AUTHOR=Alhowail Ahmad H. , Aldubayan Maha A. 

TITLE=Doxorubicin impairs cognitive function by upregulating AMPAR and NMDAR subunit expression and increasing neuroinflammation, oxidative stress, and apoptosis in the brain

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1251917

DOI=10.3389/fphar.2023.1251917

ISSN=1663-9812

ABSTRACT=<p><bold>Introduction:</bold> The anticancer drug doxorubicin (DOX) is used for various malignancies. However, it also causes cognitive impairment in cancer survivors. In order to determine the mechanisms underlying the acute effects of DOX, we assessed the mRNA and protein expression of glutamate receptors and proteins involved in cognitive function and apoptosis.</p><p><bold>Methods:</bold> Fear-conditioning memory tests were performed in rats after a single intraperitoneal injection of DOX (25 mg/kg) to evaluate short-term memory function. Rat brain samples were collected, and GluA1 mRNA and protein expression; <italic>NR2A</italic> and <italic>NR2B</italic> mRNA expression; and COX-2, NF-kB, TNF-α, and MDA, Bax, and caspase-3 levels were assessed via reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assays.</p><p><bold>Results:</bold> We observed a decreased number of entries in Y-maze, decreased exploration time to the novel object in the novel object recognition (NOR), and decreased freezing time in the fear-conditioning memory tests in DOX-treated rats relative to those in control rats, demonstrating cognitive impairment. <italic>GluA1</italic>, <italic>NR2B</italic>, and <italic>NR2A</italic> expression and MDA, NF-κB, Bax, COX-2, TNF-α, and caspase-3 levels in the brain were significantly elevated in DOX-treated rats.</p><p><bold>Conclusion:</bold> DOX induced cognitive impairment in the rats via neuronal toxicity by upregulating AMPAR and NMDAR expression and increasing neuroinflammation, oxidative stress, and apoptosis in the brain.</p>