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 alpha 7 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 alpha 7 nAChR agonist, and of PNU-282987 prevented the receptor down-regulation. On the other hand, both agonists per se up-regulated the alpha 7 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, alpha 7 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 alpha 7 AChR-dependent modulation of glial functions is suggested to distinguish rescue signals from the pathological pain-mediating pathway.

Involvement of α7 nAChR subtype in rat oxaliplatin-induced neuropathy: Effects of selective activation / L. Di Cesare Mannelli, A. Pacini, C. Matera, M. Zanardelli, T. Mello, M. De Amici, C. Dallanoce, C. Ghelardini. - In: NEUROPHARMACOLOGY. - ISSN 1873-7064. - 79:(2014), pp. 37-48. [10.1016/j.neuropharm.2013.10.034]

Involvement of α7 nAChR subtype in rat oxaliplatin-induced neuropathy: Effects of selective activation

C. Matera;M. De Amici;C. Dallanoce
Penultimo
;
2014

Abstract

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 alpha 7 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 alpha 7 nAChR agonist, and of PNU-282987 prevented the receptor down-regulation. On the other hand, both agonists per se up-regulated the alpha 7 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, alpha 7 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 alpha 7 AChR-dependent modulation of glial functions is suggested to distinguish rescue signals from the pathological pain-mediating pathway.
Astrocyte; Microglia; Neuropathic pain; Neuroprotection; Receptor down-regulation; Receptor up-regulation; α4 nAChR; α7 nAChR
Settore CHIM/08 - Chimica Farmaceutica
Settore BIO/14 - Farmacologia
10-nov-2013
Article (author)
File in questo prodotto:
File Dimensione Formato  
1-s2.0-S0028390813005108-main.pdf

accesso riservato

Descrizione: main text
Tipologia: Publisher's version/PDF
Dimensione 2.83 MB
Formato Adobe PDF
2.83 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
di cesare mannelli et al. neuropharm.pdf

accesso riservato

Descrizione: main text
Tipologia: Post-print, accepted manuscript ecc. (versione accettata dall'editore)
Dimensione 7.61 MB
Formato Adobe PDF
7.61 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/951280
Citazioni
  • ???jsp.display-item.citation.pmc??? 41
  • Scopus ND
  • ???jsp.display-item.citation.isi??? 43
social impact