Psicofarmacología 130 - Director Luis María Zieher

Psicofarmacología 22:130, octubre de 2022 cuencia del potencial de acción. La sobreexpresión de NLGN2 en dichas neuronas rescató los déficits de puntos sinápticos, mientras que la eliminación de NLGN2 en neuronas sanas resultó en una acción contraria. Las interneuronas también tenían un área nuclear significativamente más pequeña, lo que sugiere un estado de estrés oxidativo innato. La NAC aumentó el área nuclear en las interneuronas y la expresión de NLGN2 y rescató los déficits sinápticos. Estos resultados implican deficiencias específicas en la maquinaria sináptica en las interneuronas corticales como reguladores críticos de las conexiones sinápticas en la EZ y apuntan a un nexo entre el estrés oxidativo y la expresión de NLGN2 en la mediación de los déficits sinápticos (59). Conclusiones En el trascurso de los últimos años se han incrementado las evidencias sobre los mecanismos inmunitarios e inflamatorios involucrados en la fisiopatología de las enfermedades neuropsiquiátricas, lo cual contribuyó a la búsqueda de moléculas que actúan modulándolos, con el objetivo de mejorar las manifestaciones de las entidades mencionadas. Dentro de ellas, se encuentran fármacos utilizados previamente en trastornos clínicos y cardiovasculares, como la NAC, los ácidos omega 3 y 6 de cadena larga y los AINE, entre otros. En el caso de la NAC, son promisorios los resultados obtenidos a la fecha, sumado a su favorable perfil de efectos adversos y costo. No obstante, se necesitan más ensayos controlados involucrando cohortes más amplias para establecer conclusiones firmes. Referencias bibliográficas • 1. Aruoma, O, Halliwell B, Hoey B, Butler J. 1989. The antioxidant action of N acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radical Biol. Med. 6: 593–597. • 2. Bavarsad Shahripour R, Harrigan M, Alexandrov A (2014). N-acetylcysteine (NAC) in neurological disorders: mechanisms of action and therapeutic opportunities. Brain and Behavior; 4(2): 108–122. • 3. Dekhuijzen, P. 2004. Antioxidant properties of N-acetylcysteine: their relevance in relation to chronic obstructive pulmonary disease. Eur. Respir. J. 23: 629–636. • 4. Ziment I (1988). Acetylcysteine: a drug that is much more than a mucokinetic. Biomed Pharmacother;42(8): 513-9. • 5. Ramos-Villegas Y, Padilla-Zambrano H, Blanco-Teherán C, López-Cepeda D, Quintana-Pájaro L, Corrales-Santander H et al. (2017). N-Acetilcisteína en neuroprotección y lesión traumática cerebral: revisión de la literatura. Rev. Chil. Neurocirugía 43: 166- 169. • 6. Sen, C. (1997). Nutritional biochemistry of celular glutathione. J. Nutr. Biochem. 8: 660–672. • 7. Samuni, Y, Goldstein S, Dean O, Berk M (2013). The chemistry and biological activities of N-acetylcysteine. Biochim. Biophys. Acta 1830: 4117–4129. • 8. Kerksick, C, Willoughby D (2005). The antioxidant role of glutathione and N-acetyl-cysteine supplements and exercise-induced oxidative stress. J. Int. Soc. Sports Nutr. 2 :38–44. • 9. Meister A. (1995) Glutathione metabolism. Methods Enzymol. 251 :3. • 10. Xu Y, Hou X, Liu Y, Zong Y (2009). Different protection of K252a and N-acetyl-L-cysteine against amyloid-beta peptide-induced cortical neuronapoptosis involving inhibition of MLK3-MKK7-JNK3 signal cascades. J Neorosci Res, 87(4): 918-27, 2009 Mar. • 11. Tian H, Zhang Q, Li H, Zhang G (2003). Antioxidant N-acetylcysteine and AMPA/KA receptor antagonist DNQX inhibited mixed lineage kinase-3 activation following cerebral ischemia in rat hippocampus. Neurosci Res; 47(1): 47-53. • 12. Su B, Mitra S, Gregg H, Flavahan, Chotani S, Clark K, et al. (2001). Redox regulation of vascular smooth muscle cell differentiation. Circ. Res. 89:39–46. • 13. Ichiki T, Takeda K, Tokunou T, Funakoshi Y, Ito K, Iino N, et al. 2001. Hypertension 37:535–540. • 14. Ghigliotti G, Mereto E, Eisenberg P, Martelli A, Ors P, Sini D, et al. (2001). N-acetyl-cysteine reduces neointimal thickening and procoagulant activity after balloon-induced injury in abdominal aortae of New Zealand white rabbits. Thromb. Haemost. 85:724–729. • 15. Yan Z, Subbaramaiah K, Camilli T, Zhang F, Tanabe T, McCaffrey T, et al. (2000). Benzo[a]pyrene induces the transcription of cyclooxygenase-2 in vascular smooth muscle cells. Evidence for the involvement of extracelular signal-regulated kinase and NF-kappaB. J. Biol. Chem. 275: 4949–4955. • 16. Nagase M, Ando K, Nagase T, Kaname S, Sawamura T, Fujita T. (2001). Redox-sensitive regulation of lox-1 gene expression in vascular endothelium. Biochem. Biophys. Res. Commun. 281: 720–725. • 17. Mass H, Pirazzi B, Gonzalez P, Collazo V, Fitzovich D, Avakian E. (1995). N-acetylcysteine diminishes injury induced by balloon angioplasty of the carotid artery in rabbits. Biochem. Biophys. Res. Commun. 215: 613–618. • 18. De Mattia, G, Bravi M, Laurenti O, Cassone-Faldetta M, Proietti M, De Luca O et al. (1998). Reduction of oxidative stress by oral N-acetyl-L-cysteine treatment decreases plasma soluble vascular cell adhesion molecule-1 concentrations in non-obese, non-dyslipidaemic, normotensive, patients with non-insulin-dependent diabetes. Diabetologia 41: 1392–1396. • 19. Martin K, Kari F, Barrett J, French J. (2000). N-acetyl-L-cysteine simultaneously increases mitogenesis and suppresses apoptosis in mitogen-stimulated B-lymphocytes from p53 haploinsufficient Tg. AC (v-Ha-ras) mice. In Vitr. Mol. Toxicol. 13: 237–247. • 20. Galle J, Heermeier K, Wanner C. (1999). Atherogenic lipoproteins, oxidative stress, and cell death. Kidney Int.56:S62– S65. • 21. Tyagi S (1998). Homocysteine redox receptor and regulation of extracellular matrix components in vascular cells. Am. J. Physiol. 274: C396–C405. • 22. Sarker K, Abeyama K, Nishi J, Nakata M, Tokioka T, Nakajima N et al. 1999. Inhibition of thrombin-induced neuronal cell death by recombinant thrombomodulin and E5510, a synthetic thrombin receptor signaling inhibitor. Thromb. Haemost. 82: 1071–1077. • 23. Silva Rodrigues F, Patrícia Françae A, Broettoa N, Flávia Furianf A, Schneider Oliveira M, Soares Santos A et al (2020). Sustained glial reactivity induced by glutaric acid may be the trigger to learning delay in early and late phases of development: Involvement of p75NTR receptor and protection by N-acetylcysteine. Brain Research Vol 1749, 15, 147145 • 24. Abello P, Fidler S, Buchman T (1994). Thiol reducing agents modulate induced apoptosis in porcine endothelial cells. Shock 2: 79–83. • 25. Hong D, Kho A, Lee S, Jeong J, Kang B, Kang D et al. (2020). Transient Receptor EDITORIAL SCIENS // 19

Dr. José Alberto Angemi Potential Melastatin 2 (TRPM2) Inhibition by Antioxidant, N-Acetyl-l-Cysteine, Reduces Global Cerebral Ischemia-Induced Neuronal Death. Int. J. Mol. Sci. 2020, 21, 6026; doi: 10.3390 /ijms21176026. • 26. Jiang L, Yang W, Zou J, Beech D (2010). TRPM2 channel properties, functions and therapeutic potentials. Expert Opin. Ther. Targets 14, 973–988. • 27. Unnithan A, Choi H, Titler A, Posimo J, Leak R. (2012). Rescue from a two hit, high-throughput model of neurodegeneration with N-acetyl cysteine. Neurochem. Int. 61: 356–368. • 28. Arakawa M, Ito Y (2007). N-acetylcysteine and neurodegenerative diseases: basic and clinical pharmacology. Cerebellum 6: 308–314. • 29. Devi P, Pillai K, Vohora D (2006). Facilitation Action of N-Acetylcysteine on the Anticonvulsant Effect of Sodium Valproate in Mice. Basic & Clinical Pharmacology & Toxicology.98, 521–522. • 30. Behar T, Colton C (2003). Redox regulation of neuronal migration in a Down Syndrome model. Free Radical Biol. Med. 35: 566–575. • 31. Padilha Marchetti D, Donida B, Deon M, Jacques C, Bannach Jardim L, Regla Vargas C (2007). In vitro effect of N-acetyl-L-cysteine on glutathione and sulfhydryl levels in X-linked adrenoleukodystrophy patients. Clin Biomed Res;37(1): 33-37. • 32. Engelen M, Kemp S, de Visser M, Geel B, Wanders R, Auboourg P. et al. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management (2012). Orphanet J Rare Dis 7, 51. • 33. Kartha R, Zhou J, Basso L, Schröder H, Orchard P, Cloyd J (2015). Mechanisms of Antioxidant Induction with High-Dose N-Acetylcysteine in Childhood Cerebral Adrenoleukodystrophy. CNS Drugs, 29(12), 1041-1047. • 34. Sadan O, M. Bahat-Stromza, Y. Gilgun-Sherki, D. Atlas, E. Melamed, Offen D (2005). A novel brain-targeted antioxidant (AD4) attenuates haloperidol-induced abnormal movement in rats: implications for tardive dyskinesia. Clin. Neuropharmacol. 28: 285–288 • 35. Fontaine M, Geddes J, Banks A, Butterfield D (2000). Effect of exogenous and endogenous antioxidants on 3-nitropionic acid-inducedin vivo oxidative stress and striatal lesions. J. Neurochem. 75: 1709–1715. • 36. Sandhir R, Sood A, Mehrotra A, Kamboj S (2012). N-Acetylcysteine reverses mitochondrial dysfunctions and behavioral abnormalities in 3-nitropropionic acid-induced Huntington’s disease. Neurodegener Dis; 9: 145–157. • 37. Clark J, Clore E, Zheng K, Adame A, Masliah E, Simon D. (2010). Oral N-acetyl-cysteine attenuates loss of dopaminergic terminals in alpha-synuclein overexpressing mice. PLoS ONE 5: e12333. • 38. Monti D, Zabrecky G, Kremens D, Liang T, Wintering N, Cai J et al. (2016). N-Acetyl Cysteine May Support Dopamine Neurons in Parkinson’s Disease: Preliminary Clinical and Cell Line Data. PLoS One Jun 16;11(6): e0157602. • 39. Erikson M, Hansen K, Banks W (2012). Inflammation-induced dysfunction of the low-density lipoprotein receptor-related protein-1 at the blood-brainbarrier: protection by the antioxidant N-acetylcysteine. Brain Behav Immun; 26(7): 1085-94. • 40. Lehmann D, Karussis D, Misrachi-Koll R, Shezen E, Ovadia H, Abramsky O. (1994). Oral administration of the oxidant-scavenger N-acetyl-L-cysteine inhibits acute experimental autoimmune encephalomyelitis. J. Neuroimmunol. 50: 35–42. • 41. Rosen D, Siddique T, Patterson D, Figlewicz D, Sapp P, Hentati A, et al. (1993). Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362: 59–62. • 42. Vasdekis S, Athanasiadis D, Lazaris A, Martikos G, Katsanos A, Tsivgoulis G (2013). The role of remote ischemic preconditioning in the treatment of atherosclerotic diseases. Brain Behav. 3: 606–616. • 43. Morris K, H. W. Lin H, Thompson J, Perez-Pinzon A (2011). Pathways for ischemic cytoprotection: role of sirtuins in caloric restriction, resveratrol, and ischemic preconditioning. J. Cereb. Blood Flow Metab. 31: 1003–1019. • 44. Sury M, Frese- Schaper M, Mühlemann M, Schultess F, Blasig I, Ingolf E et al. (2006). Evidence that N-acetylcysteine inhibits TNF-alpha-induced cerebrovascular endothelin-1 upregulation via inhibition of mitogen- and stress-activated protein kinase. Free Radic Biol Med; 41(9): 1372-83. • 45. Sharabi H, Khatib N, Ginsberg, Y, Weiner Z, Ross M, Tamar B et al. (2019). Therapeutic N-Acetyl-Cysteine (Nac) Following Initiation of Maternal Inflammation Attenuates Long-Term Off spring Cerebral Injury, as Evident in Magnetic Resonance Imaging (MRI). Neuroscience; 403: 118-124. • 46. Simpson E, Kellendonk C, Kandel E (2010). A Possible Role for the Striatum in the Pathogenesis of the Cognitive Symptoms of Schizophrenia. Neuron 65, 585–596. • 47. Di Pietro P, Dias M, Scaini G, Burigo M, Constantino L, Machado R et al. (2008). Inhibition of brain creatine kinase activity aft er renal ischemia is attenuated by N-acetylcysteine and deferoxamine administration. Neurosci Lett; 434(1): 139-43. • 48. Kamboj S, Sandhir R (2011). Protective effect of N-acetylcysteine supplementation on mitochondrial oxidative stress and mitochondrial enzymesin cerebral cortex of streptozotocin-treated diabetic rats. Mitochondrion; 11(1): 214-22. • 49. Gipson C, Reissner K, Kupchik Y, Smith A, Stankeviciute N, Hensley-Simon M et al. (2013) Reinstatement of nicotine seeking is mediated by glutamatergic plasticity. Proc Natl Acad Sci U S A;110(22): 9124–9. • 50. Baker D, McFarland K, Lake R, Shen H, Toda T, Kalivas P (2003). N-acetyl cysteine-induced blockade of cocaine-induced reinstatement. Ann N Y Acad Sci.;1003: 349–51. • 51. Palmatier M, Liu X, Donny E, Caggiula A, Sved A (2008). Metabotropic glutamate 5 receptor (mGluR5) antagonists decrease nicotine seeking, but do not affect the reinforcement enhancing effects of nicotine. Neuropsychopharmacology, 33(9): 2139–47. • 52. Cullen K, Schreiner M, Klimes-Dougan B, Eberly L, LaRiviere L, Lim K et al. (2020). Neural correlates of clinical improvement in response to N-acetylcysteine in adolescents with non-suicidal self-injury. Prog Neuropsychopharmacol Biol Psychiatry; 99: 109778. • 53. Rosenblat J, McIntyre R (2017). Bipolar Disorder and Immune Dysfunction: Epidemiological Findings, Proposed Pathophysiology and Clinical Implications. Brain Sci. 2017, 7, 144; doi:10.3390/brainsci7110144. • 54. Lavoie S, Murray M, Patricia Deppen P, Knyazeva M, Berk M, Boulat O et al. (2008). Glutathione Precursor, N-Acetyl-Cysteine, Improves Mismatch Negativity in Schizophrenia Patients. Neuropsychopharmacology 33, 2187–2199. • 55. Gysin R, Kraftsik R, Sandell J, Bovet P, Chappuis C, Conus P et al. (2007). Impaired glutathione synthesis in schizophrenia convergent genetic and functional evidence. Proc Natl Acad Sci USA 104: 16621–16626. • 56. Robbins T (2005). Synthesizing schizophrenia: a bottom-up, symptomatic approach. Schizophr Bull 31: 854–864. • 57. Krystal J, Karper L, Seibyl J, Freeman G, Delaney R, Bremner J et al. (1994). Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51: 199–214. • 58. McQueen G, Lally J, Collier T, Zelaya F, Lythgoe D, Barker D et al. (2018). Effects of N-acetylcysteine on brain glutamate levels and resting perfusion in schizophrenia. Psychopharmacology (Ber) 235(10): 3045- 3054. • 59. Kathuria A, Lopez-Lengowski K, Watmuff B, McPhie D, Cohen B, Karmacharya R. (2019) Synaptic deficits in iPSC-derived cortical interneurons in schizophrenia are mediated by NLGN2 and rescued by N-acetylcysteine. Translational Psychiatry 9: 321. 20 // EDITORIAL SCIENS