N-acetyl cysteine (NAC) administration induces behavioral abnormalities in mice experiencing proteotoxic cardiac disease

Background: The co-occurrence of cardiac and neurological complications is becoming increasingly common among individuals diagnosed with either of these disorders. Hypothesis: We tested the hypothesis that elevating glutathione (GSH) levels through N-acetyl cysteine (NAC), a precursor for GSH synthesis, leads to behavioral abnormalities in a mouse model with proteotoxic heart disease. Approach: We used a transgenic mouse model expressing a cardiac-specific human mutant R120G-αB-crystallin (hR120GCryAB-TG), which develops progressive heart failure due to proteotoxicity. Our investigation aimed to understand the effects of NAC on brain redox and behavior in this model. Results: Administering NAC for a period of 12 weeks, we observed an increase in glutathione levels and its redox state (GSH/GSSG) in both heart (1.0 vs. 3.0 Fold in NTG vs. TG; p>0.001) and brain (1.0 vs. 4.0 Fold in NTG vs. TG; p>0.01) tissues. Interestingly, this increase was associated with exacerbated cardiac dysfunction and abnormal behavior. The administration of NAC worsened both structural and functional defects in the hearts of the transgenic (TG) mice, indicating that enhancing antioxidant defense mechanisms could trigger proteotoxic insults through reductive stress (RS). Additionally, the brain of TG mice exhibited enhanced reductive capacity (p>0.01), accompanied by significant alterations in the levels of Tau and α-Synuclein proteins, when compared to non-transgenic (NTG) mice. While NTG mice, with or without NAC treatment, displayed normal behavior, TG mice treated with NAC developed severe behavioral abnormalities, including cognitive impairment (p>0.01). Conclusions: These findings suggest that increased GSH levels (i.e. RS) in progressive heart failure could cause behavioral issues. Thus, further research into the underlying redox mechanisms in other organs, including the brain, is necessary to better understand the use of antioxidant supplements for heart failure treatment. This study will aid in developing personalized therapeutic strategies. National Institute of Health - NHLBI R01 (R01-2RHL118067; Namakkal-Soorappan) American Heart Assocaition (20POST35200085; Sunny). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.