{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T23:04:24Z","timestamp":1784329464283,"version":"3.55.0"},"reference-count":90,"publisher":"Societatea Romana de Morfologie","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Rom J Morphol Embryol"],"published-print":{"date-parts":[[2026,7,10]]},"abstract":"<jats:p>Chronic alcohol consumption is a leading cause of acquired neurodegeneration with well-documented structural and ultrastructural brain alterations. This review analyzes the cellular and molecular mechanisms underlying alcohol neurotoxicity, integrating findings from animal models, human post-mortem studies, and neuroimaging investigations. Ethanol crosses the blood\u2013brain barrier and generates toxic metabolites including acetaldehyde and reactive oxygen species, triggering oxidative stress, lipid peroxidation, and mitochondrial dysfunction. Chronic exposure induces glutamatergic and gamma-aminobutyric acid (GABA)ergic adaptations leading to excitotoxicity during withdrawal. Cell death occurs through apoptotic, necrotic, and necroptotic pathways, while microglial and astrocytic activation perpetuates neuroinflammation. Histopathological (HP) changes include selective neuronal loss in the prefrontal cortex, hippocampus, and cerebellum, dendritic simplification, and synaptic alterations. White matter pathology manifests as demyelination and axonal degeneration. Associated thiamine deficiency produces characteristic lesions in the mammillary bodies, thalamus, and cerebellar vermis. Neuroimaging techniques provide valuable HP correlates and biomarkers for disease monitoring. While some changes demonstrate partial reversibility with abstinence through remyelination and synaptic plasticity, extensive neuronal loss remains irreversible. Understanding these mechanisms is essential for developing neuroprotective therapeutic strategies.<\/jats:p>","DOI":"10.47162\/rjme.67.1.01","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T22:55:06Z","timestamp":1784328906000},"page":"5-18","source":"Crossref","is-referenced-by-count":0,"title":["Alcohol-induced structural and cellular brain alterations: molecular and histopathological mechanisms"],"prefix":"10.47162","volume":"67","author":[{"name":"Department of Psychology, University of Medicine and Pharmacy of Craiova, Romania","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iulia","family":"B\u0103lu\u0163oiu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sorin Nicolae","family":"Dinescu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Department of Epidemiology, University of Medicine and Pharmacy of Craiova, Romania","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei","family":"Gre\u015fi\u0163\u0103","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Department of Physiology, University of Medicine and Pharmacy of Craiova, Romania","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucre\u0163iu","family":"Radu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Department of Hygiene, University of Medicine and Pharmacy of Craiova, Romania","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Citto Iulian","family":"Taisescu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Department of Physiology, University of Medicine and Pharmacy of Craiova, Romania","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra-Daniela","family":"Rotaru-Z\u0103v\u0103leanu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Department of Epidemiology, University of Medicine and Pharmacy of Craiova, Romania","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u0103d\u0103lina","family":"Aldea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Department of Psychiatry, University of Medicine and Pharmacy of Craiova, Romania","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihai Andrei","family":"Ruscu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Department of Epidemiology, University of Medicine and Pharmacy of Craiova, Romania","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossy Vl\u0103du\u0163","family":"Teic\u0103","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Department of Radiology and Medical Imaging, University of Medicine and Pharmacy of Craiova, Romania","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marian Valentin","family":"Zoril\u0103","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Department of Forensic Medicine, University of Medicine and Pharmacy of Craiova, Romania","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mircea-Sebastian","family":"\u015eerb\u0103nescu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Department of Medical Informatics and Biostatistics, University of Medicine and Pharmacy of Craiova, Romania","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"26736","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"ref0","doi-asserted-by":"publisher","unstructured":"\"[1] Singh N, Nandy SK, Sharma A, Vansh, Siddiqui AJ, Sharma L. Chronic alcohol use and accelerated brain aging: shared mechanisms with Alzheimer's disease pathophysiology. Brain Sci, 2025, 16(1):35. https:\/\/doi.org\/10.3390\/brainsci16010035","DOI":"10.3390\/brainsci16010035"},{"key":"ref1","doi-asserted-by":"publisher","unstructured":"[2] Banks WA, Rhea EM, Reed MJ, Erickson MA. The penetration of therapeutics across the blood-brain barrier: classic case studies and clinical implications. Cell Rep Med, 2024, 5(11):101760. https:\/\/doi.org\/10.1016\/j.xcrm.2024.101760","DOI":"10.1016\/j.xcrm.2024.101760"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"[3] Go\u0142aszewski P, Wawrzyniak A, K\u0142osowicz M, Burbelka A, Balawender K. Neurotoxicity of chronic alcohol exposure: mechanistic insights, cellular disruption, and emerging therapeutic strategies. Int J Mol Sci, 2025, 27(1):299. https:\/\/doi.org\/10.3390\/ijms27010299","DOI":"10.3390\/ijms27010299"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"[4] Anand SK, Ahmad MH, Sahu MR, Subba R, Mondal AC. Detrimental effects of alcohol-induced inflammation on brain health: from neurogenesis to neurodegeneration. Cell Mol Neurobiol, 2023, 43(5):1885-1904. https:\/\/doi.org\/10.1007\/s10571-022-01308-2","DOI":"10.1007\/s10571-022-01308-2"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"[5] Gheorman V, Dinescu VC, Criciotoiu O, Stanca D, Calborean V, Mita A, Miscoci A, Davitoiu DV, Baleanu VD, Nedelcuta RM, Dinescu SN, Dijmarescu AL, Voiculescu DI, Udristoiu I. Clinical and biochemical changes induced by alcohol at the patients with mental illness. Rev Chim (Bucharest), 2019, 70(4):1406-1410. https:\/\/doi.org\/10.37358\/RC.19.4.7138","DOI":"10.37358\/RC.19.4.7138"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"[6] Georgescu OS, Martin L, T\u00e2rtea GC, Rotaru-Zavaleanu AD, Dinescu SN, Vasile RC, Gresita A, Gheorman V, Aldea M, Dinescu VC. Alcohol consumption and cardiovascular disease: a narrative review of evolving perspectives and long-term implications. Life (Basel), 2024, 14(9):1134. https:\/\/doi.org\/10.3390\/life14091134","DOI":"10.3390\/life14091134"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"[7] Mu\u015fat MI, Militaru F, Udri\u015ftoiu I, Mitran SI, C\u0103t\u0103lin B. Alcohol consumption is a coping mechanism for male patients with severe anxiety disorders treated with antidepressants monotherapy. J Clin Med, 2024, 13(9):2723. https:\/\/doi.org\/10.3390\/jcm13092723","DOI":"10.3390\/jcm13092723"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"[8] Mu\u015fat MI, Militaru F, Gheorman V, Udri\u015ftoiu I, Mitran SI, C\u0103t\u0103lin B. Moderate alcohol consumption increases the risk of clinical relapse in male depressed patients treated with serotonin-norepinephrine reuptake inhibitors. Diagnostics (Basel), 2024, 14(11):1140. https:\/\/doi.org\/10.3390\/diagnostics14111140","DOI":"10.3390\/diagnostics14111140"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"[9] Rotaru-Zavaleanu AD, Neac\u015fu AI, Neac\u015fu AD, Pirici D, Osiac E, C\u0103t\u0103lin B, Gheonea DI. Effects of acute sepsis on cellular dynamics and amyloid formation in a mouse model of Alzheimer's disease. Curr Issues Mol Biol, 2022, 44(9):3822-3834. https:\/\/doi.org\/10.3390\/cimb44090262","DOI":"10.3390\/cimb44090262"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"[10] Teschke R. Alcoholic liver disease: alcohol metabolism, cascade of molecular mechanisms, cellular targets, and clinical aspects. Biomedicines, 2018, 6(4):106. https:\/\/doi.org\/10.3390\/biomedicines6040106","DOI":"10.3390\/biomedicines6040106"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"[11] Galter D, Carmine A, Buervenich S, Duester G, Olson L. Distribution of class I, III and IV alcohol dehydrogenase mRNAs in the adult rat, mouse and human brain. Eur J Biochem, 2003, 270(6):1316-1326. https:\/\/doi.org\/10.1046\/j.1432-1033.2003.03502.x","DOI":"10.1046\/j.1432-1033.2003.03502.x"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"[12] Zuo L, Gelernter J, Kranzler HR, Stein MB, Zhang H, Wei F, Sen S, Poling J, Luo X. ADH1A variation predisposes to personality traits and substance dependence. Am J Med Genet B Neuropsychiatr Genet, 2010, 153B(2):376-386. https:\/\/doi.org\/10.1002\/ajmg.b.30990","DOI":"10.1002\/ajmg.b.30990"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"[13] Contreras-Zentella ML, Villalobos-Garc\u00eda D, Hern\u00e1ndez-Mu\u00f1oz R. Ethanol metabolism in the liver, the induction of oxidant stress, and the antioxidant defense system. Antioxidants (Basel), 2022, 11(7):1258. https:\/\/doi.org\/10.3390\/antiox11071258","DOI":"10.3390\/antiox11071258"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"[14] Nakamura K, Iwahashi K, Furukawa A, Ameno K, Kinoshita H, Ijiri I, Sekine Y, Suzuki K, Iwata Y, Minabe Y, Mori N. Acetaldehyde adducts in the brain of alcoholics. Arch Toxicol, 2003, 77(10):591-593. https:\/\/doi.org\/10.1007\/s00204-003-0465-8","DOI":"10.1007\/s00204-003-0465-8"},{"key":"ref14","unstructured":"[15] Tuma DJ, Hoffman T, Sorrell MF. The chemistry of acetaldehyde-protein adducts. Alcohol Alcohol Suppl, 1991, 1:271-276."},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"[16] Swenberg JA, Lu K, Moeller BC, Gao L, Upton PB, Nakamura J, Starr TB. Endogenous versus exogenous DNA adducts: their role in carcinogenesis, epidemiology, and risk assessment. Toxicol Sci, 2011, 120(Suppl 1):S130-S145. https:\/\/doi.org\/10.1093\/toxsci\/kfq371","DOI":"10.1093\/toxsci\/kfq371"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"[17] Bansal S, Srinivasan S, Anandasadagopan S, Chowdhury AR, Selvaraj V, Kalyanaraman B, Joseph J, Avadhani NG. Additive effects of mitochondrion-targeted cytochrome CYP2E1 and alcohol toxicity on cytochrome c oxidase function and stability of respirosome complexes. J Biol Chem, 2012, 287(19):15284-15297. https:\/\/doi.org\/10.1074\/jbc.M111.314062","DOI":"10.1074\/jbc.M111.314062"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"[18] Zhu Q, Xie X, Fang L, Huang C, Li J. Chronic alcohol intake disrupts cytochrome P450 enzyme activity in alcoholic fatty liver disease: insights into metabolic alterations and therapeutic targets. Front Chem, 2025, 13:1509785. https:\/\/doi.org\/10.3389\/fchem.2025.1509785","DOI":"10.3389\/fchem.2025.1509785"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"[19] Howard LA, Miksys S, Hoffmann E, Mash D, Tyndale RF. Brain CYP2E1 is induced by nicotine and ethanol in rat and is higher in smokers and alcoholics. Br J Pharmacol, 2003, 138(7):1376-1386. https:\/\/doi.org\/10.1038\/sj.bjp.0705146","DOI":"10.1038\/sj.bjp.0705146"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"[20] Garc\u00eda-Su\u00e1stegui WA, Ramos-Ch\u00e1vez LA, Rubio-Osornio M, Calvillo-Velasco M, Atzin-M\u00e9ndez JA, Guevara J, Silva-Adaya D. The role of CYP2E1 in the drug metabolism or bioactivation in the brain. Oxid Med Cell Longev, 2017, 2017:4680732. https:\/\/doi.org\/10.1155\/2017\/4680732","DOI":"10.1155\/2017\/4680732"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"[21] Lu Y, Cederbaum AI. CYP2E1 and oxidative liver injury by alcohol. Free Radic Biol Med, 2008, 44(5):723-738. https:\/\/doi.org\/10.1016\/j.freeradbiomed.2007.11.004","DOI":"10.1016\/j.freeradbiomed.2007.11.004"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"[22] Ruiter-Lopez L, Khan MAS, Wang X, Song BJ. Roles of oxidative stress and autophagy in alcohol-mediated brain damage. Antioxidants (Basel), 2025, 14(3):302. https:\/\/doi.org\/10.3390\/antiox14030302","DOI":"10.3390\/antiox14030302"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"[23] Jov\u00e9 M, Mota-Martorell N, Obis \u00c8, Sol J, Mart\u00edn-Gar\u00ed M, Ferrer I, Portero-Ot\u00edn M, Pamplona R. Lipid adaptations against oxidative challenge in the healthy adult human brain. Antioxidants (Basel), 2023, 12(1):177. https:\/\/doi.org\/10.3390\/antiox12010177","DOI":"10.3390\/antiox12010177"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"[24] Levi S, Ripamonti M, Moro AS, Cozzi A. Iron imbalance in neurodegeneration. Mol Psychiatry, 2024, 29(4):1139-1152. https:\/\/doi.org\/10.1038\/s41380-023-02399-z","DOI":"10.1038\/s41380-023-02399-z"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"[25] Montoliu C, Vall\u00e9s S, Renau-Piqueras J, Guerri C. Ethanol-induced oxygen radical formation and lipid peroxidation in rat brain: effect of chronic alcohol consumption. J Neurochem, 1994, 63(5):1855-1862. https:\/\/doi.org\/10.1046\/j.1471-4159.1994.63051855.x","DOI":"10.1046\/j.1471-4159.1994.63051855.x"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"[26] Cao H, Xiong SF, Dong LL, Dai ZT. Study on the mechanism of lipid peroxidation induced by carbonate radicals. Molecules, 2024, 29(5):1125. https:\/\/doi.org\/10.3390\/molecules29051125","DOI":"10.3390\/molecules29051125"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"[27] Ayala A, Mu\u00f1oz MF, Arg\u00fcelles S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev, 2014, 2014:360438. https:\/\/doi.org\/10.1155\/2014\/360438","DOI":"10.1155\/2014\/360438"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"[28] Yoshida Y, Umeno A, Shichiri M. Lipid peroxidation biomarkers for evaluating oxidative stress and assessing antioxidant capacity in vivo. J Clin Biochem Nutr, 2013, 52(1):9-16. https:\/\/doi.org\/10.3164\/jcbn.12-112","DOI":"10.3164\/jcbn.12-112"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"[29] Sultana R, Perluigi M, Butterfield DA. Lipid peroxidation triggers neurodegeneration: a redox proteomics view into the Alzheimer disease brain. Free Radic Biol Med, 2013, 62:157-169. https:\/\/doi.org\/10.1016\/j.freeradbiomed.2012.09.027","DOI":"10.1016\/j.freeradbiomed.2012.09.027"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"[30] Breitzig M, Bhimineni C, Lockey R, Kolliputi N. 4-Hydroxy-2-nonenal: a critical target in oxidative stress? Am J Physiol Cell Physiol, 2016, 311(4):C537-C543. https:\/\/doi.org\/10.1152\/ajpcell.00101.2016","DOI":"10.1152\/ajpcell.00101.2016"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"[31] Aslebagh R, Pfeffer BA, Fliesler SJ, Darie CC. Mass spectrometry-based proteomics of oxidative stress: identification of 4-hydroxy-2-nonenal (HNE) adducts of amino acids using lysozyme and bovine serum albumin as model proteins. Electrophoresis, 2016, 37(20):2615-2623. https:\/\/doi.org\/10.1002\/elps.201600134","DOI":"10.1002\/elps.201600134"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"[32] Green JL, Dos Santos WF, Fontana ACK. Role of glutamate excitotoxicity and glutamate transporter EAAT2 in epilepsy: opportunities for novel therapeutics development. Biochem Pharmacol, 2021, 193:114786. https:\/\/doi.org\/10.1016\/j.bcp.2021.114786","DOI":"10.1016\/j.bcp.2021.114786"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"[33] Jov\u00e9 M, Mota-Martorell N, Pradas I, Mart\u00edn-Gari M, Ayala V, Pamplona R. The advanced lipoxidation end-product malondialdehyde-lysine in aging and longevity. Antioxidants (Basel), 2020, 9(11):1132. https:\/\/doi.org\/10.3390\/antiox9111132","DOI":"10.3390\/antiox9111132"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"[34] Lim PS, Chang YM, Thien LM, Wang NP, Yang CC, Chen TT, Hsu WM. 8-Isoprostaglandin F2\u03b1 as a useful clinical biomarker of oxidative stress in ESRD patients. Blood Purif, 2002, 20(6):537-542. https:\/\/doi.org\/10.1159\/000066962","DOI":"10.1159\/000066962"},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"[35] Tsermpini EE, Plemenita\u0161 Ilje\u0161 A, Dol\u017ean V. Alcohol-induced oxidative stress and the role of antioxidants in alcohol use disorder: a systematic review. Antioxidants (Basel), 2022, 11(7):1374. https:\/\/doi.org\/10.3390\/antiox11071374","DOI":"10.3390\/antiox11071374"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"[36] Farbiszewski R, Chwiecko M, Holownia A, Pawlowska D. The decrease of superoxide dismutase activity and depletion of sulfhydryl compounds in ethanol-induced liver injury. Drug Alcohol Depend, 1991, 28(3):291-294. https:\/\/doi.org\/10.1016\/0376-8716(91)90063-5","DOI":"10.1016\/0376-8716(91)90063-5"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"[37] Bailey SM, Patel VB, Young TA, Asayama K, Cunningham CC. Chronic ethanol consumption alters the glutathione\/glutathione peroxidase-1 system and protein oxidation status in rat liver. Alcohol Clin Exp Res, 2001, 25(5):726-733.","DOI":"10.1111\/j.1530-0277.2001.tb02273.x"},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"[38] Assiri MA, Roy SR, Harris PS, Ali H, Liang Y, Shearn CT, Orlicky DJ, Roede JR, Hirschey MD, Backos DS, Fritz KS. Chronic ethanol metabolism inhibits hepatic mitochondrial superoxide dismutase via lysine acetylation. Alcohol Clin Exp Res, 2017, 41(10):1705-1714. https:\/\/doi.org\/10.1111\/acer.13473","DOI":"10.1111\/acer.13473"},{"key":"ref38","doi-asserted-by":"publisher","unstructured":"[39] Lluis JM, Colell A, Garc\u00eda-Ruiz C, Kaplowitz N, Fern\u00e1ndez-Checa JC. Acetaldehyde impairs mitochondrial glutathione transport in HepG2 cells through endoplasmic reticulum stress. Gastroenterology, 2003, 124(3):708-724. https:\/\/doi.org\/10.1053\/gast.2003.50089","DOI":"10.1053\/gast.2003.50089"},{"key":"ref39","doi-asserted-by":"publisher","unstructured":"[40] Hoyt LR, Randall MJ, Ather JL, DePuccio DP, Landry CC, Qian X, Janssen-Heininger YM, van der Vliet A, Dixon AE, Amiel E, Poynter ME. Mitochondrial ROS induced by chronic ethanol exposure promote hyperactivation of the NLRP3 inflammasome. Redox Biol, 2017, 12:883-896. https:\/\/doi.org\/10.1016\/j.redox.2017.04.020","DOI":"10.1016\/j.redox.2017.04.020"},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"[41] Tassone A, Meringolo M, Ponterio G, Bonsi P, Schirinzi T, Martella G. Mitochondrial bioenergy in neurodegenerative disease: Huntington and Parkinson. Int J Mol Sci, 2023, 24(8):7221. https:\/\/doi.org\/10.3390\/ijms24087221","DOI":"10.3390\/ijms24087221"},{"key":"ref41","doi-asserted-by":"publisher","unstructured":"[42] Kumar A, Davuluri G, Welch N, Kim A, Gangadhariah M, Allawy A, Priyadarshini A, McMullen MR, Sandlers Y, Willard B, Hoppel CL, Nagy LE, Dasarathy S. Oxidative stress mediates ethanol-induced skeletal muscle mitochondrial dysfunction and dysregulated protein synthesis and autophagy. Free Radic Biol Med, 2019, 145:284-299. https:\/\/doi.org\/10.1016\/j.freeradbiomed.2019.09.031","DOI":"10.1016\/j.freeradbiomed.2019.09.031"},{"key":"ref42","doi-asserted-by":"publisher","unstructured":"[43] Kent AC, El Baradie KBY, Hamrick MW. Targeting the mitochondrial permeability transition pore to prevent age-associated cell damage and neurodegeneration. Oxid Med Cell Longev, 2021, 2021:6626484. https:\/\/doi.org\/10.1155\/2021\/6626484","DOI":"10.1155\/2021\/6626484"},{"key":"ref43","doi-asserted-by":"publisher","unstructured":"[44] Puyal J, Ginet V, Clarke PG. Multiple interacting cell death mechanisms in the mediation of excitotoxicity and ischemic brain damage: a challenge for neuroprotection. Prog Neurobiol, 2013, 105:24-48. https:\/\/doi.org\/10.1016\/j.pneurobio.2013.03.002","DOI":"10.1016\/j.pneurobio.2013.03.002"},{"key":"ref44","doi-asserted-by":"publisher","unstructured":"[45] Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X. Cytochrome c and dATP-dependent formation of Apaf-1\/caspase-9 complex initiates an apoptotic protease cascade. Cell, 1997, 91(4):479-489. https:\/\/doi.org\/10.1016\/s0092-8674(00)80434-1","DOI":"10.1016\/S0092-8674(00)80434-1"},{"key":"ref45","unstructured":"[46] Zahr NM, Sullivan EV. Translational studies of alcoholism: bridging the gap. Alcohol Res Health, 2008, 31(3):215-230."},{"key":"ref46","doi-asserted-by":"publisher","unstructured":"[47] Liu W, Vetreno RP, Crews FT. Hippocampal TNF-death receptors, caspase cell death cascades, and IL-8 in alcohol use disorder. Mol Psychiatry, 2021, 26(6):2254-2262. https:\/\/doi.org\/10.1038\/s41380-020-0698-4","DOI":"10.1038\/s41380-020-0698-4"},{"key":"ref47","doi-asserted-by":"publisher","unstructured":"[48] Galluzzi L, Kepp O, Chan FKM, Kroemer G. Necroptosis: mechanisms and relevance to disease. Annu Rev Pathol, 2017, 12:103-130. https:\/\/doi.org\/10.1146\/annurev-pathol-052016-100247","DOI":"10.1146\/annurev-pathol-052016-100247"},{"key":"ref48","doi-asserted-by":"publisher","unstructured":"[49] Chen G, Ke Z, Xu M, Liao M, Wang X, Qi Y, Zhang T, Frank JA, Bower KA, Shi X, Luo J. Autophagy is a protective response to ethanol neurotoxicity. Autophagy, 2012, 8(11):1577-1589. https:\/\/doi.org\/10.4161\/auto.21376","DOI":"10.4161\/auto.21376"},{"key":"ref49","doi-asserted-by":"publisher","unstructured":"[50] M\u00f6ykkynen T, Korpi ER. Acute effects of ethanol on glutamate receptors. Basic Clin Pharmacol Toxicol, 2012, 111(1):4-13. https:\/\/doi.org\/10.1111\/j.1742-7843.2012.00879.x","DOI":"10.1111\/j.1742-7843.2012.00879.x"},{"key":"ref50","doi-asserted-by":"publisher","unstructured":"[51] Holmes A, Spanagel R, Krystal JH. Glutamatergic targets for new alcohol medications. Psychopharmacology (Berl), 2013, 229(3):539-554. https:\/\/doi.org\/10.1007\/s00213-013-3226-2","DOI":"10.1007\/s00213-013-3226-2"},{"key":"ref51","doi-asserted-by":"publisher","unstructured":"[52] Wu WL, Gong XX, Qin ZH, Wang Y. Molecular mechanisms of excitotoxicity and their relevance to the pathogenesis of neurodegenerative diseases - an update. Acta Pharmacol Sin, 2025, 46(12):3129-3142. https:\/\/doi.org\/10.1038\/s41401-025-01576-w","DOI":"10.1038\/s41401-025-01576-w"},{"key":"ref52","doi-asserted-by":"publisher","unstructured":"[53] Fernandez-Lizarbe S, Montesinos J, Guerri C. Ethanol induces TLR4\/TLR2 association, triggering an inflammatory response in microglial cells. J Neurochem, 2013, 126(2):261-273. https:\/\/doi.org\/10.1111\/jnc.12276","DOI":"10.1111\/jnc.12276"},{"key":"ref53","doi-asserted-by":"publisher","unstructured":"[54] Holloway KN, Douglas JC, Rafferty TM, Kane CJM, Drew PD. Ethanol induces neuroinflammation in a chronic plus binge mouse model of alcohol use disorder via TLR4 and MyD88-dependent signaling. Cells, 2023, 12(16):2109. https:\/\/doi.org\/10.3390\/cells12162109","DOI":"10.3390\/cells12162109"},{"key":"ref54","doi-asserted-by":"publisher","unstructured":"[55] Guo ML, Roodsari SK, Cheng Y, Dempsey RE, Hu W. Microglia NLRP3 inflammasome and neuroimmune signaling in substance use disorders. Biomolecules, 2023, 13(6):922. https:\/\/doi.org\/10.3390\/biom13060922","DOI":"10.3390\/biom13060922"},{"key":"ref55","doi-asserted-by":"publisher","unstructured":"[56] Crews FT, Qin L, Coleman L, Vidrascu E, Vetreno R. Cortical reactive microglia activate astrocytes, increasing neurodegeneration in human alcohol use disorder. Brain Behav Immun, 2026, 131:106156. https:\/\/doi.org\/10.1016\/j.bbi.2025.106156","DOI":"10.1016\/j.bbi.2025.106156"},{"key":"ref56","doi-asserted-by":"publisher","unstructured":"[57] Adermark L, Bowers MS. Disentangling the role of astrocytes in alcohol use disorder. Alcohol Clin Exp Res, 2016, 40(9):1802-1816. https:\/\/doi.org\/10.1111\/acer.13168","DOI":"10.1111\/acer.13168"},{"key":"ref57","doi-asserted-by":"publisher","unstructured":"[58] Kril JJ, Halliday GM, Svoboda MD, Cartwright H. The cerebral cortex is damaged in chronic alcoholics. Neuroscience, 1997, 79(4):983-998. https:\/\/doi.org\/10.1016\/s0306-4522(97)00083-3","DOI":"10.1016\/S0306-4522(97)00083-3"},{"key":"ref58","doi-asserted-by":"publisher","unstructured":"[59] Krassner MM, Kauffman J, Sowa A, Cialowicz K, Walsh S, Farrell K, Crary JF, McKenzie AT. Postmortem changes in brain cell structure: a review. Free Neuropathol, 2023, 4:10. https:\/\/doi.org\/10.17879\/freeneuropathology-2023-4790","DOI":"10.31219\/osf.io\/gj29w"},{"key":"ref59","doi-asserted-by":"publisher","unstructured":"[60] de la Monte SM, Kril JJ. Human alcohol-related neuropathology. Acta Neuropathol, 2014, 127(1):71-90. https:\/\/doi.org\/10.1007\/s00401-013-1233-3","DOI":"10.1007\/s00401-013-1233-3"},{"key":"ref60","doi-asserted-by":"publisher","unstructured":"[61] Cykowski MD, Masdeu JC. The cholinergic basal forebrain and its role in neurodegeneration. J Neuropathol Exp Neurol, 2025, 84(12):1073-1093. https:\/\/doi.org\/10.1093\/jnen\/nlaf112","DOI":"10.1093\/jnen\/nlaf112"},{"key":"ref61","doi-asserted-by":"publisher","unstructured":"[62] Li BZ, Sumera A, Booker SA, McCullagh EA. Current best practices for analysis of dendritic spine morphology and number in neurodevelopmental disorder research. ACS Chem Neurosci, 2023, 14(9):1561-1572. https:\/\/doi.org\/10.1021\/acschemneuro.3c00062","DOI":"10.1021\/acschemneuro.3c00062"},{"key":"ref62","doi-asserted-by":"publisher","unstructured":"[63] Ferrer I, F\u00e1bregues I, Rairiz J, Galofr\u00e9 E. Decreased numbers of dendritic spines on cortical pyramidal neurons in human chronic alcoholism. Neurosci Lett, 1986, 69(1):115-119. https:\/\/doi.org\/10.1016\/0304-3940(86)90425-8","DOI":"10.1016\/0304-3940(86)90425-8"},{"key":"ref63","doi-asserted-by":"publisher","unstructured":"[64] Rasool AE, Cornish JL, Prasad AA. The neuropathology of alcohol use disorder: cellular insights from human post-mortem studies. J Neurochem, 2025, 169(9):e70233. https:\/\/doi.org\/10.1111\/jnc.70233","DOI":"10.1111\/jnc.70233"},{"key":"ref64","doi-asserted-by":"publisher","unstructured":"[65] Mitoma H, Manto M, Shaikh AG. Mechanisms of ethanol-induced cerebellar ataxia: underpinnings of neuronal death in the cerebellum. Int J Environ Res Public Health, 2021, 18(16):8678. https:\/\/doi.org\/10.3390\/ijerph18168678","DOI":"10.3390\/ijerph18168678"},{"key":"ref65","doi-asserted-by":"publisher","unstructured":"[66] Olesen MA, Anc\u00eda A, Quintanilla RA. Is tau pathology a relevant factor in neuronal damage induced by alcohol and other drugs? Biochim Biophys Acta Mol Basis Dis, 2026, 1872(1):168059. https:\/\/doi.org\/10.1016\/j.bbadis.2025.168059","DOI":"10.1016\/j.bbadis.2025.168059"},{"key":"ref66","doi-asserted-by":"publisher","unstructured":"[67] Guo C, Zhang Y, Shuai S, Sigbessia A, Hao S, Xie P, Jiang X, Luo Z, Lin C. The super elongation complex (SEC) mediates phase transition of SPT5 during transcriptional pause release. EMBO Rep, 2023, 24(3):e55699. https:\/\/doi.org\/10.15252\/embr.202255699","DOI":"10.15252\/embr.202255699"},{"key":"ref67","doi-asserted-by":"publisher","unstructured":"[68] Zille M, Farr TD, Przesdzing I, M\u00fcller J, Sommer C, Dirnagl U, Wunder A. Visualizing cell death in experimental focal cerebral ischemia: promises, problems, and perspectives. J Cereb Blood Flow Metab, 2012, 32(2):213-231. https:\/\/doi.org\/10.1038\/jcbfm.2011.150","DOI":"10.1038\/jcbfm.2011.150"},{"key":"ref68","doi-asserted-by":"publisher","unstructured":"[69] Kari S, Subramanian K, Altomonte IA, Murugesan A, Yli-Harja O, Kandhavelu M. Programmed cell death detection methods: a systematic review and a categorical comparison. Apoptosis, 2022, 27(7-8):482-508. https:\/\/doi.org\/10.1007\/s10495-022-01735-y","DOI":"10.1007\/s10495-022-01735-y"},{"key":"ref69","doi-asserted-by":"publisher","unstructured":"[70] Ali-Saeed R, Alabsi AM, Al-Garadi MA, Abdelwahab SI, Samrot AV, Subramaniyan V, Fareez IM. Ultrastructure microscopic characterization of apoptosis in myelomoncytic leukemia cell line treated with velogenic viscerotropic Newcastle disease virus strain AF 2240. Asian Pac J Cancer Prev, 2024, 25(9):2991-2998. https:\/\/doi.org\/10.31557\/APJCP.2024.25.9.2991","DOI":"10.31557\/APJCP.2024.25.9.2991"},{"key":"ref70","doi-asserted-by":"publisher","unstructured":"[71] Schenone A, Massucco S, Schenone C, Venturi CB, Nozza P, Prada V, Pomili T, Di Patrizi I, Capodivento G, Nobbio L, Grandis M. Basic pathological mechanisms in peripheral nerve diseases. Int J Mol Sci, 2025, 26(7):3377. https:\/\/doi.org\/10.3390\/ijms26073377","DOI":"10.3390\/ijms26073377"},{"key":"ref71","doi-asserted-by":"publisher","unstructured":"[72] Verkhratsky A, Li B, Scuderi C, Parpura V. Principles of astrogliopathology. Adv Neurobiol, 2021, 26:55-73. https:\/\/doi.org\/10.1007\/978-3-030-77375-5_3","DOI":"10.1007\/978-3-030-77375-5_3"},{"key":"ref72","doi-asserted-by":"publisher","unstructured":"[73] Rouillard ME, Sutter PA, Durham OR, Willis CM, Crocker SJ. Astrocyte-derived extracellular vesicles (ADEVs): deciphering their influences in aging. Aging Dis, 2021, 12(6):1462-1475. https:\/\/doi.org\/10.14336\/AD.2021.0608","DOI":"10.14336\/AD.2021.0608"},{"key":"ref73","doi-asserted-by":"publisher","unstructured":"[74] Peng H, Nixon K. Microglia phenotypes following the induction of alcohol dependence in adolescent rats. Alcohol Clin Exp Res, 2021, 45(1):105-116. https:\/\/doi.org\/10.1111\/acer.14504","DOI":"10.1111\/acer.14504"},{"key":"ref74","doi-asserted-by":"publisher","unstructured":"[75] Dhir S, Tarasenko M, Napoli E, Giulivi C. Neurological, psychiatric, and biochemical aspects of thiamine deficiency in children and adults. Front Psychiatry, 2019, 10:207. https:\/\/doi.org\/10.3389\/fpsyt.2019.00207","DOI":"10.3389\/fpsyt.2019.00207"},{"key":"ref75","doi-asserted-by":"publisher","unstructured":"[76] Kril JJ, Harper CG. Neuroanatomy and neuropathology associated with Korsakoff's syndrome. Neuropsychol Rev, 2012, 22(2):72-80. https:\/\/doi.org\/10.1007\/s11065-012-9195-0","DOI":"10.1007\/s11065-012-9195-0"},{"key":"ref76","doi-asserted-by":"publisher","unstructured":"[77] Sandhu GS, Nagrale HR. Computed tomography evaluation of brain in chronic alcoholics. J Neurosci Rural Pract, 2020, 11(1):63-71. https:\/\/doi.org\/10.1055\/s-0039-1700610","DOI":"10.1055\/s-0039-1700610"},{"key":"ref77","doi-asserted-by":"publisher","unstructured":"[78] Sarkinaite M, Gleizniene R, Adomaitiene V, Dambrauskiene K, Raskauskiene N, Steibliene V. Volumetric MRI analysis of brain structures in patients with history of first and repeated suicide attempts: a cross sectional study. Diagnostics (Basel), 2021, 11(3):488. https:\/\/doi.org\/10.3390\/diagnostics11030488","DOI":"10.3390\/diagnostics11030488"},{"key":"ref78","doi-asserted-by":"publisher","unstructured":"[79] Jiang Y, Liu G, Deng B, Li X, Ren J, Zhao Y, Hu C, Xu L, Gao F, Mu X. White matter lesions and DTI metrics related to various types of dysfunction in cerebral palsy: a meta-analysis and systematic review. PLoS One, 2025, 20(1):e0312378. https:\/\/doi.org\/10.1371\/journal.pone.0312378","DOI":"10.1371\/journal.pone.0312378"},{"key":"ref79","doi-asserted-by":"publisher","unstructured":"[80] Clark JB. N-acetyl aspartate: a marker for neuronal loss or mitochondrial dysfunction. Dev Neurosci, 1998, 20(4-5):271-276. https:\/\/doi.org\/10.1159\/000017321","DOI":"10.1159\/000017321"},{"key":"ref80","doi-asserted-by":"publisher","unstructured":"[81] Hattingen E, Raab P, Franz K, Zanella FE, Lanfermann H, Pilatus U. Myo-inositol: a marker of reactive astrogliosis in glial tumors? NMR Biomed, 2008, 21(3):233-241. https:\/\/doi.org\/10.1002\/nbm.1186","DOI":"10.1002\/nbm.1186"},{"key":"ref81","doi-asserted-by":"publisher","unstructured":"[82] Galloway DA, Moore CS. miRNAs as emerging regulators of oligodendrocyte development and differentiation. Front Cell Dev Biol, 2016, 4:59. https:\/\/doi.org\/10.3389\/fcell.2016.00059","DOI":"10.3389\/fcell.2016.00059"},{"key":"ref82","doi-asserted-by":"publisher","unstructured":"[83] Li F, Sami A, Noristani HN, Slattery K, Qiu J, Groves T, Wang S, Veerasammy K, Chen YX, Morales J, Haynes P, Sehgal A, He Y, Li S, Song Y. Glial metabolic rewiring promotes axon regeneration and functional recovery in the central nervous system. Cell Metab, 2020, 32(5):767-785.e7. https:\/\/doi.org\/10.1016\/j.cmet.2020.08.015","DOI":"10.1016\/j.cmet.2020.08.015"},{"key":"ref83","doi-asserted-by":"publisher","unstructured":"[84] Rotaru-Z\u0103v\u0103leanu AD, Dinescu VC, Aldea M, Gresita A. Hydrogel-based therapies for ischemic and hemorrhagic stroke: a comprehensive review. Gels, 2024, 10(7):476. https:\/\/doi.org\/10.3390\/gels10070476","DOI":"10.3390\/gels10070476"},{"key":"ref84","doi-asserted-by":"publisher","unstructured":"[85] Musa I, Rotaru-Zavaleanu AD, Sfredel V, Aldea M, Gresita A, Glavan DG. Post-stroke recovery: a review of hydrogel-based phytochemical delivery systems. Gels, 2025, 11(4):260. https:\/\/doi.org\/10.3390\/gels11040260","DOI":"10.3390\/gels11040260"},{"key":"ref85","doi-asserted-by":"publisher","unstructured":"[86] Taisescu O, Dinescu VC, Rotaru-Zavaleanu AD, Gresita A, Hadjiargyrou M. Hydrogels for peripheral nerve repair: emerging materials and therapeutic applications. Gels, 2025, 11(2):126. https:\/\/doi.org\/10.3390\/gels11020126","DOI":"10.3390\/gels11020126"},{"key":"ref86","doi-asserted-by":"publisher","unstructured":"[87] Viezuina DM, Musa I, Aldea M, Matache IM, Rotaru Zavaleanu AD, Gresita A, Veronica S, Mitran SI. Gelatin-based hydrogels for peripheral nerve regeneration: a multifunctional vehicle for cellular, molecular, and pharmacological therapy. Gels, 2025, 11(7):490. https:\/\/doi.org\/10.3390\/gels11070490","DOI":"10.3390\/gels11070490"},{"key":"ref87","doi-asserted-by":"publisher","unstructured":"[88] Dinescu VC, Martin L, Bica M, Vasile RC, Gresita A, Bunescu M, Ruscu MA, Aldea M, Rotaru-Zavaleanu AD. Hydrogel-based innovations in carpal tunnel syndrome: bridging pathophysiological complexities and translational therapeutic gaps. Gels, 2025, 11(1):52. https:\/\/doi.org\/10.3390\/gels11010052","DOI":"10.3390\/gels11010052"},{"key":"ref88","doi-asserted-by":"publisher","unstructured":"[89] Rotaru-Zavaleanu AD, Bica M, Dinescu SN, Ruscu MA, Vasile RC, Zavate AC, Dinescu VC. Bioactive hydrogels for spinal cord injury repair: emphasis on gelatin and its derivatives. Gels, 2025, 11(7):497. https:\/\/doi.org\/10.3390\/gels11070497","DOI":"10.3390\/gels11070497"},{"key":"ref89","doi-asserted-by":"publisher","unstructured":"[90] Dumitru I, Zoril\u0103 MV, \u0162olescu R\u015e, Racil\u0103 L, Pascu CI, Oprica AC, Burghil\u0103 DV, Matei L, V\u00eelcea EJ, Popescu C, Badea-Voiculescu O, Mogoant\u0103 L. Experimental model for the study of traumatic brain injury. Rom J Morphol Embryol, 2020, 61(3):729-737. https:\/\/doi.org\/10.47162\/RJME.61.3.11\"","DOI":"10.47162\/RJME.61.3.11"}],"container-title":["Romanian Journal of Morphology and Embryology"],"original-title":[],"link":[{"URL":"https:\/\/rjme.ro\/RJME\/resources\/files\/670126005018.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T22:56:53Z","timestamp":1784329013000},"score":1,"resource":{"primary":{"URL":"https:\/\/rjme.ro\/archive\/67\/1\/1\/"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,2]]},"references-count":90,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,7,12]]},"published-print":{"date-parts":[[2026,7,12]]}},"URL":"https:\/\/doi.org\/10.47162\/rjme.67.1.01","relation":{},"ISSN":["1220-0522","2066-8279"],"issn-type":[{"value":"1220-0522","type":"print"},{"value":"2066-8279","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,2]]}}}