Doxorubicin-induced elevated oxidative stress and neurochemical alterations in brain and cognitive decline: protection by MESNA and insights into mechanisms of chemotherapy-induced cognitive impairment (“chemobrain”)

Abstract

Chemotherapy-induced cognitive impairment (CICI) is now widely recognized as a real and too common complication of cancer chemotherapy experienced by an ever-growing number of cancer survivors. Previously, we reported that doxorubicin (Dox), a prototypical reactive oxygen species (ROS)-producing anti-cancer drug, results in oxidation of plasma proteins, including apolipoprotein A-I (ApoA-I) leading to tumor necrosis factor-alpha (TNF-α)-mediated oxidative stress in plasma and brain. We also reported that co-administration of the antioxidant drug, 2-mercaptoethane sulfonate sodium (MESNA), prevents Dox-induced protein oxidation and subsequent TNF-α elevation in plasma. In this study, we measured oxidative stress in both brain and plasma of Dox-treated mice both with and without MESNA. MESNA ameliorated Dox-induced oxidative protein damage in plasma, confirming our prior studies, and in a new finding led to decreased oxidative stress in brain. This study also provides further functional and biochemical evidence of the mechanisms of CICI. Using novel object recognition (NOR), we demonstrated the Dox administration resulted in memory deficits, an effect that was rescued by MESNA. Using hydrogen magnetic resonance imaging spectroscopy (H1-MRS) techniques, we demonstrated that Dox administration led to a dramatic decrease in choline-containing compounds assessed by (Cho)/creatine ratios in the hippocampus in mice. To better elucidate a potential mechanism for this MRS observation, we tested the activities of the phospholipase enzymes known to act on phosphatidylcholine (PtdCho), a key component of phospholipid membranes and a source of choline for the neurotransmitter, acetylcholine (ACh). The activities of both phosphatidylcholine-specific phospholipase C (PC-PLC) and phospholipase D were severely diminished following Dox administration. The activity of PC-PLC was preserved when MESNA was co-administered with Dox; however, PLD activity was not protected. This study is the first to demonstrate the protective effects of MESNA on Dox-related protein oxidation, cognitive decline, phosphocholine (PCho) levels, and PC-PLC activity in brain and suggests novel potential therapeutic targets and strategies to mitigate CICI.

Cellular mechanisms and treatments for chemobrain: insight from aging and neurodegenerative diseases

“…In addition, increased acetylcholine esterase activity was observed in the hippocampus of rats treated with doxorubicin (El‐Agamy et al , ). A reduction in choline content, the precursor for acetylcholine, was also observed after doxorubicin treatment (Keeney et al , ), suggesting that reduced cholinergic activity may be a factor in chemobrain.…”

Chemobrain as a Product of Growing Success in Chemotherapy - Focus On Glia As Both A Victim And A Cure

“…[47]. It has been recently shown that co-administration of the antioxidant drug, 2-mercaptoethane sulfonate sodium [48,49], astaxanthin, a naturally occurring carotenoid [50], catechin, a tea polyphenol [51] as well as rutin, a glycoside abundant in citrus fruits [52] prevent doxorubicin-induced cognitive decline in animal model and the suggested mechanism is through impact on oxidative and inflammatory machineries. Of note, however that blunting oxidative stress may also potentially decrease anticancer activity [53].…”

The impact of high-intensity interval training exercise on breast cancer survivors: a pilot study to explore fitness, cardiac regulation and biomarkers of the stress systems

“…This occurs by a combination of sympathetic overactivity and parasympathetic underactivity negatively impacting health by causing adverse effects such as hypertension and CVD [ 42 , 43 ]. Chemotherapy could potentially impact acetylcholine levels [ 44 ] directly impacting the PNS, suggesting that the vagus nerve could be implicated via the same mechanism caused by chemotherapy. These changes may be reflected in lower resting HRV in breast cancer survivors.…”