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Neuroprotective Effects of Lithium in Chemotherapy‐induced Cognitive Impairments
Author(s) -
Nguyen Lien D.,
Fischer Tom T.,
Ehrlich Barbara E.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.00558
Subject(s) - neuroprotection , hippocampus , paclitaxel , lithium (medication) , medicine , cognition , chemotherapy , neuroscience , hippocampal formation , psychology , pharmacology
Chemotherapy, a life‐saving treatment for cancer patients, is often associated with debilitating, sometimes irreversible, side effects. Approximately 40% of cancer survivors suffer from cognitive impairments, with symptoms including memory lapses, learning difficulties, and troubles with focusing, planning, multi‐tasking, and verbal communication. However, essential questions concerning the specific cognitive functions affected, the trajectories of cognitive changes, and the underlying mechanisms remain unclear. We aimed to investigate these questions by developing a mouse model of paclitaxel‐induced cognitive impairments. We also examined the potential neuroprotective effects of lithium, a compound previously shown to be beneficial in multiple neuropsychiatric and neurodegenerative disorders. Mice receiving four intraperitoneal injections of paclitaxel showed impaired short‐term spatial memory acquisition within a week of the last injection, which persisted for at least three weeks. Using Golgi‐Cox staining, we observed reduced dendritic arborization and spine density in the hippocampus and the cortex following paclitaxel injection, suggesting that these regions were particularly vulnerable. Importantly, lithium pretreatment completely rescued the behavioral and cellular deficits observed. Subsequently, we showed that paclitaxel treatment resulted in the upregulation of protein kinase C (PKC) both acutely and chronically, suggesting that dysregulated PKC signaling contributed to the neurological dysfunctions observed. In conclusion, we establish a molecular and cellular basis for paclitaxel‐induced cognitive impairments. Our findings also suggest a role for lithium as a protective agent to prevent cognitive impairments induced by paclitaxel and other chemotherapeutics.