{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T01:29:54Z","timestamp":1777426194685,"version":"3.51.4"},"reference-count":113,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,10,22]],"date-time":"2022-10-22T00:00:00Z","timestamp":1666396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Ministry of Research, Innovation and Digitization, CCCDI-UEFISCDI","award":["PN-III-P2-2.1-PED-2021-2146"],"award-info":[{"award-number":["PN-III-P2-2.1-PED-2021-2146"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Lithium is a source of great scientific interest because although it has such a simple structure, relatively easy-to-analyze chemistry, and well-established physical properties, the plethora of effects on biological systems\u2014which influence numerous cellular and molecular processes through not entirely explained mechanisms of action\u2014generate a mystery that modern science is still trying to decipher. Lithium has multiple effects on neurotransmitter-mediated receptor signaling, ion transport, signaling cascades, hormonal regulation, circadian rhythm, and gene expression. The biochemical mechanisms of lithium action appear to be multifactorial and interrelated with the functioning of several enzymes, hormones, vitamins, and growth and transformation factors. The widespread and chaotic marketing of lithium salts in potions and mineral waters, always at inadequate concentrations for various diseases, has contributed to the general disillusionment with empirical medical hypotheses about the therapeutic role of lithium. Lithium salts were first used therapeutically in 1850 to relieve the symptoms of gout, rheumatism, and kidney stones. In 1949, Cade was credited with discovering the sedative effect of lithium salts in the state of manic agitation, but frequent cases of intoxication accompanied the therapy. In the 1960s, lithium was shown to prevent manic and also depressive recurrences. This prophylactic effect was first demonstrated in an open-label study using the \u201cmirror\u201d method and was later (after 1970) confirmed by several placebo-controlled double-blind studies. Lithium prophylaxis was similarly effective in bipolar and also unipolar patients. In 1967, the therapeutic value of lithemia was determined, included in the range of 0.5\u20131.5 mEq\/L. Recently, new therapeutic perspectives on lithium are connected with improved neurological outcomes after ischemic stroke. The effects of lithium on the development and maintenance of neuroprotection can be divided into two categories: short-term effects and long-term effects. Unfortunately, the existing studies do not fully explain the lithium biological action mechanisms after ischemic stroke.<\/jats:p>","DOI":"10.3390\/life12111680","type":"journal-article","created":{"date-parts":[[2022,10,24]],"date-time":"2022-10-24T04:40:36Z","timestamp":1666586436000},"page":"1680","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Lithium Biological Action Mechanisms after Ischemic Stroke"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1084-7710","authenticated-orcid":false,"given":"Constantin","family":"Munteanu","sequence":"first","affiliation":[{"name":"Faculty of Medical Bioengineering, University of Medicine and Pharmacy \u201cGrigore T. Popa\u201d Ia\u0219i, 700454 Ia\u0219i, Romania"},{"name":"Teaching Emergency Hospital \u201cBagdasar-Arseni\u201d, 041915 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariana","family":"Rotariu","sequence":"additional","affiliation":[{"name":"Faculty of Medical Bioengineering, University of Medicine and Pharmacy \u201cGrigore T. Popa\u201d Ia\u0219i, 700454 Ia\u0219i, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marius","family":"Turnea","sequence":"additional","affiliation":[{"name":"Faculty of Medical Bioengineering, University of Medicine and Pharmacy \u201cGrigore T. Popa\u201d Ia\u0219i, 700454 Ia\u0219i, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ligia Gabriela","family":"T\u0103t\u0103ranu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Medicine and Pharmacy \u201cCarol Davila\u201d, 020022 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriela","family":"Dogaru","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cIuliu Hatieganu\u201d University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"},{"name":"Clinical Rehabilitation Hospital, 400437 Cluj-Napoca, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Popescu","sequence":"additional","affiliation":[{"name":"Teaching Emergency Hospital \u201cBagdasar-Arseni\u201d, 041915 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aura","family":"Sp\u00eenu","sequence":"additional","affiliation":[{"name":"Teaching Emergency Hospital \u201cBagdasar-Arseni\u201d, 041915 Bucharest, Romania"},{"name":"Faculty of Medicine, University of Medicine and Pharmacy \u201cCarol Davila\u201d, 020022 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ioana","family":"Andone","sequence":"additional","affiliation":[{"name":"Teaching Emergency Hospital \u201cBagdasar-Arseni\u201d, 041915 Bucharest, Romania"},{"name":"Faculty of Medicine, University of Medicine and Pharmacy \u201cCarol Davila\u201d, 020022 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena Valentina","family":"Ionescu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Ovidius University of Constanta, 900470 Constanta, Romania"},{"name":"Balneal and Rehabilitation Sanatorium of Techirghiol, 906100 Techirghiol, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2841-3336","authenticated-orcid":false,"given":"Roxana Elena","family":"\u021aucmeanu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Ovidius University of Constanta, 900470 Constanta, Romania"},{"name":"Balneal and Rehabilitation Sanatorium of Techirghiol, 906100 Techirghiol, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmen","family":"Oprea","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Ovidius University of Constanta, 900470 Constanta, Romania"},{"name":"Balneal and Rehabilitation Sanatorium of Techirghiol, 906100 Techirghiol, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alin","family":"\u021aucmeanu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Ovidius University of Constanta, 900470 Constanta, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6485-7180","authenticated-orcid":false,"given":"Carmen Nistor","family":"Cseppento","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Oradea, 410073 Oradea, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S\u00eenziana Calina","family":"Sili\u0219teanu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Biological Sciences, \u201cStefan cel Mare\u201d University of Suceava, 720229 Suceava, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6346-8941","authenticated-orcid":false,"given":"Gelu","family":"Onose","sequence":"additional","affiliation":[{"name":"Teaching Emergency Hospital \u201cBagdasar-Arseni\u201d, 041915 Bucharest, Romania"},{"name":"Faculty of Medicine, University of Medicine and Pharmacy \u201cCarol Davila\u201d, 020022 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/s42003-022-03051-2","article-title":"The neuroprotective mechanism of lithium after ischaemic stroke","volume":"5","author":"Chen","year":"2022","journal-title":"Commun. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4172\/1939-067X.1000154","article-title":"Pharmacological Modulation of Autophagy for Neuroprotection in Ischaemic Stroke","volume":"11","author":"Gunn","year":"2018","journal-title":"J. Exp. Stroke Transl. Med."},{"key":"ref_3","first-page":"98","article-title":"The effect of lithium on brain-derived neurotrophic factor\u2014Level in patients with ischemic stroke: A clinical trial","volume":"5","author":"Majdinasab","year":"2016","journal-title":"Int. J. Hosp. Res."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Onose, G., Anghelescu, A., Blendea, D., Ciobanu, V., Daia, C., Firan, F.C., Oprea, M., Spinu, A., Popescu, C., and Ionescu, A. (2022). Cellular and Molecular Targets for Non-Invasive, Non-Pharmacological Therapeutic\/Rehabilitative Interventions in Acute Ischemic Stroke. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23020907"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"196","DOI":"10.12680\/balneo.2021.439","article-title":"Water intake meets the Water from inside the human body\u2014Physiological, cultural, and health perspectives\u2014Synthetic and Systematic literature review","volume":"12","author":"Munteanu","year":"2021","journal-title":"Balneo PRM Res. J."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Munteanu, C., Rotariu, M., Turnea, M., Ionescu, A.M., Popescu, C., Spinu, A., Ionescu, E.V., Oprea, C., \u021aucmeanu, R.E., and T\u0103t\u0103ranu, L.G. (2022). Main Cations and Cellular Biology of Traumatic Spinal Cord Injury. Cells, 11.","DOI":"10.3390\/cells11162503"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Bulboaca, A.E., Boarescu, P.-M., Porfire, A.S., Dogaru, G., Barbalata, C., Valeanu, M., Munteanu, C., R\u00e2jnoveanu, R.M., Nicula, C.A., and Stanescu, I.C. (2020). The Effect of Nano-Epigallocatechin-Gallate on Oxidative Stress and Matrix Metalloproteinases in Experimental Diabetes Mellitus. Antioxidants, 9.","DOI":"10.3390\/antiox9020172"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.pharmthera.2010.07.006","article-title":"Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders","volume":"128","author":"Chiu","year":"2010","journal-title":"Pharmacol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1021\/cn500040g","article-title":"A New Avenue for Lithium: Intervention in Traumatic Brain Injury","volume":"5","author":"Leeds","year":"2014","journal-title":"ACS Chem. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e01541","DOI":"10.1016\/j.heliyon.2019.e01541","article-title":"Effects of lithium and valproate on ERK\/JNK signaling pathway in an animal model of mania induced by amphetamine","volume":"5","author":"Valvassori","year":"2019","journal-title":"Heliyon"},{"key":"ref_11","unstructured":"Munteanu, C. (2013). Lithium Biology, Editura Balneara."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1111\/cns.13832","article-title":"Lithium attenuates blood\u2013brain barrier damage and brain edema following intracerebral hemorrhage via an endothelial Wnt\/\u03b2-catenin signaling-dependent mechanism in mice","volume":"28","author":"Song","year":"2022","journal-title":"CNS Neurosci. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"15","DOI":"10.3389\/fnmol.2011.00015","article-title":"GSK-3 as a Target for Lithium-Induced Neuroprotection Against Excitotoxicity in Neuronal Cultures and Animal Models of Ischemic Stroke","volume":"4","author":"Chuang","year":"2011","journal-title":"Front. Mol. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Sheikh, M., Qassem, M., Triantis, I.F., and Kyriacou, P.A. (2022). Advances in Therapeutic Monitoring of Lithium in the Management of Bipolar Disorder. Sensors, 22.","DOI":"10.3390\/s22030736"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1152\/physiol.00015.2009","article-title":"Molecular Mechanisms of Ischemic Cerebral Edema: Role of Electroneutral Ion Transport","volume":"24","author":"Kahle","year":"2009","journal-title":"Physiology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1097\/WNF.0000000000000028","article-title":"The effect of lithium in post-stroke motor recovery: A double-blind, placebo-controlled, randomized clinical trial","volume":"37","author":"Mohammadianinejad","year":"2014","journal-title":"Clin. Neuropharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Cramer, S.C., and Nudo, R.J. (2010). Brain Repair after Stroke, Cambridge University Press.","DOI":"10.1017\/CBO9780511777547"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Chen, H.-J., Shen, Y.-C., Shiao, Y.-J., Liou, K.-T., Hsu, W.-H., Hsieh, P.-H., Lee, C.-Y., Chen, Y.-R., and Lin, Y.-L. (2015). Multiplex Brain Proteomic Analysis Revealed the Molecular Therapeutic Effects of Buyang Huanwu Decoction on Cerebral Ischemic Stroke Mice. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0140823"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1161\/STROKEAHA.107.507392","article-title":"Gray Matter Atrophy in Patients With Ischemic Stroke With Cognitive Impairment","volume":"39","author":"Stebbins","year":"2008","journal-title":"Stroke"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1192\/bjp.2019.76","article-title":"Clinical and biological effects of long-term lithium treatment in older adults with amnestic mild cognitive impairment: Randomised clinical trial","volume":"215","author":"Forlenza","year":"2019","journal-title":"Br. J. Psychiatry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"100932","DOI":"10.1016\/j.yfrne.2021.100932","article-title":"Brain to periphery in acute ischemic stroke: Mechanisms and clinical significance","volume":"63","author":"Cui","year":"2021","journal-title":"Front. Neuroendocr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9115","DOI":"10.1073\/pnas.1821979116","article-title":"Protease-independent action of tissue plasminogen activator in brain plasticity and neurological recovery after ischemic stroke","volume":"116","author":"Pu","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1161\/STROKEAHA.107.497115","article-title":"Mechanical thrombectomy for acute ischemic stroke: Final results of the multi MERCI trial","volume":"39","author":"Smith","year":"2008","journal-title":"Stroke"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.expneurol.2007.05.018","article-title":"Lithium enhances proliferation and neuronal differentiation of neural progenitor cells in vitro and after transplantation into the adult rat spinal cord","volume":"206","author":"Su","year":"2007","journal-title":"Exp. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zheng, M.X., Haupt, B.M., B\u00e4hr, M., Tatenhorst, L., and Doeppner, T.R. (2021). Treating cerebral ischemia: Novel therapeutic strategies from experimental stroke research. Cereb. Ischemia, Exon Publications.","DOI":"10.36255\/exonpublications.cerebralischemia.2021.therapy"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"108474","DOI":"10.1016\/j.neuropharm.2021.108474","article-title":"Lithium alleviates blood-brain barrier breakdown after cerebral ischemia and reperfusion by upregulating endothelial Wnt\/\u03b2-catenin signaling in mice","volume":"186","author":"Ji","year":"2021","journal-title":"Neuropharmacology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1177\/0271678X16647738","article-title":"Lithium-induced neuroprotection in stroke involves increased miR-124 expression, reduced RE1-silencing transcription factor abundance and decreased protein deubiquitination by GSK3\u03b2 inhibition-independent pathways","volume":"37","author":"Doeppner","year":"2017","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.3727\/096368916X691411","article-title":"Phase I\u2013II Clinical Trial Assessing Safety and Efficacy of Umbilical Cord Blood Mononuclear Cell Transplant Therapy of Chronic Complete Spinal Cord Injury","volume":"25","author":"Zhu","year":"2016","journal-title":"Cell Transplant."},{"key":"ref_29","first-page":"234","article-title":"Lithium prevents cell apoptosis through autophagy induction","volume":"119","author":"Kazemi","year":"2018","journal-title":"Bratisl. Lek. Listy"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1038\/npp.2010.41","article-title":"Lithium-Induced Gray Matter Volume Increase As a Neural Correlate of Treatment Response in Bipolar Disorder: A Longitudinal Brain Imaging Study","volume":"35","author":"Lyoo","year":"2010","journal-title":"Neuropsychopharmacology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.1016\/j.bbrc.2017.12.119","article-title":"Lithium chloride contributes to blood\u2013spinal cord barrier integrity and functional recovery from spinal cord injury by stimulating autophagic flux","volume":"495","author":"Tong","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"593","DOI":"10.3389\/fphys.2016.00593","article-title":"Low-Dose Lithium Stabilizes Human Endothelial Barrier by Decreasing MLC Phosphorylation and Universally Augments Cholinergic Vasorelaxation Capacity in a Direct Manner","volume":"7","author":"Bosche","year":"2016","journal-title":"Front. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.52586\/5020","article-title":"Non-invasive, non-pharmacological\/bio-technological interventions towards neurorestoration upshot after ischemic stroke, in adults\u2014Systematic, synthetic, literature review","volume":"26","author":"Onose","year":"2021","journal-title":"Front. Biosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1161\/01.STR.29.12.2455","article-title":"Timing for Fever-Related Brain Damage in Acute Ischemic Stroke","volume":"29","author":"Castillo","year":"1998","journal-title":"Stroke"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"39","DOI":"10.15616\/BSL.2017.23.1.39","article-title":"Hypothermia Regulates Insulin-like Growth Factor 1 Gene Expression in PC12 Cells","volume":"23","author":"Yoo","year":"2017","journal-title":"Biomed. Sci. Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.5114\/aoms.2015.56342","article-title":"Brain-derived neurotrophic factor and its clinical implications","volume":"11","author":"Bathina","year":"2015","journal-title":"Arch. Med. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2174","DOI":"10.4103\/1673-5374.147950","article-title":"Thermomineral water promotes axonal sprouting but does not reduce glial scar formation in a mouse model of spinal cord injury","volume":"9","author":"Divac","year":"2014","journal-title":"Neural Regen. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1192\/bjp.2018.203","article-title":"Mood stabilisers and risk of stroke in bipolar disorder","volume":"215","author":"Chen","year":"2019","journal-title":"Br. J. Psychiatry"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1007\/s00232-017-9998-2","article-title":"Towards a Unified Understanding of Lithium Action in Basic Biology and its Significance for Applied Biology","volume":"250","author":"Jakobsson","year":"2017","journal-title":"J. Membr. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/sc.2011.126","article-title":"Efficacy and safety of lithium carbonate treatment of chronic spinal cord injuries: A double-blind, randomized, placebo-controlled clinical trial","volume":"50","author":"Yang","year":"2012","journal-title":"Spinal Cord"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"951","DOI":"10.3727\/096368909X471251","article-title":"Review of Lithium Effects on Brain and Blood","volume":"18","author":"Young","year":"2009","journal-title":"Cell Transplant."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2383","DOI":"10.4103\/1673-5374.313015","article-title":"Lithium beyond psychiatric indications: The reincarnation of a new old drug","volume":"16","author":"Doeppner","year":"2021","journal-title":"Neural Regen. Res."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Ramli, F.F., Cowen, P.J., and Godlewska, B.R. (2022). The Potential Use of Ebselen in Treatment-Resistant Depression. Pharmaceuticals, 15.","DOI":"10.3390\/ph15040485"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"108357","DOI":"10.1016\/j.neuropharm.2020.108357","article-title":"Lithium enhances post-stroke blood-brain barrier integrity, activates the MAPK\/ERK1\/2 pathway and alters immune cell migration in mice","volume":"181","author":"Haupt","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1177\/0963689717752945","article-title":"Transplantation of a Peripheral Nerve with Neural Stem Cells Plus Lithium Chloride Injection Promote the Recovery of Rat Spinal Cord Injury","volume":"27","author":"Zhang","year":"2018","journal-title":"Cell Transplant."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1021\/cn5000309","article-title":"Neuroprotective effects of lithium: Implications for the treatment of Alzheimer\u2019s disease and related neurodegenerative disorders","volume":"5","author":"Forlenza","year":"2014","journal-title":"ACS Chem. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"E402","DOI":"10.1503\/jpn.200185","article-title":"Chronic lithium treatment alters the excitatory\/inhibitory balance of synaptic networks and reduces mGluR5\u2013PKC signalling in mouse cortical neurons","volume":"46","author":"Khayachi","year":"2021","journal-title":"J. Psychiatry Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2642","DOI":"10.1073\/pnas.95.5.2642","article-title":"Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-D-aspartate receptor-mediated calcium influx","volume":"95","author":"Nonaka","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"6039","DOI":"10.1074\/jbc.274.10.6039","article-title":"Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression: A prominent role in neuroprotection against excitotoxicity","volume":"274","author":"Chen","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1046\/j.1471-4159.2001.00410.x","article-title":"Lithium inhibits caspase 3 activation and dephosphorylation of PKB and GSK3 induced by K+ deprivation in cerebellar granule cells","volume":"78","author":"Mora","year":"2001","journal-title":"J. Neurochem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"8745","DOI":"10.1073\/pnas.96.15.8745","article-title":"Lithium activates the serine\/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons","volume":"96","author":"Chuang","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"403","DOI":"10.3389\/fnins.2015.00403","article-title":"Potential application of lithium in Parkinson\u2019s and other neurodegenerative diseases","volume":"9","author":"Lazzara","year":"2015","journal-title":"Front. Neurosci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"112719","DOI":"10.1016\/j.bbr.2020.112719","article-title":"Neuroprotective effect of lithium in cold- induced traumatic brain injury in mice","volume":"392","author":"Ciftci","year":"2020","journal-title":"Behav. Brain Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.bbi.2018.03.007","article-title":"Cognitive benefits of lithium chloride in APP\/PS1 mice are associated with enhanced brain clearance of \u03b2-amyloid","volume":"70","author":"Pan","year":"2018","journal-title":"Brain Behav. Immun."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1089\/neu.2011.1942","article-title":"Lithium Ameliorates Neurodegeneration, Suppresses Neuroinflammation, and Improves Behavioral Performance in a Mouse Model of Traumatic Brain Injury","volume":"29","author":"Yu","year":"2012","journal-title":"J. Neurotrauma"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/s41398-021-01695-y","article-title":"Lithium treatment and human hippocampal neurogenesis","volume":"11","author":"Palmos","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Stoica, S.I., Bleotu, C., Ciobanu, V., Ionescu, A.M., Albadi, I., Onose, G., and Munteanu, C. (2022). Considerations about Hypoxic Changes in Neuraxis Tissue Injuries and Recovery. Biomedicines, 10.","DOI":"10.3390\/biomedicines10020481"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Wu, H.-C., Chou, F.H.-C., Tsai, K.-Y., Su, C.-Y., Shen, S.-P., and Chung, T.-C. (2013). The Incidence and Relative Risk of Stroke among Patients with Bipolar Disorder: A Seven-Year Follow-Up Study. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0073037"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1111\/bdi.12336","article-title":"A reduced risk of stroke with lithium exposure in bipolar disorder: A population-based retrospective cohort study","volume":"17","author":"Lan","year":"2015","journal-title":"Bipolar Disord."},{"key":"ref_60","first-page":"E2","article-title":"Experimental neuroprotection in ischemic stroke: A concise review","volume":"42","author":"Rajah","year":"2017","journal-title":"Neurosurg. Focus"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"207","DOI":"10.5115\/acb.2017.50.3.207","article-title":"Lithium ameliorates rat spinal cord injury by suppressing glycogen synthase kinase-3\u03b2 and activating heme oxygenase-1","volume":"50","author":"Kim","year":"2017","journal-title":"Anat. Cell Biol."},{"key":"ref_62","first-page":"106","article-title":"GSK-3\u03b2 expression after treatment of glial cells with lithium and Maria lithium mineral water from Malna\u015f-B\u0103i","volume":"4","author":"Munteanu","year":"2009","journal-title":"Maedica J. Clin. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1161\/01.STR.0000066308.25088.64","article-title":"Chronic Treatment With a Low Dose of Lithium Protects the Brain Against Ischemic Injury by Reducing Apoptotic Death","volume":"34","author":"Xu","year":"2003","journal-title":"Stroke"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.4103\/1673-5374.327348","article-title":"Lithium promotes recovery after spinal cord injury","volume":"17","author":"He","year":"2022","journal-title":"Neural Regen. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.2174\/0929867321666131228205146","article-title":"Innate inflammatory responses in stroke: Mechanisms and potential therapeutic targets","volume":"21","author":"Masahito","year":"2014","journal-title":"Curr. Med. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Schepetkin, I.A., Chernysheva, G.A., Aliev, O.I., Kirpotina, L.N., Smol\u2019Yakova, V.I., Osipenko, A.N., Plotnikov, M.B., Kovrizhina, A.R., Khlebnikov, A.I., and Plotnikov, E.V. (2022). Neuroprotective Effects of the Lithium Salt of a Novel JNK Inhibitor in an Animal Model of Cerebral Ischemia\u2013Reperfusion. Biomedicines, 10.","DOI":"10.3390\/biomedicines10092119"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1590\/1516-4446-2017-0001","article-title":"Effects of lithium on inflammatory and neurotrophic factors after an immune challenge in a lisdexamfetamine animal model of mania","volume":"41","author":"Bristot","year":"2019","journal-title":"Braz. J. Psychiatry"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"916234","DOI":"10.1155\/2015\/916234","article-title":"Effects of Acute Lithium Treatment on Brain Levels of Inflammatory Mediators in Poststroke Rats","volume":"2015","author":"Boyko","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"297","DOI":"10.3389\/fnmol.2018.00297","article-title":"Molecular Mechanisms of Lithium Action: Switching the Light on Multiple Targets for Dementia Using Animal Models","volume":"11","author":"Kerr","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e13275","DOI":"10.1111\/cpr.13275","article-title":"The PI3K\/AKT signalling pathway in inflammation, cell death and glial scar formation after traumatic spinal cord injury: Mechanisms and therapeutic opportunities","volume":"55","author":"He","year":"2022","journal-title":"Cell Prolif."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1084\/jem.194.11.1617","article-title":"A Mediator Role For Metallothionein in Tumor Necrosis Factor\u2013induced Lethal Shock","volume":"194","author":"Waelput","year":"2001","journal-title":"J. Exp. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"502","DOI":"10.12680\/balneo.2022.502","article-title":"Effects of ethanol and deferoxamine on rat primary glial cell cultures, in regard with ischemia induced by traumatic spinal cord injury","volume":"13","author":"Stoica","year":"2022","journal-title":"Balneo PRM Res. J."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"761273","DOI":"10.3389\/fcell.2021.761273","article-title":"Biological Functions and Therapeutic Potential of Autophagy in Spinal Cord Injury","volume":"9","author":"Liao","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"109","DOI":"10.3892\/etm.2020.9237","article-title":"Lithium chloride ameliorated spatial cognitive impairment through activating mTOR phosphorylation and inhibiting excessive autophagy in the repeated cerebral ischemia-reperfusion mouse model","volume":"20","author":"Xiao","year":"2020","journal-title":"Exp. Ther. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.4103\/1673-5374.241473","article-title":"Lithium promotes recovery of neurological function after spinal cord injury by inducing autophagy","volume":"13","author":"Zhang","year":"2018","journal-title":"Neural Regen. Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s13041-022-00899-7","article-title":"The dual roles of autophagy and the GPCRs-mediating autophagy signaling pathway after cerebral ischemic stroke","volume":"15","author":"Hou","year":"2022","journal-title":"Mol. Brain"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"6210","DOI":"10.1073\/pnas.0937423100","article-title":"Postinsult treatment with lithium reduces brain damage and facilitates neurological recovery in a rat ischemia\/reperfusion model","volume":"100","author":"Ren","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40345-016-0068-y","article-title":"Lithium side effects and toxicity: Prevalence and management strategies","volume":"4","author":"Gitlin","year":"2016","journal-title":"Int. J. Bipolar Disord."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1089\/ct.2015;27.315-316","article-title":"Lithium Use Is Associated with an Increased Risk of Hypothyroidism","volume":"278","author":"Leung","year":"2015","journal-title":"Clin. Thyroidol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1681\/ASN.2005080884","article-title":"Development of Lithium-Induced Nephrogenic Diabetes Insipidus Is Dissociated from Adenylyl Cyclase Activity","volume":"17","author":"Li","year":"2006","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_81","first-page":"141","article-title":"Lithium Associated Side Effects and Neurotoxicity: Is Lithium Neurotoxicity Related to Iron Deposition? Psikiyatr Guncel Yaklasimlar","volume":"11","year":"2019","journal-title":"Curr. Approaches Psychiatry"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"bcr2017222920","DOI":"10.1136\/bcr-2017-222920","article-title":"The effect of a therapeutic lithium level on a stroke-related cerebellar tremor","volume":"2018","author":"Orleans","year":"2018","journal-title":"BMJ Case Rep."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"349","DOI":"10.3389\/fnmol.2018.00349","article-title":"Challenging the Negative Perception of Lithium and Optimizing Its Long-Term Administration","volume":"11","author":"Rybakowski","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1016\/j.euroneuro.2009.06.002","article-title":"Response to prophylactic lithium in bipolar disorder may be associated with a preservation of executive cognitive functions","volume":"19","author":"Rybakowski","year":"2009","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Chen, S., Underwood, B.R., Jones, P.B., Lewis, J.R., and Cardinal, R.N. (2022). Association between lithium use and the incidence of dementia and its subtypes: A retrospective cohort study. PLoS Med., 19.","DOI":"10.1371\/journal.pmed.1003941"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1017\/S1461145705006243","article-title":"Effect of lithium and lithium withdrawal on potassium-evoked dopamine release and tyrosine hydroxylase expression in the rat","volume":"9","author":"Ferrie","year":"2006","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1038\/mp.2015.4","article-title":"Lithium in the treatment of bipolar disorder: Pharmacology and pharmacogenetics","volume":"20","author":"Alda","year":"2016","journal-title":"Mol. Psychiatry"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1159\/000480349","article-title":"Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature","volume":"3","author":"Saxena","year":"2017","journal-title":"Complex Psychiatry"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"8358","DOI":"10.1073\/pnas.91.18.8358","article-title":"Lithium stimulates glutamate \u201crelease\u201d and inositol 1,4,5-trisphosphate accumulation via activation of the N-methyl-D-aspartate receptor in monkey and mouse cerebral cortex slices","volume":"91","author":"Dixon","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Rijal, S., Jang, S., Park, S., and Han, S. (2021). Lithium Enhances the GABAergic Synaptic Activities on the Hypothalamic Preoptic Area (hPOA) Neurons. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22083908"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1042\/BJ20070796","article-title":"Enhancement by lithium of cAMP-induced CRE\/CREB-directed gene transcription conferred by TORC on the CREB basic leucine zipper domain","volume":"408","author":"Eglins","year":"2007","journal-title":"Biochem. J."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"407","DOI":"10.3389\/fncel.2015.00407","article-title":"X MARCKS the spot: Myristoylated alanine-rich C kinase substrate in neuronal function and disease","volume":"9","author":"Brudvig","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2058739219852855","DOI":"10.1177\/2058739219852855","article-title":"The effect of lithium chloride on the motor function of spinal cord injury\u2013controlled rat and the relevant mechanism","volume":"17","author":"Chen","year":"2019","journal-title":"Eur. J. Inflamm."},{"key":"ref_94","first-page":"16","article-title":"Effect of Tamoxifen and Lithium on Treatment of Acute Mania Symptoms in Children and Adolescents","volume":"10","author":"Fallah","year":"2016","journal-title":"Iran. J. Child Neurol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"14","DOI":"10.3389\/fnmol.2012.00014","article-title":"Inhibition of GSK3 by lithium, from single molecules to signaling networks","volume":"5","author":"Freland","year":"2012","journal-title":"Front. Mol. Neurosci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1177\/2045125312471963","article-title":"Lithium: The pharmacodynamic actions of the amazing ion","volume":"3","author":"Brown","year":"2013","journal-title":"Ther. Adv. Psychopharmacol."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Snitow, M.E., Bhansali, R.S., and Klein, P.S. (2021). Lithium and Therapeutic Targeting of GSK-3. Cells, 10.","DOI":"10.3390\/cells10020255"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"6027","DOI":"10.1128\/MCB.23.17.6027-6036.2003","article-title":"Lithium Blocks the c-Jun Stress Response and Protects Neurons via Its Action on Glycogen Synthase Kinase 3","volume":"23","author":"Hongisto","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"ref_99","first-page":"226","article-title":"Lithium treatment reduces brain injury induced by focal ischemia with partial reperfusion and the protective mechanisms dispute the importance of akt activity","volume":"3","author":"Takahashi","year":"2012","journal-title":"Aging Dis."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.biopsych.2006.10.027","article-title":"Greater Cortical Gray Matter Density in Lithium-Treated Patients with Bipolar Disorder","volume":"62","author":"Bearden","year":"2007","journal-title":"Biol. Psychiatry"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1038\/mp.2016.72","article-title":"Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: Evidence from voxel-based meta-analysis","volume":"22","author":"Wise","year":"2017","journal-title":"Mol. Psychiatry"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1503\/jpn.110143","article-title":"Smaller hippocampal volumes in patients with bipolar disorder are masked by exposure to lithium: A meta-analysis","volume":"37","author":"Hajek","year":"2012","journal-title":"J. Psychiatry Neurosci."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1007\/s00213-014-3770-4","article-title":"Lithium and GSK-3\u03b2 promoter gene variants influence cortical gray matter volumes in bipolar disorder","volume":"232","author":"Benedetti","year":"2015","journal-title":"Psychopharmacology"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1016\/j.biopsych.2010.01.020","article-title":"Voxelwise Meta-Analysis of Gray Matter Abnormalities in Bipolar Disorder","volume":"67","author":"Bora","year":"2010","journal-title":"Biol. Psychiatry"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1097\/JCP.0000000000000981","article-title":"Lithium Carbonate in a Poststroke Population: Exploratory Analyses of Neuroanatomical and Cognitive Outcomes","volume":"39","author":"Sun","year":"2019","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.jad.2019.04.075","article-title":"White matter microstructural properties in bipolar disorder in relationship to the spatial distribution of lithium in the brain","volume":"253","author":"Necus","year":"2019","journal-title":"J. Affect. Disord."},{"key":"ref_107","unstructured":"Sun, Y.R. (2022, October 02). Lithium Carbonate in a Post-Stroke Population: Preliminary Analyses of Neuroanatomical and Neuropsychiatric Outcomes, and Associations with BDNF from a Pilot Study. Available online: https:\/\/hdl.handle.net\/1807\/79365."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1001\/archpsyc.65.9.1017","article-title":"Meta-analysis, database, and meta-regression of 98 structural imaging studies in bipolar disorder","volume":"65","author":"Kempton","year":"2008","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1016\/S0140-6736(00)02793-8","article-title":"Lithium-induced increase in human brain grey matter","volume":"356","author":"Moore","year":"2000","journal-title":"Lancet"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/s41398-020-0784-z","article-title":"Integrative analysis of lithium treatment associated effects on brain structure and peripheral gene expression reveals novel molecular insights into mechanism of action","volume":"10","author":"Anand","year":"2020","journal-title":"Transl. Psychiatry"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1503\/jpn.110011","article-title":"A role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health","volume":"37","author":"Beaulieu","year":"2012","journal-title":"J. Psychiatry Neurosci."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"275","DOI":"10.2147\/NDT.S123612","article-title":"A fully integrated new paradigm for lithium\u2019s mode of action\u2014Lithium utilizes latent cellular fail-safe mechanisms","volume":"13","year":"2017","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/s40560-017-0257-5","article-title":"Lithium: One drug, five complications","volume":"5","author":"Zaworski","year":"2017","journal-title":"J. Intensive Care."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/12\/11\/1680\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:00:56Z","timestamp":1760144456000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/12\/11\/1680"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,22]]},"references-count":113,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["life12111680"],"URL":"https:\/\/doi.org\/10.3390\/life12111680","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,22]]}}}