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.

Doxorubicin and cyclophosphamide induce cognitive dysfunction and activate the ERK and AKT signaling pathways

“…We found that the Akt and ERK1/2 pathways were involved in doxorubicin and cyclophosphamide induced cognitive changes and need to be further studied. Our finding that both ERK1/2 and Akt pathways are activated are similar to those recently of Briones et al [32], however, these investigators did not use intact female rats in their study as a comparison.…”

Clinical characteristics, pathophysiology, and management of noncentral nervous system cancer‐related cognitive impairment in adults

“…Unraveling the precise mechanisms underlying CRCI may facilitate the identification of novel pharmacologic treatment strategies. Several animal studies focusing on the impact of chemotherapy on cognition have suggested promising interventions, such as preventing oxidative stress associated with chemotherapy using 2‐Mercaptoethane sulfonate, N‐acetylcysteine, or melatonin; stimulating neurogenesis with insulin‐like growth factor‐1, fluoxetine, or glucose; and treatments with glutamate receptor antagonists, such as dextromethorphan or memantine, that ameliorate chemotherapy‐induced CRCI. The arrival of new targeted agents and immunotherapies that may influence cognition, either alone or in combination with traditional anticancer agents, will necessitate further preclinical work to understand and potentially improve adverse side effects on cognition.…”

Protocol for the “Chemobrain in Motion – study” (CIM – study): a randomized placebo-controlled trial of the impact of a high-intensity interval endurance training on cancer related cognitive impairments in women with breast cancer receiving first-line chemotherapy

“…At the same time, antiinflammatory cytokines, such as Interleukin-1 receptor antagonist (IL-1RA) and Interleukin-10 (IL-10) are decreased [ 30 ]. Hypothesized mechanisms of CRCI also include decreased levels of neurotrophic and growth factors, such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) [ 31 – 35 ].…”