Involvement of α7 nAChR subtype in rat oxaliplatin-induced neuropathy: effects of selective activation.
Oxaliplatin, unlike other platinum anticancer agents, has only mild toxic effects on the hematopoietic, urinary and gastrointestinal systems. Its dose-limiting side effect is neurotoxicity that may evolve to a neuropathic syndrome which is difficult to treat. In this study we treated rats with oxaliplatin (2.4 mg/kg/day intraperitoneally, for 3 weeks), and observed that expression levels of the α7 nicotinic acetylcholine receptor (nAChR) subunit were dramatically decreased both in the peripheral and central nervous system. The repeated administration (30 mg/kg/day per os, for 3 weeks) of (R)-ICH3, the most active enantiomer of a novel α7 nAChR agonist, and of PNU-282987 prevented the receptor down-regulation. On the other hand, both agonists per se up-regulated the α7 nAChR subunit compared to control. (R)-ICH3 and PNU-282987 significantly reduced oxaliplatin-dependent alterations of the pain threshold when noxious or non-noxious stimuli were used. Further ex vivo analysis highlighted their neuroprotective effects in dorsal root ganglia and peripheral nerves. The two agonists did not prevent the increase in microglia cell number induced by oxaliplatin in the central nervous system. Astrocyte density was enhanced by the agonist treatment in the spinal cord, thalamus and somatosensory area 1 as opposed to the effects of oxaliplatin treatment. (R)-ICH3 and PNU-282987 per se increased glial cell number in a region-specific manner. In summary, α7 nAChR is involved in oxaliplatin-dependent neuropathology and the agonists (R)-ICH3 and PNU-282987 reduce pain and protect nervous tissue with concomitant glial activation. Since glial cells play a role both in pain and in neuroprotection, an α7 AChR-dependent modulation of glial functions is suggested to distinguish rescue signals from the pathological pain-mediating pathway.
Università di Firenze, Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino - Neurofarba - Sezione di Farmacologia e Tossicologia, Viale Pieraccini 6, 50139 Firenze, Italy. Electronic address: lorenzo.mannelli@unifi.it.
Lorenzo
L
Di Cesare Mannelli
Università di Firenze, Dipartimento di Medicina Sperimentale e Clinica - DMSC - Sezione di Anatomia e Istology, Largo Brambilla 1, 50134 Firenze, Italy.
Alessandra
A
Pacini
Università degli Studi di Milano, Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica "Pietro Pratesi", Via L. Mangiagalli 25, 20133 Milano, Italy.
Carlo
C
Matera
Università di Firenze, Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino - Neurofarba - Sezione di Farmacologia e Tossicologia, Viale Pieraccini 6, 50139 Firenze, Italy.
Matteo
M
Zanardelli
Università di Firenze, Dipartimento di Scienze Biomediche, Sperimentali e Cliniche - SBSC, Viale Morgagni 50, 50134 Firenze, Italy.
Tommaso
T
Mello
Università degli Studi di Milano, Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica "Pietro Pratesi", Via L. Mangiagalli 25, 20133 Milano, Italy.
Marco
M
De Amici
Università degli Studi di Milano, Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica "Pietro Pratesi", Via L. Mangiagalli 25, 20133 Milano, Italy.
Clelia
C
Dallanoce
Università di Firenze, Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino - Neurofarba - Sezione di Farmacologia e Tossicologia, Viale Pieraccini 6, 50139 Firenze, Italy.
Carla
C
Ghelardini
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D001549:Benzamides / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000503:physiopathology; D017613:Iodine Compounds / Q000494:pharmacology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D009944:Organoplatinum Compounds / Q000633:toxicity*; D000077150:Oxaliplatin; D017288:Pain Threshold / Q000187:drug effects; D010525:Peripheral Nerves / Q000187:drug effects / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013003:Somatosensory Cortex / Q000187:drug effects / Q000503:physiopathology; D013237:Stereoisomerism; D013788:Thalamus / Q000187:drug effects / Q000503:physiopathology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists / Q000378:metabolism*
D000970:Antineoplastic Agents; D001549:Benzamides; D001643:Bridged Bicyclo Compounds; C579165:Chrna7 protein, rat; D017613:Iodine Compounds; D018696:Neuroprotective Agents; D018722:Nicotinic Agonists; D009944:Organoplatinum Compounds; C498513:PNU-282987; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000077150:Oxaliplatin
Astrocyte; Microglia; Neuropathic pain; Neuroprotection; Receptor down-regulation; Receptor up-regulation; α4 nAChR; α7 nAChR;