for the non-compact myelin protein 2',3'-cyclic-nucleotide-3'-phosphodiesterase whose expression level was similarly increased by 3α,5α-THP in controls and OXAL-treated rat nerves. Together, these results may be interesting for the development of natural or safe neurosteroid-based neuroprotective strategy against anticancer drug-evoked painful neuropathy.
Equipe Stéroïdes, Neuromodulateurs et Neuropathologies, EA-4438 Université de Strasbourg, Bâtiment 3 de la Faculté de Médecine, 11 rue Humann, 67 000 Strasbourg, France.
Laurence
L
Meyer
Christine
C
Patte-Mensah
Omar
O
Taleb
Ayikoe Guy
AG
Mensah-Nyagan
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000777:Anesthetics / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005106:Exploratory Behavior / Q000187:drug effects; D005727:Ganglia, Spinal / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D008297:Male; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D009431:Neural Conduction / Q000187:drug effects; D009437:Neuralgia / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D016900:Neurofilament Proteins / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000009:adverse effects*; D000077150:Oxaliplatin; D017288:Pain Threshold / Q000187:drug effects; D011280:Pregnanolone / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D018709:Statistics, Nonparametric; D013997:Time Factors
D000777:Anesthetics; D016900:Neurofilament Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C051774:neurofilament protein H; D011280:Pregnanolone; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases