Can Insulin-like Growth Factor 1 Protect Against Chemo Brain?

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Chemotherapy recipients have long complained of decreased mental function during and after treatment, yet the medical community has only recently acknowledged the reality of chemo brain, the term for chemotherapy’s degenerative effect on normal cognitive function. In an article in Cancer Investigation, researchers at the University of Rochester Medical Center (URMC) in New York said the cause of chemo brain remains a mystery but numerous studies have shown that patients undergoing chemotherapy demonstrate “memory lapses, trouble concentrating, difficulty in word association, confusion, trouble multitasking, and slow thinking and information processing,” and these effects often persist ≥5 years after discontinuing therapy.

Neuroimaging studies support the clinical evidence of chemo brain, showing restricted blood flow and other abnormalities in areas of the brain where many cognitive functions transpire. Using mice, the URMC researchers have isolated a possible cause for chemo brain and identified insulin-like growth factor 1 (IGF-1), known to increase neural cell proliferation, as a possible treatment.

The team had hypothesized that chemotherapy drugs such as cyclophosphamide (Cytoxan) and fluorouracil (5-FU), known to cross the blood-brain barrier, were responsible for impairing neural cell proliferation and that agents like paclitaxel and doxorubicin (Adriamycin), which cross the bloodbrain barrier infrequently, would be less likely to cause chemo brain. Instead, the researchers found all four drugs significantly reduced brain cell proliferation, contradicting the study’s hypothesis. Mice received one of the chemotherapy drugs or saline. Data showed a 15.4% reduction in cell regeneration associated with paclitaxel, 30.5% for 5-FU, 22.4% for cyclophosphamide, and 36% for doxorubicin compared with saline (P <.05).

In a press release, Robert Gross, MD, PhD, professor of Neurology and Pharmacology and Physiology at URMC and principal investigator of the study, said, “It could be that all of the chemo drugs cross into the brain after all, or that they act via peripheral mechanisms such as inflammation that could open up the blood-brain barrier.”

While the study failed to isolate a drug attribute responsible for chemo brain, the results with IGF-1 were more auspicious. Preclinical studies had demonstrated that IGF-1 facilitates neurogenesis, leading the URMC researchers to test it in mice to see whether it might mitigate chemotherapy-related cognitive impairment. The team administered IGF-1 before and after a conventional multiple-dose regimen of cyclophosphamide and a single high-dose regimen. IGF-1 appeared to increase brain cell proliferation in both treatment groups compared with the mice who received saline, but the effects of IGF-1 on the mice that received the low-dose regimen were not significant. The high-dose model results proved more effective, with a mean increase in new cells of 27.5% compared with saline.

“It is not yet clear how our results can be generally applied to humans, but we have taken a very significant step toward reproducing a debilitating condition and finding ways to treat it,” said Gross.

The research team intends to examine further the effects of IGF-1 and other chemotherapy drugs on brain cell growth. “Neurogenesis can also be altered by stress, sleep deprivation, and depression, all of which are common among cancer patients,” said Michelle Janelsins, PhD, research assistant professor of Radiation Oncology at the James P. Wilmot Cancer Center and co-investigator and lead author of the study. “More thorough studies are needed to understand the interplay of these factors and the long-term effects of chemotherapy on the brain.”