Abstract
Cognitive impairments are a common side effect of chemotherapy that often persists long after treatment completion. There are no FDA-approved interventions to treat these cognitive deficits also called ‘chemobrain’. We hypothesized that nasal administration of mesenchymal stem cells (MSC) reverses chemobrain. To test this hypothesis, we used a mouse model of cognitive deficits induced by cisplatin that we recently developed. Mice were treated with two cycles of cisplatin followed by nasal administration of MSC. Cisplatin treatment induced deficits in the puzzle box, novel object/place recognition and Y-maze tests, indicating cognitive impairment. Nasal MSC treatment fully reversed these cognitive deficits in males and females. MSC also reversed the cisplatin-induced damage to cortical myelin. Resting state functional MRI and connectome analysis revealed a decrease in characteristic path length after cisplatin, while MSC treatment increased path length in cisplatin-treated mice. MSCs enter the brain but did not survive longer than 12-72 hrs, indicating that they do not replace damaged tissue. RNA-sequencing analysis identified mitochondrial oxidative phosphorylation as a top pathway activated by MSC administration to cisplatin-treated mice. Consistently, MSC treatment restored the cisplatin-induced mitochondrial dysfunction and structural abnormalities in brain synaptosomes. Nasal administration of MSC did not interfere with the peripheral anti-tumor effect of cisplatin. In conclusion, nasal administration of MSC may represent a powerful, non-invasive, and safe regenerative treatment for resolution of chemobrain.
Highlights
Chemotherapy is still one of the most effective treatments to combat cancer
Male and female mice were treated with two cycles of cisplatin (2.3 mg/kg for 5 days), [15] followed by nasal administration of mesenchymal stem cells (MSC) at 48 and 96 h after the last dose of cisplatin
In both male and female mice nasal administration of two doses of 1×106 MSC at 48 and 96 h after completion of cisplatin treatment completely reversed the impaired executive function induced by cisplatin (Figure 1A and Supplementary Figure 2A)
Summary
Chemotherapy is still one of the most effective treatments to combat cancer. Chemotherapy is associated with many negative side effects, including fatigue, pain, numbness and tingling in hands and feet, and cognitive impairments [1,2,3,4]. In view of the rapidly growing number of cancer survivors, there is an urgent need for an effective therapeutic intervention to treat these neurotoxicities. Chemobrain has been observed in 78% of cross-sectional and 69% of prospective longitudinal studies performed between 1995 and 2012 in patients treated for breast cancer [3]. In approximately 30% of patients, symptoms of chemobrain persist long after completion of treatment thereby severely hampering quality of life and limiting their home and occupational activities [4]. There is a growing concern that chemotherapy may increase the risk for accelerated aging and later neurodegenerative conditions [6]
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