Protective Effect of Erythropoietin and Its Carbamylated Derivative in Experimental Cisplatin Peripheral Neurotoxicity

Abstract

Purpose: 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. Experimental Design: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 Ag/kg/d thrice weekly) on CDDP (2 mg/kg/d i.p. twice weekly for 4 weeks) neurotoxicity in vivo.Results: CDDP given toWistar 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.Chemotherapy-induced peripheral neurotoxicity (CIPN) is a major clinical problem because it is a dose-limiting side effect of important and effective antineoplastic drugs (1). The incidence, severity, and clinical symptoms and signs of CIPN depend on the drug given and its schedules. Severe neuropathy can occur in 3% to 7% of treated cases with single agents but can increase to 38% with combined regimens (2, 3). Moreover, even when CIPN is not dose-limiting, it may severely affect the quality of life of cancer patients and cause chronic discomfort. Therefore, effective prevention and/or treatment of CIPN would be a major advance for cancer patients.Cisplatin (CDDP) and the other platinum-derived drugs are among the most effective antineoplastic agents, but they are severely neurotoxic. The clinical features of CDDP neurotoxicity in humans are mainly ataxia, pain, and sensory impairment secondary to accumulation of CDDP in the dorsal root ganglia (DRG) and subsequent damage, resulting in secondary nerve fiber axonopathy.We have developed an experimental model of peripheral n...

Animal Models of Chemotherapy-Evoked Painful Peripheral Neuropathies

“…According to Bianchi et al, 81,82 co-administration of cisplatin and erythropoietin, or carbamylated erythropoietin, partially but significantly prevented the thermal heat hypoalgesia without affecting tumor growth. In regard to human recombinant NGF, co-administrered with cisplatin in the rat, it prevents or delays the impaired proprioception.…”

Recombinant human erythropoietin counteracts cisplatin-induced visceral hyperalgesia

“…The effect of rhEPO on cisplatin-induced neurotoxicity had been demonstrated previously [20] . Here no difference in sensory nerve conduction velocity was found between control and cisplatin+rhEPO groups.…”

Carbamylated Erythropoietin and Its Role of Tissue Protection

“…It conducted central neuroprotective effects in disparate models, such as focal cerebral ischemia (10), embolic stroke (11), traumatic brain injury (TBI) (12), and traumatic brain injury-induced diffuse edema (13). Subsequently, CEPO was shown to exert peripheral nerve protective effect, through which it prevented chemotherapy-induced sensory nerve conduction velocity reduction (14), and reduced motoneuron degeneration in vitro and vivo (15). In addition, Wang et al (16) employed a neurosphere assay to find that CEPO also enhanced neurogenesis and selectively promotes neural progenitor cell differentiation into neurons, indicating that CEPO could mediate cell differentiation.…”