Подходы к изучению каппа-опиоидных лигандов на моделях нейровоспаления

Разработка новых препаратов для коррекции нейровоспаления вызывает повышенный интерес, поскольку открывает возможности лечения широкого ряда заболеваний, включая болезнь Альцгеймера, болезнь Паркинсона, эпилепсию, шизофрению, депрессию и др. Каппа-опиоидные агонисты представляют собой перспективный класс соединений, обладающих высоким потенциалом применения при патологических состояниях, сопровождающихся развитием нейровоспаления.

Цель. Резюмировать информацию о текущих стратегиях, используемых для оценки нейротропных противовоспалительных эффектов каппа-опиоидных лигандов у лабораторных животных с индуцированным нейровоспалением.

Материалы и методы. В качестве средств поиска использовались поисковые системы и базы данных Google Scholar, PubMed, ScienceDirect, Scopus, e-Library. Поиск проводился по следующим ключевым словам и словосочетаниям: kappa opioids + neuroinflammation; kappa opioid receptors + neuroinflammation; neuroinflammation models; neuroinflammation models in rat; neuroinflammation models in mice, а также по их русскоязычным аналогам. Были найдены 148 релевантных статей, из которых 122 были включены в настоящий обзор.

Результаты. В настоящем обзоре были рассмотрены различные экспериментальные модели нейровоспаления, индуцированного химическими агентами и бактериальным эндотоксином, а также травматические и генетические модели на мышах и крысах. Кроме того, были критически оценены сильные стороны и ограничения каждой модели для определения наиболее подходящей стратегии исследования взаимосвязей между нейровоспалением и сигнальными путями каппа-опиоидной рецепторной системы.

Заключение. Рассмотрены особенности нейротропной противовоспалительной активности каппа-опиоидных лигандов. В обзоре обсуждаются как экспериментальные модели, в которых изучались эффекты агонистов каппа-опиоидных рецепторов, так и модели, в которых противовоспалительные свойства агонистов каппа-опиоидов еще не изучены.

1. Григорьев Е.В., Шукевич Д.Л., Плотников Г.П., Хуторная М.В., Цепокина А., Радивилко А.С. Нейровоспаление в критических состояниях: механизмы и протективная роль гипотермии // Фундаментальная и клиническая медицина. – 2016. – Т. 1, № 3. – С. 88–96.

2. Denny L., Al Abadey A., Robichon K., Templeton N., Prisinzano T.E., Kivell B.M., La Flamme A.C. Nalfurafine reduces neuroinflammation and drives remyelination in models of CNS demyelinating disease // Clinical & translational immunology. – 2021. – Vol. 10, No. 1. – Art. ID: e1234. DOI:10.1002/cti2.1234

3. Campos A.C.P., Antunes G.F., Matsumoto M., Pagano R.L., Martinez R.C.R. Neuroinflammation, pain and depression: an overview of the main findings // Frontiers in Psychology. – 2020. – Vol. 11. – Art. ID: 1825. DOI:10.3389/fpsyg.2020.01825

4. Zindler E., Zipp F. Neuronal injury in chronic CNS inflammation // Best. Pract. Res. Clin. Anaesthesiol. – 2010. – Vol. 24, No.4. – P. 551–562. DOI:10.1016/j.bpa.2010.11.001

5. Boche D., Perry V.H., Nicoll J.A. Review: activation patterns of microglia and their identification in the human brain // Neuropathol. Appl. Neurobiol. – 2013. – Vol. 39, No. 1. – P. 3–18. DOI:10.1111/nan.12011

6. Ahn J.J., Abu-Rub M., Miller R.H. B Cells in Neuroinflammation: New Perspectives and Mechanistic Insights // Cells. – 2021. – Vol. 10, No. 7. –Art. ID: 1605. DOI:10.3390/cells10071605

7. Lenz K.M., Nelson L.H. Microglia and Beyond: Innate Immune Cells As Regulators of Brain Development and Behavioral Function // Front Immunol. – 2018. – Vol. 9. – Art. ID: 698. DOI:10.3389/fimmu.2018.00698

8. DiSabato D.J., Quan N., Godbout J.P. Neuroinflammation: the devil is in the details // J. Neurochem. – 2016. – Vol. 139, Suppl. 2. – P. 136–153. DOI:10.1111/jnc.13607

9. Wang W.Y., Tan M.S., Yu J.T., Tan L. Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease // Ann. Transl. Med. – 2015. – Vol. 3, No. 10. – Art. ID: 136. DOI:10.3978/j.issn.2305-5839.2015.03.49

10. Wang Q., Liu Y., Zhou J. Neuroinflammation in Parkinson’s disease and its potential as therapeutic target // Transl. Neurodegener. – 2015. – Vol. 4. – Art. ID: 19. DOI:10.1186/s40035-015-0042-0

11. Levey D.F., Stein M.B., Wendt F.R., Pathak G.A., Zhou H., Aslan M., Quaden R., Harrington K.M., Nuñez Y.Z., Overstreet C., Radhakrishnan K., Sanacora G., McIntosh A.M., Shi J., Shringarpure S.S.; 23andMe Research Team; Million Veteran Program; Concato J., Polimanti R., Gelernter J. Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions // Nat. Neurosci. – 2021. – Vol. 24, No. 7. – P. 954–963. DOI:10.1038/s41593-021-00860-2

12. Wittenberg G.M., Greene J., Vértes P.E., Drevets W.C., Bullmore E.T. Major Depressive Disorder Is Associated With Differential Expression of Innate Immune and Neutrophil-Related Gene Networks in Peripheral Blood: A Quantitative Review of Whole-Genome Transcriptional Data From Case-Control Studies // Biol. Psychiatry. – 2020. – Vol. 88, No. 8. – P. 625–637. DOI:10.1016/j.biopsych.2020.05.006

13. Hodes G.E., Pfau M.L., Leboeuf M., Golden S.A., Christoffel D.J., Bregman D., Rebusi N., Heshmati M., Aleyasin H., Warren B.L., Lebonté B., Horn S., Lapidus K.A., Stelzhammer V., Wong E.H., Bahn S., Krishnan V., Bolaños-Guzman C.A., Murrough J.W., Merad M., Russo S.J. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress // Proc. Natl. Acad. Sci. U S A. – 2014. – Vol. 111, No. 45. – P. 16136–16141. DOI:10.1073/pnas.1415191111

14. Troubat R., Barone P., Leman S., Desmidt T., Cressant A., Atanasova B., Brizard B., El Hage W., Surget A., Belzung C., Camus V. Neuroinflammation and depression: A review // Eur. J. Neurosci. – 2021. – Vol. 53, No. 1. – P. 151–171. DOI:10.1111/ejn.14720

15. Lotrich F.E. Major depression during interferon-alpha treatment: vulnerability and prevention // Dialogues Clin. Neurosci. – 2009. – Vol. 11, No. 4. – P. 417–425. DOI:10.31887/DCNS.2009.11.4/felotrich

16. Khansari P.S., Sperlagh B. Inflammation in neurological and psychiatric diseases // Inflammopharmacology. – 2012. – Vol. 20, No. 3. – P. 103–107. DOI:10.1007/s10787-012-0124-x

17. Liu L., Xu Y., Dai H., Tan S., Mao X., Chen Z. Dynorphin activation of kappa opioid receptor promotes microglial polarization toward M2 phenotype via TLR4/NF-κB pathway // Cell Biosci. – 2020. – Vol. 10. – Art. ID: 42. DOI:10.1186/s13578-020-00387-2

18. Kip E., Parr-Brownlie L.C. Reducing neuroinflammation via therapeutic compounds and lifestyle to prevent or delay progression of Parkinson’s disease // Ageing Res. Rev. – 2022. – Vol. 78. – Art. ID: 101618. DOI:10.1016/j.arr.2022.101618

19. Tangherlini G., Kalinin D.V., Schepmann D., Che T., Mykicki N., Ständer S., Loser K., Wünsch B. Development of Novel Quinoxaline-Based κ-Opioid Receptor Agonists for the Treatment of Neuroinflammation // J. Med. Chem. – 2019. – Vol. 62, No. 2. – P. 893–907. DOI:10.1021/acs.jmedchem.8b01609

20. Peng J., Sarkar S., Chang S.L. Opioid receptor expression in human brain and peripheral tissues using absolute quantitative real-time RT-PCR // Drug Alcohol. Depend. – 2012. – Vol. 124, No. 3. – P. 223–228. DOI:10.1016/j.drugalcdep.2012.01.013

21. Stein C., Schäfer M., Machelska H. Attacking pain at its source: new perspectives on opioids // Nat. Med. – 2003. – Vol. 9, No. 8. – P. 1003–1008. DOI:10.1038/nm908

22. Kalitin K.Y., Grechko O.U., Spasov A.A., Anisimova V.A. Anticonvulsant Effect of Novel Benzimidazole Derivative (RU-1205) in Chronic Intermittent Ethanol Vapor Exposure Model in Mice // Eksp. Klin. Farmakol. – 2015. – Vol. 78, No. 4. – P. 3–5.

23. Paton K.F., Atigari D.V., Kaska S., Prisinzano T., Kivell B.M. Strategies for Developing κ Opioid Receptor Agonists for the Treatment of Pain with Fewer Side Effects // J. Pharmacol. Exp. Ther. – 2020. – Vol. 375, No. 2. – P. 332–348. DOI:10.1124/jpet.120.000134

24. Hauser K.F., Aldrich J.V., Anderson K.J., Bakalkin G., Christie M.J., Hall E.D., Knapp P.E., Scheff S.W., Singh I.N., Vissel B., Woods A.S., Yakovleva T., Shippenberg T.S. Pathobiology of dynorphins in trauma and disease // Front. Biosci. – 2005. – Vol. 10. – P. 216–235. DOI:10.2741/1522

25. Rogers T.J. Kappa Opioid Receptor Expression and Function in Cells of the Immune System // Handb. Exp. Pharmacol. – 2022. – Vol. 271. – P. 419–433. DOI:10.1007/164_2021_441

26. Schank J.R., Goldstein A.L., Rowe K.E., King C.E., Marusich J.A., Wiley J.L., Carroll F.I., Thorsell A., Heilig M. The kappa opioid receptor antagonist JDTic attenuates alcohol seeking and withdrawal anxiety // Addict. Biol. – 2012. – Vol. 17, No. 3. – P. 634–647. DOI:10.1111/j.1369-1600.2012.00455.x

27. Al-Hasani R., Bruchas M.R. Molecular mechanisms of opioid receptor-dependent signaling and behavior // Anesthesiology. – 2011. – Vol. 115, No. 6. – P. 1363–1381. DOI:10.1097/ALN.0b013e318238bba6

28. Bruchas M.R., Chavkin C. Kinase cascades and ligand-directed signaling at the kappa opioid receptor // Psychopharmacology (Berl). – 2010. – Vol. 210, No. 2. – P. 137–147. DOI:10.1007/s00213-010-1806-y

29. Machelska H., Stein C. Leukocyte-derived opioid peptides and inhibition of pain // J. Neuroimmune Pharmacol. – 2006. – Vol. 1, No. 1. – P. 90–97. DOI:10.1007/s11481-005-9002-2

30. Borniger J.C., Hesp Z.C. Enhancing Remyelination through a Novel Opioid-Receptor Pathway // J. Neurosci. – 2016. – Vol. 36, No. 47. – P. 11831–11833. DOI:10.1523/JNEUROSCI.2859-16.2016

31. Macdonald R.L., Werz M.A. Dynorphin A decreases voltage-dependent calcium conductance of mouse dorsal root ganglion neurons // J. Physiol. – 1986. – Vol. 377. – P. 237–249. DOI:10.1113/jphysiol.1986.sp016184

32. Rusin K.I., Giovannucci D.R., Stuenkel E.L., Moises H.C. Kappa-opioid receptor activation modulates Ca2+ currents and secretion in isolated neuroendocrine nerve terminals // J. Neurosci. – 1997. – Vol. 17, No. 17. – P. 6565–6574. DOI:10.1523/JNEUROSCI.17-17-06565.1997

33. Gannon R.L., Terrian D.M. Kappa opioid agonists inhibit transmitter release from guinea pig hippocampal mossy fiber synaptosomes // Neurochem. Res. – 1992. – Vol. 17, No. 8. – P. 741–747. DOI:10.1007/BF00969007

34. Hauser K.F., Aldrich J.V., Anderson K.J., Bakalkin G., Christie M.J., Hall E.D., Knapp P.E., Scheff S.W., Singh I.N., Vissel B., Woods A.S., Yakovleva T., Shippenberg T.S. Pathobiology of dynorphins in trauma and disease // Front. Biosci. – 2005. – Vol. 10. – P. 216–235. DOI:10.2741/1522

35. Li R., Zhou Y., Zhang S., Li J., Zheng Y., Fan X. The natural (poly)phenols as modulators of microglia polarization via TLR4/NF-κB pathway exert anti-inflammatory activity in ischemic stroke // Eur. J. Pharmacol. – 2022. – Vol. 914. – Art. ID: 174660. DOI:10.1016/j.ejphar.2021.174660

36. Missig G., Fritsch E.L., Mehta N., Damon M.E., Jarrell E.M., Bartlett A.A., Carroll F.I., Carlezon W.A. Jr. Blockade of kappa-opioid receptors amplifies microglia-mediated inflammatory responses // Pharmacol. Biochem. Behav. – 2022. – Vol. 212. – Art. ID: 173301. DOI:10.1016/j.pbb.2021.173301

37. Parkhill A.L., Bidlack J.M. Reduction of lipopolysaccharide-induced interleukin-6 production by the kappa opioid U50,488 in a mouse monocyte-like cell line // Int. Immunopharmacol. – 2006. – Vol. 6, No. 6. – P. 1013-1019. DOI:10.1016/j.intimp.2006.01.012

38. Tan Y.L., Yuan Y., Tian L. Microglial regional heterogeneity and its role in the brain // Mol. Psychiatry. – 2020. – Vol. 25, No. 2. – P. 351–367. DOI:10.1038/s41380-019-0609-8

39. Saunders A., Macosko E.Z., Wysoker A., Goldman M., Krienen F.M., de Rivera H., Bien E., Baum M., Bortolin L., Wang S., Goeva A., Nemesh J., Kamitaki N., Brumbaugh S., Kulp D., McCarroll S.A. Molecular Diversity and Specializations among the Cells of the Adult Mouse Brain // Cell. – 2018. – Vol. 174, No. 4. – P. 1015–1030.e16. DOI:10.1016/j.cell.2018.07.028

40. Carlezon W.A. Jr., Kim W., Missig G., Finger B.C., Landino S.M., Alexander A.J., Mokler E.L., Robbins J.O., Li Y., Bolshakov V.Y., McDougle C.J., Kim K.S. Maternal and early postnatal immune activation produce sex-specific effects on autism-like behaviors and neuroimmune function in mice // Sci. Rep. – 2019. – Vol. 9, No. 1. – Art. ID: 16928. DOI:10.1038/s41598-019-53294-z

41. Conway S.M., Puttick D., Russell S., Potter D., Roitman M.F., Chartoff E.H. Females are less sensitive than males to the motivational- and dopamine-suppressing effects of kappa opioid receptor activation // Neuropharmacology. – 2019. – Vol. 146. – P. 231–241. DOI:10.1016/j.neuropharm.2018.12.002

42. Bardou I., Kaercher R.M., Brothers H.M., Hopp S.C., Royer S., Wenk G.L. Age and duration of inflammatory environment differentially affect the neuroimmune response and catecholaminergic neurons in the midbrain and brainstem // Neurobiol. Aging. – 2014. – Vol. 35, No. 5. – P. 1065–1073. DOI:10.1016/j.neurobiolaging.2013.11.006

43. Kotanidou A., Xagorari A., Bagli E., Kitsanta P., Fotsis T., Papapetropoulos A., Roussos C. Luteolin reduces lipopolysaccharide-induced lethal toxicity and expression of proinflammatory molecules in mice // Am. J. Respir. Crit. Care Med. – 2002. – Vol. 165, No. 6. – P. 818–823. DOI:10.1164/ajrccm.165.6.2101049

44. Aviello G., Borrelli F., Guida F., Romano B., Lewellyn K., De Chiaro M., Luongo L., Zjawiony J.K., Maione S., Izzo A.A., Capasso R. Ultrapotent effects of salvinorin A, a hallucinogenic compound from Salvia divinorum, on LPS-stimulated murine macrophages and its anti-inflammatory action in vivo // J. Mol. Med. (Berl). – 2011. – Vol. 89, No. 9. – P. 891–902. DOI:10.1007/s00109-011-0752-4

45. Cario E., Podolsky D.K. Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease // Infect. Immun. – 2000. – Vol. 68, No. 12. – P. 7010–7017. DOI:10.1128/IAI.68.12.7010-7017.2000

46. Krstic D., Knuesel I. Deciphering the mechanism underlying late-onset Alzheimer disease // Nat. Rev. Neurol. – 2013. – Vol. 9, No. 1. – P. 25–34. DOI:10.1038/nrneurol.2012.236

47. Krstic D., Madhusudan A., Doehner J., Vogel P., Notter T., Imhof C., Manalastas A., Hilfiker M., Pfister S., Schwerdel C., Riether C., Meyer U., Knuesel I. Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice // J. Neuroinflammation. – 2012. – Vol. 9. – Art. ID: 151. DOI:10.1186/1742-2094-9-151

48. Town T., Jeng D., Alexopoulou L., Tan J., Flavell R.A. Microglia recognize double-stranded RNA via TLR3 // J. Immunol. – 2006. – Vol. 176, No. 6. – P. 3804–3812. DOI:10.4049/jimmunol.176.6.3804

49. De Miranda J., Yaddanapudi K., Hornig M., Villar G., Serge R., Lipkin WI. Induction of Toll-like receptor 3-mediated immunity during gestation inhibits cortical neurogenesis and causes behavioral disturbances // mBio. – 2010. – Vol. 1, No. 4. – Art. ID: e00176–10. DOI:10.1128/mBio.00176-10

50. Giridharan V.V., Scaini G., Colpo G.D., Doifode T., Pinjari O.F., Teixeira A.L., Petronilho F., Macêdo D., Quevedo J., Barichello T. Clozapine Prevents Poly (I:C) Induced Inflammation by Modulating NLRP3 Pathway in Microglial Cells // Cells. – 2020. – Vol. 9, No. 3. – Art. ID: 577. DOI:10.3390/cells9030577

51. de Oliveira A.C., Yousif N.M., Bhatia H.S., Hermanek J., Huell M., Fiebich B.L. Poly (I:C) increases the expression of mPGES-1 and COX-2 in rat primary microglia // J. Neuroinflammation. – 2016. – Vol. 13. – Art. ID: 11. DOI:10.1186/s12974-015-0473-7

52. Steer S.A., Moran J.M., Christmann B.S., Maggi L.B. Jr., Corbett J.A. Role of MAPK in the regulation of double-stranded RNA- and encephalomyocarditis virus-induced cyclooxygenase-2 expression by macrophages // J. Immunol. – 2006. – Vol. 177, No. 5. – P. 3413–3420. DOI:10.4049/jimmunol.177.5.3413

53. Kato H., Takeuchi O., Sato S., Yoneyama M., Yamamoto M., Matsui K., Uematsu S., Jung A., Kawai T., Ishii K.J., Yamaguchi O., Otsu K., Tsujimura T., Koh C.S., Reis e Sousa C., Matsuura Y., Fujita T., Akira S. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses // Nature. – 2006. – Vol. 441, No. 7089. – P. 101–105. DOI:10.1038/nature04734

54. Rajan J.V., Warren S.E., Miao E.A., Aderem A. Activation of the NLRP3 inflammasome by intracellular poly I:C // FEBS Lett. – 2010. – Vol. 584, No. 22. – P. 4627–4632. DOI:10.1016/j.febslet.2010.10.036

55. Ren H., Han R., Chen X., Liu X., Wan J., Wang L., Yang X., Wang J. Potential therapeutic targets for intracerebral hemorrhage-associated inflammation: An update // J. Cereb. Blood Flow Metab. – 2020. – Vol. 40, No. 9. – P. 1752–1768. DOI:10.1177/0271678X20923551

56. Moore T.C., Petro T.M. IRF3 and ERK MAP-kinases control nitric oxide production from macrophages in response to poly-I:C // FEBS Lett. – 2013. – Vol. 587, No. 18. – P. 3014–3020. DOI:10.1016/j.febslet.2013.07.025

57. Miller S.D., Karpus W.J., Davidson T.S. Experimental autoimmune encephalomyelitis in the mouse // Current protocols in immunology. – 2010 Feb. – Vol. 88, No. 1. – P. 1–20. DOI:10.1002/0471142735.im1501s88

58. Shahi S.K., Freedman S.N., Dahl R.A., Karandikar N.J., Mangalam A.K. Scoring disease in an animal model of multiple sclerosis using a novel infrared-based automated activity-monitoring system // Sci. Rep. – 2019. – Vol. 9, No. 1. – Art. ID: 19194. DOI:10.1111/j.1476-5381.2011.01302.x

59. 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. – Vol. 164, No. 4. – P. 1079–1106. DOI:10.1111/j.1476-5381.2011.01302.x

60. Like A.A., Rossini A.A. Streptozotocin-induced pancreatic insulitis: new model of diabetes mellitus // Science. – 1976. – Vol. 193, No. 4251. – P. 415–417. DOI:10.1126/science.180605

61. Lenzen S. The mechanisms of alloxan-and streptozotocin-induced diabetes // Diabetologia. – 2008. – Vol. 51, No. 2. – P. 216–226. DOI:10.1007/s00125-007-0886-7

62. Wang J.Q., Yin J., Song Y.F., Zhang L., Ren Y.X., Wang D.G., Gao L.P., Jing Y.H. Brain aging and AD-like pathology in streptozotocin-induced diabetic rats // J. Diabetes Res. – 2014. – Vol. 2014. – Art. ID: 796840. DOI:10.1155/2014/796840

63. Turk J., Corbett J.A., Ramanadham S., Bohrer A., McDaniel M.L. Biochemical evidence for nitric oxide formation from streptozotocin in isolated pancreatic islets // Biochem. Biophys. Res. Commun. – 1993. – Vol. 197, No. 3. – P. 1458–1464. DOI:10.1006/bbrc.1993.2641

64. Takasu N., Komiya I., Asawa T., Nagasawa Y., Yamada T. Streptozocin- and alloxan-induced H2O2 generation and DNA fragmentation in pancreatic islets. H2O2 as mediator for DNA fragmentation // Diabetes. – 1991. – Vol. 40, No. 9. – P. 1141–1145. DOI:10.2337/diab.40.9.1141

65. Nazem A., Sankowski R., Bacher M., Al-Abed Y. Rodent models of neuroinflammation for Alzheimer’s disease // J. Neuroinflammation. – 2015. – Vol. 12. – Art. ID: 74. DOI:10.1186/s12974-015-0291-y

66. Chen Y., Liang Z., Blanchard J., Dai C.L., Sun S., Lee M.H., Grundke-Iqbal I., Iqbal K., Liu F., Gong C.X. A non-transgenic mouse model (icv-STZ mouse) of Alzheimer’s disease: similarities to and differences from the transgenic model (3xTg-AD mouse) // Molecular neurobiology. – 2013. – Vol. 47. – P. 711–725. DOI:10.1007/s12035-012-8375-5

67. Liu P., Zou L.B., Wang L.H., Jiao Q., Chi T.Y., Ji X.F., Jin G. Xanthoceraside attenuates tau hyperphosphorylation and cognitive deficits in intracerebroventricular-streptozotocin injected rats // Psychopharmacology. – 2014. – Vol. 231. – P. 345–356. DOI:10.1007/s00213-013-3240-4

68. Grieb P. Intracerebroventricular streptozotocin injections as a model of Alzheimer’s disease: in search of a relevant mechanism // Mol. Neurobiol. – 2016. – Vol. 53. – P. 1741–1752. DOI:10.1007/s12035-015-9132-3

69. Dai H., Wang P., Mao H., Mao X., Tan S., Chen Z. Dynorphin activation of kappa opioid receptor protects against epilepsy and seizure-induced brain injury via PI3K/Akt/Nrf2/HO-1 pathway // Cell Cycle. – 2019. – Vol. 18, No. 2. – P. 226–237. DOI:10.1080/15384101.2018.1562286

70. McNay E.C., Pearson-Leary J. GluT4: A central player in hippocampal memory and brain insulin resistance // Exp. Neurol. – 2020. – Vol. 323. – Art. ID: 113076. DOI:10.1016/j.expneurol.2019.113076

71. Shang Y., Guo F., Li J., Fan R., Ma X., Wang Y., Feng N., Yin Y., Jia M., Zhang S., Zhou J., Wang H., Pei J. Activation of κ-opioid receptor exerts the glucose-homeostatic effect in streptozotocin-induced diabetic mice // J. Cell Biochem. – 2015. – Vol. 116, No. 2. – P. 252–259. DOI:10.1002/jcb.24962

72. Kong C., Miao F., Wu Y., Wang T. Oxycodone suppresses the apoptosis of hippocampal neurons induced by oxygen-glucose deprivation/recovery through caspase-dependent and caspase-independent pathways via κ- and δ-opioid receptors in rats // Brain Res. – 2019. – Vol. 1721. – Art. ID: 146319. DOI:10.1016/j.brainres.2019.146319

73. Schattauer S.S., Bedini A., Summers F., Reilly-Treat A., Andrews M.M., Land B.B., Chavkin C. Reactive oxygen species (ROS) generation is stimulated by κ opioid receptor activation through phosphorylated c-Jun N-terminal kinase and inhibited by p38 mitogen-activated protein kinase (MAPK) activation // J. Biol. Chem. – 2019. – Vol. 294, No. 45. – P. 16884–16896. DOI:10.1074/jbc.RA119.009592

74. Tapia R., Peña F., Arias C. Neurotoxic and synaptic effects of okadaic acid, an inhibitor of protein phosphatases // Neurochem. Res. – 1999. – Vol. 24, No. 11. – P. 1423–1430. DOI:10.1023/a:1022588808260

75. Sontag J.M., Sontag E. Protein phosphatase 2A dysfunction in Alzheimer’s disease // Front. Mol. Neurosci. – 2014. – Vol. 7. – Art. ID: 16. DOI:10.3389/fnmol.2014.00016

76. Arendt T., Holzer M., Fruth R., Brückner M.K., Gärtner U. Phosphorylation of tau, Abeta-formation, and apoptosis after in vivo inhibition of PP-1 and PP-2A // Neurobiol. Aging. – 1998. – Vol. 19, No. 1. – P. 3–13. DOI:10.1016/s0197-4580(98)00003-7

77. Lee J., Hong H., Im J., Byun H., Kim D. The formation of PHF-1 and SMI-31 positive dystrophic neurites in rat hippocampus following acute injection of okadaic acid // Neurosci. Lett. – 2000. – Vol. 282, No. 1-2. – P. 49–52. DOI:10.1016/s0304-3940(00)00863-6

78. Kamat P.K., Rai S., Nath C. Okadaic acid induced neurotoxicity: an emerging tool to study Alzheimer’s disease pathology // Neurotoxicology. – 2013. – Vol. 37. – P. 163–172. DOI:10.1016/j.neuro.2013.05.002

79. Costa A.P., Tramontina A.C., Biasibetti R., Batassini C., Lopes M.W., Wartchow K.M., Bernardi C., Tortorelli L.S., Leal R.B., Gonçalves C.A. Neuroglial alterations in rats submitted to the okadaic acid-induced model of dementia. // Behav. Brain Res. – 2012. – Vol. 226, No. 2. – P. 420–427. DOI:10.1016/j.bbr.2011.09.035

80. Kamat P.K., Tota S., Saxena G., Shukla R., Nath C. Okadaic acid (ICV) induced memory impairment in rats: a suitable experimental model to test anti-dementia activity // Brain Res. – 2010. – Vol. 1309. – P. 66–74. DOI:10.1016/j.brainres.2009.10.064

81. Kamat P.K., Rai S., Swarnkar S., Shukla R., Ali S., Najmi A.K., Nath C. Okadaic acid-induced Tau phosphorylation in rat brain: role of NMDA receptor // Neuroscience. – 2013. – Vol. 238. – P. 97–113. DOI:10.1016/j.neuroscience.2013.01.075

82. Kumar A., Seghal N., Naidu P.S., Padi S.S., Goyal R. Colchicines-induced neurotoxicity as an animal model of sporadic dementia of Alzheimer’s type // Pharmacol. Rep. – 2007. – Vol. 59, No. 3. – P. 274–283.

83. Ding G., Li D., Sun Y., Chen K., Song D. Healthcare Engineering JO. Retracted: κ-Opioid Receptor Agonist Ameliorates Postoperative Neurocognitive Disorder by Activating the Ca2+/CaMKII/CREB Pathway // J. Healthc. Eng. – 2022. – Vol. 2022. – Art. ID: 9841213. DOI:10.1155/2022/9841213

84. Tilson H.A., Rogers B.C., Grimes L., Harry G.J., Peterson N.J., Hong J.S., Dyer R.S. Time-dependent neurobiological effects of colchicine administered directly into the hippocampus of rats // Brain Res. – 1987. – Vol. 408, No. 1–2. – P. 163–172. DOI:10.1016/0006-8993(87)90368-4

85. Sil S., Ghosh T. Role of cox-2 mediated neuroinflammation on the neurodegeneration and cognitive impairments in colchicine induced rat model of Alzheimer’s Disease // J. Neuroimmunol. – 2016. – Vol. 291. – P. 115–124. DOI:10.1016/j.jneuroim.2015.12.003

86. Zeng S., Zhong Y., Xiao J., Ji J., Xi J., Wei X., Liu R. Kappa Opioid Receptor on Pulmonary Macrophages and Immune Function // Transl. Perioper. Pain Med. – 2020. – Vol. 7, No. 3. – P. 225-233. DOI:10.31480/2330-4871/117

87. Alboni S., Cervia D., Sugama S., Conti B. Interleukin 18 in the CNS // J. Neuroinflammation. – 2010. – Vol. 7. – Art. ID: 9. DOI:10.1186/1742-2094-7-9

88. Shaftel S.S., Kyrkanides S., Olschowka J.A., Miller J.N., Johnson R.E., O’Banion M.K. Sustained hippocampal IL-1 beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology // J. Clin. Invest. – 2007. – Vol. 117, No. 6. – P. 1595–1604. DOI:10.1172/JCI31450

89. Matousek S.B., Ghosh S., Shaftel S.S., Kyrkanides S., Olschowka J.A., O’Banion M.K. Chronic IL-1β-mediated neuroinflammation mitigates amyloid pathology in a mouse model of Alzheimer’s disease without inducing overt neurodegeneration // J. Neuroimmune Pharmacol. – 2012. – Vol. 7, No. 1. – P. 156–164. DOI:10.1007/s11481-011-9331-2

90. Moore A.H., Wu M., Shaftel S.S., Graham K.A., O’Banion M.K. Sustained expression of interleukin-1beta in mouse hippocampus impairs spatial memory // Neuroscience. – 2009. – Vol. 164, No. 4. – P. 1484–1495. DOI:10.1016/j.neuroscience.2009.08.073

91. Giridharan V.V., Scaini G., Colpo G.D., Doifode T., Pinjari O.F., Teixeira A.L., Petronilho F., Macêdo D., Quevedo J., Barichello T. Clozapine Prevents Poly (I:C) Induced Inflammation by Modulating NLRP3 Pathway in Microglial Cells // Cells. – 2020. – Vol. 9, No. 3. – Art. ID: 577. DOI:10.3390/cells9030577

92. Morgan D.O. Cyclin-dependent kinases: engines, clocks, and microprocessors // Annu. Rev. Cell Dev. Biol. – 1997. – Vol. 13. – P. 261–291. DOI:10.1146/annurev.cellbio.13.1.261

93. Kamei H., Saito T., Ozawa M., Fujita Y., Asada A., Bibb J.A., Saido T.C., Sorimachi H., Hisanaga S. Suppression of calpain-dependent cleavage of the CDK5 activator p35 to p25 by site-specific phosphorylation // J. Biol. Chem. – 2007. – Vol. 282, No. 3. – P. 1687–1694. DOI:10.1074/jbc.M610541200

94. Patrick G.N., Zukerberg L., Nikolic M., de la Monte S., Dikkes P., Tsai L.H. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration // Nature. – 1999. – Vol. 402, No. 6762. – P. 615–622. DOI:10.1038/45159

95. Lee M.S., Kwon Y.T., Li M., Peng J., Friedlander R.M., Tsai L.H. Neurotoxicity induces cleavage of p35 to p25 by calpain // Nature. – 2000. – Vol. 405, No. 6784. – P. 360–364. DOI:10.1038/35012636

96. Ahlijanian M.K., Barrezueta N.X., Williams R.D., Jakowski A., Kowsz K.P., McCarthy S., Coskran T., Carlo A., Seymour P.A., Burkhardt J.E., Nelson R.B., McNeish J.D. Hyperphosphorylated tau and neurofilament and cytoskeletal disruptions in mice overexpressing human p25, an activator of cdk5 // Proc. Natl. Acad. Sci. USA. – 2000. – Vol. 97, No. 6. – P. 2910–2915. DOI:10.1073/pnas.040577797

97. Sundaram J.R., Chan E.S., Poore C.P., Pareek T.K., Cheong W.F., Shui G., Tang N., Low C.M., Wenk M.R., Kesavapany S. Cdk5/p25-induced cytosolic PLA2-mediated lysophosphatidylcholine production regulates neuroinflammation and triggers neurodegeneration // J. Neurosci. – 2012. – Vol. 32, No. 3. – P. 1020–1034. DOI:10.1523/JNEUROSCI.5177-11.2012

98. Fischer A., Sananbenesi F., Pang P.T., Lu B., Tsai L.H. Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory // Neuron. – 2005. – Vol. 48, No. 5. – P. 825–838. DOI:10.1016/j.neuron.2005.10.033

99. Muyllaert D., Terwel D., Kremer A., Sennvik K., Borghgraef P., Devijver H., Dewachter I., Van Leuven F. Neurodegeneration and neuroinflammation in cdk5/p25-inducible mice: a model for hippocampal sclerosis and neocortical degeneration // Am. J. Pathol. – 2008. – Vol. 172, No. 2. – P. 470–485. DOI:10.2353/ajpath.2008.070693

100. De Rosa R., Garcia A.A., Braschi C., Capsoni S., Maffei L., Berardi N., Cattaneo A. Intranasal administration of nerve growth factor (NGF) rescues recognition memory deficits in AD11 anti-NGF transgenic mice // Proc. Natl. Acad. Sci. USA. – 2005. – Vol. 102, No. 10. – P. 3811–3816. DOI:10.1073/pnas.0500195102

101. Capsoni S., Giannotta S., Cattaneo A. Beta-amyloid plaques in a model for sporadic Alzheimer’s disease based on transgenic anti-nerve growth factor antibodies // Mol. Cell Neurosci. – 2002. – Vol. 21, No. 1. – P. 15–28. DOI:10.1006/mcne.2002.1163

102. D’Onofrio M., Arisi I., Brandi R., Di Mambro A., Felsani A., Capsoni S., Cattaneo A. Early inflammation and immune response mRNAs in the brain of AD11 anti-NGF mice // Neurobiol. Aging. – 2011. – Vol. 32, No. 6. – P. 1007–1022. DOI:10.1016/j.neurobiolaging.2009.05.023

103. Zhang P., Yang M., Chen C., Liu L., Wei X., Zeng S. Toll-Like Receptor 4 (TLR4)/Opioid Receptor Pathway Crosstalk and Impact on Opioid Analgesia, Immune Function, and Gastrointestinal Motility // Front. Immunol. – 2020. – Vol. 11. – Art. ID: 1455. DOI:10.3389/fimmu.2020.01455

104. Flanders K.C., Ren R.F., Lippa C.F. Transforming growth factor-betas in neurodegenerative disease // Prog. Neurobiol. – 1998. – Vol. 54, No. 1. – P. 71–85. DOI:10.1016/s0301-0082(97)00066-x

105. Unsicker K., Krieglstein K. TGF-betas and their roles in the regulation of neuron survival // Adv. Exp. Med. Biol. – 2002. – Vol. 513. – P. 353–374. DOI:10.1007/978-1-4615-0123-7_13

106. Wyss-Coray T., Lin C., Yan F., Yu G.Q., Rohde M., McConlogue L., Masliah E., Mucke L. TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice // Nat. Med. – 2001. – Vol. 7, No. 5. – P. 612–618. DOI:10.1038/87945

107. Buckwalter M.S., Wyss-Coray T. Modelling neuroinflammatory phenotypes in vivo // J. Neuroinflammation. – 2004. – Vol. 1, No. 1. – Art. ID: 10. DOI:10.1186/1742-2094-1-10

108. Grammas P., Ovase R. Cerebrovascular transforming growth factor-beta contributes to inflammation in the Alzheimer’s disease brain // Am. J. Pathol. – 2002. – Vol. 160, No. 5. – P. 1583–1587. DOI:10.1016/s0002-9440(10)61105-4

109. Ueberham U., Ueberham E., Brückner M.K., Seeger G., Gärtner U., Gruschka H., Gebhardt R., Arendt T. Inducible neuronal expression of transgenic TGF-beta1 in vivo: dissection of short-term and long-term effects // Eur. J. Neurosci. – 2005. – Vol. 22, No. 1. – P. 50–64. DOI:10.1111/j.1460-9568.2005.04189.x

110. Kovacs Z.I., Kim S., Jikaria N., Qureshi F., Milo B., Lewis B.K., Bresler M., Burks S.R., Frank J.A. Disrupting the blood-brain barrier by focused ultrasound induces sterile inflammation // Proc. Natl. Acad. Sci. U S A. – 2017. – Vol. 114, No. 1. – P. 75–84. DOI:10.1073/pnas.1614777114

111. Kaplan A., Li M.J., Malani R. Treatments on the Horizon: Breast Cancer Patients with Central Nervous System Metastases // Curr. Oncol. Rep. – 2022. – Vol. 24, No. 3. – P. 343–350. DOI:10.1007/s11912-022-01206-2

112. Aryal M., Arvanitis C.D., Alexander P.M., McDannold N. Ultrasound-mediated blood-brain barrier disruption for targeted drug delivery in the central nervous system // Adv. Drug. Deliv. Rev. – 2014. – Vol. 72. – P. 94–109. DOI:10.1016/j.addr.2014.01.008

113. Lozano D., Gonzales-Portillo G.S., Acosta S., de la Pena I., Tajiri N., Kaneko Y., Borlongan C.V. Neuroinflammatory responses to traumatic brain injury: etiology, clinical consequences, and therapeutic opportunities // Neuropsychiatr. Dis. Treat. – 2015. – Vol. 11. – P. 97–106. DOI:10.2147/NDT.S65815

114. Woodcock T., Morganti-Kossmann M.C. The role of markers of inflammation in traumatic brain injury // Front. Neurol. – 2013. – Vol. 4. – Art. ID: 18. DOI:10.3389/fneur.2013.00018

115. Tweedie D., Rachmany L., Kim D.S., Rubovitch V., Lehrmann E., Zhang Y., Becker K.G., Perez E., Pick C.G., Greig N.H. Mild traumatic brain injury-induced hippocampal gene expressions: The identification of target cellular processes for drug development // J. Neurosci. Methods. – 2016. – Vol. 272. – P. 4–18. DOI:10.1016/j.jneumeth.2016.02.003

116. Tweedie D., Rachmany L., Rubovitch V., Li Y., Holloway H.W., Lehrmann E., Zhang Y., Becker K.G., Perez E., Hoffer B.J., Pick C.G., Greig N.H. Blast traumatic brain injury-induced cognitive deficits are attenuated by preinjury or postinjury treatment with the glucagon-like peptide-1 receptor agonist, exendin-4 // Alzheimers Dement. – 2016. – Vol. 12, No. 1. – P. 34–48. DOI:10.1016/j.jalz.2015.07.489

117. Harry G.J. Microglia during development and aging // Pharmacol. Ther. – 2013. – Vol. 139, No. 3. – P. 313–326. DOI:10.1016/j.pharmthera.2013.04.013

118. Zhu Y.J., Peng K., Meng X.W., Ji F.H. Attenuation of neuroinflammation by dexmedetomidine is associated with activation of a cholinergic anti-inflammatory pathway in a rat tibial fracture model // Brain Res. – 2016. – Vol. 1644. – P. 1–8. DOI:10.1016/j.brainres.2016.04.074

119. Shultz S.R., Sun M., Wright D.K., Brady R.D., Liu S., Beynon S., Schmidt S.F., Kaye A.H., Hamilton J.A., O’Brien T.J., Grills B.L., McDonald S.J. Tibial fracture exacerbates traumatic brain injury outcomes and neuroinflammation in a novel mouse model of multitrauma // J. Cereb. Blood Flow. Metab. – 2015. – Vol. 35, No. 8. – P. 1339–1347. DOI:10.1038/jcbfm.2015.56

120. Schindeler A., McDonald M.M., Bokko P., Little D.G. Bone remodeling during fracture repair: The cellular picture // Semin. Cell Dev. Biol. – 2008. – Vol. 19, No. 5. – P. 459–466. DOI:10.1016/j.semcdb.2008.07.004

121. Сабиров Д.М., Росстальная А.Л., Махмудов М.А. Эпидемиологические особенности черепно-мозгового травматизма // Вестник экстренной медицины. – 2019. – Т. 12, № 2. – С. 61–66.

122. Dewan M.C., Rattani A., Gupta S., Baticulon R.E., Hung Y.C., Punchak M., Agrawal A., Adeleye A.O., Shrime M.G., Rubiano A.M., Rosenfeld J.V., Park K.B. Estimating the global incidence of traumatic brain injury // J. Neurosurg. – 2018. – P. 1–18. DOI:10.3171/2017.10.JNS17352