Основные принципы микродиализа головного мозга и современные возможности его применения в экспериментальной нейробиологии и нейрохимии

Благодаря своей универсальности микродиализ представляет собой популярный метод, используемый в различных областях, особенно в фармакологии, неврологии и биомедицинских исследованиях. Потенциальная и ценная роль этого метода заключается в использовании этой техники в качестве локального устройства для взятия проб и решения задач метаболомики, тем самым обнаружения молекул-маркеров и следов фармакотерапевтических вмешательств. В настоящее время микродиализ чаще используется в качестве метода сбора или распределения определенного вещества в определенном месте. Этот метод успешно применяется в различных исследованиях, где необходим отбор несвязанных эндогенных и экзогенных веществ из внеклеточной жидкости широкого спектра тканей организма, доставка лекарств в ткани-мишени и даже в качестве инструмента для мониторинга веществ в тканевой инженерии. Микродиализ является малоинвазивным средством обеспечения практически непрерывного измерения метаболизма любого органа или ткани, в том числе и головного мозга, который позволяет обнаружить признаки клеточного дистресса до системных проявлений. Церебральный микродиализ явялется безопасным методом мониторинга региональной биохимии мозга. Анализ биологической жидкости центральной нервной системы может помочь в принятии клинических решений, ориентировать фармакотерапию и помочь в прогнозировании результатов лечения пациентов. Межклеточные взаимодействия, влияния гормонов, цитокинов, нейромедиаторов, продукция внеклеточной жидкости (в том числе и ликвора), а также площадь и тип поверхности мембраны направляющей канюли, скорость подачи изотонической жидкости, которая регулируется шприцевым и плунжерным насосами, влияют на финальные концентрации целевых компонентов в диализате. Вышеперечисленные параметры тесно связаны между собой и при их несоблюдении в процессе анализа впоследствии могут быть выявлены неточности. В данной публикации рассматриваются основные аспекты и параметры, которые могут оказать влияние на процесс сбора аналита и его содержание, а также области применения микродиализа в нейробиологии и нейрохимии.

1. Baumann KY, Church MK, Clough GF, Quist SR, Schmelz M, Skov PS, Anderson CD, Tannert LK, Giménez-Arnau AM, Frischbutter S, Scheffel J, Maurer M. Skin microdialysis: methods, applications and future opportunities an EAACI position paper. Clin Transl Allergy. 2019;9:24. https://doi.org/10.1186/s13601-019-0262-y

2. KALANT H. A microdialysis procedure for extraction and isolation of corticosteroids from peripheral blood plasma. Biochem J. 1958;69(1):99-103. https://doi.org/10.1042/bj0690099

3. Bito L, Davson H, Levin E, Murray M, Snider N. The concentrations of free amino acids and other electrolytes in cerebrospinal fluid, in vivo dialysate of brain, and blood plasma of the dog. J Neurochem. 1966;13(11):1057-1067. https://doi.org/10.1111/j.1471-4159.1966.tb04265.x

4. Wang X, Stenken JA. Microdialysis sampling membrane performance during in vitro macromolecule collection. Anal Chem. 2006;78(17):6026-6034. https://doi.org/10.1021/ac0602930

5. Cirrito JR, May PC, O'Dell MA, Taylor JW, Parsadanian M, Cramer JW, Audia JE, Nissen JS, Bales KR, Paul SM, DeMattos RB, Holtzman DM. In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life. J Neurosci. 2003;23(26):8844-8853. https://doi.org/10.1523/JNEUROSCI.23-26-08844.2003

6. Thelin EP, Nelson DW, Ghatan PH, Bellander BM. Microdialysis Monitoring of CSF Parameters in Severe Traumatic Brain Injury Patients: A Novel Approach. Front Neurol. 2014;5:159. https://doi.org/10.3389/fneur.2014.00159

7. Zeiler FA, Thelin EP, Czosnyka M, Hutchinson PJ, Menon DK, Helmy A. Cerebrospinal Fluid and Microdialysis Cytokines in Severe Traumatic Brain Injury: A Scoping Systematic Review. Front Neurol. 2017;8:331. https://doi.org/10.3389/fneur.2017.00331

8. Tsitsopoulos PP, Marklund N. Amyloid-β peptides and tau protein as biomarkers in cerebrospinal and interstitial fluid following traumatic brain injury: a review of experimental and clinical studies. Front Neurol. 2013;4:79. https://doi.org/10.3389/neur.2013.00079

9. Kho CM, Enche Ab Rahim SK, Ahmad ZA, Abdullah NS. A Review on Microdialysis Calibration Methods: the Theory and Current Related Efforts. Mol Neurobiol. 2017;54(5):3506-3527. https://doi.org/10.1007/s12035-016-9929-8

10. Chefer VI, Thompson AC, Zapata A, Shippenberg TS. Overview of Brain Microdialysis. Curr Protoc Neurosci. 2009;Chapter 7:Unit 7.1. https://doi.org/10.1002/0471142301.ns0701s47

11. Lee MKK, Di L. Crosstalk the Microdialysis in Scientific Research: from Principle to its Applications. Pharm Anal Acta. 2013;5(1):276-296. https://doi.org/10.4172/2153-2435.1000276

12. van den Brink WJ, Wong YC, Gulave B, van der Graaf PH, de Lange EC. Revealing the neuroendocrine response after remoxipride treatment using multi-biomarker discovery and quantifying it by PK/PD modeling. AAPS J. 2017;19(1):274- 285. https://doi.org/10.1208/s12248-016-0002-3

13. Hillered L, Dahlin AP, Clausen F, Chu J, Bergquist J, Hjort K, Enblad P, Lewén A. Cerebral microdialysis for protein biomarker monitoring in the neurointensive care setting - a technical approach. Front Neurol. 2014;5:245. https://doi.org/10.3389/fneur.2014.00245

14. Wang M, Roman GT, Perry ML, Kennedy RT. Microfluidic chip for high efficiency electrophoretic analysis of segmented flow from a microdialysis probe and in vivo chemical monitoring. Anal Chem. 2009;81(21):9072-9078. https://doi.org/10.1021/ac901731v

15. Wang M, Slaney T, Mabrouk O, Kennedy RT. Collection of nanoliter microdialysate fractions in plugs for off-line in vivo chemical monitoring with up to 2s temporal resolution. J Neurosci Methods. 2010;190(1):39-48. https://doi.org/10.1016/j.jneumeth.2010.04.023

16. Slaney TR, Nie J, Hershey ND, Linderman J, Burns MA, Kennedy RT. Push–pull perfusion sampling with segmented flow for high temporal and spatial resolution in vivo chemical monitoring. Anal Chem. 2011;83(13):5207-5213. https://doi.org/10.1021/ac2003938

17. Rogers M, Leong C, Niu X, de Mello A, Parker KH, Boutelle MG. Optimisation of a microfluidic analysis chamber for the placement of microelectrodes. Phys Chem Chem Phys. 2011;13(12):5298-5303. https://doi.org/10.1039/c0cp02810j

18. Song P, Hershey ND, Mabrouk OS, Slaney TR, Kennedy RT. Mass spectrometry ‘‘sensor’’ for in vivo acetylcholine monitoring. Anal Chem. 2012;84(11):4659-4664. https://doi.org/10.1021/ac301203m

19. Kao C-Y, Anderzhanova E, Asara JM, Wotjak CT, Turck CW. NextGen Brain Microdialysis: Applying Modern Metabolomics Technology to the Analysis of Extracellular Fluid in the Central Nervous System. Mol Neuropsychiatry. 2015;1(1):60-67. https://doi.org/10.1159/000381855

20. Lukas M, Neumann ID. Oxytocin and vasopressin in rodent behaviors related to social dysfunctions in autism spectrum disorders. Behav Brain Res. 2013;251:85-94. https://doi.org/10.1016/j.bbr.2012.08.011

21. Bouw MR, Gardmark M, Hammarlund-Udenaes M. Pharmacokinetic-pharmacodynamic modelling of morphine transport across the blood-brain barrier as a cause of the antinociceptive effect delay in rats--a microdialysis study. Pharm Res. 2000;17(10):1220-1227. https://doi.org/10.1023/a:1026414713509

22. Bostrom E, Hammarlund-Udenaes M, Simonsson US. Bloodbrain barrier transport helps to explain discrepancies in in vivo potency between oxycodone and morphine barrier transport helps to explain discrepancies in in vivo potency between oxycodone and morphine. Anesthesiology. 2008;108(3):495- 505. https://doi.org/10.1097/ALN.0b013e318164cf9e

23. Bouw MR, Xie R, Tunblad K, Hammarlund-Udenaes M. Bloodbrain barrier transport and brain distribution of morphine-6- glucuronide in relation to the antinociceptive effect in ratspharmacokinetic/pharmacodynamic modelling. Br J Pharmacol. 2001;134(8):1796-1804. https://doi.org/10.1038/sj.bjp.0704406

24. Min KC, Aziz A, Ahmad ZA, Rahim SK, Abdullah NS. Initial efforts in modelling mass transport in microdialysis probes: physical characterization of the microdialysis probe membrane. Adv Mater Res. 2015;1087:365-369. https://doi.org/10.4028/www.scientific.net/AMR.1087.365

25. Ungerstedt U. Microdialysis-principles and applications for studies in animals and man. J Intern Med. 1991;230(4):365-373. https://doi.org/10.1111/j.1365-2796.1991.tb00459.x

26. Osipova ED, Komleva YK, Morgun AV, Lopatina OL, Panina YA, Olovyannikova RY, Vais EF, Salmin VV, Salmina AB. Designing in vitro Blood -brain barrier Models Reprodusing Alterations in Brain Aging. Front Aging Neurosci. 2018;10:1- 14. https://doi.org/10.3389/fnagi.2018.00234

27. Кувачева Н.В., Салмина А.Б., Комаева Ю.К., Малиновская Н.А., Моргун А.В., Пожиленкова Е.А., Замай Г.С., Яузина Н.А., Петрова М.М. Проницаемость гематоэнцефалического барьера в норме, при нарушении развития головного мозга и нейродегенерации. Журнал неврологии и психиатрии им. С.С. Корсакова. 2013;113(4):80-85 [Kuvacheva NV, Salmina AB, Komaeva YuK, Malinovskaya NA, Morgun AV, Pozhilenkova EA, Zamai G.S., Yauzina N.A., Petrova M.M. Permeability of the hematoencephalic barrier in normalcy, brain development pathology and neurodegeneration. Korsakov Journal of Neurology and Psychiatry. 2013;113(4):80-85. (In Russ.).]

28. Моргун А.В., Кувачева Н.В., Хилажева Е.Д., Горина Я.В., Таранушенко Т.Е., Пожиленкова Е.А., Салмина А.Б. Перинатальное поражение центральной нервной системы: повреждение и возможности восстановления гематоэнцефалического барьера. Вопросы практической педиатрии. 2015;10(4):29-37 [Morgun AV, Kuvacheva NV, Khilazheva ED, Gorina YaV, Taranushenko TE, Pozhilenkova EA, Salmina AB. Perinatal lesion of the central nervous system: damage and possibilities of restoring the blood-brain barrier. Clinical Practice in Pediatrics. 2015;10(4):29-37. (In Russ.).]

29. Салмина А.Б., Бойцова Е.Б., Моргун А.В., Панина Ю.А., Горина Я.В., Писарева Н.В., Нода М., Кутищева И.А., Мартынова Г.П. Экспрессия NLRP3 инфламмасом церебрального эндотелия при воспалении вирусного генеза in vitro. Бюллетень сибирской медицины. 2017;16(4):242-249 [Salmina AB, Boytsova EB, Morgun AV, Panina YuA, Gorina YaV, Pisareva NV, Kutishcheva IA, Noda M, Martynova GP. Еxpression of cerebral endothelial NLRP3 inflammasome in viral inflammation in vitro. Bulletin of Siberian Medicine. 2017;16(4):242-249. (In Russ.).] https://doi.org/10.20538/1682-0363-2017-4-242-249

30. Моргун А.В., Салмин В.В., Успенская Ю.А., Тепляшина Е.А., Салмина А.Б. Микрофлюидные технологии в изучении и моделировании гематоэнцефалического барьера. Биомедицина. 2016;4:22-23 [Morgun AV, Salmin VV, Uspenskaya YuA, Teplyashina EA, Salmina AB. Microfluidic technologies in studying and modelling the blood-brain barrier. Biomedicine. 2016;4:22-23. (In Russ.).]

31. Anand G, Sharma S, Dutta AK, Kumar SK, Belfort G. Conformational transitions of adsorbed proteins on surfaces of varying polarity. Langmuir. 2010;6(26):10803-10811. https://doi.org/10.1021/la1006132

32. Olivecrona M, Rodling-Wahlström M, Naredi S, Koskinen LO. Prostacyclin Treatment in Severe Traumatic Brain Injury: A Microdialysis and Outcome Study. J Neurotrauma. 2009;26(8):1251-1262. https://doi.org/10.1089=neu.2008.0605

33. Thompson AC, Zapata A, Justice JB, Vaughan RA, Sharpe LG, Shippenberg TS. Kappa-opioid receptor activation modifies dopamine uptake in the nucleus accumbens and opposes the effects of cocaine. J Neurosci. 2000;20(24):9333-9340. https://doi.org/10.1523/JNEUROSCI.20-24-09333.2000

34. Deguchi Y, Terasaki T, Kawasaki S, Tsuji A. Muscle microdialysis as a model study to relate the drug concentration in tissue intersticial fluid and dialysate. J Pharmacobiodyn. 1991;14(8):483-492.

35. Zestos AG, Kennedy RT. Microdialysis Coupled with LC-MS/MS for In Vivo Neurochemical Monitoring. AAPS J. 2017;19(5):1284- 1293. https://doi.org/10.1208/s12248-017-0114-4

36. Löscher W, Friedman A. Structural, Molecular, and Functional Alterations of the Blood-Brain Barrier during Epileptogenesis and Epilepsy: A Cause, Consequence, or Both?. Int J Mol Sci. 2020;21(2):591. https://doi.org/10.3390/ijms21020591

37. Potschka H, Baltes S, Fedrowitz M, Löscher W. Impact of seizure activity on free extracellular phenytoin concentrations in amygdala-kindled rats. Neuropharmacology. 2011;61(5-6):909- 917. https://doi.org/:10.1016/j.neuropharm.2011.06.018

38. Zieminska E, Toczylowska B, Diamandakis D, Hilgier W, Filipkowski RK, Polowy R, Orzel J, Gorka M, Lazarewicz JW. Glutamate, Glutamine and GABA Levels in Rat Brain Measured Using MRS, HPLC and NMR Methods in Study of Two Models of Autism. Front Mol Neurosci. 2018;11:418. https://doi.org/10.3389/fnmol.2018.00418

39. Potschka H, Fedrowitz M, Löscher W. P-Glycoprotein-mediated efflux of phenobarbital, lamotrigine, and felbamate at the bloodbrain barrier: evidence from microdialysis experiments in rats. Neurosci Lett. 2002;26;327(3):173-176. https://doi.org/10.1016/s0304-3940(02)00423-8

40. Hu Y, Rip J, Gaillard PJ, de Lange ECM, Hammarlund-Udenaes M. The Impact of Liposomal Formulations on the Release and Brain Delivery of Methotrexate: An In Vivo Microdialysis Study. J Pharm Sci. 2017.106(9):2606-2613. https://doi.org/10.1016/j.xphs.2017.03.009

41. Ding JH, Sha LL, Chang J, Zhou XQ, Fan Y, Hu G. Alterations of striatal neurotransmitter release in aquaporin-4 deficient mice: An in vivo microdialysis study. Neurosci Lett. 2007.422(3):175- 180. https://doi.org/10.1016/j.neulet.2007.06.018

42. Wakabayashi T, Yamaguchi K, Matsui K, Sano T, Kubota T, Hashimoto T, Mano A, Yamada K, Matsuo Y, Kubota N, Kadowaki T, Iwatsubo T. Differential effects of diet- and genetically-induced brain insulin resistance on amyloid pathology in a mouse model of Alzheimer's disease. Mol Neurodegener. 2019;14(1):15. https://doi.org/10.1186/s13024-019-0315-7

43. Liu CC, Zhao N, Fu Y Wang N, Linares C, Tsai CW, Bu G. ApoE4 Accelerates Early Seeding of Amyloid Pathology. Neuron. 2017;96(5):1024-1032.e3. https://doi.org/10.1016/j.neuron.2017.11.013

44. Białon M, Żarnowska M, Antkiewicz-Michaluk L, Wąsik A. Procognitive effect of 1MeTIQ on recognition memory in the ketamine model of schizophrenia in rats: the behavioural and neurochemical effects. Psychopharmacology (Berl). 2020;237(6):1577-1593. https://doi.org/10.1007/s00213-020-05484-1

45. Hettinger JC, Lee H, Bu G, Holtzman DM, Cirrito JR. AMPA-ergic regulation of amyloid-β levels in an Alzheimer's disease mouse model. Mol Neurodegener. 2018;13(1):22. https://doi.org/10.1186/s13024-018-0256-6

46. Wilson RE, Jaquins-Gerstl A, Weber SG. On-Column Dimethylation with Capillary Liquid Chromatography-Tandem Mass Spectrometry for Online Determination of Neuropeptides in Rat Brain Microdialysate. Anal Chem. 2018;90(7):4561- 4568. https://doi.org/10.1021/acs.analchem.7b04965

47. Wang Y, Liu S, Wang R, Shi L, Liu Z, Liu Z. Study on the therapeutic material basis and effect of Acanthopanax senticosus (Rupr. et Maxim.) Harms leaves in the treatment of ischemic stroke by PK-PD analysis based on online microdialysis-LCMS/MS method. Food Funct. 2020;11(3):2005-2016. https://doi.org/10.1039/c9fo02475a

48. Papadimitriou L,Manganas P, Ranella A, Stratakis E. Biofabrication for neural tissue engineering applications. Mater Today Bio. 2020;6:100043. https://doi.org/10.1016/j.mtbio.2020.100043

49. Saylor RA, Lunte SM. A review of microdialysis coupled to microchip electrophoresis for monitoring biological events. J Chromatogr A. 2015;1382:48-64. https://doi.org/10.1016/j.chroma.2014.12.086

50. Nandi P, Lunte SM. Recent trends in microdialysis sampling integrated with conventional and microanalytical systems for monitoring biological events: A review. Anal Chim Acta. 2009;651(1):1-14. https://doi.org/10.1016/j.aca.2009.07.064

51. Sandlin ZD, Shou M, Shackman JG, Kennedy RT. Microfluidic electrophoresis chip coupled to microdialysis for in vivo monitoring of amino acid neurotransmitters. Anal Chem. 2005;77(23):7702-7708. https://doi.org/10.1021/ac051044z

52. Samper IC, Gowers SAN, Rogers ML, Murray DRK, Jewell SL, Pahl C, Strong AJ, Boutelle MG. 3D printed microfluidic device for online detection of neurochemical changes with high temporal resolution in human brain microdialysate. Lab Chip. 2019;19(11):2038-2048. https://doi.org/10.1039/c9lc00044e

53. van den Brink FTG, Phisonkunkasem T, Asthana A, Bomer JG, van den Maagdenberg AMJM, Tolner EA, Odijk M. A miniaturized push–pull-perfusion probe for fewsecond sampling of neurotransmitters in the mouse brain. Lab Chip. 2019;19(8):1332-1343. https://doi.org/10.1039/c8lc0113 7k

54. Nielsen TH, Olsen NV, Toft P, Nordström CH. Cerebral energy metabolism during mitochondrial dysfunction induced by cyanide in piglets. Acta Anaesthesiol Scand. 2013;57(6):793- 801. https://doi.org/10.1111/aas.12092

55. Havelund JF, Nygaard KH, Nielsen TH, Nordström CH, Poulsen FR, Færgeman NJ, Forsse A, Gramsbergen JB. In Vivo Microdialysis of Endogenous and 13C-labeled TCA Metabolites in Rat Brain: Reversible and Persistent Effects of Mitochondrial Inhibition and Transient Cerebral Ischemia. Metabolites. 2019;9(10):E204. https://doi.org/10.3390/metabo9100204

56. Thelin EP, Carpenter KL, Hutchinson PJ. Helmy A. Microdialysis Monitoring in Clinical Traumatic Brain Injury and Ist Role in Neuroprotective Drug Development. AAPS J. 2017;19(2):367- 376. https://doi.org/10.1208/s12248-016-0027-7

57. Nordström CH, Nielsen TH, Schalén W, Reinstrup P, Ungerstedt U. Biochemical indications of cerebral ischaemia and mitochondrial dysfunction in severe brain trauma analysed with regard to type of lesion. Acta Neurochir (Wien). 2016;158(7):1231-1240. https://doi.org/10.1007/s00701-016-283