Skip to main content
PMC home page
Springer Nature - PMC COVID-19 Collection logoLink to Springer Nature - PMC COVID-19 Collection
. 2022 Mar 18;52(2):196–201. doi: 10.1007/s11055-022-01223-5

Neuroinflammation and Neuropathology

R G Esin 1,2,✉, D R Safina 2, A R Khakimova 1, O R Esin 2
PMCID: PMC8930459  PMID: 35317271

Abstract

This review addresses the current understanding of the role of autoimmune neuroinflammation in the pathogenesis of vascular, neurodegenerative, and other diseases of the nervous system. The mechanisms of responses of resident CNS cells (glial cells, astrocytes) and peripheral immune system cells are presented. The therapeutic potentials of phosphodiesterase inhibitors, which have antiaggregant properties and can suppress autoimmune inflammation, are discussed. The phosphodiesterase inhibitor dipyridamole is regarded as a potential drug for this purpose.

Keywords: neuroinflammation, microglia, astrocytes, blood–brain barrier, dipyridamole

Footnotes

Translated from Zhurnal Nevrologii i Psikhiatrii imeni S. S. Korsakova, Vol. 121, No. 4, Iss. 1, pp. 107–112, April, 2021.

References

  • 1.DiSabato D, Quan N, Godbout J. Neuroinflammation: the devil is in the details. J. Neurochem. 2016;139:136–153. doi: 10.1111/jnc.13607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Brambilla R. Neuroinflammation, the thread connecting neurological disease. Acta Neuropathol. 2019;137(5):689–691. doi: 10.1007/s00401-019-02009-9. [DOI] [PubMed] [Google Scholar]
  • 3.Jayaraj R, Azimullah S, Beiram R, et al. Neuroinflammation: friend and foe for ischemic stroke. J. Neuroinflammation. 2019;16(1):142. doi: 10.1186/s12974-019-1516-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Guruswamy R, El Ali A. Complex roles of microglial cells in ischemic stroke pathobiology: New insights and future directions. Int. J. Mol. Sci. 2017;18(3):496. doi: 10.3390/ijms18030496. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nat. Med. 2011;17(7):796–808. doi: 10.1038/nm.2399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Kim J, Kawabori M, Yenari M. Innate inflammatory responses in stroke: mechanisms and potential therapeutic targets. Curr. Med. Chem. 2014;21(18):2076–2097. doi: 10.2174/0929867321666131228205146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Tanaka R, Komine-Kobayashi M, Mochizuki H, et al. Migration of enhanced green fluorescent protein expressing bone marrow-derived microglia/macrophage into the mouse brain following permanent focal ischemia. Neuroscience. 2003;117(3):531–539. doi: 10.1016/s0306-4522(02)00954-5. [DOI] [PubMed] [Google Scholar]
  • 8.R. Taylor and L. Sansing, “Microglial responses after ischemic stroke and intracerebral hemorrhage,” Clin. Dev. Immunol., 2013, No. 1–10 (2013), 10.1155/2013/746068. [DOI] [PMC free article] [PubMed]
  • 9.Kokovay E, Li L, Cunningham L. Angiogenic recruitment of pericytes from bone marrow after stroke. J. Cereb. Blood Flow Metab. 2005;26(4):545–555. doi: 10.1038/sj.jcbfm.9600214. [DOI] [PubMed] [Google Scholar]
  • 10.Hennessy E, Griffin E, Cunningham C. Astrocytes are primed by chronic neurodegeneration to produce exaggerated chemokine and cell infiltration responses to acute stimulation with the cytokines IL-1β and TNF-α. J. Neurosci. 2015;35(22):8411–8422. doi: 10.1523/jneurosci.2745-14.2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Wang H, Song G, Chuang H, et al. Portrait of glial scar in neurological diseases. Int. J. Immunopathol. Pharmacol. 2018;31:205873841880140. doi: 10.1177/2058738418801406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Rempe R, Hartz A, Bauer B. Matrix metalloproteinases in the brain and blood–brain barrier: Versatile breakers and makers. J. Cereb. Blood Flow Metab. 2016;36(9):1481–1507. doi: 10.1177/0271678x16655551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Overman J, Clarkson A, Wanner I, et al. A role for ephrin-A5 in axonal sprouting, recovery, and activity-dependent plasticity after stroke. Proc. Natl. Acad. Sci. USA. 2012;109(33):2230–2239. doi: 10.1073/pnas.1204386109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Li M, Li Z, Yao Y, et al. Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity. Proc. Natl. Acad. Sci. USA. 2016;114(3):396–405. doi: 10.1073/pnas.1612930114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Weston R, Jones N, Jarrott B, Callaway J. Inflammatory cell infiltration after endothelin-1-induced cerebral ischemia: histochemical and myeloperoxidase correlation with temporal changes in brain injury. J. Cereb. Blood Flow Metab. 2006;27(1):100–114. doi: 10.1038/sj.jcbfm.9600324. [DOI] [PubMed] [Google Scholar]
  • 16.Watcharotayangul J, Mao L, Xu H, et al. Post-ischemic vascular adhesion protein-1 inhibition provides neuroprotection in a rat temporary middle cerebral artery occlusion model. J. Neurochem. 2012;123:116–124. doi: 10.1111/j.1471-4159.2012.07950.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Perez-de-Puig I, Miró-Mur F, Ferrer-Ferrer M, et al. Neutrophil recruitment to the brain in mouse and human ischemic stroke. Acta Neuropathol. 2014;129(2):239–257. doi: 10.1007/s00401-014-1381-0. [DOI] [PubMed] [Google Scholar]
  • 18.Gelderblom M, Leypoldt F, Steinbach K, et al. Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke. 2009;40(5):1849–1857. doi: 10.1161/strokeaha.108.534503. [DOI] [PubMed] [Google Scholar]
  • 19.Yilmaz G, Arumugam T, Stokes K, Granger D. Role of T lymphocytes and interferon-γ in ischemic stroke. Circulation. 2006;113(17):2105–2112. doi: 10.1161/circulationaha.105.593046. [DOI] [PubMed] [Google Scholar]
  • 20.Hum P, Subramanian S, Parker S, et al. T- and B-cell-deficient mice with experimental stroke have reduced lesion size and inflammation. J. Cereb. Blood Flow Metab. 2007;27(11):1798–1805. doi: 10.1038/sj.jcbfm.9600482. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Xie L, Yang S. Interaction of astrocytes and T cells in physiological and pathological conditions. Brain Res. 2015;1623:63–73. doi: 10.1016/j.brainres.2015.03.026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Liesz A, Suri-Payer E, Veltkamp C, et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat. Med. 2009;15(2):192–199. doi: 10.1038/nm.1927. [DOI] [PubMed] [Google Scholar]
  • 23.Fu Y, Yan Y. Emerging role of immunity in cerebral small vessel disease. Front. Immunol. 2018;9:67. doi: 10.3389/fimmu.2018.00067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Beard R, Reynolds J, Bearden S. Hyperhomocysteinemia increases permeability of the blood–brain barrier by NMDA receptor-dependent regulation of adherens and tight junctions. Blood. 2011;118(7):2007–2014. doi: 10.1182/blood-2011-02-338269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Wardlaw J, Doubal F, Armitage P, et al. Lacunar stroke is associated with diffuse blood–brain barrier dysfunction. Ann. Neurol. 2009;65(2):194–202. doi: 10.1002/ana.21549. [DOI] [PubMed] [Google Scholar]
  • 26.Wuerfel J, Haertle M, Waiczies H, et al. Perivascular spaces – MRI marker of inflammatory activity in the brain? Brain. 2008;131(9):2332–2340. doi: 10.1093/brain/awn171. [DOI] [PubMed] [Google Scholar]
  • 27.Murr C, Widner B, Wirleitner B, Fuchs D. Neopterin as a marker for immune system activation. Curr. Drug Metab. 2002;3(2):175–187. doi: 10.2174/1389200024605082. [DOI] [PubMed] [Google Scholar]
  • 28.Suidan G, Brill A, De Meyer S, et al. Endothelial Von Willebrand factor promotes blood–brain barrier flexibility and provides protection from hypoxia and seizures in mice. Arterioscler. Thromb. Vasc. Biol. 2013;33(9):21102–2120. doi: 10.1161/atvbaha.113.301362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Deanfield J, Halcox J, Rabelink T. Endothelial function and dysfunction. Circulation. 2007;115(10):1285–1295. doi: 10.1161/circulationaha.106.652859. [DOI] [PubMed] [Google Scholar]
  • 30.Nachman R, Rafii S. Platelets, petechiae, and preservation of the vascular wall. N. Engl. J. Med. 2008;359(12):1261–1270. doi: 10.1056/nejmra0800887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Zhang J, Li M, Zhang H, et al. Association of serum vascular endothelial growth factor levels and cerebral microbleeds in patients with Alzheimer’s disease. Eur. J. Neurol. 2016;23(8):1337–1342. doi: 10.1111/ene.13030. [DOI] [PubMed] [Google Scholar]
  • 32.Dassan P, Brown M, Gregoire S, et al. Association of cerebral microbleeds in acute ischemic stroke with high serum levels of vascular endothelial growth factor. Arch. Neurol. 2012;69(9):1186–1189. doi: 10.1001/archneurol.2012.459. [DOI] [PubMed] [Google Scholar]
  • 33.Meyer PF, Tremblay-Mercier J, Leoutsakos J, et al. INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease. Neurology. 2019;92(18):2070–2080. doi: 10.1212/WNL.0000000000007232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Lucin K, Wyss-Coray T. Immune activation in brain aging and neurodegeneration: Too much or too little? Neuron. 2009;64(1):110–122. doi: 10.1016/j.neuron.2009.08.039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Wyss-Coray T, Mucke L. Inflammation in neurodegenerative disease – A double-edged sword. Neuron. 2002;35(3):419–432. doi: 10.1016/s0896-6273(02)00794-8. [DOI] [PubMed] [Google Scholar]
  • 36.Ransohoff R. How neuroinflammation contributes to neurodegeneration. Science. 2016;353(6301):777–783. doi: 10.1126/science.aag2590. [DOI] [PubMed] [Google Scholar]
  • 37.Maccioni R, Rojo L, Fernández J, Kuljis R. The role of neuroimmunomodulation in Alzheimer’s disease. Ann. N. Y. Acad. Sci. 2009;1153(1):240–246. doi: 10.1111/j.1749-6632.2008.03972.x. [DOI] [PubMed] [Google Scholar]
  • 38.Lull M, Block M. Microglial activation and chronic neurodegeneration. Neurotherapeutics. 2010;7(4):354–365. doi: 10.1016/j.nurt.2010.05.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Asai H, Ikezu S, Tsunoda S, et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 2015;18(11):1584–1593. doi: 10.1038/nn.4132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Morales I, Farías G, Maccioni R. Neuroimmunomodulation in the pathogenesis of Alzheimer’s disease. Neuroimmunomodulation. 2010;17(3):202–204. doi: 10.1159/000258724. [DOI] [PubMed] [Google Scholar]
  • 41.Cortés N, Andrade V, Guzmán-Martínez L, et al. Neuroimmune tau mechanisms: Their role in the progression of neuronal degeneration. Int. J. Mol. Sci. 2018;19(4):956. doi: 10.3390/ijms19040956. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Collins L, Toulouse A, Connor T, Nolan Y. Contributions of central and systemic inflammation to the pathophysiology of Parkinson’s disease. Neuropharmacology. 2012;62(7):2154–2168. doi: 10.1016/j.neuropharm.2012.01.028. [DOI] [PubMed] [Google Scholar]
  • 43.Bruunsgaard H, Pedersen M, Pedersen B. Aging and proin-flammatory cytokines. Curr. Opin. Hematol. 2001;8(3):131–136. doi: 10.1097/00062752-200105000-00001. [DOI] [PubMed] [Google Scholar]
  • 44.Fagiolo U, Cossarizza A, Santacaterina S, et al. Increased cytokine production by peripheral blood mononuclear cells from healthy elderly people. Ann. N. Y. Acad. Sci. 1992;663(1):490–493. doi: 10.1111/j.1749-6632.1992.tb38712.x. [DOI] [PubMed] [Google Scholar]
  • 45.Bernstein E, Kaye D, Abrutyn E, et al. Immune response to influenza vaccination in a large healthy elderly population. Vaccine. 1999;17(1):82–94. doi: 10.1016/s0264-410x(98)00117-0. [DOI] [PubMed] [Google Scholar]
  • 46.Fagiolo U, Cossarizza A, Scala E, et al. Increased cytokine production in mononuclear cells of healthy elderly people. Eur. J. Immunol. 1993;23(9):2375–2378. doi: 10.1002/eji.1830230950. [DOI] [PubMed] [Google Scholar]
  • 47.Johnson F, Dawson A, Meyer R. Activity-dependent refinement in the goldfish retinotectal system is mediated by the dynamic regulation of processes withdrawal: An in vivo imaging study. J. Comp. Neurol. 1999;406(4):548–562. doi: 10.1002/(sici)1096-9861(19990419)406:4<548::aidcne8>3.0.co;2-3. [DOI] [PubMed] [Google Scholar]
  • 48.Capuron L, Su S, Miller A, et al. Depressive symptoms and metabolic syndrome: Is inflammation the underlying link? Biol. Psychiatry. 2008;64(10):896–900. doi: 10.1016/j.biopsych.2008.05.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Gibbs C, Lip G. Do we still need dipyridamole? Br. J. Clin. Pharmacol. 1998;45(4):323–328. doi: 10.1046/j.1365-2125.1998.t01-1-00677.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Weyrich A, Denis M, Kuhlmann-Eyre J, et al. Dipyridamole selectively inhibits inflammatory gene expression in platelet-monocyte aggregates. Circulation. 2005;111(5):633–642. doi: 10.1161/01.cir.0000154607.90506.45. [DOI] [PubMed] [Google Scholar]
  • 51.Shi Y, Wardlaw J. Update on cerebral small vessel disease: a dynamic whole-brain disease. BMJ. 2016;1(3):83–92. doi: 10.1136/svn-2016-000035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Miller M. Phosphodiesterase inhibition in the treatment of autoimmune and inflammatory diseases: current status and potential. J. Receptor Ligand Channel Res. 2015;8:19–30. doi: 10.2147/JRLCR.S50401. [DOI] [Google Scholar]
  • 53.Hernández-Flórez D, Valor L. Inhibidores selectivos de fosfodiesterasas, una nueva opción terapéutica eninflamación y autoinmunidad. Reumatología Clínica. 2016;12(6):303–306. doi: 10.1016/j.reuma.2016.07.011. [DOI] [PubMed] [Google Scholar]
  • 54.Sloka S, Metz L, Hader W, et al. Reduction of microglial activity in a model of multiple sclerosis by dipyridamole. J. Neuroinflammation. 2013;10(1):89. doi: 10.1186/1742-2094-10-89. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Kim H, Liao J. Translational therapeutics of dipyridamole. Arterioscler. Thromb. Vasc. Biol. 2008;28(3):39–42. doi: 10.1161/atvbaha.107.160226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Chakrabarti S, Freedman J. Dipyridamole, cerebrovascular disease, and the vasculature. Vascul. Pharmacol. 2008;48(4–6):143–149. doi: 10.1016/j.vph.2007.12.004. [DOI] [PubMed] [Google Scholar]
  • 57.Guo S, Stins M, Ning M, Lo E. Amelioration of inflammation and cytotoxicity by dipyridamole in brain endothelial cells. Cerebrovasc. Dis. 2010;30(3):290–296. doi: 10.1159/000319072. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Balakumar P, Nyo Y, Renushia R, et al. Classical and pleiotropic actions of dipyridamole: Not enough light to illuminate the dark tunnel? Pharmacol. Res. 2014;87:144–150. doi: 10.1016/j.phrs.2014.05.008. [DOI] [PubMed] [Google Scholar]
  • 59.Ciacciarelli M, Zerbinati C, Violi F, Iuliano L. Dipyridamole: A drug with unrecognized antioxidant activity. Curr. Top. Med. Chem. 2015;15(9):822–829. doi: 10.2174/1568026615666150220111942. [DOI] [PubMed] [Google Scholar]
  • 60.Macatangay B, Jackson E, Abebe K, et al. A randomized, placebo-controlled, pilot clinical trial of dipyridamole to decrease human immunodeficiency virus-associated chronic inflammation. J. Infect. Dis. 2019;221(10):1598–1606. doi: 10.1093/infdis/jiz344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.X. Liu, Z. Li, S. Liu, and B., et al., “Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19,” Acta Pharmac. Sin., 10, No. 7, 1205–1215 (2020), 10.1016/j.apsb.2020.04.008. [DOI] [PMC free article] [PubMed]
  • 62.Aliter K, Al-Horani R. Potential therapeutic benefits of dipyridamole in COVID-19 patients. Curr. Pharm. Des. 2020;26:1. doi: 10.2174/1381612826666201001125604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Kurantil N 75 (CURANTYL): Instructions for Use, VIDAL, 2019. 01.22, https://www.vidal.ru/drugs/curantyl_n_75__35270, acc. Nov. 15, 2020.

Articles from Neuroscience and Behavioral Physiology are provided here courtesy of Nature Publishing Group

RESOURCES