Beneficial Effects of Spirulina Consumption on Brain Health

Teresa Trotta, Chiara Porro, Antonia Cianciulli, Maria Antonietta Panaro, Teresa Trotta, Chiara Porro, Antonia Cianciulli, Maria Antonietta Panaro

Abstract

Spirulina is a microscopic, filamentous cyanobacterium that grows in alkaline water bodies. It is extensively utilized as a nutraceutical food supplement all over the world due to its high levels of functional compounds, such as phycocyanins, phenols and polysaccharides, with anti-inflammatory, antioxidant, immunomodulating properties both in vivo and in vitro. Several scientific publications have suggested its positive effects in various pathologies such as cardiovascular diseases, hypercholesterolemia, hyperglycemia, obesity, hypertension, tumors and inflammatory diseases. Lately, different studies have demonstrated the neuroprotective role of Spirulina on the development of the neural system, senility and a number of pathological conditions, including neurological and neurodegenerative diseases. This review focuses on the role of Spirulina in the brain, highlighting how it exerts its beneficial anti-inflammatory and antioxidant effects, acting on glial cell activation, and in the prevention and/or progression of neurodegenerative diseases, in particular Parkinson's disease, Alzheimer's disease and Multiple Sclerosis; due to these properties, Spirulina could be considered a potential natural drug.

Keywords: Alzheimer’s disease; Parkinson’s disease; astrocytes; microglia; multiple sclerosis; neurodegeneration diseases; neuroinflammation; phycocyanin; spirulina.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Role of Spirulina in glial cells. Spirulina exerts anti-inflammatory activity with consequent neuronal damage and the onset of neuroinflammatory and/or neurodegenerative disorders, reducing (↓) glial cell activation and proinflammatory molecules, and up-regulating (↑) superoxide dismutase (SOD) and neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF).
Figure 2
Figure 2
Effects of Spirulina in neurodegenerative diseases.

References

    1. Kulshreshtha A., Zacharia A.J., Jarouliya U., Bhadauriya P., Prasad G.B.K.S., Bisen P.S. Spirulina in health care management. Curr. Pharm. Biotechnol. 2008;9:400–405. doi: 10.2174/138920108785915111.
    1. Sinha S., Patro N., Patro I.K. Maternal Protein Malnutrition: Current and Future Perspectives of Spirulina Supplementation in Neuroprotection. Front. Neurosci. 2018;12:966. doi: 10.3389/fnins.2018.00966.
    1. López-Romero D., Izquierdo-Vega J.A., Morales-González J.A., Madrigal-Bujaidar E., Chamorro-Cevallos G., Sánchez-Gutiérrez M., Betanzos-Cabrera G., Alvarez-Gonzalez I., Morales-González Á., Madrigal-Santillán E. Evidence of Some Natural Products with Antigenotoxic Effects. Part 2: Plants, Vegetables, and Natural Resin. Nutrients. 2018;10:1954. doi: 10.3390/nu10121954.
    1. Gutiérrez-Salmeán G., Fabila-Castillo L., Chamorro-Cevallos G. Nutritional and toxicological aspects of Spirulina (Arthrospira) Nutr. Hosp. 2015;32:34–40.
    1. Costa J.A.V., Freitas B.C.B., Rosa G.M., Moraes L., Morais M.G., Mitchell B.G. Operational and economic aspects of Spirulina-based biorefinery. Bioresour. Technol. 2019;292:121946. doi: 10.1016/j.biortech.2019.121946.
    1. Marles R.J., Barrett M.L., Barnes J., Chavez M.L., Gardiner P., Ko R., Mahady G.B., Dog T.L., Sarma N.D., Giancaspro G.I., et al. United States pharmacopeia safety evaluation of spirulina. Crit. Rev. Food Sci. Nutr. 2011;51:593–604. doi: 10.1080/10408391003721719.
    1. Hutadilok-Towatana N., Reanmongkol W., Panichayupakaranant P. Evaluation of the toxicity of Arthrospira (Spirulina) platensis extract. J. Appl. Phycol. 2010;22:599–605. doi: 10.1007/s10811-009-9499-5.
    1. Lafarga T., Fernández-Sevilla J.M., González-López C., Acién-Fernández F.G. Spirulina for the food and functional food industries. Food Res. Int. 2020;137:109356. doi: 10.1016/j.foodres.2020.109356.
    1. Wu Q., Liu L., Miron A., Klímová B., Wan D., Kuča K. The antioxidant, immunomodulatory, and anti-inflammatory activities of Spirulina: An overview. Arch. Toxicol. 2016;90:1817–1840. doi: 10.1007/s00204-016-1744-5.
    1. Liu Q., Huang Y., Zhang R., Cai T., Cai Y. Medical Application of Spirulina platensis Derived C-Phycocyanin. Evid. Based Complement. Alternat. Med. 2016;2016:7803846.
    1. Finkel Z.V., Follows M.J., Liefer J.D., Brown C.M., Benner I., Irwin A.J. Phylogenetic Diversity in the Macromolecular Composition of Microalgae. PLoS ONE. 2016;11:e0155977. doi: 10.1371/journal.pone.0155977.
    1. Ljubic A., Safafar H., Holdt S.L., Jacobsen C. Biomass composition of Arthrospira platensis during cultivation on industrial process water and harvesting. J. Appl. Phycol. 2018;30:943–954. doi: 10.1007/s10811-017-1332-y.
    1. Madrigal-Santillán E., Madrigal-Bujaidar E., Álvarez-González I., Sumaya-Martínez M.T., Gutiérrez-Salinas J., Bautista M., Morales-González Á., García-Luna y González-Rubio M., Aguilar-Faisal J.L., Morales-González J.A. Review of natural products with hepatoprotective effects. World J. Gastroenterol. 2014;20:14787–14804. doi: 10.3748/wjg.v20.i40.14787.
    1. Nicoletti M. Microalgae Nutraceuticals. Foods. 2016;5:54. doi: 10.3390/foods5030054.
    1. Deng R., Chow T.-J. Hypolipidemic, antioxidant, and antiinflammatory activities of microalgae Spirulina. Cardiovasc. Ther. 2010;28:e33–e45. doi: 10.1111/j.1755-5922.2010.00200.x.
    1. Finamore A., Palmery M., Bensehaila S., Peluso I. Antioxidant, Immunomodulating, and Microbial-Modulating Activities of the Sustainable and Ecofriendly Spirulina. Oxid. Med. Cell. Longev. 2017;2017:3247528. doi: 10.1155/2017/3247528.
    1. Qureshi M.A., Garlich J.D., Kidd M.T. Dietary Spirulina platensis enhances humoral and cell-mediated immune functions in chickens. Immunopharmacol. Immunotoxicol. 1996;18:465–476. doi: 10.3109/08923979609052748.
    1. Reboreda-Hernandez O.A., Juarez-Serrano A.L., Garcia-Luna I., Rivero-Ramirez N.L., Ortiz-Butron R., Nogueda-Torres B., Gonzalez-Rodriguez N. Arthrospira maxima Paradoxical Effect on Trypanosoma cruzi Infection. Iran. J. Parasitol. 2020;15:223–232. doi: 10.18502/ijpa.v15i2.3304.
    1. Al-Batshan H.A., Al-Mufarrej S.I., Al-Homaidan A.A., Qureshi M.A. Enhancement of chicken macrophage phagocytic function and nitrite production by dietary Spirulina platensis. Immunopharmacol. Immunotoxicol. 2001;23:281–289. doi: 10.1081/IPH-100103866.
    1. Løbner M., Walsted A., Larsen R., Bendtzen K., Nielsen C.H. Enhancement of human adaptive immune responses by administration of a high-molecular-weight polysaccharide extract from the cyanobacterium Arthrospira platensis. J. Med. Food. 2008;11:313–322. doi: 10.1089/jmf.2007.564.
    1. Trushina E.N., Gladkikh O., Gadzhieva Z.M., Mustafina O.K., Pozdniakov A.L. The influence of Spirulina and Selen-Spirulina on some indexes of rat’s immune status. Vopr. Pitan. 2007;76:21–25.
    1. Reddy C.M., Bhat V.B., Kiranmai G., Reddy M.N., Reddanna P., Madyastha K.M. Selective inhibition of cyclooxygenase-2 by C-phycocyanin, a biliprotein from Spirulina platensis. Biochem. Biophys. Res. Commun. 2000;277:599–603. doi: 10.1006/bbrc.2000.3725.
    1. Abdelkhalek N.K.M., Ghazy E.W., Abdel-Daim M.M. Pharmacodynamic interaction of Spirulina platensis and deltamethrin in freshwater fish Nile tilapia, Oreochromis niloticus: Impact on lipid peroxidation and oxidative stress. Environ. Sci. Pollut. Res. 2015;22:3023–3031. doi: 10.1007/s11356-014-3578-0.
    1. Gemma C., Mesches M.H., Sepesi B., Choo K., Holmes D.B., Bickford P.C. Diets enriched in foods with high antioxidant activity reverse age-induced decreases in cerebellar β-adrenergic function and increases in proinflammatory cytokines. J. Neurosci. 2002;22:6114–6120. doi: 10.1523/JNEUROSCI.22-14-06114.2002.
    1. Sagara T., Nishibori N., Kishibuchi R., Itoh M., Morita K. Non-protein components of Arthrospira (Spirulina) platensis protect PC12 cells against iron-evoked neurotoxic injury. J. Appl. Phycol. 2015;27:849–855. doi: 10.1007/s10811-014-0388-1.
    1. Padyana A.K., Bhat V.B., Madyastha K.M., Rajashankar K.R., Ramakumar S. Crystal structure of a light-harvesting protein C-phycocyanin from Spirulina platensis. Biochem. Biophys. Res. Commun. 2001;282:893–898. doi: 10.1006/bbrc.2001.4663.
    1. McCarty M.F., Barroso-Aranda J., Contreras F. Oral phycocyanobilin may diminish the pathogenicity of activated brain microglia in neurodegenerative disorders. Med. Hypotheses. 2010;74:601–605. doi: 10.1016/j.mehy.2008.09.061.
    1. Minic S.L., Stanic-Vucinic D., Mihailovic J., Krstic M., Nikolic M.R., Velickovic T.C. Digestion by pepsin releases biologically active chromopeptides from C-phycocyanin, a blue-colored biliprotein of microalga Spirulina. J. Proteom. 2016;147:132–139. doi: 10.1016/j.jprot.2016.03.043.
    1. Minic S., Stanic-Vucinic D., Radomirovic M., Radibratovic M., Milcic M., Nikolic M., Velickovic T.C. Characterization and effects of binding of food-derived bioactive phycocyanobilin to bovine serum albumin. Food Chem. 2018;239:1090–1099. doi: 10.1016/j.foodchem.2017.07.066.
    1. McCarty M.F. Clinical potential of Spirulina as a source of phycocyanobilin. J. Med. Food. 2007;10:566–570. doi: 10.1089/jmf.2007.621.
    1. Riss J., Décordé K., Sutra T., Delage M., Baccou J.-C., Jouy N., Brune J.-P., Oréal H., Cristol J.-P., Rouanet J.-M. Phycobiliprotein C-phycocyanin from Spirulina platensis is powerfully responsible for reducing oxidative stress and NADPH oxidase expression induced by an atherogenic diet in hamsters. J. Agric. Food Chem. 2007;55:7962–7967. doi: 10.1021/jf070529g.
    1. Cherdkiatikul T., Suwanwong Y. Production of the α and β Subunits of Spirulina Allophycocyanin and C-Phycocyanin in Escherichia coli: A Comparative Study of Their Antioxidant Activities. J. Biomol. Screen. 2014;19:959–965. doi: 10.1177/1087057113520565.
    1. Vo T.S., Ryu B., Kim S.K. Purification of novel anti-inflammatory peptides from enzymatic hydrolysate of the edible microalgal Spirulina maxima. J. Funct. Foods. 2013;5:1336–1346. doi: 10.1016/j.jff.2013.05.001.
    1. Shimamatsu H. A pond for edible Spirulina production and its hydraulic studies. Hydrobiologia. 1987;151:83–89. doi: 10.1007/BF00046111.
    1. Bai S.-K., Lee S.-J., Na H.-J., Ha K.-S., Han J.-A., Lee H., Kwon Y.-G., Chung C.-K., Kim Y.-M. β-Carotene inhibits inflammatory gene expression in lipopolysaccharide-stimulated macrophages by suppressing redox-based NF-kappaB activation. Exp. Mol. Med. 2005;37:323–334. doi: 10.1038/emm.2005.42.
    1. Katsuura S., Imamura T., Bando N., Yamanishi R. β-Carotene and β-cryptoxanthin but not lutein evoke redox and immune changes in RAW264 murine macrophages. Mol. Nutr. Food Res. 2009;53:1396–1405. doi: 10.1002/mnfr.200800566.
    1. Yogianti F., Kunisada M., Nakano E., Ono R., Sakumi K., Oka S., Nakabeppu Y., Nishigori C. Inhibitory effects of dietary Spirulina platensis on UVB-induced skin inflammatory responses and carcinogenesis. J. Investig. Dermatol. 2014;134:2610–2619. doi: 10.1038/jid.2014.188.
    1. Kim K.M., Lee J.Y., Im A.-R., Chae S. Phycocyanin Protects Against UVB-induced Apoptosis Through the PKC α/βII-Nrf-2/HO-1 Dependent Pathway in Human Primary Skin Cells. Molecules. 2018;23:478. doi: 10.3390/molecules23020478.
    1. Khan M., Varadharaj S., Ganesan L.P., Shobha J.C., Naidu M.U., Parinandi N.L., Tridandapani S., Kutala V.K., Kuppusamy P. C-phycocyanin protects against ischemia-reperfusion injury of heart through involvement of p38 MAPK and ERK signaling. Am. J. Physiol. Heart Circ. Physiol. 2006;290:H2136–H2145. doi: 10.1152/ajpheart.01072.2005.
    1. Patil J., Matte A., Mallard C., Sandberg M. Spirulina diet to lactating mothers protects the antioxidant system and reduces inflammation in post-natal brain after systemic inflammation. Nutr. Neurosci. 2018;21:59–69. doi: 10.1080/1028415X.2016.1221496.
    1. Patro N., Sharma A., Kariaya K., Patro I. Spirulina platensis protects neurons via suppression of glial activation and peripheral sensitization leading to restoration of motor function in collagen-induced arthritic rats. Indian J. Exp. Biol. 2011;49:739–748.
    1. Tocher D.R., Betancor M.B., Sprague M., Olsen R.E., Napier J.A. Omega-3 Long-Chain Polyunsaturated Fatty Acids, EPA and DHA: Bridging the Gap between Supply and Demand. Nutrients. 2019;11:89. doi: 10.3390/nu11010089.
    1. Capelli B., Cysewski G.R. Potential health benefits of spirulina microalgae. Nutrafoods. 2010;9:19–26. doi: 10.1007/BF03223332.
    1. Cianciulli A., Calvello R., Porro C., Trotta T., Panaro M.A. Understanding the role of SOCS signaling in neurodegenerative diseases: Current and emerging concepts. Cytokine Growth Factor Rev. 2017;37:67–79. doi: 10.1016/j.cytogfr.2017.07.005.
    1. Finkel T., Holbrook N.J. Oxidants, oxidative stress and the biology of ageing. Nature. 2000;408:239–247. doi: 10.1038/35041687.
    1. Bickford P.C., Gould T., Briederick L., Chadman K., Pollock A., Young D., Shukitt-Hale B., Joseph J. Antioxidant-rich diets improve cerebellar physiology and motor learning in aged rats. Brain Res. 2000;866:211–217. doi: 10.1016/S0006-8993(00)02280-0.
    1. Joseph J.A., Shukitt-Hale B., Denisova N.A., Bielinski D., Martin A., McEwen J.J., Bickford P.C. Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. J. Neurosci. 1999;19:8114–8121. doi: 10.1523/JNEUROSCI.19-18-08114.1999.
    1. Wang Y., Chang C.-F., Chou J., Chen H.-L., Deng X., Harvey B.K., Cadet J.L., Bickford P.C. Dietary supplementation with blueberries, spinach, or spirulina reduces ischemic brain damage. Exp. Neurol. 2005;193:75–84. doi: 10.1016/j.expneurol.2004.12.014.
    1. Abdullahi D., Annuar A.A., Sanusi J. Improved spinal cord gray matter morphology induced by Spirulina platensis following spinal cord injury in rat models. Ultrastruct. Pathol. 2020;44:359–371. doi: 10.1080/01913123.2020.1792597.
    1. Double K.L., Gerlach M., Youdim M.B., Riederer P. Impaired iron homeostasis in Parkinson’s disease. J. Neural. Transm. Suppl. 2000;6:37–58.
    1. Hirsch E.C., Faucheux B.A. Iron metabolism and Parkinson’s disease. Mov. Disord. 1998;13:39–45.
    1. Cornett C.R., Markesbery W.R., Ehmann W.D. Imbalances of trace elements related to oxidative damage in Alzheimer’s disease brain. Neurotoxicology. 1998;19:339–345.
    1. Smith M.A., Wehr K., Harris P.L., Siedlak S.L., Connor J.R., Perry G. Abnormal localization of iron regulatory protein in Alzheimer’s disease. Brain Res. 1998;788:232–236. doi: 10.1016/S0006-8993(98)00002-X.
    1. Zhang X., Xie W., Qu S., Pan T., Wang X., Le W. Neuroprotection by iron chelator against proteasome inhibitor-induced nigral degeneration. Biochem. Biophys. Res. Commun. 2005;333:544–549. doi: 10.1016/j.bbrc.2005.05.150.
    1. Zheng H., Weiner L.M., Bar-Am O., Epsztejn S., Cabantchik Z.I., Warshawsky A., Youdim M.B.H., Fridkin M. Design, synthesis, and evaluation of novel bifunctional iron-chelators as potential agents for neuroprotection in Alzheimer’s, Parkinson’s, and other neurodegenerative diseases. Bioorg. Med. Chem. 2005;13:773–783. doi: 10.1016/j.bmc.2004.10.037.
    1. Opara E.C. Oxidative stress. Dis. Mon. 2006;52:183–198. doi: 10.1016/j.disamonth.2006.05.003.
    1. Bermejo-Bescós P., Piñero-Estrada E., del Fresno A.M.V. Neuroprotection by Spirulina platensis protean extract and phycocyanin against iron-induced toxicity in SH-SY5Y neuroblastoma cells. Toxicol. In Vitro. 2008;22:1496–1502. doi: 10.1016/j.tiv.2008.05.004.
    1. Healy S.D., Rowe C. A critique of comparative studies of brain size. Proc. Biol. Sci. 2007;274:453–464. doi: 10.1098/rspb.2006.3748.
    1. Coviello C., Keunen K., Kersbergen K.J., Groenendaal F., Leemans A., Peels B., Isgum I., Viergever M.A., de Vries L.S., Buonocore G., et al. Effects of early nutrition and growth on brain volumes, white matter microstructure, and neurodevelopmental outcome in preterm newborns. Pediatr. Res. 2018;83:102–110. doi: 10.1038/pr.2017.227.
    1. Steenweg-de Graaff J., Tiemeier H., Steegers-Theunissen R.P.M., Hofman A., Jaddoe V.W.V., Verhulst F.C., Roza S.J. Maternal dietary patterns during pregnancy and child internalising and externalising problems. The Generation R Study. Clin. Nutr. 2014;33:115–121. doi: 10.1016/j.clnu.2013.03.002.
    1. Takeda A., Suzuki M., Tempaku M., Ohashi K., Tamano H. Influx of extracellular Zn(2+) into the hippocampal CA1 neurons is required for cognitive performance via long-term potentiation. Neuroscience. 2015;304:209–216. doi: 10.1016/j.neuroscience.2015.07.042.
    1. Reyes-Castro L.A., Padilla-Gómez E., Parga-Martínez N.J., Castro-Rodríguez D.C., Quirarte G.L., Díaz-Cintra S., Nathanielsz P.W., Zambrano E. Hippocampal mechanisms in impaired spatial learning and memory in male offspring of rats fed a low-protein isocaloric diet in pregnancy and/or lactation. Hippocampus. 2018;28:18–30. doi: 10.1002/hipo.22798.
    1. Sinha S., Patro N., Patro I.K. Amelioration of neurobehavioral and cognitive abilities of F1 progeny following dietary supplementation with Spirulina to protein malnourished mothers. Brain Behav. Immun. 2020;85:69–87. doi: 10.1016/j.bbi.2019.08.181.
    1. Sinha S., Patro N., Tiwari P.K., Patro I.K. Maternal Spirulina supplementation during pregnancy and lactation partially prevents oxidative stress, glial activation and neuronal damage in protein malnourished F1 progeny. Neurochem. Int. 2020;141:104877. doi: 10.1016/j.neuint.2020.104877.
    1. Pavón-Fuentes N., Marín-Prida J., Llópiz-Arzuaga A., Falcón-Cama V., Campos-Mojena R., Cervantes-Llanos M., Piniella-Matamoros B., Pentón-Arias E., Pentón-Rol G. Phycocyanobilin reduces brain injury after endothelin-1- induced focal cerebral ischaemia. Clin. Exp. Pharmacol. Physiol. 2020;47:383–392. doi: 10.1111/1440-1681.13214.
    1. Song X., Zhang L., Hui X., Sun X., Yang J., Wang J., Wu H., Wang X., Zheng Z., Che F., et al. Selenium-containing protein from selenium-enriched Spirulina platensis antagonizes oxygen glucose deprivation-induced neurotoxicity by inhibiting ROS-mediated oxidative damage through regulating mPTP opening. Pharm. Biol. 2021;59:629–638. doi: 10.1080/13880209.2021.1928715.
    1. Koh E.-J., Seo Y.-J., Choi J., Lee H.Y., Kang D.-H., Kim K.-J., Lee B.-Y. Spirulina maxima Extract Prevents Neurotoxicity via Promoting Activation of BDNF/CREB Signaling Pathways in Neuronal Cells and Mice. Molecules. 2017;22:1363. doi: 10.3390/molecules22081363.
    1. Koh E.-J., Kim K.-J., Choi J., Kang D.-H., Lee B.-Y. Spirulina maxima extract prevents cell death through BDNF activation against amyloid β 1-42 (Aβ 1-42) induced neurotoxicity in PC12 cells. Neurosci. Lett. 2018;673:33–38. doi: 10.1016/j.neulet.2018.02.057.
    1. Glass C.K., Saijo K., Winner B., Marchetto M.C., Gage F.H. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140:918–934. doi: 10.1016/j.cell.2010.02.016.
    1. Spencer J.P.E., Vafeiadou K., Williams R.J., Vauzour D. Neuroinflammation: Modulation by flavonoids and mechanisms of action. Mol. Asp. Med. 2012;33:83–97. doi: 10.1016/j.mam.2011.10.016.
    1. Schain M., Kreisl W.C. Neuroinflammation in Neurodegenerative Disorders-a Review. Curr. Neurol. Neurosci. Rep. 2017;17:25. doi: 10.1007/s11910-017-0733-2.
    1. Matejuk A., Ransohoff R.M. Crosstalk Between Astrocytes and Microglia: An Overview. Front. Immunol. 2020;11:1416. doi: 10.3389/fimmu.2020.01416.
    1. Napoli I., Neumann H. Microglial clearance function in health and disease. Neuroscience. 2009;158:1030–1038. doi: 10.1016/j.neuroscience.2008.06.046.
    1. Diaz-Aparicio I., Beccari S., Abiega O., Sierra A. Clearing the corpses: Regulatory mechanisms, novel tools, and therapeutic potential of harnessing microglial phagocytosis in the diseased brain. Neural Regen. Res. 2016;11:1533–1539.
    1. Mosser C.-A., Baptista S., Arnoux I., Audinat E. Microglia in CNS development: Shaping the brain for the future. Prog. Neurobiol. 2017;150:1–20. doi: 10.1016/j.pneurobio.2017.01.002.
    1. Colonna M., Butovsky O. Microglia Function in the Central Nervous System During Health and Neurodegeneration. Annu. Rev. Immunol. 2017;35:441–468. doi: 10.1146/annurev-immunol-051116-052358.
    1. Liddelow S.A., Guttenplan K.A., Clarke L.E., Bennett F.C., Bohlen C.J., Schirmer L., Bennett M.L., Münch A.E., Chung W.-S., Peterson T.C., et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541:481–487. doi: 10.1038/nature21029.
    1. Kumar H., Lim H.-W., More S.V., Kim B.-W., Koppula S., Kim I.S., Choi D.-K. The role of free radicals in the aging brain and Parkinson’s Disease: Convergence and parallelism. Int. J. Mol. Sci. 2012;13:10478–10504. doi: 10.3390/ijms130810478.
    1. Bolós M., Perea J.R., Avila J. Alzheimer’s disease as an inflammatory disease. Biomol. Concepts. 2017;8:37–43. doi: 10.1515/bmc-2016-0029.
    1. Liguori I., Russo G., Curcio F., Bulli G., Aran L., Della-Morte D., Gargiulo G., Testa G., Cacciatore F., Bonaduce D., et al. Oxidative stress, aging, and diseases. Clin. Interv. Aging. 2018;13:757–772. doi: 10.2147/CIA.S158513.
    1. Skaper S.D., Facci L., Zusso M., Giusti P. Corrigendum: An Inflammation-Centric View of Neurological Disease: Beyond the Neuron. Front. Cell Neurosci. 2020;13:578. doi: 10.3389/fncel.2019.00578.
    1. Piovan A., Battaglia J., Filippini R., Dalla Costa V., Facci L., Argentini C., Pagetta A., Giusti P., Zusso M. Pre- and Early Post-treatment With Arthrospira platensis (Spirulina) Extract Impedes Lipopolysaccharide-triggered Neuroinflammation in Microglia. Front. Pharmacol. 2021;12:724993. doi: 10.3389/fphar.2021.724993.
    1. Mitra S., Siddiqui W.A., Khandelwal S. C-Phycocyanin protects against acute tributyltin chloride neurotoxicity by modulating glial cell activity along with its anti-oxidant and anti-inflammatory property: A comparative efficacy evaluation with N-acetyl cysteine in adult rat brain. Chem. Biol. Interact. 2015;238:138–150. doi: 10.1016/j.cbi.2015.06.016.
    1. McCarty M.F. NADPH Oxidase Activity in Cerebral Arterioles Is a Key Mediator of Cerebral Small Vessel Disease-Implications for Prevention. Healthcare. 2015;3:233–251. doi: 10.3390/healthcare3020233.
    1. Rimbau V., Camins A., Romay C., González R., Pallàs M. Protective effects of C-phycocyanin against kainic acid-induced neuronal damage in rat hippocampus. Neurosci. Lett. 1999;276:75–78. doi: 10.1016/S0304-3940(99)00792-2.
    1. Pérez-Juárez A., Chamorro G., Alva-Sánchez C., Paniagua-Castro N., Pacheco-Rosado J. Neuroprotective effect of Arthrospira (Spirulina) platensis against kainic acid-neuronal death. Pharm. Biol. 2016;54:1408–1412. doi: 10.3109/13880209.2015.1103756.
    1. Piniella-Matamoros B., Marin-Prida J., Penton-Rol G. Nutraceutical and therapeutic potential of Phycocyanobilin for treating Alzheimer’s disease. J. Biosci. 2021;46:42. doi: 10.1007/s12038-021-00161-7.
    1. Pabon M.M., Jernberg J.N., Morganti J., Contreras J., Hudson C.E., Klein R.L., Bickford P.C. A spirulina-enhanced diet provides neuroprotection in an α-synuclein model of Parkinson’s disease. PLoS ONE. 2012;7:e45256. doi: 10.1371/journal.pone.0045256.
    1. Tobón-Velasco J.C., Palafox-Sánchez V., Mendieta L., García E., Santamaría A., Chamorro-Cevallos G., Limón I.D. Anti-oxidant effect of Spirulina (Arthrospira) maxima in a neurotoxic model caused by 6-OHDA in the rat striatum. J. Neural. Transm. 2013;120:1179–1189. doi: 10.1007/s00702-013-0976-2.
    1. Chamorro G., Pérez-Albiter M., Serrano-García N., Mares-Sámano J.J., Rojas P. Spirulina maxima pretreatment partially protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity. Nutr. Neurosci. 2006;9:207–212. doi: 10.1080/10284150600929748.
    1. Zhang F., Lu J., Zhang J.-G., Xie J.-X. Protective effects of a polysaccharide from Spirulina platensis on dopaminergic neu-rons in an MPTP-induced Parkinson’s disease model in C57BL/6J mice. Neural Regen Res. 2015;10:308–313. doi: 10.4103/1673-5374.152387.
    1. Koh E.-J., Kim K.-J., Song J.-H., Choi J., Lee H.Y., Kang D.-H., Heo H.J., Lee B.-Y. Spirulina maxima Extract Ameliorates Learning and Memory Impairments via Inhibiting GSK-3β Phosphorylation Induced by Intracerebroventricular Injection of Amyloid-β 1-42 in Mice. Int. J. Mol. Sci. 2017;18:2401. doi: 10.3390/ijms18112401.
    1. Marín-Prida J., Pavón-Fuentes N., Llópiz-Arzuaga A., Fernández-Massó J.R., Delgado-Roche L., Mendoza-Marí Y., San-tana S.P., Cruz-Ramírez A., Valenzuela-Silva C., Nazábal-Gálvez M., et al. Phycocyanobilin promotes PC12 cell survival and modulates immune and inflammatory genes and oxidative stress markers in acute cerebral hypoperfusion in rats. Toxicol. Appl. Pharmacol. 2013;272:49–60. doi: 10.1016/j.taap.2013.05.021.
    1. Agrawal M., Perumal Y., Bansal S., Arora S., Chopra K. Phycocyanin alleviates ICV-STZ induced cognitive and molecular deficits via PI3-Kinase dependent pathway. Food Chem. Toxicol. 2020;145:111684. doi: 10.1016/j.fct.2020.111684.
    1. Cervantes-Llanos M., Lagumersindez-Denis N., Marín-Prida J., Pavón-Fuentes N., Falcon-Cama V., Piniella-Matamoros B., Camacho-Rodríguez H., Fernández-Massó J.R., Valenzuela-Silva C., Raíces-Cruz I., et al. Beneficial effects of oral ad-ministration of C-Phycocyanin and Phycocyanobilin in rodent models of experimental autoimmune encephalomyelitis. Life Sci. 2018;194:130–138. doi: 10.1016/j.lfs.2017.12.032.
    1. Pentón-Rol G., Marín-Prida J., Pardo-Andreu G., Martínez-Sánchez G., Acosta-Medina E.F., Valdivia-Acosta A., Lagumersindez-Denis N., Rodríguez-Jiménez E., Llópiz-Arzuaga A., López-Saura P.A., et al. C-Phycocyanin is neuropro-tective against global cerebral ischemia/reperfusion injury in gerbils. Brain Res. Bull. 2011;86:42–52. doi: 10.1016/j.brainresbull.2011.05.016.
    1. Elsonbaty S.M., Ismail A.F.M. Nicotine encourages oxidative stress and impairment of rats’ brain mitigated by Spirulina platensis lipopolysaccharides and low-dose ionizing radiation. Arch. Biochem. Biophys. 2020;689:108382. doi: 10.1016/j.abb.2020.108382.
    1. Min S.K., Park J.S., Luo L., Kwon Y.S., Lee H.C., Shim H.J., Kim I.-D., Lee J.-K., Shin H.S. Assessment of C-phycocyanin effect on astrocytes-mediated neuroprotection against oxidative brain injury using 2D and 3D astrocyte tissue model. Sci. Rep. 2015;5:14418. doi: 10.1038/srep14418.
    1. Hefti F., Hartikka J., Knusel B. Function of neurotrophic factors in the adult and aging brain and their possible use in the treatment of neurodegenerative diseases. Neurobiol. Aging. 1989;10:515–533. doi: 10.1016/0197-4580(89)90118-8.
    1. Chen A., Xiong L.-J., Tong Y., Mao M. The neuroprotective roles of BDNF in hypoxic ischemic brain injury. Biomed. Rep. 2013;1:167–176. doi: 10.3892/br.2012.48.
    1. Pentón-Rol G., Marín-Prida J., Falcón-Cama V. C-Phycocyanin and Phycocyanobilin as Remyelination Therapies for Enhancing Recovery in Multiple Sclerosis and Ischemic Stroke: A Preclinical Perspective. Behav. Sci. 2018;8:15. doi: 10.3390/bs8010015.
    1. Bachstetter A.D., Jernberg J., Schlunk A., Vila J.L., Hudson C., Cole M.J., Shytle R.D., Tan J., Sanberg P.R., Sanberg C.D., et al. Spirulina promotes stem cell genesis and protects against LPS induced declines in neural stem cell proliferation. PLoS ONE. 2010;5:e10496. doi: 10.1371/journal.pone.0010496.
    1. Sweeney P., Park H., Baumann M., Dunlop J., Frydman J., Kopito R., McCampbell A., Leblanc G., Venkateswaran A., Nurmi A., et al. Protein misfolding in neurodegenerative diseases: Implications and strategies. Transl. Neurodegener. 2017;6:6. doi: 10.1186/s40035-017-0077-5.
    1. Elbaz A., Carcaillon L., Kab S., Moisan F. Epidemiology of Parkinson’s disease. Rev. Neurol. 2016;172:14–26. doi: 10.1016/j.neurol.2015.09.012.
    1. Balestrino R., Schapira A.H.V. Parkinson disease. Eur. J. Neurol. 2020;27:27–42. doi: 10.1111/ene.14108.
    1. Ascherio A., Schwarzschild M.A. The epidemiology of Parkinson’s disease: Risk factors and prevention. Lancet Neurol. 2016;15:1257–1272. doi: 10.1016/S1474-4422(16)30230-7.
    1. Deng H., Wang P., Jankovic J. The genetics of Parkinson disease. Ageing Res. Rev. 2018;42:72–85. doi: 10.1016/j.arr.2017.12.007.
    1. Bras J.M., Singleton A. Genetic susceptibility in Parkinson’s disease. Biochim. Biophys. Acta. 2009;1792:597–603. doi: 10.1016/j.bbadis.2008.11.008.
    1. Sveinbjornsdottir S. The clinical symptoms of Parkinson’s disease. J. Neurochem. 2016;139:318–324. doi: 10.1111/jnc.13691.
    1. Chaudhuri K.R., Healy D.G., Schapira A.H.V. Non-motor symptoms of Parkinson’s disease: Diagnosis and management. Lancet Neurol. 2006;5:235–245. doi: 10.1016/S1474-4422(06)70373-8.
    1. Kaur R., Mehan S., Singh S. Understanding multifactorial architecture of Parkinson’s disease: Pathophysiology to management. Neurol. Sci. 2019;40:13–23. doi: 10.1007/s10072-018-3585-x.
    1. Teravskis P.J., Covelo A., Miller E.C., Singh B., Martell-Martínez H.A., Benneyworth M.A., Gallardo C., Oxnard B.R., Araque A., Lee M.K., et al. A53T Mutant α-Synuclein Induces Tau-Dependent Postsynaptic Impairment Independently of Neurodegenerative Changes. J. Neurosci. 2018;38:9754–9767. doi: 10.1523/JNEUROSCI.0344-18.2018.
    1. Wakabayashi K., Tanji K., Odagiri S., Miki Y., Mori F., Takahashi H. The Lewy body in Parkinson’s disease and related neurodegenerative disorders. Mol. Neurobiol. 2013;47:495–508. doi: 10.1007/s12035-012-8280-y.
    1. Reale M., Greig N.H., Kamal M.A. Peripheral chemo-cytokine profiles in Alzheimer’s and Parkinson’s diseases. Mini Rev. Med. Chem. 2009;9:1229–1241. doi: 10.2174/138955709789055199.
    1. Reale M., Iarlori C., Thomas A., Gambi D., Perfetti B., Di Nicola M., Onofrj M. Peripheral cytokines profile in Parkinson’s disease. Brain Behav. Immun. 2009;23:55–63. doi: 10.1016/j.bbi.2008.07.003.
    1. Rojanathammanee L., Murphy E.J., Combs C.K. Expression of mutant α-synuclein modulates microglial phenotype in vitro. J. Neuroinflamm. 2011;8:44. doi: 10.1186/1742-2094-8-44.
    1. Hou L., Bao X., Zang C., Yang H., Sun F., Che Y., Wu X., Li S., Zhang D., Wang Q. Integrin CD11b mediates α-synuclein-induced activation of NADPH oxidase through a Rho-dependent pathway. Redox Biol. 2018;14:600–608. doi: 10.1016/j.redox.2017.11.010.
    1. Liu Y., Jovcevski B., Pukala T.L. C-Phycocyanin from Spirulina Inhibits α-Synuclein and Amyloid-β Fibril Formation but Not Amorphous Aggregation. J. Nat. Prod. 2019;82:66–73. doi: 10.1021/acs.jnatprod.8b00610.
    1. Huang Z., Guo B.J., Wong R.N.S., Jiang Y. Characterization and antioxidant activity of selenium-containing phycocyanin isolated from Spirulina platensis. Food Chem. 2007;100:1137–1143. doi: 10.1016/j.foodchem.2005.11.023.
    1. Thaakur S.R., Jyothi B. Effect of spirulina maxima on the haloperidol induced tardive dyskinesia and oxidative stress in rats. J. Neural. Transm. 2007;114:1217–1225. doi: 10.1007/s00702-007-0744-2.
    1. McGeer P.L., McGeer E.G. The α-synuclein burden hypothesis of Parkinson disease and its relationship to Alzheimer disease. Exp. Neurol. 2008;212:235–238. doi: 10.1016/j.expneurol.2008.04.008.
    1. Godoy M.C.P., Tarelli R., Ferrari C.C., Sarchi M.I., Pitossi F.J. Central and systemic IL-1 exacerbates neurodegeneration and motor symptoms in a model of Parkinson’s disease. Brain. 2008;131:1880–1894. doi: 10.1093/brain/awn101.
    1. Zujovic V., Benavides J., Vigé X., Carter C., Taupin V. Fractalkine modulates TNF-αsecretion and neurotoxicity induced by microglial activation. Glia. 2000;29:305–315. doi: 10.1002/(SICI)1098-1136(20000215)29:4<305::AID-GLIA2>;2-V.
    1. Zujovic V., Schussler N., Jourdain D., Duverger D., Taupin V. In vivo neutralization of endogenous brain fractalkine increases hippocampal TNF-α and 8-isoprostane production induced by intracerebroventricular injection of LPS. J. Neuroimmunol. 2001;115:135–143. doi: 10.1016/S0165-5728(01)00259-4.
    1. Strömberg I., Gemma C., Vila J., Bickford P.C. Blueberry- and spirulina-enriched diets enhance striatal dopamine recovery and induce a rapid, transient microglia activation after injury of the rat nigrostriatal dopamine system. Exp. Neurol. 2005;196:298–307. doi: 10.1016/j.expneurol.2005.08.013.
    1. Pabon M.M., Bachstetter A.D., Hudson C.E., Gemma C., Bickford P.C. CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson’s disease. J. Neuroinflamm. 2011;8:9. doi: 10.1186/1742-2094-8-9.
    1. Kumar A., Christian P.K., Panchal K., Guruprasad B.R., Tiwari A.K. Supplementation of Spirulina (Arthrospira platensis) Improves Lifespan and Locomotor Activity in Paraquat-Sensitive DJ-1β Δ93 Flies, a Parkinson’s Disease Model in Drosophila melanogaster. J. Diet. Suppl. 2017;14:573–588. doi: 10.1080/19390211.2016.1275917.
    1. Pan R.-Y., Ma J., Kong X.-X., Wang X.-F., Li S.-S., Qi X.-L., Yan Y.-H., Cheng J., Liu Q., Jin W., et al. Sodium rutin ameliorates Alzheimer’s disease-like pathology by enhancing microglial amyloid-β clearance. Sci. Adv. 2019;5:eaau6328. doi: 10.1126/sciadv.aau6328.
    1. De la Monte S.M. Contributions of brain insulin resistance and deficiency in amyloid-related neurodegeneration in Alzheimer’s disease. Drugs. 2012;72:49–66. doi: 10.2165/11597760-000000000-00000.
    1. Magalingam K.B., Radhakrishnan A., Ping N.S., Haleagrahara N. Current Concepts of Neurodegenerative Mechanisms in Alzheimer’s Disease. Biomed. Res. Int. 2018;2018:3740461. doi: 10.1155/2018/3740461.
    1. Kim H.Y., Kim H.V., Jo S., Lee C.J., Choi S.Y., Kim D.J., Kim Y. Corrigendum: EPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by disaggregation of amyloid-β oligomers and plaques. Nat. Commun. 2016;7:10755. doi: 10.1038/ncomms10755.
    1. Ono K. Alzheimer’s disease as oligomeropathy. Neurochem. Int. 2018;119:57–70. doi: 10.1016/j.neuint.2017.08.010.
    1. Borutaite V., Morkuniene R., Valincius G. β-amyloid oligomers: Recent developments. Biomol. Concepts. 2011;2:211–222. doi: 10.1515/bmc.2011.019.
    1. Guo J.-P., Yu S., McGeer P.L. Simple in vitro assays to identify amyloid-βaggregation blockers for Alzheimer’s disease therapy. J. Alzheimer’s Dis. 2010;19:1359–1370. doi: 10.3233/JAD-2010-1331.
    1. Kim J., Lee H.J., Lee K.W. Naturally occurring phytochemicals for the prevention of Alzheimer’s disease. J. Neurochem. 2010;112:1415–1430. doi: 10.1111/j.1471-4159.2009.06562.x.
    1. Luo Y.-C., Jing P. Molecular Interaction of Protein-Pigment C-Phycocyanin with Bovine Serum Albumin in a Gomphosis Structure Inhibiting Amyloid Formation. Int. J. Mol. Sci. 2020;21:8207. doi: 10.3390/ijms21218207.
    1. Singh N.K., Hasan S.S., Kumar J., Raj I., Pathan A.A., Parmar A., Shakil S., Gourinath S., Madamwar D. Crystal structure and interaction of phycocyanin with β-secretase: A putative therapy for Alzheimer’s disease. CNS Neurol. Disord. Drug Targets. 2014;13:691–698. doi: 10.2174/1871527313666140228114456.
    1. Das B., Yan R. A Close Look at BACE1 Inhibitors for Alzheimer’s Disease Treatment. CNS Drugs. 2019;33:251–263. doi: 10.1007/s40263-019-00613-7.
    1. Ozben T., Ozben S. Neuro-inflammation and anti-inflammatory treatment options for Alzheimer’s disease. Clin. Biochem. 2019;72:87–89. doi: 10.1016/j.clinbiochem.2019.04.001.
    1. Ugolini F., Lana D., Nardiello P., Nosi D., Pantano D., Casamenti F., Giovannini M.G. Different Patterns of Neurodegeneration and Glia Activation in CA1 and CA3 Hippocampal Regions of TgCRND8 Mice. Front. Aging Neurosci. 2018;10:372. doi: 10.3389/fnagi.2018.00372.
    1. Li Z., Gan L., Yan S., Yan Y., Huang W. Effect of C-phycocyanin on HDAC3 and miRNA-335 in Alzheimer’s disease. Transl. Neurosci. 2020;11:161–172. doi: 10.1515/tnsci-2020-0101.
    1. Pham T.X., Park Y.-K., Lee J.-Y. Anti-Inflammatory Effects of Spirulina platensis Extract via the Modulation of Histone Deacetylases. Nutrients. 2016;8:381. doi: 10.3390/nu8060381.
    1. Zhu X., Wang S., Yu L., Jin J., Ye X., Liu Y., Xu Y. HDAC3 negatively regulates spatial memory in a mouse model of Alzheimer’s disease. Aging Cell. 2017;16:1073–1082. doi: 10.1111/acel.12642.
    1. Janczura K.J., Volmar C.-H., Sartor G.C., Rao S.J., Ricciardi N.R., Lambert G., Brothers S.P., Wahlestedt C. Inhibition of HDAC3 reverses Alzheimer’s disease-related pathologies in vitro and in the 3xTg-AD mouse model. Proc. Natl. Acad. Sci. USA. 2018;115:E11148–E11157. doi: 10.1073/pnas.1805436115.
    1. Walker D.G., Lue L.-F., Tang T.M., Adler C.H., Caviness J.N., Sabbagh M.N., Serrano G.E., Sue L.I., Beach T.G. Changes in CD200 and intercellular adhesion molecule-1 (ICAM-1) levels in brains of Lewy body disorder cases are associated with amounts of Alzheimer’s pathology not α-synuclein pathology. Neurobiol. Aging. 2017;54:175–186. doi: 10.1016/j.neurobiolaging.2017.03.007.
    1. Frohman E.M., Frohman T.C., Gupta S., de Fougerolles A., van den Noort S. Expression of intercellular adhesion molecule 1 (ICAM-1) in Alzheimer’s disease. J. Neurol. Sci. 1991;106:105–111. doi: 10.1016/0022-510X(91)90202-I.
    1. Guha S., Paidi R.K., Goswami S., Saha P., Biswas S.C. ICAM-1 protects neurons against Amyloid-β and improves cognitive behaviors in 5xFAD mice by inhibiting NF-Κb. Brain Behav. Immun. 2021;100:194–210. doi: 10.1016/j.bbi.2021.11.021.
    1. De Paola M., Buanne P., Biordi L., Bertini R., Ghezzi P., Mennini T. Chemokine MIP-2/CXCL2, acting on CXCR2, induces motor neuron death in primary cultures. Neuroimmunomodulation. 2007;14:310–316. doi: 10.1159/000123834.
    1. Nylander A., Hafler D.A. Multiple sclerosis. J. Clin. Investig. 2012;122:1180–1188. doi: 10.1172/JCI58649.
    1. Sospedra M., Martin R. Immunology of multiple sclerosis. Annu. Rev. Immunol. 2005;23:683–747. doi: 10.1146/annurev.immunol.23.021704.115707.
    1. Correale J., Marrodan M., Ysrraelit M.C. Mechanisms of Neurodegeneration and Axonal Dysfunction in Progressive Multiple Sclerosis. Biomedicines. 2019;7:14. doi: 10.3390/biomedicines7010014.
    1. Friese M.A., Schattling B., Fugger L. Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat. Rev. Neurol. 2014;10:225–238. doi: 10.1038/nrneurol.2014.37.
    1. Pentón-Rol G., Martínez-Sánchez G., Cervantes-Llanos M., Lagumersindez-Denis N., Acosta-Medina E.F., Falcón-Cama V., Alonso-Ramírez R., Valenzuela-Silva C., Rodríguez-Jiménez E., Llópiz-Arzuaga A., et al. C-Phycocyanin ameliorates experimental autoimmune encephalomyelitis and induces regulatory T cells. Int. Immunopharmacol. 2011;11:29–38. doi: 10.1016/j.intimp.2010.10.001.
    1. Martin R., McFarland H.F. Immunological aspects of experimental allergic encephalomyelitis and multiple sclerosis. Crit. Rev. Clin. Lab. Sci. 1995;32:121–182. doi: 10.3109/10408369509084683.
    1. Constantinescu C.S., Farooqi N., O’Brien K., Gran B. Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS) Br. J. Pharmacol. 2011;164:1079–1106. doi: 10.1111/j.1476-5381.2011.01302.x.
    1. Bittner S., Afzali A.M., Wiendl H., Meuth S.G. Myelin oligodendrocyte glycoprotein (MOG35-55) induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. J. Vis. Exp. 2014;15:51275.
    1. Khoury S.J., Hancock W.W., Weiner H.L. Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor β, interleukin 4, and prostaglandin E expression in the brain. J. Exp. Med. 1992;176:1355–1364.
    1. Pentón-Rol G., Lagumersindez-Denis N., Muzio L., Bergami A., Furlan R., Fernández-Massó J.R., Nazabal-Galvez M., Llópiz-Arzuaga A., Herrera-Rolo T., Veliz-Rodriguez T., et al. Comparative Neuroregenerative Effects of C-Phycocyanin and IFN-β in a Model of Multiple Sclerosis in Mice. J. Neuroimmune Pharmacol. 2016;11:153–167. doi: 10.1007/s11481-015-9642-9.
    1. Carlson N.G., Bellamkonda S., Schmidt L., Redd J., Huecksteadt T., Weber L.M., Davis E., Wood B., Maruyama T., Rose J.W. The role of the prostaglandin E2 receptors in vulnerability of oligodendrocyte precursor cells to death. J. Neuroinflamm. 2015;12:101. doi: 10.1186/s12974-015-0323-7.
    1. Shiow L.R., Favrais G., Schirmer L., Schang A.-L., Cipriani S., Andres C., Wright J.N., Nobuta H., Fleiss B., Gressens P., et al. Reactive astrocyte COX2-PGE2 production inhibits oligodendrocyte maturation in neonatal white matter injury. Glia. 2017;65:2024–2037. doi: 10.1002/glia.23212.

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