1. The Potential of N-Acetyl-L-Cysteine (NAC) in the Treatment of Psychiatric Disorders
Richard C J Bradlow, Michael Berk, Peter W Kalivas, Sudie E Back, Richard A Kanaan CNS Drugs. 2022 May;36(5):451-482. doi: 10.1007/s40263-022-00907-3. Epub 2022 Mar 22.
N-acetyl-L-cysteine (NAC) is a compound of increasing interest in the treatment of psychiatric disorders. Primarily through its antioxidant, anti-inflammatory, and glutamate modulation activity, NAC has been investigated in the treatment of neurodevelopmental disorders, schizophrenia spectrum disorders, bipolar-related disorders, depressive disorders, anxiety disorders, obsessive compulsive-related disorders, substance-use disorders, neurocognitive disorders, and chronic pain. Whilst there is ample preclinical evidence and theoretical justification for the use of NAC in the treatment of multiple psychiatric disorders, clinical trials in most disorders have yielded mixed results. However, most studies have been underpowered and perhaps too brief, with some evidence of benefit only after months of treatment with NAC. Currently NAC has the most evidence of having a beneficial effect as an adjuvant agent in the negative symptoms of schizophrenia, severe autism, depression, and obsessive compulsive and related disorders. Future research with well-powered studies that are of sufficient length will be critical to better understand the utility of NAC in the treatment of psychiatric disorders.
2. N-Acetyl-L-Cysteine Potentially Inhibits Complement Activation in Transplantation-Associated Thrombotic Microangiopathy
Jiaqian Qi, Shuhong Hu, Xuefeng He, Tingting Pan, Liping Yang, Rui Zhang, Yaqiong Tang, Depei Wu, Yue Han Transplant Cell Ther. 2022 Apr;28(4):216.e1-216.e5. doi: 10.1016/j.jtct.2021.12.018. Epub 2021 Dec 31.
Transplant-associated thrombotic microangiopathy (TA-TMA) has a high mortality rate and lacks effective treatments. We searched the GEO database and analyzed RNA-seq data and whole-genome sequencing data from patients' blood samples. We identified N-acetyl-L-cysteine (NAC) as a possible therapeutic target for TA-TMA. In vitro experiments showed that NAC reduced complement activation and VWF multimerization in HUVECs. We also treated a 36-year-old female TA-TMA patient with NAC. Hemoglobin, platelet counts, lactate dehydrogenase levels, and sC5b-9 levels and schistocytes were normalized after using NAC. It shows that NAC may be an effective drug to improve TA-TMA symptoms by inhibiting complement activation.
3. N-Acetyl-L-cysteine in human rheumatoid arthritis and its effects on nitric oxide (NO) and malondialdehyde (MDA): analytical and clinical considerations
Dimitrios Tsikas, Marie Mikuteit Amino Acids. 2022 Sep;54(9):1251-1260. doi: 10.1007/s00726-022-03185-x. Epub 2022 Jul 13.
N-Acetyl-L-cysteine (NAC) is an endogenous cysteine metabolite. The drug is widely used in chronic obstructive pulmonary disease (COPD) and as antidote in acetaminophen (paracetamol) intoxication. Currently, the utility of NAC is investigated in rheumatoid arthritis (RA), which is generally considered associated with inflammation and oxidative stress. Besides clinical laboratory parameters, the effects of NAC are evaluated by measuring in plasma or serum nitrite, nitrate or their sum (NOx) as measures of nitric oxide (NO) synthesis. Malondialdehyde (MDA) and relatives such as 4-hydroxy-nonenal and 15(S)-8-iso-prostaglandin F2α serve as measures of oxidative stress, notably lipid peroxidation. In this work, we review recent clinico-pharmacological studies on NAC in rheumatoid arthritis. We discuss analytical, pre-analytical and clinical issues and their potential impact on the studies outcome. Major issues include analytical inaccuracy due to interfering endogenous substances and artefactual formation of MDA and relatives during storage in long-term studies. Differences in the placebo and NAC groups at baseline with respect to these biomarkers are also a serious concern. Modern applied sciences are based on data generated using commercially available instrumental physico-chemical and immunological technologies and assays. The publication process of scientific work rarely undergoes rigorous peer review of the analytical approaches used in the study in terms of accuracy/trueness. There is pressing need of considering previously reported reference concentration ranges and intervals as well as specific critical issues such as artefactual formation of particular biomarkers during sample storage. The latter especially applies to surrogate biomarkers of oxidative stress, notably MDA and relatives. Reported data on NO, MDA and clinical parameters, including C-reactive protein, interleukins and tumour necrosis factor α, are contradictory in the literature. Furthermore, reported studies do not allow any valid conclusion about utility of NAC in RA. Administration of NAC patients with rheumatoid arthritis is not recommended in current European and American guidelines.
