Protective effect of erythropoietin and its carbamylated derivative in experimental Cisplatin peripheral neurotoxicity.
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.
Bianchi
Roberto
R
Mario Negri Institute for Pharmacological Research, Milan, Italy. robbia@marionegri.it
Brines
Michael
M
Lauria
Giuseppe
G
Savino
Costanza
C
Gilardini
Alessandra
A
Nicolini
Gabriella
G
Rodriguez-Menendez
Virginia
V
Oggioni
Norberto
N
Canta
Annalisa
A
Penza
Paola
P
Lombardi
Raffaella
R
Minoia
Claudio
C
Ronchi
Anna
A
Cerami
Anthony
A
Ghezzi
Pietro
P
Cavaletti
Guido
G
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
D000970:Antineoplastic Agents; D018696:Neuroprotective Agents; C488171:carbamylated erythropoietin; D004921:Erythropoietin; D002945:Cisplatin