Ghrelin agonist HM01 attenuates chemotherapy-induced neurotoxicity in rodent models

Alessia Chiorazzi, Krystyna M. Wozniak, Rana Rais, Ying Wu, Alexandra J. Gadiano, Mohamed H. Farah, Ying Liu, Annalisa Canta, Paola Alberti, Virginia Rodriguez-Menendez, Cristina Meregalli, Giulia Fumagalli, Laura Monza, Eleonora Pozzi, James J. Vornov, Michael Polydefkis, Claudio Pietra, Barbara S. Slusher, Guido Cavaletti

Research output: Contribution to journalArticlepeer-review

Abstract

Chemotherapy-Induced Peripheral Neurotoxicity (CIPN) is often dose-limiting and impacts life quality and survival of cancer patients. Ghrelin agonists have neuroprotectant effects and may have a role in treating or preventing CIPN. We evaluated the CNS-penetrant ghrelin agonist HM01 in three experimental models of CIPN at doses of 3–30 mg/kg p.o. daily monitoring orexigenic properties, nerve conduction, mechanical allodynia, and intra-epidermal nerve fiber density (IENFD). In a cisplatin-based study, rats were dosed daily for 3 days (0.5 mg/kg i.p.) + HM01. Cisplatin treatment induced mechanical hypersensitivity which was significantly reduced by HM01. In a second study, oxaliplatin was administered to mice (6 mg/kg i.p. 3 times/week for 4 weeks) resulting in significant digital nerve conduction velocity (NCV) deficits and reduction of IENFD. Concurrent HM01 dose dependently prevented the decline in NCV and attenuated the reduction in IENFD. Pharmacokinetic studies showed HM01 accumulation in the dorsal root ganglia and sciatic nerves which reached concentrations > 10 fold that of plasma. In a third model, HM01 was tested in preventive and therapeutic paradigms in a bortezomib-based rat model (0.2 mg/kg i.v., 3 times/week for 8 weeks). In the preventive setting, HM01 blocked bortezomib-induced hyperalgesia and IENFD reduction at all doses tested. In the therapeutic setting, significant effect was observed, but only at the highest dose. Altogether, the robust peripheral nervous system penetration of HM01 and its ability to improve multiple oxaliplatin-, cisplatin-, and bortezomib-induced neurotoxicities suggest that HM01 may be a useful neuroprotective adjuvant for CIPN.

Original languageEnglish (US)
Pages (from-to)89-103
Number of pages15
JournalEuropean Journal of Pharmacology
Volume840
DOIs
StatePublished - Dec 5 2018

Keywords

  • Bortezomib
  • Chemotherapy-induced neurotoxicity
  • Cisplatin
  • Ghrelin agonist
  • Oxaliplatin

ASJC Scopus subject areas

  • Pharmacology

Fingerprint Dive into the research topics of 'Ghrelin agonist HM01 attenuates chemotherapy-induced neurotoxicity in rodent models'. Together they form a unique fingerprint.

Cite this