{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T18:09:18Z","timestamp":1780337358519,"version":"3.54.1"},"reference-count":49,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","award":["101136570"],"award-info":[{"award-number":["101136570"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001870","name":"Foundation for Polish Science","doi-asserted-by":"crossref","award":["FENG.02.01-IP.05-T005\/23"],"award-info":[{"award-number":["FENG.02.01-IP.05-T005\/23"]}],"id":[{"id":"10.13039\/501100001870","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Retinal ganglion cells (RGCs) are vulnerable to excitotoxic damage mediated by excessive NMDA receptor activation and calcium overload. Extracellular magnesium (Mg\n                    <jats:sup>2+<\/jats:sup>\n                    ) blocks NMDA receptors in a voltage-dependent manner, offering potential neuroprotection. However, the optimal Mg\n                    <jats:sup>2+<\/jats:sup>\n                    concentrations and timing for effective intervention remain poorly defined. We developed a conductance-based computational model of an RGC incorporating Hodgkin-Huxley dynamics, AMPA and NMDA receptor-mediated synaptic transmission, and intracellular calcium dynamics. We systematically varied Mg\n                    <jats:sup>2+<\/jats:sup>\n                    concentration (0.2\u20132.5 mM) and stimulation frequency (10\u2013100 Hz) to identify therapeutic windows balancing neuroprotection with function preservation. At physiological frequencies (10\u201360 Hz), elevated Mg\n                    <jats:sup>2+<\/jats:sup>\n                    reduced calcium (Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ) accumulation by 50\u201385% without affecting spike output. At excitotoxic frequencies (80 Hz), a narrow therapeutic window of 1.6\u20132.0 mM was identified, lying within a broader 1.4\u20132.0 mM spike-loss plateau (20% loss), where calcium additionally fell below the toxicity threshold while spike output was preserved. Intervention timing analysis revealed that Mg\n                    <jats:sup>2+<\/jats:sup>\n                    protection efficacy is maximal with pre-treatment or immediate intervention (100%), and declines steeply with delay\u2014reflecting the rapid early rise in Ca\n                    <jats:sup>2+<\/jats:sup>\n                    rather than a fixed biological deadline (\u226550% protection requires intervention within 0.2 s in our abrupt-onset protocol; \u223c11% by 0.5 s). Re-analysis in terms of normalized Ca\n                    <jats:sup>2+<\/jats:sup>\n                    progress revealed that the critical constraint for \u226550% protection is intervention before \u223c35% of peak Ca\n                    <jats:sup>2+<\/jats:sup>\n                    accumulation\u2014a state-based threshold reflecting relative phase sensitivity that generalizes across timescales. Sensitivity analyses confirmed robustness of the therapeutic window across physiologically plausible parameter ranges, and numerical validation demonstrated accuracy of the computational approach. These findings demonstrate that Mg\n                    <jats:sup>2+<\/jats:sup>\n                    -mediated neuroprotection is highly dependent on both concentration and timing, with implications for therapeutic strategies targeting glutamate excitotoxicity in glaucoma and retinal ischemia.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0348068","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T17:38:38Z","timestamp":1780335518000},"page":"e0348068","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Magnesium neuroprotection in retinal ganglion cells: A computational study of frequency-dependent therapeutic windows and intervention timing"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0469-0902","authenticated-orcid":true,"given":"Mehdi","family":"Borjkhani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hadi","family":"Borjkhani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1469-6910","authenticated-orcid":true,"given":"Morteza A.","family":"Sharif","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"issue":"2","key":"pone.0348068.ref001","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.neuron.2012.10.002","article-title":"The neuronal organization of the retina","volume":"76","author":"RH Masland","year":"2012","journal-title":"Neuron"},{"issue":"4","key":"pone.0348068.ref002","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1111\/j.1442-9071.2012.02773.x","article-title":"Definition of glaucoma: clinical and experimental concepts","volume":"40","author":"RJ Casson","year":"2012","journal-title":"Clin Exp Ophthalmol"},{"issue":"1","key":"pone.0348068.ref003","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.preteyeres.2003.12.001","article-title":"Retinal ischemia: mechanisms of damage and potential therapeutic strategies","volume":"23","author":"NN Osborne","year":"2004","journal-title":"Prog Retin Eye Res"},{"issue":"11","key":"pone.0348068.ref004","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1016\/j.ophtha.2014.05.013","article-title":"Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis","volume":"1210","author":"Y-C Tham","year":"2014","journal-title":"Ophthalmology"},{"issue":"18","key":"pone.0348068.ref005","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1001\/jama.2014.3192","article-title":"The pathophysiology and treatment of glaucoma: a review","volume":"311","author":"RN Weinreb","year":"2014","journal-title":"JAMA"},{"key":"pone.0348068.ref006","doi-asserted-by":"crossref","first-page":"1586240","DOI":"10.3389\/fcell.2025.1586240","article-title":"Caspase-mediated pathways in retinal ganglion cell injury: a novel therapeutic target for glaucoma","volume":"13","author":"N Rajakrishna","year":"2025","journal-title":"Front Cell Dev Biol"},{"issue":"1","key":"pone.0348068.ref007","doi-asserted-by":"crossref","first-page":"160","DOI":"10.18240\/ijo.2025.01.20","article-title":"Glaucomatous retinal ganglion cells: death and protection","volume":"18","author":"N Cui","year":"2025","journal-title":"Int J Ophthalmol"},{"issue":"2","key":"pone.0348068.ref008","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.preteyeres.2011.11.002","article-title":"The molecular basis of retinal ganglion cell death in glaucoma","volume":"31","author":"M Almasieh","year":"2012","journal-title":"Prog Retin Eye Res"},{"issue":"17","key":"pone.0348068.ref009","doi-asserted-by":"crossref","first-page":"6145","DOI":"10.3390\/jcm14176145","article-title":"Next-Gen Neuroprotection in Glaucoma: Synergistic Molecules for Targeted Therapy","volume":"14","author":"A Martucci","year":"2025","journal-title":"J Clin Med"},{"key":"pone.0348068.ref010","doi-asserted-by":"crossref","first-page":"100881","DOI":"10.1016\/j.preteyeres.2020.100881","article-title":"Retinal energy metabolism in health and glaucoma","volume":"81","author":"RJ Casson","year":"2021","journal-title":"Prog Retin Eye Res"},{"issue":"3","key":"pone.0348068.ref011","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1124\/pr.109.002451","article-title":"Glutamate receptor ion channels: structure, regulation, and function","volume":"62","author":"SF Traynelis","year":"2010","journal-title":"Pharmacol Rev"},{"issue":"4","key":"pone.0348068.ref012","doi-asserted-by":"crossref","first-page":"275","DOI":"10.32598\/bcn.9.4.275","article-title":"Assessing the Effects of Opioids on Pathological Memory by a Computational Model","volume":"9","author":"M Borjkhani","year":"2018","journal-title":"Basic Clin Neurosci"},{"issue":"1","key":"pone.0348068.ref013","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/0896-6273(93)90277-X","article-title":"Fractional contribution of calcium to the cation current through glutamate receptor channels","volume":"11","author":"R Schneggenburger","year":"1993","journal-title":"Neuron"},{"issue":"7","key":"pone.0348068.ref014","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/nrm1150","article-title":"Regulation of cell death: the calcium-apoptosis link","volume":"4","author":"S Orrenius","year":"2003","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"6","key":"pone.0348068.ref015","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.neuropharm.2007.07.013","article-title":"Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system","volume":"530","author":"CG Parsons","year":"2007","journal-title":"Neuropharmacology"},{"issue":"5965","key":"pone.0348068.ref016","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/309261a0","article-title":"Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones","volume":"309","author":"ML Mayer","year":"1984","journal-title":"Nature"},{"issue":"5950","key":"pone.0348068.ref017","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1038\/307462a0","article-title":"Magnesium gates glutamate-activated channels in mouse central neurones","volume":"3070","author":"L Nowak","year":"1984","journal-title":"Nature"},{"issue":"9","key":"pone.0348068.ref018","doi-asserted-by":"crossref","first-page":"3178","DOI":"10.1523\/JNEUROSCI.10-09-03178.1990","article-title":"Voltage dependence of NMDA-activated macroscopic conductances predicted by single-channel kinetics","volume":"10","author":"CE Jahr","year":"1990","journal-title":"J Neurosci"},{"issue":"7","key":"pone.0348068.ref019","doi-asserted-by":"crossref","DOI":"10.1016\/j.neuron.2025.01.021","article-title":"Structural insights into the diverse actions of magnesium on NMDA receptors","volume":"113","author":"X Huang","year":"2025","journal-title":"Neuron"},{"key":"pone.0348068.ref020","doi-asserted-by":"crossref","first-page":"1561956","DOI":"10.3389\/fphar.2025.1561956","article-title":"Inhibition of NMDA receptors and other ion channel types by membrane-associated drugs","volume":"16","author":"EG Neureiter","year":"2025","journal-title":"Front Pharmacol"},{"issue":"2","key":"pone.0348068.ref021","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1227\/01.NEU.0000043984.42487.0E","article-title":"Hypomagnesemia after aneurysmal subarachnoid hemorrhage","volume":"52","author":"WM van den Bergh","year":"2003","journal-title":"Neurosurgery"},{"issue":"925","key":"pone.0348068.ref022","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1136\/pmj.78.925.641","article-title":"Magnesium in stroke treatment","volume":"78","author":"KW Muir","year":"2002","journal-title":"Postgrad Med J"},{"issue":"6","key":"pone.0348068.ref023","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1056\/NEJMoa1408827","article-title":"Prehospital use of magnesium sulfate as neuroprotection in acute stroke","volume":"372","author":"JL Saver","year":"2015","journal-title":"N Engl J Med"},{"issue":"4","key":"pone.0348068.ref024","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1684\/mrh.2009.0187","article-title":"Magnesium homeostasis and aging","volume":"22","author":"M Barbagallo","year":"2009","journal-title":"Magnes Res"},{"issue":"21","key":"pone.0348068.ref025","doi-asserted-by":"crossref","first-page":"9587","DOI":"10.1523\/JNEUROSCI.19-21-09587.1999","article-title":"Synaptic basis of cortical persistent activity: the importance of NMDA receptors to working memory","volume":"19","author":"XJ Wang","year":"1999","journal-title":"J Neurosci"},{"key":"pone.0348068.ref026","volume-title":"Theoretical Neuroscience: Computational and Mathematical Modeling of Neural Systems","author":"P Dayan","year":"2001"},{"issue":"4","key":"pone.0348068.ref027","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1113\/jphysiol.1952.sp004764","article-title":"A quantitative description of membrane current and its application to conduction and excitation in nerve","volume":"117","author":"AL HODGKIN","year":"1952","journal-title":"J Physiol"},{"issue":"4","key":"pone.0348068.ref028","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1152\/jn.1997.78.4.1935","article-title":"Impulse encoding mechanisms of ganglion cells in the tiger salamander retina","volume":"78","author":"JF Fohlmeister","year":"1997","journal-title":"J Neurophysiol"},{"issue":"4","key":"pone.0348068.ref029","doi-asserted-by":"crossref","first-page":"045015","DOI":"10.1088\/1741-2552\/abab47","article-title":"The relationship between morphological properties and thresholds to extracellular electric stimulation in \u03b1 RGCs","volume":"17","author":"P Werginz","year":"2020","journal-title":"J Neural Eng"},{"issue":"2","key":"pone.0348068.ref030","doi-asserted-by":"crossref","first-page":"025005","DOI":"10.1088\/1741-2560\/13\/2\/025005","article-title":"Electrical activity of ON and OFF retinal ganglion cells: a modelling study","volume":"13","author":"T Guo","year":"2016","journal-title":"J Neural Eng"},{"issue":"3","key":"pone.0348068.ref031","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0193410","article-title":"Computational modeling of opioid-induced synaptic plasticity in hippocampus","volume":"13","author":"M Borjkhani","year":"2018","journal-title":"PLoS One"},{"issue":"1","key":"pone.0348068.ref032","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/S0006-3495(00)76293-X","article-title":"Direct measurement of specific membrane capacitance in neurons","volume":"79","author":"LJ Gentet","year":"2000","journal-title":"Biophys J"},{"issue":"1","key":"pone.0348068.ref033","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1113\/jphysiol.1971.sp009366","article-title":"Prediction of repetitive firing behaviour from voltage clamp data on an isolated neurone soma","volume":"213","author":"JA Connor","year":"1971","journal-title":"J Physiol"},{"key":"pone.0348068.ref034","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1113\/jphysiol.1987.sp016864","article-title":"Kinetic and pharmacological properties distinguishing three types of calcium currents in chick sensory neurones","volume":"394","author":"AP Fox","year":"1987","journal-title":"J Physiol"},{"issue":"4","key":"pone.0348068.ref035","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/S0166-2236(96)80026-9","article-title":"Ca(2+)-activated K+ currents in neurones: types, physiological roles and modulation","volume":"19","author":"P Sah","year":"1996","journal-title":"Trends Neurosci"},{"issue":"22","key":"pone.0348068.ref036","doi-asserted-by":"crossref","first-page":"5994","DOI":"10.1523\/JNEUROSCI.0130-07.2007","article-title":"Different mechanisms generate maintained activity in ON and OFF retinal ganglion cells","volume":"27","author":"DJ Margolis","year":"2007","journal-title":"J Neurosci"},{"key":"pone.0348068.ref037","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1113\/jphysiol.2001.013009","article-title":"Intrinsic physiological properties of cat retinal ganglion cells","volume":"538","author":"BJ O\u2019Brien","year":"2002","journal-title":"J Physiol"},{"issue":"3","key":"pone.0348068.ref038","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/BF00961734","article-title":"Synthesis of models for excitable membranes, synaptic transmission and neuromodulation using a common kinetic formalism","volume":"1","author":"A Destexhe","year":"1994","journal-title":"J Comput Neurosci"},{"issue":"7","key":"pone.0348068.ref039","doi-asserted-by":"crossref","first-page":"2385","DOI":"10.1523\/JNEUROSCI.10-07-02385.1990","article-title":"Structure-activity relationships for amino acid transmitter candidates acting at N-methyl-D-aspartate and quisqualate receptors","volume":"10","author":"DK Patneau","year":"1990","journal-title":"J Neurosci"},{"issue":"1","key":"pone.0348068.ref040","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/0896-6273(92)90232-3","article-title":"The kinetics of the response to glutamate and kainate in neurons of the avian cochlear nucleus","volume":"9","author":"IM Raman","year":"1992","journal-title":"Neuron"},{"issue":"6284","key":"pone.0348068.ref041","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/346565a0","article-title":"Channel kinetics determine the time course of NMDA receptor-mediated synaptic currents","volume":"346","author":"RA Lester","year":"1990","journal-title":"Nature"},{"issue":"5400","key":"pone.0348068.ref042","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1126\/science.283.5400.381","article-title":"Emergent properties of networks of biological signaling pathways","volume":"283","author":"US Bhalla","year":"1999","journal-title":"Science"},{"issue":"17","key":"pone.0348068.ref043","doi-asserted-by":"crossref","first-page":"6669","DOI":"10.1523\/JNEUROSCI.17-17-06669.1997","article-title":"Ionized intracellular calcium concentration predicts excitotoxic neuronal death: observations with low-affinity fluorescent calcium indicators","volume":"17","author":"K Hyrc","year":"1997","journal-title":"J Neurosci"},{"issue":"6","key":"pone.0348068.ref044","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1016\/j.cell.2007.11.028","article-title":"Calcium signaling","volume":"131","author":"DE Clapham","year":"2007","journal-title":"Cell"},{"issue":"5087","key":"pone.0348068.ref045","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1126\/science.1359647","article-title":"The time course of glutamate in the synaptic cleft","volume":"258","author":"JD Clements","year":"1992","journal-title":"Science"},{"issue":"1","key":"pone.0348068.ref046","doi-asserted-by":"crossref","first-page":"15","DOI":"10.32598\/bcn.2021.1150.2","article-title":"Investigating the Cocaine-induced Reduction of Potassium Current on the Generation of Action Potentials Using a Computational Model","volume":"13","author":"H Borjkhani","year":"2022","journal-title":"Basic Clin Neurosci"},{"issue":"9407","key":"pone.0348068.ref047","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/S0140-6736(04)15490-1","article-title":"Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): randomised controlled trial","volume":"363","author":"Intravenous Magnesium Efficacy in Stroke (IMAGES) Study Investigators","year":"2004","journal-title":"Lancet"},{"issue":"9","key":"pone.0348068.ref048","doi-asserted-by":"crossref","first-page":"643","DOI":"10.3390\/cells14090643","article-title":"Survival and Axonal Regeneration of Retinal Ganglion Cells in a Mouse Optic Nerve Crush Model After a Cell-Based Intravitreal Co-Administration of Ciliary Neurotrophic Factor and Glial Cell Line-Derived Neurotrophic Factor at Different Post-Lesion Time Points","volume":"14","author":"Y Hu","year":"2025","journal-title":"Cells"},{"issue":"2","key":"pone.0348068.ref049","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/S0896-6273(03)00639-1","article-title":"Local calcium signaling in neurons","volume":"40","author":"GJ Augustine","year":"2003","journal-title":"Neuron"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0348068","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T17:38:46Z","timestamp":1780335526000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0348068"}},"subtitle":[],"editor":[{"given":"Gennady S.","family":"Cymbalyuk","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,6,1]]},"references-count":49,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6,1]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0348068","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,1]]}}}