title: Protective effect of erythropoietin and its carbamylated derivative in experimental Cisplatin peripheral neurotoxicity.
abstract: OBJECTIVE
  Antineoplastic drugs, such as cisplatin (CDDP), are severely neurotoxic, causing disabling peripheral neuropathies with clinical signs known as chemotherapy-induced peripheral neurotoxicity. Cotreatment with neuroprotective agents and CDDP has been proposed for preventing or reversing the neuropathy. Erythropoietin given systemically has a wide range of neuroprotective actions in animal models of central and peripheral nervous system damage. However, the erythropoietic action is a potential cause of side effects if erythropoietin is used for neuroprotection. We have successfully identified derivatives of erythropoietin, including carbamylated erythropoietin, which do not raise the hematocrit but retain the neuroprotective action exerted by erythropoietin.
  
  
  METHODS
  We have developed previously an experimental chemotherapy-induced peripheral neurotoxicity that closely resembles CDDP neurotoxicity in humans. The present study compared the effects of erythropoietin and carbamylated erythropoietin (50 microg/kg/d thrice weekly) on CDDP (2 mg/kg/d i.p. twice weekly for 4 weeks) neurotoxicity in vivo.
  
  
  RESULTS
  CDDP given to Wistar rats significantly lowered their growth rate (P < 0.05), with slower sensory nerve conduction velocity (P < 0.001) and reduced intraepidermal nerve fibers density (P < 0.001 versus controls). Coadministration of CDDP and erythropoietin or carbamylated erythropoietin partially but significantly prevented the sensory nerve conduction velocity reduction. Both molecules preserved intraepidermal nerve fiber density, thus confirming their neuroprotective effect at the pathologic level. The protective effects were not associated with any difference in platinum concentration in dorsal root ganglia, sciatic nerve, or kidney specimens.
  
  
  CONCLUSIONS
  These results widen the spectrum of possible use of erythropoietin and carbamylated erythropoietin as neuroprotectant drugs, strongly supporting their effectiveness.
authors.affiliation: Mario Negri Institute for Pharmacological Research, Milan, Italy. robbia@marionegri.it
authors.forename: Roberto
authors.initials: R
authors.lastname: Bianchi
authors.forename: Michael
authors.initials: M
authors.lastname: Brines
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lauria
authors.forename: Costanza
authors.initials: C
authors.lastname: Savino
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gilardini
authors.forename: Gabriella
authors.initials: G
authors.lastname: Nicolini
authors.forename: Virginia
authors.initials: V
authors.lastname: Rodriguez-Menendez
authors.forename: Norberto
authors.initials: N
authors.lastname: Oggioni
authors.forename: Annalisa
authors.initials: A
authors.lastname: Canta
authors.forename: Paola
authors.initials: P
authors.lastname: Penza
authors.forename: Raffaella
authors.initials: R
authors.lastname: Lombardi
authors.forename: Claudio
authors.initials: C
authors.lastname: Minoia
authors.forename: Anna
authors.initials: A
authors.lastname: Ronchi
authors.forename: Anthony
authors.initials: A
authors.lastname: Cerami
authors.forename: Pietro
authors.initials: P
authors.lastname: Ghezzi
authors.forename: Guido
authors.initials: G
authors.lastname: Cavaletti
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D002945:Cisplatin / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004921:Erythropoietin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000378:metabolism; D013623:Tail / Q000187:drug effects / Q000294:innervation / Q000503:physiopathology
chemical_list: D000970:Antineoplastic Agents; D018696:Neuroprotective Agents; C488171:carbamylated erythropoietin; D004921:Erythropoietin; D002945:Cisplatin