Oxaliplatin-induced neuropathy: oxidative stress as pathological mechanism. Protective effect of silibinin.
Oxaliplatin is the standard treatment for advanced colorectal cancer. Its dose-limiting toxicity is the development of a painful neuropathic syndrome sustained by unclear mechanisms. Although the oxidative hypothesis is a matter of debate, direct data about oxidative damage induced in vivo by anticancer agents are lacking and the efficacy of the available antioxidant compounds are unsatisfactory. In a rat model of painful oxaliplatin-induced neuropathy (2.4 mgkg(-1) i.p., daily for 21 days), we described an important component of oxidative stress. In the plasma of oxaliplatin-treated rats, the increases in carbonylated protein and thiobarbituric acid reactive substances were the index of the resultant protein oxidation and lipoperoxidation, respectively. The same pattern of oxidation was revealed also in the sciatic nerve, and in the spinal cord where the damage reached the DNA level. The antioxidant compound silibinin (100 mgkg(-1) per os), administered once a day, starting from the first day of oxaliplatin injection until the 20th, prevented oxidative damage as did α-tocopherol. Repetitive administration of silibinin, as well as α-tocopherol, reduced oxaliplatin-dependent pain induced by mechanical and thermal stimuli. Antioxidants were also able to improve motor coordination. The antineuropathic effect of both molecules improved by about 50% oxaliplatin-induced behavioral alterations.


CONCLUSIONS
This study characterizes oxidative stress parameters in a rat model of oxaliplatin-induced neuropathy. A relationship between the improvement of oxidative alterations and pain relief is established in rats treated with natural antioxidant compounds like α-tocopherol and silibinin. Silibinin could be a valid therapeutic option for chemotherapy-induced neuropathy.
Deparment of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy. lorenzo.mannelli@unifi.it
Lorenzo
L
Di Cesare Mannelli
Matteo
M
Zanardelli
Paola
P
Failli
Carla
C
Ghelardini
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D000975:Antioxidants / Q000494:pharmacology*; D004195:Disease Models, Animal; D008297:Male; D009944:Organoplatinum Compounds / Q000633:toxicity; D000077150:Oxaliplatin; D018384:Oxidative Stress / Q000187:drug effects*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*; D024502:alpha-Tocopherol / Q000494:pharmacology
D000970:Antineoplastic Agents; D000975:Antioxidants; D009944:Organoplatinum Compounds; D012838:Silymarin; D000077150:Oxaliplatin; D000077385:Silybin; D024502:alpha-Tocopherol