Current NeuropharmacologyCurrent NeuropharmacologyCurrent Neuropharmacology1570-159X1875-6190Bentham Science64458510.2174/1570159X22999240223153901NeurologyResearch ArticleReduced Serum Brain-Derived Neurotrophic Factor in Infants Affected by Severe BronchiolitisNennaRaffaellainfo@benthamscience.netPetrellaCarlainfo@benthamscience.netBonciEneainfo@benthamscience.netPapoffPaolainfo@benthamscience.netJorgiMargheritainfo@benthamscience.netPetrarcaLaurainfo@benthamscience.netContiMariainfo@benthamscience.netBarbatoChristianinfo@benthamscience.netPietrangeliAlessandrainfo@benthamscience.netFioreMarcoinfo@benthamscience.netMidullaFabioinfo@benthamscience.netGroupBROMEinfo@benthamscience.netDepartment of Experimental Medicine, Medical Faculty, Sapienza University of RomeDepartment of Sense Organs, Medical Faculty, Institute of Biochemistry and Cell Biology (IBBC-CNR), Sapienza University of RomeDepartment of Experimental Medicine, Medical Faculty, Sapienza University of Rome,Virology Laboratory, Department of Molecular Medicine, Sapienza" UniversityDepartment of Maternal Infantile and Urological Sciences, Sapienza University of RomeDepartment of Experimental Medicine, Medical Faculty,, Sapienza University of Rome1507202422142433244207012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://journals.eco-vector.com/1570-159X/article/view/644585

Background:Bronchiolitis is an acute viral infection of the lower respiratory tract, typical of infants in their first year of life and causing hypoxia in the most serious cases. Bronchiolitis recognizes various demographic risk factors that are associated with greater clinical severity; however, no laboratory factors are yet able to correlate with the clinical severity. Neurotrophins as Brain-Derived Neurotrophic Factor (BDNF) are mediators of neuronal plasticity. BDNF is constitutively expressed in smooth muscle cells and epithelium of the lower respiratory tract, and as it is released during inflammatory conditions, serum levels may have a relevant role in the prognosis of infants with bronchiolitis.

Objective:In the present pilot study, we aimed to disclose the presence of serum BDNF in infants hospitalized with bronchiolitis at discharge as a disease severity indicator.

Methods and Results:Serum BDNF, measured at hospital discharge, was significantly lower in severe bronchiolitis (expressed as O2-supplemented infants). Furthermore, no changes were disclosed for the Tropomyosin receptor kinase B, the main BDNF receptor and neurofilament light chain, a biomarker of neuronal degeneration.

Conclusion:Low serum BDNF in infants with severe bronchiolitis could be associated with a higher utilization by lung cells or with an altered production by lung cells. Therefore, further research is required to study if a decreased production or increased consumption of this biomarker is at the base of the above-mentioned findings.

NeurotrophinBDNFTrkBNflbronchiolitisRSVO&ampltsub&ampgt2&lt/sub&ampgtsupplementation.Midulla, F.; Petrarca, L.; Frassanito, A.; Di Mattia, G.; Zicari, A.M.; Nenna, R. Bronchiolitis clinics and medical treatment. Minerva Pediatr., 2018, 70(6), 600-611. doi: 10.23736/S0026-4946.18.05334-3 PMID: 30334624Shi, T.; McAllister, D.A.; O’Brien, K.L.; Simoes, E.A.F.; Madhi, S.A.; Gessner, B.D.; Polack, F.P.; Balsells, E.; Acacio, S.; Aguayo, C.; Alassani, I.; Ali, A.; Antonio, M.; Awasthi, S.; Awori, J.O.; Azziz-Baumgartner, E.; Baggett, H.C.; Baillie, V.L.; Balmaseda, A.; Barahona, A.; Basnet, S.; Bassat, Q.; Basualdo, W.; Bigogo, G.; Bont, L.; Breiman, R.F.; Brooks, W.A.; Broor, S.; Bruce, N.; Bruden, D.; Buchy, P.; Campbell, S.; Carosone-Link, P.; Chadha, M.; Chipeta, J.; Chou, M.; Clara, W.; Cohen, C.; de Cuellar, E.; Dang, D.A.; Dash-yandag, B.; Deloria-Knoll, M.; Dherani, M.; Eap, T.; Ebruke, B.E.; Echavarria, M.; de Freitas, L.E.C.C.; Fasce, R.A.; Feikin, D.R.; Feng, L.; Gentile, A.; Gordon, A.; Goswami, D.; Goyet, S.; Groome, M.; Halasa, N.; Hirve, S.; Homaira, N.; Howie, S.R.C.; Jara, J.; Jroundi, I.; Kartasasmita, C.B.; Khuri-Bulos, N.; Kotloff, K.L.; Krishnan, A.; Libster, R.; Lopez, O.; Lucero, M.G.; Lucion, F.; Lupisan, S.P.; Marcone, D.N.; McCracken, J.P.; Mejia, M.; Moisi, J.C.; Montgomery, J.M.; Moore, D.P.; Moraleda, C.; Moyes, J.; Munywoki, P.; Mutyara, K.; Nicol, M.P.; Nokes, D.J.; Nymadawa, P.; da Costa Oliveira, M.T.; Oshitani, H.; Pandey, N.; Paranhos-Baccalà, G.; Phillips, L.N.; Picot, V.S.; Rahman, M.; Rakoto-Andrianarivelo, M.; Rasmussen, Z.A.; Rath, B.A.; Robinson, A.; Romero, C.; Russomando, G.; Salimi, V.; Sawatwong, P.; Scheltema, N.; Schweiger, B.; Scott, J.A.G.; Seidenberg, P.; Shen, K.; Singleton, R.; Sotomayor, V.; Strand, T.A.; Sutanto, A.; Sylla, M.; Tapia, M.D.; Thamthitiwat, S.; Thomas, E.D.; Tokarz, R.; Turner, C.; Venter, M.; Waicharoen, S.; Wang, J.; Watthanaworawit, W.; Yoshida, L.M.; Yu, H.; Zar, H.J.; Campbell, H.; Nair, H. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: A systematic review and modelling study. Lancet, 2017, 390(10098), 946-958. doi: 10.1016/S0140-6736(17)30938-8 PMID: 28689664Manti, S.; Staiano, A.; Orfeo, L.; Midulla, F.; Marseglia, G.L.; Ghizzi, C.; Zampogna, S.; Carnielli, V.P.; Favilli, S.; Ruggieri, M.; Perri, D.; Di Mauro, G.; Gattinara, G.C.; D’Avino, A.; Becherucci, P.; Prete, A.; Zampino, G.; Lanari, M.; Biban, P.; Manzoni, P.; Esposito, S.; Corsello, G.; Baraldi, E. UPDATE - 2022 Italian guidelines on the management of bronchiolitis in infants. Ital. J. Pediatr., 2023, 49(1), 19. doi: 10.1186/s13052-022-01392-6 PMID: 36765418Øymar, K.; Skjerven, H.O.; Mikalsen, I.B. Acute bronchiolitis in infants, a review. Scand. J. Trauma Resusc. Emerg. Med., 2014, 22(1), 23. doi: 10.1186/1757-7241-22-23 PMID: 24694087Bukiya, A.N. Fetal cerebral artery mitochondrion as target of prenatal alcohol exposure. Int. J. Environ. Res. Public Health, 2019, 16(9), 1586. doi: 10.3390/ijerph16091586 PMID: 31067632de Sonnaville, E.S.V.; Oosterlaan, J.; Ghiassi, S.A.; van Leijden, O.; van Ewijk, H.; Knoester, H.; van Woensel, J.B.M.; Kӧnigs, M. Long-term neurocognitive outcomes after pediatric intensive care: Exploring the role of drug exposure. Pediatr. Res., 2023, 94(2), 603-610. doi: 10.1038/s41390-022-02460-7 PMID: 36694029Shein, S.L.; Slain, K.N.; Clayton, J.A.; McKee, B.; Rotta, A.T.; Wilson-Costello, D. Neurologic and functional morbidity in critically ill children with bronchiolitis. Pediatr. Crit. Care Med., 2017, 18(12), 1106-1113. doi: 10.1097/PCC.0000000000001337 PMID: 28930814Andrade, C.A.; Kalergis, A.M.; Bohmwald, K. Potential neurocognitive symptoms due to respiratory syncytial virus infection. Pathogens, 2021, 11(1), 47. doi: 10.3390/pathogens11010047 PMID: 35055995Nenna, R.; Cutrera, R.; Frassanito, A.; Alessandroni, C.; Nicolai, A.; Cangiano, G.; Petrarca, L.; Arima, S.; Caggiano, S.; Ullmann, N.; Papoff, P.; Bonci, E.; Moretti, C.; Midulla, F. Modifiable risk factors associated with bronchiolitis. Ther. Adv. Respir. Dis., 2017, 11(10), 393-401. doi: 10.1177/1753465817725722 PMID: 28812472Di Mattia, G.; Nenna, R.; Mancino, E.; Rizzo, V.; Pierangeli, A.; Villani, A.; Midulla, F. During the COVID‐19 pandemic where has respiratory syncytial virus gone? Pediatr. Pulmonol., 2021, 56(10), 3106-3109. doi: 10.1002/ppul.25582 PMID: 34273135Nenna, R.; Evangelisti, M.; Frassanito, A.; Scagnolari, C.; Pierangeli, A.; Antonelli, G.; Nicolai, A.; Arima, S.; Moretti, C.; Papoff, P.; Villa, M.P.; Midulla, F. Respiratory syncytial virus bronchiolitis, weather conditions and air pollution in an Italian urban area: An observational study. Environ. Res., 2017, 158, 188-193. doi: 10.1016/j.envres.2017.06.014 PMID: 28647513Panickar, J.R.; Dodd, S.R.; Smyth, R.L.; Couriel, J.M. Trends in deaths from respiratory illness in children in England and Wales from 1968 to 2000. Thorax, 2005, 60(12), 1035-1038. doi: 10.1136/thx.2005.044750 PMID: 16143582Be’er, M.; Bushmitz, S.; Cahal, M.; Sadot, E.; Yochpaz, S.; Besor, O.; Amirav, I.; Lavie, M. Asthma risk after a pediatric intensive care unit admission for respiratory syncytial virus bronchiolitis. Pediatr. Pulmonol., 2022, 57(7), 1677-1683. doi: 10.1002/ppul.25953 PMID: 35579122Jartti, T.; Mäkelä, M.J.; Vanto, T.; Ruuskanen, O. The link between bronchiolitis and asthma. Infect. Dis. Clin. North Am., 2005, 19(3), 667-689. doi: 10.1016/j.idc.2005.05.010 PMID: 16102655Nenna, R.; Ferrara, M.; Nicolai, A.; Pierangeli, A.; Scagnolari, C.; Papoff, P.; Antonelli, G.; Moretti, C.; Midulla, F. Viral load in infants hospitalized for respiratory syncytial virus bronchiolitis correlates with recurrent wheezing at thirty-six-month follow-up. Pediatr. Infect. Dis. J., 2015, 34(10), 1131-1132. doi: 10.1097/INF.0000000000000825 PMID: 26132826Kneyber, M.C.J.; Steyerberg, E.W.; de Groot, R.; Moll, H.A. Long‐term effects of respiratory syncytial virus (RSV) bronchiolitis in infants and young children: A quantitative review. Acta Paediatr., 2000, 89(6), 654-660. doi: 10.1111/j.1651-2227.2000.tb00359.x PMID: 10914957Vanker, A.; Gie, R.P.; Zar, H.J. The association between environmental tobacco smoke exposure and childhood respiratory disease: A review. Expert Rev. Respir. Med., 2017, 11(8), 661-673. doi: 10.1080/17476348.2017.1338949 PMID: 28580865Frassanito, A.; Nenna, R.; Arima, S.; Petrarca, L.; Pierangeli, A.; Scagnolari, C.; Di Mattia, G.; Mancino, E.; Matera, L.; Porta, D.; Rusconi, F.; Midulla, F. Modifiable environmental factors predispose term infants to bronchiolitis but bronchiolitis itself predisposes to respiratory sequelae. Pediatr. Pulmonol., 2022, 57(3), 640-647. doi: 10.1002/ppul.25794 PMID: 34918490Brown, P.M.; Schneeberger, D.L.; Piedimonte, G. Biomarkers of respiratory syncytial virus (RSV) infection: specific neutrophil and cytokine levels provide increased accuracy in predicting disease severity. Paediatr. Respir. Rev., 2015, 16(4), 232-240. doi: 10.1016/j.prrv.2015.05.005 PMID: 26074450Fiore, M.; Triaca, V.; Amendola, T.; Tirassa, P.; Aloe, L. Brain NGF and EGF administration improves passive avoidance response and stimulates brain precursor cells in aged male mice. Physiol. Behav., 2002, 77(2-3), 437-443. doi: 10.1016/S0031-9384(02)00875-2 PMID: 12419420Carito, V.; Ceccanti, M.; Ferraguti, G.; Coccurello, R.; Ciafrè, S.; Tirassa, P.; Fiore, M. NGF and BDNF alterations by prenatal alcohol exposure. Curr. Neuropharmacol., 2019, 17(4), 308-317. doi: 10.2174/1570159X15666170825101308 PMID: 28847297Ricci, A.; Felici, L.; Mariotta, S.; Mannino, F.; Schmid, G.; Terzano, C.; Cardillo, G.; Amenta, F.; Bronzetti, E. Neurotrophin and neurotrophin receptor protein expression in the human lung. Am. J. Respir. Cell Mol. Biol., 2004, 30(1), 12-19. doi: 10.1165/rcmb.2002-0110OC PMID: 12791675Ricci, A.; Graziano, P.; Bronzetti, E.; Saltini, C.; Sciacchitano, S.; Cherubini, E.; Renzoni, E.; Du Bois, R.M.; Grutters, J.C.; Mariotta, S. Increased pulmonary neurotrophin protein expression in idiopathic interstitial pneumonias. Sarcoidosis Vasc. Diffuse Lung Dis., 2007, 24(1), 13-23. PMID: 18069415Stoll, P.; Wuertemberger, U.; Bratke, K.; Zingler, C.; Virchow, C.J.; Lommatzsch, M. Stage-dependent association of BDNF and TGF-β1 with lung function in stable COPD. Respir. Res., 2012, 13(1), 116. doi: 10.1186/1465-9921-13-116 PMID: 23245944Braun, A.; Lommatzsch, M.; Neuhaus-Steinmetz, U.; Quarcoo, D.; Glaab, T.; McGregor, G.P.; Fischer, A.; Renz, H. Brain‐derived neurotrophic factor (BDNF) contributes to neuronal dysfunction in a model of allergic airway inflammation. Br. J. Pharmacol., 2004, 141(3), 431-440. doi: 10.1038/sj.bjp.0705638 PMID: 14718253Rochlitzer, S.; Nassenstein, C.; Braun, A. The contribution of neurotrophins to the pathogenesis of allergic asthma. Biochem. Soc. Trans., 2006, 34(4), 594-599. doi: 10.1042/BST0340594 PMID: 16856870Joachim, R.A.; Noga, O.; Sagach, V.; Hanf, G.; Fliege, H.; Kocalevent, R.D.; Peters, E.M.; Klapp, B.F. Correlation between immune and neuronal parameters and stress perception in allergic asthmatics. Clin. Exp. Allergy, 2008, 38(2), 283-290. doi: 10.1111/j.1365-2222.2007.02899.x PMID: 18070153Lommatzsch, M.; Niewerth, A.; Klotz, J.; Schulte-Herbrüggen, O.; Zingler, C.; Schuff-Werner, P.; Virchow, J.C. Platelet and plasma BDNF in lower respiratory tract infections of the adult. Respir. Med., 2007, 101(7), 1493-1499. doi: 10.1016/j.rmed.2007.01.003 PMID: 17317133Tortorolo, L.; Langer, A.; Polidori, G.; Vento, G.; Stampachiacchere, B.; Aloe, L.; Piedimonte, G. Neurotrophin overexpression in lower airways of infants with respiratory syncytial virus infection. Am. J. Respir. Crit. Care Med., 2005, 172(2), 233-237. doi: 10.1164/rccm.200412-1693OC PMID: 15879412Chmielewska, N.; Szyndler, J.; Makowska, K.; Wojtyna, D.; Maciejak, P.; Płaźnik, A. Looking for novel, brain-derived, peripheral biomarkers of neurological disorders. Neurol. Neurochir. Pol., 2018, 52(3), 318-325. doi: 10.1016/j.pjnns.2018.02.002 PMID: 29478670Giovannoni, G. Peripheral blood neurofilament light chain levels: The neurologist’s C-reactive protein? Brain, 2018, 141(8), 2235-2237. doi: 10.1093/brain/awy200 PMID: 30060019Nayani, K.; Naeem, R.; Munir, O.; Naseer, N.; Feroze, A.; Brown, N.; Mian, A.I. The clinical respiratory score predicts paediatric critical care disposition in children with respiratory distress presenting to the emergency department. BMC Pediatr., 2018, 18(1), 339. doi: 10.1186/s12887-018-1317-2 PMID: 30376827Destino, L.; Weisgerber, M.C.; Soung, P.; Bakalarski, D.; Yan, K.; Rehborg, R.; Wagner, D.R.; Gorelick, M.H.; Simpson, P. Validity of respiratory scores in bronchiolitis. Hosp. Pediatr., 2012, 2(4), 202-209. doi: 10.1542/hpeds.2012-0013 PMID: 24313026Nenna, R.; Fedele, G.; Frassanito, A.; Petrarca, L.; Di Mattia, G.; Pierangeli, A.; Scagnolari, C.; Papoff, P.; Schiavoni, I.; Leone, P.; Moretti, C.; Midulla, F. Increased T-helper Cell 2 response in infants with respiratory syncytial virus bronchiolitis hospitalized outside epidemic peak. Pediatr. Infect. Dis. J., 2020, 39(1), 61-67. doi: 10.1097/INF.0000000000002505 PMID: 31815840Tore, F.; Tonchev, A.; Fiore, M.; Tuncel, N.; Atanassova, P.; Aloe, L.; Chaldakov, G. From adipose tissue protein secretion to adipopharmacology of disease. Immunol. Endocr. Metab. Agents Med. Chem., 2007, 7(2), 149-155. doi: 10.2174/187152207780363712Yano, H.; Chao, M.V. Neurotrophin receptor structure and interactions. Pharm. Acta Helv., 2000, 74(2-3), 253-260. doi: 10.1016/S0031-6865(99)00036-9 PMID: 10812966Pramanik, S.; Sulistio, Y.A.; Heese, K. Neurotrophin signaling and stem cells—implications for neurodegenerative diseases and stem cell therapy. Mol. Neurobiol., 2017, 54(9), 7401-7459. doi: 10.1007/s12035-016-0214-7 PMID: 27815842Ebadi, M.; Bashir, R.M.; Heidrick, M.L.; Hamada, F.M.; El Refaey, E.; Hamed, A.; Helal, G.; Baxi, M.D.; Cerutis, D.R.; Lassi, N.K. Neurotrophins and their receptors in nerve injury and repair. Neurochem. Int., 1997, 30(4-5), 347-374. doi: 10.1016/S0197-0186(96)00071-X PMID: 9106250Prakash, Y.S.; Martin, R.J. Brain-derived neurotrophic factor in the airways. Pharmacol. Ther., 2014, 143(1), 74-86. doi: 10.1016/j.pharmthera.2014.02.006 PMID: 24560686Zingaropoli, M.A.; Pasculli, P.; Barbato, C.; Petrella, C.; Fiore, M.; Dominelli, F.; Latronico, T.; Ciccone, F.; Antonacci, M.; Liuzzi, G.M.; Talarico, G.; Bruno, G.; Galardo, G.; Pugliese, F.; Lichtner, M.; Mastroianni, C.M.; Minni, A.; Ciardi, M.R. Biomarkers of neurological damage: From acute stage to post-acute sequelae of COVID-19. Cells, 2023, 12(18), 2270. doi: 10.3390/cells12182270 PMID: 37759493Petrella, C.; Nenna, R.; Petrarca, L.; Tarani, F.; Paparella, R.; Mancino, E.; Di Mattia, G.; Conti, M.G.; Matera, L.; Bonci, E.; Ceci, F.M.; Ferraguti, G.; Gabanella, F.; Barbato, C.; Di Certo, M.G.; Cavalcanti, L.; Minni, A.; Midulla, F.; Tarani, L.; Fiore, M. Serum NGF and BDNF in Long-COVID-19 adolescents: A pilot study. Diagnostics, 2022, 12(5), 1162. doi: 10.3390/diagnostics12051162 PMID: 35626317Petrella, C.; Zingaropoli, M.A.; Ceci, F.M.; Pasculli, P.; Latronico, T.; Liuzzi, G.M.; Ciardi, M.R.; Angeloni, A.; Ettorre, E.; Menghi, M.; Barbato, C.; Ferraguti, G.; Minni, A.; Fiore, M. COVID-19 affects serum brain-derived neurotrophic factor and neurofilament light chain in aged men: Implications for morbidity and mortality. Cells, 2023, 12(4), 655. doi: 10.3390/cells12040655 PMID: 36831321Serafim Junior, V.; Fernandes, G.M.M.; Oliveira-Cucolo, J.G.; Pavarino, E.C.; Goloni-Bertollo, E.M. Role of Tropomyosin-related kinase B receptor and brain-derived neurotrophic factor in cancer. Cytokine, 2020, 136, 155270. doi: 10.1016/j.cyto.2020.155270Hang, P.Z.; Ge, F.Q.; Li, P.F.; Liu, J.; Zhu, H.; Zhao, J. The regulatory role of the BDNF/TrkB pathway in organ and tissue fibrosis. Histol. Histopathol., 2021, 36(11), 1133-1143. doi: 10.14670/HH-18-368 PMID: 34327702Matera, L.; Nenna, R.; Frassanito, A.; Petrarca, L.; Mancino, E.; Rizzo, V.; Di Mattia, G.; La Regina, D.P.; Pierangeli, A.; Midulla, F. Low lymphocyte count: A clinical severity marker in infants with bronchiolitis. Pediatr. Pulmonol., 2022, 57(7), 1770-1775. doi: 10.1002/ppul.25919 PMID: 35411598Binns, E.; Tuckerman, J.; Licciardi, P.V.; Wurzel, D. Respiratory syncytial virus, recurrent wheeze and asthma: A narrative review of pathophysiology, prevention and future directions. J. Paediatr. Child Health, 2022, 58(10), 1741-1746. doi: 10.1111/jpc.16197 PMID: 36073299Nievas-Soriano, B.J.; Martín-Latorre, M.M.; Martín-González, M.; Manzano-Agugliaro, F.; Castro-Luna, G. Worldwide research trends on bronchiolitis in pediatrics. Pediatr. Pulmonol., 2023, 58(8), 2189-2203. doi: 10.1002/ppul.26453 PMID: 37154529Zang, N.; Li, S.; Li, W.; Xie, X.; Ren, L.; Long, X.; Xie, J.; Deng, Y.; Fu, Z.; Xu, F.; Liu, E. Resveratrol suppresses persistent airway inflammation and hyperresponsivess might partially via nerve growth factor in respiratory syncytial virus-infected mice. Int. Immunopharmacol., 2015, 28(1), 121-128. doi: 10.1016/j.intimp.2015.05.031 PMID: 26044349Kyo, M.; Zhu, Z.; Nanishi, M.; Shibata, R.; Ooka, T.; Freishtat, R.J.; Mansbach, J.M.; Camargo, C.A., Jr; Hasegawa, K. Association of nasopharyngeal and serum glutathione metabolism with bronchiolitis severity and asthma risk: A prospective multicenter cohort study. Metabolites, 2022, 12(8), 674. doi: 10.3390/metabo12080674 PMID: 35893241Zhu, Y.; Fan, Q.; Cheng, L.; Chen, B. Diagnostic errors in initial misdiagnosis of foreign body aspiration in children: A retrospective observational study in a tertiary care hospital in China. Front Pediatr., 2021, 9, 694211. doi: 10.3389/fped.2021.694211 PMID: 34722414Zhu, Z.; Camargo, C.A., Jr; Raita, Y.; Fujiogi, M.; Liang, L.; Rhee, E.P.; Woodruff, P.G.; Hasegawa, K. Metabolome subtyping of severe bronchiolitis in infancy and risk of childhood asthma. J. Allergy Clin. Immunol., 2022, 149(1), 102-112. doi: 10.1016/j.jaci.2021.05.036 PMID: 34119532Calabrese, V.; Cornelius, C.; Dinkova-Kostova, A.T.; Calabrese, E.J.; Mattson, M.P. Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic intervention in neurodegenerative disorders. Antioxid. Redox Signal., 2010, 13(11), 1763-1811. doi: 10.1089/ars.2009.3074 PMID: 20446769Calabrese, V.; Mancuso, C.; Calvani, M.; Rizzarelli, E.; Butterfield, D.A.; Stella, A.M. Nitric oxide in the central nervous system: Neuroprotection versus neurotoxicity. Nat. Rev. Neurosci., 2007, 8(10), 766-775. doi: 10.1038/nrn2214 PMID: 17882254Calabrese, V.; Cornelius, C.; Dinkova-Kostova, A.T.; Calabrese, E.J. Vitagenes, cellular stress response, and acetylcarnitine: Relevance to hormesis. Biofactors, 2009, 35(2), 146-160. doi: 10.1002/biof.22 PMID: 19449442