Chemotherapy-induced cognitive impairment - also known as “chemobrain”- is a negative side effect observed in patients treated with certain drugs. Chemobrain impairments include defects in memory, attention, executive function, and processing speed that can persist in patients long after treatment is concluded. Neuroimaging evaluation of patients with chemobrain indicates structural alterations in white and gray matter with regional changes in brain activity and a global disruption in connectivity. Previous studies have focused on effects of methotrexate- and cyclophosphamide-based treatments for breast cancer. These drugs are known to contribute to cognitive impairment via neuro-inflammation and defective neurogenesis. Recently, researchers have turned their attention to the cognitive impairment seen in cancer patients treated with platinum- based compounds such as cisplatin. To further understand the neurological consequences of cisplatin treatment, a team led by Dr. Cobi Heijen at University of Texas MD Anderson Cancer Center established a mouse model of cisplatin-induced cognitive impairment and identified structural cerebral pathology associated with cisplatin treatment. Building on previous research that metformin, a safe and commonly used anti-diabetic treatment, prevented the development of cisplatin-induced peripheral neuropathy, the Heijin team evaluated whether co-administration of metformin would also prevent cisplatin-induced pathology in the CNS and associated cognitive dysfunction (Zhou W, Kavelaars A, Heijnen CJ. 2016).
To induce “chemobrain” in the mice, the Heijin group treated C57BL/6J (000664) female mice from The Jackson Laboratory for five days with daily injections followed by five days of rest for three cycles. To evaluate the effectiveness of metformin at preventing the cisplatin-induce defects, mice received co-administration of metformin starting one day prior to and ending one day after the cisplatin treatments in each cycle. For all behavioral tests mice were assessed one week after the last cisplatin treatment cycle.
To assess cognitive function treated mice were evaluated in novel object and place recognition test (NOPRT) and social recognition tests. In the NOPRT, mice were exposed to two identical objects during the training phase. They were then exposed to one familiar object and one novel object placed in a novel location. Cognitive impairment is indicated by a reduction in preference for the novel object in the novel place. Mice that received cisplatin alone demonstrated reduced preference for the novel object, which was abolished when metformin was co-administered. In the social recognition test, the treated mice were acclimated to a novel juvenile mouse. After a break period, the treated mice were exposed to the now familiar mouse and another novel mouse. As with the NOPRT, mice that received cisplatin showed less preference for the novel mouse whereas mice that received cisplatin with metformin spent more time investigating and exploring the new mouse, similar to control mice that were treated with just saline or saline and metformin. The reduced social discrimination score in the the cisplatin-only group is indicative of cognitive impairment.
The Heijen team had demonstrated previously that co-administration of metformin with cisplatin could prevent cisplatin-induced peripheral neuropathy as assessed by measuring mechanical allodynia (pain in response to light touch or pressure that is not normally painful). The metformin dosages used in those studies were higher than what they found was sufficient to protect the mice from cisplatin-induced cognitive defects. In their latest study they found that the same lower metformin dose that protected the mice against cisplatin-induced cognitive defects also protected the mice from the cisplatin-induced effects on pain thresholds.
During the initial characterization of brain morphology in cisplatin-treated mice, neuron organization in the cingulate cortex showed the most prominent changes. In addition to being integral to the limbic system, which is important in emotion processing, learning, and memory, the cingulate cortex is important in cognitive function, particularly in spatial recognition. To quantitate the effects of cisplatin and metformin on neural organization in the cingulate cortex, the MD Anderson investigators used myelin basic protein (MBP) fiber analysis. Cisplatin treatment resulted in an increase of MBP-positive fibers, indicating decreased white matter. The cisplatin-induced increase in MBP-positive fibers was prevented by co-administration with metformin. Additionally, metformin prevented a cisplatin-induced decrease in dendritic spine density in pyramidal neurons in the cingulate cortex, further supporting the protective role of metformin on cognitive function.
Increases in glial activation in the spinal cord from platinum-based compounds are associated with neuropathic pain development. Interestingly, no increases in glial activation were detected in the brains of cisplatin-treated mice. This data suggests that the spinal cord may be the area associated with cisplatin-induced peripheral neuropathy via glial activation, but additional studies are needed to confirm this directly.
In summary, the Heijin team showed that metformin, the commonly used anti-diabetic drug, protects against cisplatin-induced cognitive impairment and also supports recent findings that metformin prevents the development of cisplatin-induced peripheral neuropathy. Because many cancer patients that take platinum-based compounds develop chemobrain, these findings advocate for clinical trials to evaluate the efficacy of metformin co-administration in preventing “chemobrain” in patients.
Zhou W, Kavelaars A, Heijnen CJ. 2016. Metformin prevents cisplatin-induced cognitive impairment and brain damage in mice. PLos One. PMID: 27018597