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.