Pharmacological rescue of cognitive function in a mouse model of chemobrain

Autor: Lien D. Nguyen, Barbara E. Ehrlich, Tom T. Fischer
Rok vydání: 2020
Předmět:
0301 basic medicine
Lithium (medication)
Paclitaxel
medicine.medical_treatment
Hippocampus
Pharmacology
Spines
03 medical and health sciences
Cellular and Molecular Neuroscience
chemistry.chemical_compound
Mice
0302 clinical medicine
Cognition
Chemotherapy-Related Cognitive Impairment
Protein kinase C
medicine
Animals
Inositol 1
4
5-Trisphosphate Receptors
Prefrontal cortex
RC346-429
Molecular Biology
Chemotherapy
business.industry
RC952-954.6
Dendrites
Inositol trisphosphate receptor
Molecular medicine
Antineoplastic Agents
Phytogenic
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
Chelerythrine
Neuroprotective Agents
chemistry
Geriatrics
Female
Calcium
Neurology (clinical)
Neurology. Diseases of the nervous system
business
Lithium Chloride
030217 neurology & neurosurgery
medicine.drug
Research Article
Zdroj: Molecular Neurodegeneration
Molecular Neurodegeneration, Vol 16, Iss 1, Pp 1-16 (2021)
ISSN: 1750-1326
Popis: Background After chemotherapy, many cancer survivors suffer from long-lasting cognitive impairment, colloquially known as “chemobrain.” However, the trajectories of cognitive changes and the underlying mechanisms remain unclear. We previously established paclitaxel-induced inositol trisphosphate receptor (InsP3R)-dependent calcium oscillations as a mechanism for peripheral neuropathy, which was prevented by lithium pretreatment. Here, we investigated if a similar mechanism also underlay paclitaxel-induced chemobrain. Method Mice were injected with 4 doses of 20 mg/kg paclitaxel every other day to induced cognitive impairment. Memory acquisition was assessed with the displaced object recognition test. The morphology of neurons in the prefrontal cortex and the hippocampus was analyzed using Golgi-Cox staining, followed by Sholl analyses. Changes in protein expression were measured by Western blot. Results Mice receiving paclitaxel showed impaired short-term spatial memory acquisition both acutely 5 days post injection and chronically 23 days post injection. Dendritic length and complexity were reduced in the hippocampus and the prefrontal cortex after paclitaxel injection. Concurrently, the expression of protein kinase C α (PKCα), an effector in the InsP3R pathway, was increased. Treatment with lithium before or shortly after paclitaxel injection rescued the behavioral, cellular, and molecular deficits observed. Similarly, memory and morphological deficits could be rescued by pretreatment with chelerythrine, a PKC inhibitor. Conclusion We establish the InsP3R calcium pathway and impaired neuronal morphology as mechanisms for paclitaxel-induced cognitive impairment. Our findings suggest lithium and PKC inhibitors as candidate agents for preventing chemotherapy-induced cognitive impairment.
Databáze: OpenAIRE
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