Cognitive dysfunction induced by chronic administration of common cancer chemotherapeutics in rats
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Although cognitive dysfunction manifested by severe memory and attention deficits has been reported in up to 70% of cancer patients undergoing chemotherapy, the mechanisms of this serious side effect have not been defined. In particular, it has not been decisively resolved whether the dysfunction is attributable to the chemotherapy or to the malignancy itself. In the present study we tested whether cognitive dysfunction can be induced in an experimental setting by the administration of commonly used chemotherapeutics to rats. Female 10 month old Sprague–Dawley rats were injected intraperitoneally with a combination of 2.5 mg/kg of adriamycin (ADR) and 25 mg/kg of cytoxan (CTX). A total of four doses were given at weekly intervals. The control group was treated with saline only. No mortality and no apparent morbidity were observed in either group. However, the chemotherapeutic treatment severely impaired memory function of rats as measured by a passive avoidance test. This memory deficiency was fully prevented by the administration of an antioxidant, N-acetyl cysteine (NAC) injected subcutaneously three times a week at 200 mg/kg in the course of chemotherapeutic treatment. These results indicate that chemotherapeutic agents alone, i.e., in the absence of malignancy, damage the brain resulting in memory dysfunction. Moreover, the results strongly indicate that the damaging effect is mediated by oxidative stress, as memory dysfunction is preventable by the co-administration of NAC.
KeywordsAdriamycin Cytoxan N-Acetyl cysteine Memory impairment
This study was supported by DOD research grant DAMD17-02-1-0621.
- Ahles TA, Saykin AJ, Furstenberg CT, Cole B, Mott LA, Skalla K, Whedon MB, Bivens S, Mitchell T, Greenberg ER, Silberfarb PM (2002) Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma. J Clin Oncol 20:485–493PubMedCrossRefGoogle Scholar
- Bhattacharya A, Lawrence RA, Krishnan A, Zaman K, Sun D, Fernandes G (2003) Effect of dietary n-3 and n-6 oils with and without food restriction on activity of antioxidant enzymes and lipid peroxidation in livers of cyclophosphamide treated autoimmune-prone NZB/W female mice. J Am Coll Nutr 22:388–399PubMedGoogle Scholar
- Durken M, Herrnring C, Finckh B, Nagel S, Nielsen P, Fischer R, Berger HM, Moison RM, Pichlmeier U, Kohlschutter B, Zander AR, Kohlschutter A (2000) Impaired plasma antioxidative defense and increased nontransferrin-bound iron during high-dose chemotherapy and radiochemotherapy preceding bone marrow transplantation. Free Radic Biol Med 28:887–894PubMedCrossRefGoogle Scholar
- Joshi G, Hardas S, Sultana R, St Clair DK, Vore M, Butterfield DA (2007) Glutathione elevation by gamma-glutamyl cysteine ethyl ester as a potential therapeutic strategy for preventing oxidative stress in brain mediated by in vivo administration of adriamycin: Implication for chemobrain. J Neurosci Res 85:497–503PubMedCrossRefGoogle Scholar
- Tanaka M, Yoshida S (1980) Mechanism of the inhibition of calf thymus DNA polymerases alpha and beta by daunomycin and adriamycin. J Biochem (Tokyo) 87:911–918Google Scholar
- van Dam FS, Schagen SB, Muller MJ, Boogerd W, vd Wall E, Droogleever Fortuyn ME, Rodenhuis S (1998) Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. J Natl Cancer Inst 90:210–218PubMedCrossRefGoogle Scholar
- Zhang HT, Zhao Y, Huang Y, Dorairaj NR, Chandler LJ, O’Donnell JM (2004) Inhibition of the phosphodiesterase 4 (PDE4) enzyme reverses memory deficits produced by infusion of the MEK inhibitor U0126 into the CA1 subregion of the rat hippocampus. Neuropsychopharmacology 29:1432–1439PubMedCrossRefGoogle Scholar