Re: N-acetylcysteine의 도파민뉴런 기능개선을 통한 파킨슨치료 기전

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beyond reason

There are data to support that NAC may increase intraplatelet levels of glutathione and decrease ROS.7 Glutathione itself has poor absorption and does not seem to improve markers of oxidative stress or even change the measured levels of endogenous glutathione, and there is insufficient data on other modes of administration.8–10 However, magnetic resonance spectroscopy (MRS) has shown increased blood and brain glutathione11 as a result of NAC infusions.

A Review of Dietary (Phyto)Nutrients for Glutathione Support 논문에서 자료가져옴

N-Acetyl Cysteine Is Associated With Dopaminergic Improvement in Parkinson's Disease.pdf

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N-Acetyl Cysteine Is Associated With Dopaminergic Improvement in Parkinson's Disease

Daniel A. Monti1,2, George Zabrecky1,2, Daniel Kremens3 , Tsao-Wei Liang3 , Nancy A. Wintering1,2, Anthony J. Bazzan1,2, Li Zhong2 , Brendan K. Bowens2 , Inna Chervoneva4 , Charles Intenzo5 and Andrew B. Newberg1,2,5,*

This study assessed the biological and clinical effects in patients with Parkinson’s disease (PD) of N-acetyl-cysteine (NAC), the prodrug to l-cysteine, a precursor to the natural biological antioxidant glutathione. Forty-two patients with PD were randomized to either weekly intravenous infusions of NAC (50 mg/kg) plus oral doses (500 mg twice per day) for 3 months or standard of care only. Participants received prebrain and postbrain imaging with ioflupane (DaTscan) to measure dopamine transporter (DAT) binding. In the NAC group, significantly increased DAT binding was found in the caudate and putamen (mean increase from 3.4% to 8.3%) compared with controls (P < 0.05), along with significantly improved PD symptoms (P < 0.0001). The results suggest NAC may positively affect the dopaminergic system in patients with PD, with corresponding positive clinical effects. Larger scale studies are warranted.

Parkinson’s disease (PD) is a chronic disorder that causes degeneration in the dopamine-producing neurons in the brain. The disease affects > 1 million Americans and, currently, there are no therapeutic interventions specifically that slow the progression of the disease process.1 Standard medical care for PD is primarily focused on symptom management, usually with dopaminergic agents. Additionally, some supportive therapies, such as exercise, have resulted in improved quality of life in patients with PD.2,3 Hence, there is a significant need to explore therapeutic approaches that could positively impact the disease process, both physiologically and clinically.

There is growing literature that suggests oxidative stress plays a key role in the pathophysiology of PD. Oxidative stress is defined as a redox imbalance where there is a decrease in natural antioxidants and excess formation of reactive oxygen species (ROS), which are chemically reactive molecules that contain oxygen. 4 These ROS can damage key cellular components, such as lipids, proteins, and DNA. Evidence for oxidative damage in the brains of patients with PD includes the finding of increased lipid peroxidation products, such as malondialdehyde and 4-hydroxynonenal, increased protein oxidation, as evidenced by protein cross-linking and fragmentation, and increased concentration of 8-hydroxy-2′-deoxyguanosine, a product of DNA oxidation.5 Due to the presence of high amounts of polyunsaturated fatty acids, the brain is prone to oxidative stress, particularly in persons with PD. Low quantities of endogenous antioxidants, such as glutathione and substantial iron content, can be found in specific dopaminergic areas of the brain, such as the globus pallidus and substantia nigra.5 Because neurons function in a postmitotic state, it is unlikely that neurons will easily recover from an oxidative stress insult without intervention.

We previously reported findings from cell line data and preliminary clinical effects of N-acetyl-cysteine (NAC), which suggested possible improvements in dopamine transporter (DAT) binding in a small number of patients with PD who received NAC, using ioflupane DaTscan single photon emission computed tomography (SPECT) imaging.6 Three months of NAC treatment resulted in increased DAT binding in the basal ganglia; hence, the present study extends those results with a more robust study number and comprehensive analyses. NAC is worthy of exploration in patients with PD for several reasons.

There are data to support that NAC may increase intraplatelet levels of glutathione and decrease ROS.7 Glutathione itself has poor absorption and does not seem to improve markers of oxidative stress or even change the measured levels of endogenous glutathione, and there is insufficient data on other modes of administration.8–10 However, magnetic resonance spectroscopy (MRS) has shown increased blood and brain glutathione11 as a result of NAC infusions.

Although NAC also has variable oral absorption,12 it is available in an approved injectable medication that is used to prevent liver damage in acetaminophen overdose. Thus, for our study, we used the injectable NAC to help ensure consistent dosing, and oral NAC was given between infusions. Ioflupane DaTscan SPECT imaging is a unique modality to measure regional DAT binding in the caudate and putamen in the striatum in the midbrain, showing the tone of the dopamine nervous system.13 A reduction in DAT binding in the caudate and putamen is often reduced significantly in persons with PD.14 In the United States, DaTscan is approved for clinical use. Published research has shown that DaTscan can differentiate PD from controls15,16 and can correlate DAT binding with disease severity.17,18 DaTscan has been studied in published research to measure treatment effects in patients with PD; however, the value of measuring DAT in clinical trials in PD is still an important question.19,20 In addition, because DaTscan is nxxonselective and can be taken up not only by the DAT but by the serotonin transporter (SERT), measures of midbrain activity represent the amount of SERT binding.21 In the pilot study mentioned above,6 we used ioflupane DaTscan SPECT imaging and the Unified Parkinson’s Disease Rating Scale (UPDRS) scores to assess whether there was any positive signal from the NAC treatment. The primary goals of the present study were to provide expanded data regarding the effect of NAC administration on DAT binding and symptoms in patients with PD. We further used this larger population to assess whether specific factors, such as age, gender, disease duration and severity, or medication use might interact with the changes observed with NAC.