RETRACTED: Involvement of insulin-like growth factor-1 in chemotherapy-related cognitive impairment

Abstract

Here we examined the involvement of insulin-like growth factor 1 (IGF-1) on chemotherapy-induced cognitive impairment. Sixty-four ovariectomized female Sprague-Dawley rats were included in the study and given cyclophosphamide, methothrexate, and 5-fluorouracil (CMF) drug combination or saline (control). CMF was given once a week for 4 weeks. In one experiment, behavioral testing using the cued learning and spontaneous object recognition tasks were performed either: at the end of treatment or 4 weeks after treatment. In another experiment, rats from the chemotherapy and saline groups received either: continuous insulin-like growth factor 1 (IGF-1) or vehicle delivered subcutaneously via osmotic pump for 21 days (started the week after completion of therapy). Bromodeoxyuridine injections were given for 3 consecutive days starting at 2 weeks after completion of chemotherapy to assess the survival of proliferating cells. Increased levels of IGF-1 and activation of its receptor as well as increased activation of Akt and Erk1/2, its downstream signaling pathways was seen immediately after completion of chemotherapy but decreased 4 weeks after treatment. Behavioral testing showed CMF-induced cognitive impairment after completion of therapy and persisted for 4 weeks. We also found that giving IGF-1 significantly increased activation of its receptor, and the Akt and Erk1/2 pathways, and most importantly attenuated chemotherapy-induced cognitive impairment. CMF-induced neuronal apoptosis was also seen and the ratio of surviving cells that proliferate was higher compared to the number of apoptotic cells in the CMF rats given IGF-1. These results suggest that IGF-1 is involved in CMF-induced cognitive impairment by modulating cell death and cell proliferation.