N-Acetylcysteine amide and Central Nervous System: human studies and animal models
Subject Areas : Regenerative Medicine
vahed ebrahimi
1
,
Zafar Gholinejad
2
1 - Department of Biochemistry, Science and Research Branch, Islamic Azad University, Tehran, Iran
2 - Department of Medical Laboratory Sciences, Urmia Branch, Islamic Azad University, Urmia, Iran
Keywords: Toxicity, Oxidative stress, Brain, N-acetylcysteine amide,
Abstract :
Brain structure is always the first dam against effect drug delivery to treatment of neurologic disorders. Oxidative stress is a critical condition in the pathogenesis of neurologic disorders. N-acetylcysteine amide(NACA), a lipophilic derives of N-acetylcysteine (NAC) that showed a great potential to treatment of oxidative based disorder especially in the brain. we evaluated 83 publications whose title contain NACA. Cast a glance on all the document which showed NACA has protective effect on toxins-drugs toxicity. Most of the articles reported that NACA is a great therapeutic option for cataracts and eye disorders. Hematologic problem and kidney related disorders is a target for NACA. Then, we focused on the neurological application of NACA. It is well-documented that the bio effects of NACA is mediated by antioxidant properties via –SH group. It is more bioavailable and potent than NAC. is significantly higher than NAC. The lipophilic structure confers promising effect to NACA for brain disorders treatment range from trauma to toxins and neurotransmitter toxicity.
[1] K Sunitha , M Hemshekhar, R M Thushara, M Sebastin Santhosh, M Yariswamy, K Kemparaju and et al., N-Acetylcysteine amide: a derivative to fulfill the promises of N-Acetylcysteine. Free Radical Research. 2013; 47(5): 357-67. doi:10.3109/10715762.2013.781595
[2] Carey JW, Pinarci EY, Penugonda S, Karacal H, Ercal N. In vivo inhibition of l-buthionine-(S,R)-sulfoximine-induced cataracts by a novel antioxidant, N-acetylcysteine amide. Free Radical Biology and Medicine. 2011; 50(6): 722-29. doi.org/10.1016/j.freeradbiomed.2010.12.017.
[3] Galano A. Mechanism and kinetics of the hydroxyl and hydroperoxyl radical scavenging activity of N-acetylcysteine amide. Theoretical Chemistry Accounts. 2011;130(1):51-60. doi.org/10.1007/s00214-011-0958-0
[4] He R, Zheng W, Ginman T, Ottosson H, Norgren S, Zhao Y and et al. Pharmacokinetic profile of N-acetylcysteine amide and its main metabolite in mice using new analytical method. European Journal of Pharmaceutical Sciences, 2020; 143: 105158. doi.org/10.1016/j.ejps.2019.105158
[5] Maddirala Y, Tobwala S, Karacal H, Ercal N. Prevention and reversal of selenite-induced cataracts by N-acetylcysteine amide in Wistar rats. BMC ophthalmology. 2017; 17(1):1-12. doi.org/ 10.1186/s12886-017-0443-1
[6] Carver KA, Yang D. N-acetylcysteine amide protects against oxidative stress–induced microparticle release from human retinal pigment epithelial cells. Investigative Ophthalmology & Visual Science. 2016; 57(2): 360-71. doi.org/ 10.1167/iovs.15-17117.
[7] Gong X, Celsi G, Carlsson K, Norgren S. Protective effects of N-acetylcysteine amide (NACA) on gentamicin-induced apoptosis in LLC-PK1 cells. Renal Failure. 2012; 34(4): 487-94. doi.org/10.3109/0886022X.2012.655684
[8] Hassan M, Ljungman P, He R, Norgren S, Zheng W, Zhao Y, and et al. N-acetylcysteine amide alleviates cyclophosphamide-induced endothelial damage. Blood. 2021; 138:3821. doi.org/10.1182/blood-2021-152815
[9] Chen W, Ercal N, Huynh T, Volkov A, Chusuei CC. Characterizing N-acetylcysteine (NAC) and N-acetylcysteine amide (NACA) binding for lead poisoning treatment. Journal of Colloid and Interface Science. 2012; 371(1):144-49.
doi.org/ 10.1016/j.jcis.2011.12.052
[10] Wu W, Abraham L, Ogony J, Matthews R, Goldstein G, Ercal N. Effects of N-acetylcysteine amide (NACA), a thiol antioxidant on radiation-induced cytotoxicity in Chinese hamster ovary cells. Life Sciences. 2008; 82(21-22): 1122-30.
doi.org/ 10.1016/j.lfs.2008.03.016
[11] Erol G, Kartal H, Comu FM, Cetin E, Demirdas E, Sicim H. Effects of N-acetylcysteine and N-acetylcysteine amide on erythrocyte deformability and oxidative stress in a rat model of lower extremity ischemia-reperfusion injury. Cardiology Research and Practice. 2020; 2020. doi.org/ 10.1155/2020/6841835
[12] Pandya JD, Readnower RD, Patel SP, Yonutas HM, Pauly JR, Goldstein GA and et al. N-acetylcysteine amide confers neuroprotection, improves bioenergetics and behavioral outcome following TBI. Experimental Neurology. 2014; 257: 106-13.
doi.org/ 10.1016/j.expneurol.2014.04.020
[13] Zhou Y, Wang HD, Zhou XM, Fang J, Zhu L, Ding K, and et al. N-acetylcysteine amide provides neuroprotection via Nrf2-ARE pathway in a mouse model of traumatic brain injury. Drug Design, Development and Therapy. 2018; 12: 4117. doi.org/ 10.2147/DDDT.S179227
[14] Günther M, Davidsson J, Plantman S, Norgren S, Mathiesen T, Risling M and et al. Neuroprotective effects of N-acetylcysteine amide on experimental focal penetrating brain injury in rats. Journal of Clinical Neuroscience. 2015; 22(9):1477-83.
doi.org/ 10.1016/j.jocn.2015.03.025
[15] Patel SP, Sullivan PG, Pandya JD, Goldstein GA, VanRooyen JL, Yonutas HM, and et al. N-acetylcysteine amide preserves mitochondrial bioenergetics and improves functional recovery following spinal trauma. Experimental neurology. 2014; 257: 95-105.
doi.org/ 10.1016/j.expneurol.2014.04.026
[16] Kawoos U, Abutarboush R, Zarriello S, Qadri A, Ahlers ST, McCarron RM, and et al. N-acetylcysteine amide ameliorates blast-induced changes in blood-brain barrier integrity in rats. Frontiers in Neurology. 2019; 10. 650. doi.org/ 10.3389/fneur.2019.00650
[17] Banerjee A, Zhang X, Manda KR, Banks WA, Ercal N. HIV proteins (gp120 and Tat) and methamphetamine in oxidative stress-induced damage in the brain: potential role of the thiol antioxidant N-acetylcysteine amide. Free Radical Biology and Medicine. 2010; 48(10): 1388-98. doi.org/10.1016/j.freeradbiomed
[18] Zeng XF, Li Q, Li J, Wong N, Li Z, Huang J. HIV-1 Tat and methamphetamine co-induced oxidative cellular injury is mitigated by N-acetylcysteine amide (NACA) through rectifying mTOR signaling. Toxicology Letters. 2018; 299: 159-71. doi.org/ 10.1016/j.toxlet.2018.09.009
[19] Price TO, Uras F, Banks WA, Ercal N. A novel antioxidant N-acetylcysteine amide prevents gp120- and Tat-induced oxidative stress in brain endothelial cells. Experimental Neurology. 2006; 201(1): 193-202.
doi.org/ 10.1016/j.expneurol.2006.03.030
[20] Zhang X, Banerjee A, Banks WA, Ercal N. N-Acetylcysteine amide protects against methamphetamine-induced oxidative stress and neurotoxicity in immortalized human brain endothelial cells. Brain Research. 2009; 1275: 87-95. doi.org/ 10.1016/j.brainres.2009.04.008
[21] Zhang X, Tobwala S, Ercal N. N-acetylcysteine amide protects against methamphetamine-induced tissue damage in CD-1 mice. Human & Experimental Toxicology. 2012; 31(9): 931-44. doi.org/ 10.1177/0960327112438287
[22] Koriem KM, Selim AY, Mazen RA. N-acetylcysteine-amide improves tissue oxidative stress, DNA damage, and proteins disappearance in methamphetamine toxicity more efficiently than N-acetyl-L-cysteine. Toxicologie Analytique et Clinique. 2021; 33(2):123-135. doi.org/10.1016/j.ejps.2019.105158
[23] Penugonda S, Mare S, Goldstein G, Banks WA, Ercal N. Effects of N-acetylcysteine amide (NACA), a novel thiol antioxidant against glutamate-induced cytotoxicity in neuronal cell line PC12. Brain Research, 2005; 1056(2): 132-8. doi.org/10.1016/j.brainres.2005.07.032
[24] Penugonda S, Mare S, Lutz P, Banks WA, Ercal N. Potentiation of lead-induced cell death in PC12 cells by glutamate: protection by N-acetylcysteine amide (NACA), a novel thiol antioxidant. Toxicology and Applied pharmacology. 2006; 216(2): 197-205. doi.org/10.1016/j.taap.2006.05.002
[25] Jastrzębska J, Frankowska M, Filip M , Atlas D. N-acetylcysteine amide (AD4) reduces cocaine-induced reinstatement. Psychopharmacology. 2016; 233(18): 3437-48. doi.org/10.1007/s00213-016-4388-5
[26] Ates B, Vardi N, Parlakpinar H, Karaaslan MG, Yilmaz I, Ercal N. The protective effect of N-acetylcysteine amide against paraquat-induced neurotoxicity. Turkish Journal of Chemistry. 2019; 43(1): 39-49. doi.org/10.3906/kim-1706-827
[27]Matthiesen I, Voulgaris D, Nikolakopoulou P, Winkler TE, Herland, A. Continuous monitoring reveals protective effects of N‐acetylcysteine amide on an isogenic microphysiological model of the neurovascular unit. Small. 2021; 17(32): 2101785. doi.org/10.1002/smll.202101785
[28] Liang KX, Vatne GH, Kristiansen CK, Ievglevskyi O, Kondratskaya E, Glover JC and et al. N-acetylcysteine amide ameliorates mitochondrial dysfunction and reduces oxidative stress in hiPSC-derived dopaminergic neurons with POLG mutation. Experimental Neurology. 2021; 337: 113536. doi.org/ 10.1016/j.expneurol.2020.113536
[29] Herrera-Marschitz M, Neira-Pena T, Rojas-Mancilla E, Espina-Marchant P, Esmar D, Perez R, and et al. Perinatal asphyxia: CNS development and deficits with delayed onset. Frontiers in Neuroscience. 2014; 8: 47. doi.org/ 10.3389/fnins.2014.00047
[30] Benterud T, Ystgaard MB, Manueldas S, Pankratov L, Alfaro-Cervello C, Florholmen G, and et al. N-acetylcysteine amide exerts possible neuroprotective effects in newborn pigs after perinatal asphyxia. Neonatology. 2017; 111(1): 12-21. doi.org/10.1159/000447255
[31] Reis CG, Mocelin R, Benvenutti R, Marcon M, Sachett A, Herrmann AP, and et al. Effects of N-acetylcysteine amide on anxiety and stress behavior in zebrafish. Naunyn-Schmiedeberg's Archives of Pharmacology. 2020; 393(4): 591-601. doi.org/10.1007/s00210-019-01762-8.