{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T13:03:31Z","timestamp":1789909411682,"version":"4.0.1"},"reference-count":64,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,3,15]],"date-time":"2019-03-15T00:00:00Z","timestamp":1552608000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,3,15]],"date-time":"2019-03-15T00:00:00Z","timestamp":1552608000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hydrogen sulphide has recently drawn much attention due to its potent anti-inflammatory and neuroprotective roles in brain functions. The purpose of the current study was to exploit these beneficial properties of H<jats:sub>2<\/jats:sub>S to design a new agent for the treatment of Alzheimer\u2019s disease (AD). To pursue our aims, we replaced the free amine group of memantine with an isothiocyanate functionality as a putative H<jats:sub>2<\/jats:sub>S-donor moiety. The new chemical entity, named memit, was then tested <jats:italic>in vitro<\/jats:italic> to determine whether it retains the pharmacological profile of the \u201cnative drug\u201d, while also providing a source of H<jats:sub>2<\/jats:sub>S in the CNS. Indeed, Memit showed the ability to release H<jats:sub>2<\/jats:sub>S through a cysteine-mediated mechanism, thus generating memantine. Moreover, the new hybrid molecule exerts protective effects against neuronal inflammation and induces a drastic fall in ROS production. In addition, memit was also able to reduce the A\u03b2(1-42) self-induced aggregation and exerted cytoprotective effect against A\u03b2 oligomers-induced damage in both human neurons and rat microglia cells. Finally, similarly to memantine, the new compound promotes autophagy, a complex process required for cellular homeostasis in cell survival that results to be altered in neurodegenerative diseases. In conclusion, our study revealed that memit is a prodrug of memantine. Further <jats:italic>in vivo<\/jats:italic> studies will be necessary to fully investigate the synergic or cumulative effects due to the H<jats:sub>2<\/jats:sub>S-releasing moiety and the native drug.<\/jats:p>","DOI":"10.1038\/s41598-019-40925-8","type":"journal-article","created":{"date-parts":[[2019,3,15]],"date-time":"2019-03-15T11:02:32Z","timestamp":1552647752000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":82,"title":["Memantine prodrug as a new agent for Alzheimer\u2019s Disease"],"prefix":"10.1038","volume":"9","author":[{"given":"Simona","family":"Sestito","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Daniele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Pietrobono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Citi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenza","family":"Bellusci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grazia","family":"Chiellini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Calderone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Martini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0146-6358","authenticated-orcid":false,"given":"Simona","family":"Rapposelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,3,15]]},"reference":[{"key":"40925_CR1","doi-asserted-by":"publisher","first-page":"1328","DOI":"10.1046\/j.1471-4159.1996.67031328.x","volume":"67","author":"LD Morrison","year":"1996","unstructured":"Morrison, L. D., Smith, D. D. & Kish, S. J. Brain S\u2010adenosylmethionine levels are severely decreased in Alzheimer\u2019s disease. Journal of neurochemistry 67, 1328\u20131331 (1996).","journal-title":"Journal of neurochemistry"},{"key":"40925_CR2","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1021\/cn500185g","volume":"5","author":"X Zhang","year":"2014","unstructured":"Zhang, X. & Bian, J.-S. Hydrogen sulfide: A neuromodulator and neuroprotectant in the central nervous system. ACS chemical neuroscience 5, 876\u2013883 (2014).","journal-title":"ACS chemical neuroscience"},{"key":"40925_CR3","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1523\/JNEUROSCI.16-03-01066.1996","volume":"16","author":"K Abe","year":"1996","unstructured":"Abe, K. & Kimura, H. The possible role of hydrogen sulfide as an endogenous neuromodulator. Journal of Neuroscience 16, 1066\u20131071 (1996).","journal-title":"Journal of Neuroscience"},{"key":"40925_CR4","first-page":"2246","volume":"88","author":"X Liu","year":"2008","unstructured":"Liu, X., Jiang, P., Huang, H. & Yan, Y. Plasma levels of endogenous hydrogen sulfide and homocysteine in patients with Alzheimer\u2019s disease and vascular dementia and the significance thereof. Zhonghua yi xue za zhi 88, 2246\u20132249 (2008).","journal-title":"Zhonghua yi xue za zhi"},{"key":"40925_CR5","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1385\/MN:26:1:013","volume":"26","author":"H Kimura","year":"2002","unstructured":"Kimura, H. Hydrogen sulfide as a neuromodulator. Molecular neurobiology 26, 13\u201319 (2002).","journal-title":"Molecular neurobiology"},{"key":"40925_CR6","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1016\/j.neuint.2013.09.003","volume":"63","author":"H Kimura","year":"2013","unstructured":"Kimura, H. Physiological role of hydrogen sulfide and polysulfide in the central nervous system. Neurochemistry international 63, 492\u2013497 (2013).","journal-title":"Neurochemistry international"},{"key":"40925_CR7","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1096\/fj.03-1052fje","volume":"18","author":"Y Nagai","year":"2004","unstructured":"Nagai, Y., Tsugane, M., Oka, J.-I. & Kimura, H. Hydrogen sulfide induces calcium waves in astrocytes. The FASEB journal 18, 557\u2013559 (2004).","journal-title":"The FASEB journal"},{"key":"40925_CR8","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.nlm.2013.05.006","volume":"104","author":"D Giuliani","year":"2013","unstructured":"Giuliani, D. et al. Hydrogen sulfide slows down progression of experimental Alzheimer\u2019s disease by targeting multiple pathophysiological mechanisms. Neurobiology of Learning and Memory 104, 82\u201391, https:\/\/doi.org\/10.1016\/j.nlm.2013.05.006 (2013).","journal-title":"Neurobiology of Learning and Memory"},{"key":"40925_CR9","doi-asserted-by":"publisher","first-page":"72","DOI":"10.3389\/fchem.2017.00072","volume":"5","author":"S Sestito","year":"2017","unstructured":"Sestito, S., Nesi, G., Pi, R., Macchia, M. & Rapposelli, S. Hydrogen sulfide: a worthwhile tool in the design of new multitarget drugs. Frontiers in Chemistry 5, 72 (2017).","journal-title":"Frontiers in Chemistry"},{"key":"40925_CR10","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.neuint.2007.05.016","volume":"52","author":"K Qu","year":"2008","unstructured":"Qu, K., Lee, S., Bian, J., Low, C.-M. & Wong, P.-H. Hydrogen sulfide: neurochemistry and neurobiology. Neurochemistry international 52, 155\u2013165 (2008).","journal-title":"Neurochemistry international"},{"key":"40925_CR11","doi-asserted-by":"publisher","first-page":"1665","DOI":"10.1016\/j.jocn.2014.01.006","volume":"21","author":"H-J Wei","year":"2014","unstructured":"Wei, H.-J., Li, X. & Tang, X.-Q. Therapeutic benefits of H2S in Alzheimer\u2019s disease. Journal of Clinical Neuroscience 21, 1665\u20131669 (2014).","journal-title":"Journal of Clinical Neuroscience"},{"key":"40925_CR12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1089\/ars.2008.2282","volume":"12","author":"Y Kimura","year":"2010","unstructured":"Kimura, Y., Goto, Y.-I. & Kimura, H. Hydrogen sulfide increases glutathione production and suppresses oxidative stress in mitochondria. Antioxidants & redox signaling 12, 1\u201313 (2010).","journal-title":"Antioxidants & redox signaling"},{"key":"40925_CR13","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1016\/j.neuint.2013.04.001","volume":"62","author":"J Jia","year":"2013","unstructured":"Jia, J. et al. Differential mechanisms underlying neuroprotection of hydrogen sulfide donors against oxidative stress. Neurochemistry international 62, 1072\u20131078 (2013).","journal-title":"Neurochemistry international"},{"key":"40925_CR14","doi-asserted-by":"publisher","first-page":"2531","DOI":"10.1089\/ars.2013.5604","volume":"21","author":"Z-Z Xie","year":"2014","unstructured":"Xie, Z.-Z. et al. Sulfhydration of p66Shc at cysteine59 mediates the antioxidant effect of hydrogen sulfide. Antioxidants & redox signaling 21, 2531\u20132542 (2014).","journal-title":"Antioxidants & redox signaling"},{"key":"40925_CR15","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.3233\/JAD-2010-101002","volume":"22","author":"Y Liu","year":"2010","unstructured":"Liu, Y. & Bian, J. Hydrogen sulfide protects amyloid-\u03b2 induced cell toxicity in microglia. Journal of Alzheimer\u2019s disease: JAD 22, 1189 (2010).","journal-title":"Journal of Alzheimer\u2019s disease: JAD"},{"key":"40925_CR16","doi-asserted-by":"publisher","first-page":"296","DOI":"10.7555\/JBR.27.20120100","volume":"27","author":"H Fan","year":"2013","unstructured":"Fan, H. et al. Hydrogen sulfide protects against amyloid beta-peptide induced neuronal injury via attenuating inflammatory responses in a rat model. Journal of Biomedical Research 27, 296\u2013304, https:\/\/doi.org\/10.7555\/JBR.27.20120100 (2013).","journal-title":"Journal of Biomedical Research"},{"key":"40925_CR17","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1111\/j.1471-4159.2006.04283.x","volume":"100","author":"LF Hu","year":"2007","unstructured":"Hu, L. F., Wong, P. T. H., Moore, P. K. & Bian, J. S. Hydrogen sulfide attenuates lipopolysaccharide\u2010induced inflammation by inhibition of p38 mitogen\u2010activated protein kinase in microglia. Journal of neurochemistry 100, 1121\u20131128 (2007).","journal-title":"Journal of neurochemistry"},{"key":"40925_CR18","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1016\/j.tips.2003.10.007","volume":"24","author":"PK Moore","year":"2003","unstructured":"Moore, P. K., Bhatia, M. & Moochhala, S. Hydrogen sulfide: from the smell of the past to the mediator of the future? Trends in pharmacological sciences 24, 609\u2013611 (2003).","journal-title":"Trends in pharmacological sciences"},{"key":"40925_CR19","doi-asserted-by":"publisher","first-page":"1694","DOI":"10.2174\/0929867311320130009","volume":"20","author":"Z Chen","year":"2013","unstructured":"Chen, Z., Han, L., Xu, M., Xu, Y. & Qian, X. Rationally designed multitarget anticancer agents. Current medicinal chemistry 20, 1694\u20131714 (2013).","journal-title":"Current medicinal chemistry"},{"key":"40925_CR20","doi-asserted-by":"publisher","first-page":"2531","DOI":"10.2174\/092986711795933768","volume":"18","author":"U Trstenjak","year":"2011","unstructured":"Trstenjak, U. & Kikelj, D. Multitarget cardiovascular drugs. Curr Med Chem 18, 2531\u20132542 (2011).","journal-title":"Curr Med Chem"},{"key":"40925_CR21","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1016\/j.cbpa.2009.04.619","volume":"13","author":"ML Bolognesi","year":"2009","unstructured":"Bolognesi, M. L., Matera, R., Minarini, A., Rosini, M. & Melchiorre, C. Alzheimer\u2019s disease: new approaches to drug discover. y. Current Opinion in Chemical Biology 13, 303\u2013308, https:\/\/doi.org\/10.1016\/j.cbpa.2009.04.619 (2009).","journal-title":"y. Current Opinion in Chemical Biology"},{"key":"40925_CR22","doi-asserted-by":"publisher","unstructured":"Nesi, G., Sestito, S., Digiacomo, M. & Rapposelli, S. Oxidative Stress, Mitochondrial Abnormalities and Proteins Deposition: Multitarget Approaches in Alzheimer\u2019s Disease. Current topics in medicinal chemistry, https:\/\/doi.org\/10.2174\/1568026617666170607114232 (2017).","DOI":"10.2174\/1568026617666170607114232"},{"key":"40925_CR23","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1139\/cjpp-2015-0316","volume":"94","author":"DK Mostafa","year":"2016","unstructured":"Mostafa, D. K., El Azhary, N. M. & Nasra, R. A. The hydrogen sulfide releasing compounds ATB-346 and diallyl trisulfide attenuate streptozotocin-induced cognitive impairment, neuroinflammation, and oxidative stress in rats: involvement of asymmetric dimethylarginine. Canadian journal of physiology and pharmacology 94, 699\u2013708 (2016).","journal-title":"Canadian journal of physiology and pharmacology"},{"key":"40925_CR24","doi-asserted-by":"publisher","first-page":"1807","DOI":"10.1111\/bph.13025","volume":"172","author":"J Egea","year":"2015","unstructured":"Egea, J. et al. Melatonin\u2013sulforaphane hybrid ITH12674 induces neuroprotection in oxidative stress conditions by a \u2018drug\u2013prodrug\u2019mechanism of action. British journal of pharmacology 172, 1807\u20131821 (2015).","journal-title":"British journal of pharmacology"},{"key":"40925_CR25","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1111\/cbdd.12633","volume":"87","author":"RS Keri","year":"2016","unstructured":"Keri, R. S. et al. New Tacrine Hybrids with Natural\u2010Based Cysteine Derivatives as Multitargeted Drugs for Potential Treatment of Alzheimer\u2019s Diseas. e. Chemical biology & drug design 87, 101\u2013111 (2016).","journal-title":"e. Chemical biology & drug design"},{"key":"40925_CR26","doi-asserted-by":"publisher","first-page":"1823","DOI":"10.1021\/acschemneuro.7b00270","volume":"8","author":"S Alam","year":"2017","unstructured":"Alam, S., Lingenfelter, K. S., Bender, A. M. & Lindsley, C. W. Classics in Chemical. Neuroscience: Memantine. 8, 1823\u20131829, https:\/\/doi.org\/10.1021\/acschemneuro.7b00270 (2017).","journal-title":"Neuroscience: Memantine."},{"key":"40925_CR27","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1055\/s-0034-1368591","volume":"80","author":"V Citi","year":"2014","unstructured":"Citi, V. et al. Hydrogen sulfide releasing capacity of natural isothiocyanates: is it a reliable explanation for the multiple biological effects of Brassicaceae? Planta medica 80, 610\u2013613 (2014).","journal-title":"Planta medica"},{"key":"40925_CR28","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.vph.2013.11.003","volume":"60","author":"A Martelli","year":"2014","unstructured":"Martelli, A. et al. Pharmacological characterization of the vascular effects of aryl isothiocyanates: is hydrogen sulfide the real player? Vascular pharmacology 60, 32\u201341, https:\/\/doi.org\/10.1016\/j.vph.2013.11.003 (2014).","journal-title":"Vascular pharmacology"},{"key":"40925_CR29","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1021\/ml400239a","volume":"4","author":"A Martelli","year":"2013","unstructured":"Martelli, A. et al. Arylthioamides as H2S donors: L-cysteine-activated releasing properties and vascular effects in vitro and in vivo. ACS medicinal chemistry letters 4, 904\u2013908, https:\/\/doi.org\/10.1021\/ml400239a (2013).","journal-title":"ACS medicinal chemistry letters"},{"key":"40925_CR30","doi-asserted-by":"publisher","first-page":"7512","DOI":"10.1021\/acs.jmedchem.7b00888","volume":"60","author":"E Barresi","year":"2017","unstructured":"Barresi, E. et al. Iminothioethers as hydrogen sulfide donors: from the gasotransmitter release to the vascular effects. Journal of Medicinal Chemistry 60, 7512\u20137523 (2017).","journal-title":"Journal of Medicinal Chemistry"},{"key":"40925_CR31","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1007\/BF00772006","volume":"25","author":"YN Klimochkin","year":"1991","unstructured":"Klimochkin, Y. N. et al. Synthesis and antiviral activity of sulfur-containing derivatives of adamantane. Pharmaceutical Chemistry Journal 25, 489\u2013492, https:\/\/doi.org\/10.1007\/BF00772006 (1991).","journal-title":"Pharmaceutical Chemistry Journal"},{"key":"40925_CR32","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-015-0446-x","volume":"12","author":"S Daniele","year":"2015","unstructured":"Daniele, S., Zappelli, E. & Martini, C. Trazodone regulates neurotrophic\/growth factors, mitogen-activated protein kinases and lactate release in human primary astrocytes. Journal of neuroinflammation 12, 1 (2015).","journal-title":"Journal of neuroinflammation"},{"key":"40925_CR33","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1016\/j.bbrc.2011.12.026","volume":"417","author":"L Liu","year":"2012","unstructured":"Liu, L., Liu, C., Zhong, Y., Apostolou, A. & Fang, S. ER stress response during the differentiation of H9 cells induced by retinoic acid. Biochemical and biophysical research communications 417, 738\u2013743 (2012).","journal-title":"Biochemical and biophysical research communications"},{"key":"40925_CR34","doi-asserted-by":"publisher","first-page":"846","DOI":"10.1046\/j.1471-4159.2001.00075.x","volume":"76","author":"SW Barger","year":"2001","unstructured":"Barger, S. W. & Basile, A. S. Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cystine exchange and attenuates synaptic function. Journal of neurochemistry 76, 846\u2013854 (2001).","journal-title":"Journal of neurochemistry"},{"key":"40925_CR35","unstructured":"Ni, M. & Aschner, M. Neonatal rat primary microglia: isolation, culturing, and selected applications. Current protocols in toxicology, 12.17. 11-12.17. 16 (2010)."},{"key":"40925_CR36","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1021\/acschemneuro.6b00078","volume":"7","author":"S Daniele","year":"2016","unstructured":"Daniele, S., Da Pozzo, E., Iofrida, C. & Martini, C. Human Neural Stem Cell Aging Is Counteracted by \u03b1-Glycerylphosphorylethanolamine. ACS chemical neuroscience 7, 952\u2013963 (2016).","journal-title":"ACS chemical neuroscience"},{"key":"40925_CR37","doi-asserted-by":"publisher","first-page":"905","DOI":"10.3389\/fphar.2017.00905","volume":"8","author":"L Bellusci","year":"2017","unstructured":"Bellusci, L. et al. New Insights into the Potential Roles of 3-Iodothyronamine (T1AM) and Newly Developed Thyronamine-like TAAR1 Agonists in Neuroprotection. Frontiers in Pharmacology 8, 905 (2017).","journal-title":"Frontiers in Pharmacology"},{"key":"40925_CR38","doi-asserted-by":"publisher","first-page":"9708","DOI":"10.1021\/jm3009458","volume":"55","author":"E Simoni","year":"2012","unstructured":"Simoni, E. et al. Combining Galantamine and Memantine in Multitargeted, New Chemical Entities Potentially Useful in Alzheimer\u2019s Disease. Journal of Medicinal Chemistry 55, 9708\u20139721, https:\/\/doi.org\/10.1021\/jm3009458 (2012).","journal-title":"Journal of Medicinal Chemistry"},{"key":"40925_CR39","doi-asserted-by":"publisher","first-page":"1609","DOI":"10.1016\/j.cellsig.2015.04.006","volume":"27","author":"S Daniele","year":"2015","unstructured":"Daniele, S., Da Pozzo, E., Zappelli, E. & Martini, C. Trazodone treatment protects neuronal-like cells from inflammatory insult by inhibiting NF-\u03baB, p38 and JNK. Cellular signalling 27, 1609\u20131629 (2015).","journal-title":"Cellular signalling"},{"key":"40925_CR40","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1007\/s11064-015-1807-7","volume":"41","author":"F-l Zhao","year":"2016","unstructured":"Zhao, F.-l. et al. Hydrogen Sulfide Selectively Inhibits \u03b3-Secretase Activity and Decreases Mitochondrial A\u03b2 Production in Neurons from APP\/PS1 Transgenic Mice. Neurochemical research 41, 1145\u20131159 (2016).","journal-title":"Neurochemical research"},{"key":"40925_CR41","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1038\/nm.3232","volume":"19","author":"RA Nixon","year":"2013","unstructured":"Nixon, R. A. The role of autophagy in neurodegenerative disease. Nat Med 19, 983\u2013997, https:\/\/doi.org\/10.1038\/nm.3232 (2013).","journal-title":"Nat Med"},{"key":"40925_CR42","first-page":"379","volume":"12","author":"PB Crino","year":"2016","unstructured":"Crino, P. B. The mTOR signalling cascade: paving new roads to cure neurological disease. Nature Reviews. Neurology 12, 379\u2013393 (2016).","journal-title":"Neurology"},{"key":"40925_CR43","doi-asserted-by":"publisher","first-page":"157","DOI":"10.3389\/fncel.2016.00157","volume":"10","author":"C Garza-Lombo","year":"2016","unstructured":"Garza-Lombo, C. & Gonsebatt, M. E. Mammalian Target of Rapamycin: Its Role in Early Neural Development and in Adult and Aged Brain Function. Front Cell Neurosci 10, 157, https:\/\/doi.org\/10.3389\/fncel.2016.00157 (2016).","journal-title":"Front Cell Neurosci"},{"key":"40925_CR44","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1007\/978-1-61779-430-8_22","volume":"821","author":"QW Fan","year":"2012","unstructured":"Fan, Q. W. & Weiss, W. A. Inhibition of PI3K-Akt-mTOR signaling in glioblastoma by mTORC1\/2 inhibitors. Methods in molecular biology (Clifton, N.J.) 821, 349\u2013359, https:\/\/doi.org\/10.1007\/978-1-61779-430-8_22 (2012).","journal-title":"Methods in molecular biology (Clifton, N.J.)"},{"key":"40925_CR45","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.brainres.2012.11.044","volume":"1495","author":"A Arcella","year":"2013","unstructured":"Arcella, A. et al. Rapamycin inhibits the growth of glioblastoma. Brain research 1495, 37\u201351 (2013).","journal-title":"Brain research"},{"key":"40925_CR46","doi-asserted-by":"publisher","first-page":"1612","DOI":"10.1016\/j.molonc.2015.04.016","volume":"9","author":"M Catalano","year":"2015","unstructured":"Catalano, M. et al. Autophagy induction impairs migration and invasion by reversing EMT in glioblastoma cells. Mol Oncol 9, 1612\u20131625, https:\/\/doi.org\/10.1016\/j.molonc.2015.04.016 (2015).","journal-title":"Mol Oncol"},{"key":"40925_CR47","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/j.cell.2010.01.028","volume":"140","author":"N Mizushima","year":"2010","unstructured":"Mizushima, N., Yoshimori, T. & Levine, B. Methods in mammalian autophagy research. Cell 140, 313\u2013326, https:\/\/doi.org\/10.1016\/j.cell.2010.01.028 (2010).","journal-title":"Cell"},{"key":"40925_CR48","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1083\/jcb.200507002","volume":"171","author":"G Bj\u00f8rk\u00f8y","year":"2005","unstructured":"Bj\u00f8rk\u00f8y, G. et al. p62\/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. The Journal of cell biology 171, 603\u2013614 (2005).","journal-title":"The Journal of cell biology"},{"key":"40925_CR49","doi-asserted-by":"publisher","first-page":"2694","DOI":"10.1016\/j.cellsig.2014.08.019","volume":"26","author":"D Heras-Sandoval","year":"2014","unstructured":"Heras-Sandoval, D., Perez-Rojas, J. M., Hernandez-Damian, J. & Pedraza-Chaverri, J. The role of PI3K\/AKT\/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cell Signal 26, 2694\u20132701, https:\/\/doi.org\/10.1016\/j.cellsig.2014.08.019 (2014).","journal-title":"Cell Signal"},{"key":"40925_CR50","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1016\/S0166-2236(02)02245-2","volume":"25","author":"SA Lipton","year":"2002","unstructured":"Lipton, S. A. et al. Cysteine regulation of protein function\u2013as exemplified by NMDA-receptor modulation. Trends in neurosciences 25, 474\u2013480 (2002).","journal-title":"Trends in neurosciences"},{"key":"40925_CR51","first-page":"311","volume":"43","author":"M Wojtera","year":"2005","unstructured":"Wojtera, M., Sikorska, B. & Sobow, T. Microglial cells in neurodegenerative disorders. Folia neuropathologica 43, 311\u2013321 (2005).","journal-title":"Folia neuropathologica"},{"key":"40925_CR52","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1002\/glia.20362","volume":"54","author":"SW Lee","year":"2006","unstructured":"Lee, S. W. et al. Hydrogen sulphide regulates calcium homeostasis in microglial cells. Glia 54, 116\u2013124 (2006).","journal-title":"Glia"},{"key":"40925_CR53","doi-asserted-by":"crossref","unstructured":"Alam, S., Lingenfelter, K. S., Bender, A. M. & Lindsley, C. W. Classics in Chemical Neuroscience: Memantine. ACS Chemical Neuroscience (2017).","DOI":"10.1021\/acschemneuro.7b00270"},{"key":"40925_CR54","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1186\/1742-2094-9-202","volume":"9","author":"A Xuan","year":"2012","unstructured":"Xuan, A. et al. Hydrogen sulfide attenuates spatial memory impairment and hippocampal neuroinflammation in beta-amyloid rat model of Alzheimer\u2019s diseas. e. J Neuroinflammation 9, 202, https:\/\/doi.org\/10.1186\/1742-2094-9-202 (2012).","journal-title":"e. J Neuroinflammation"},{"key":"40925_CR55","doi-asserted-by":"publisher","first-page":"474","DOI":"10.3109\/1547691","volume":"13","author":"S Sil","year":"2016","unstructured":"Sil, S., Ghosh, T. & Ghosh, R. NMDA receptor is involved in neuroinflammation in intracerebroventricular colchicine-injected rats. Journal of immunotoxicology 13, 474\u2013489, https:\/\/doi.org\/10.3109\/1547691 (2016).","journal-title":"Journal of immunotoxicology"},{"key":"40925_CR56","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.neulet.2009.11.016","volume":"470","author":"B Ray","year":"2010","unstructured":"Ray, B., Banerjee, P. K., Greig, N. H. & Lahiri, D. K. Memantine treatment decreases levels of secreted Alzheimer\u2019s amyloid precursor protein (APP) and amyloid beta (A beta) peptide in the human neuroblastoma cells. Neurosci Lett 470, 1\u20135, https:\/\/doi.org\/10.1016\/j.neulet.2009.11.016 (2010).","journal-title":"Neurosci Lett"},{"key":"40925_CR57","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1002\/jnr.22172","volume":"88","author":"GM Alley","year":"2010","unstructured":"Alley, G. M. et al. Memantine lowers amyloid-beta peptide levels in neuronal cultures and in APP\/PS1 transgenic mice. J Neurosci Res 88, 143\u2013154, https:\/\/doi.org\/10.1002\/jnr.22172 (2010).","journal-title":"J Neurosci Res"},{"key":"40925_CR58","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1021\/jp508471v","volume":"119","author":"MF Rosario-Alomar","year":"2015","unstructured":"Rosario-Alomar, M. F. et al. Hydrogen sulfide inhibits amyloid formation. The journal of physical chemistry. B 119, 1265\u20131274, https:\/\/doi.org\/10.1021\/jp508471v (2015).","journal-title":"The journal of physical chemistry. B"},{"key":"40925_CR59","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1080\/14728222.2018.1515917","volume":"22","author":"N Gupta","year":"2018","unstructured":"Gupta, N. et al. Recent progress in therapeutic strategies for microglia-mediated neuroinflammation in neuropathologies. Expert opinion on therapeutic targets 22, 765\u2013781 (2018).","journal-title":"Expert opinion on therapeutic targets"},{"key":"40925_CR60","doi-asserted-by":"publisher","first-page":"255","DOI":"10.3389\/fnins.2018.00255","volume":"12","author":"N Fujikake","year":"2018","unstructured":"Fujikake, N., Shin, M. & Shimizu, S. Association Between Autophagy and Neurodegenerative Diseases. Frontiers in neuroscience 12, 255, https:\/\/doi.org\/10.3389\/fnins.2018.00255 (2018).","journal-title":"Frontiers in neuroscience"},{"key":"40925_CR61","doi-asserted-by":"publisher","first-page":"375","DOI":"10.3389\/fncel.2017.00375","volume":"11","author":"AV Yakovlev","year":"2017","unstructured":"Yakovlev, A. V., Kurmasheva, E. D., Ishchenko, Y., Giniatullin, R. & Sitdikova, G. F. Age-Dependent, Subunit Specific Action of Hydrogen Sulfide on GluN1\/2A and GluN1\/2B NMDA Receptors. Frontiers in cellular neuroscience 11, 375 (2017).","journal-title":"Frontiers in cellular neuroscience"},{"key":"40925_CR62","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.1002\/jcp.22459","volume":"226","author":"MJ Chen","year":"2011","unstructured":"Chen, M. J. et al. Gene profiling reveals hydrogen sulphide recruits death signaling via the N-methyl-D-aspartate receptor identifying commonalities with excitotoxicity. J Cell Physiol 226, 1308\u20131322, https:\/\/doi.org\/10.1002\/jcp.22459 (2011).","journal-title":"J Cell Physiol"},{"key":"40925_CR63","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1006\/bbrc.1999.1915","volume":"267","author":"H Kimura","year":"2000","unstructured":"Kimura, H. Hydrogen sulfide induces cyclic AMP and modulates the NMDA receptor. Biochem Biophys Res Commun 267, 129\u2013133, https:\/\/doi.org\/10.1006\/bbrc.1999.1915 (2000).","journal-title":"Biochem Biophys Res Commun"},{"key":"40925_CR64","doi-asserted-by":"publisher","first-page":"1358","DOI":"10.1242\/jcs.002154","volume":"120","author":"JY Joo","year":"2007","unstructured":"Joo, J. Y. et al. Activation of NMDA receptors increases proliferation and differentiation of hippocampal neural progenitor cells. J Cell Sci 120, 1358\u20131370, https:\/\/doi.org\/10.1242\/jcs.002154 (2007).","journal-title":"J Cell Sci"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-40925-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-40925-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-40925-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T07:40:00Z","timestamp":1671262800000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-40925-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,15]]},"references-count":64,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["40925"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-40925-8","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,15]]},"assertion":[{"value":"22 October 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 February 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 March 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"4612"}}