Dados do Trabalho

Título

THE BRAIN TISSUE SAMPLES OF NEWBORN INFANTS SUFFERING FROM HYPOXIC-ISCHEMIC INSULT IN GERMINAL MATRIX REGION: NF-KB/PARKIN/VEGFR-1 PATHWAY

Introdução

The hypoxic-ischemic insult is one of the current leading causes of neonatal deaths. The germinal matrix(GM) of the Central Nervous System (CNS) is a highly vascularized region susceptible to hemorrhagic damage in the face of a hypoxic environment. Considering the high activity of the GM until the thirty-sixth gestational week and its intrinsic link to hypoxemia and, consequently, neural damage with sequelae or death, investigating molecular pathways associated with the hypoxemic event is crucial to mitigate morbidity and mortality.

Objetivo

Therefore, the present study evaluated, throughout immunohistochemistry, cell survival markers (AKT-3, Parkin, and TRK-C), cell transcription(NF-kB), and angiogenic factor(VEGFR-1), to understand the connection of these markers in the GM and the hypoxic-ischemic insult of newborns.

Método

The study comprised 118 post-mortem samples of a paraffin-embedded GM from premature and full-term patients who died within the first 28 days of life, divided into two groups related to CNS immaturity (extremely immature CNS and not immature CNS). Histopathological and immunohistochemical were used to analyze the AKT-3, NF-kB, Parkin, TRK-C, and VEGFR-1 markers in the conditions of asphyxia, prematurity, and death events within 24h.

Resultados e Conclusões

By evaluating the tissue immunoexpression of the markers in term and premature newborns, a possible molecular pathway was found with the interaction between the temporality of death within the first 24 hours and the transcription factor NF-kB and the angiogenic marker VEGFR-1, which were significantly decreased. Furthermore, there was an increase in tissue immunoexpression of NF-kB, AKT-3, and Parkin markers in the GM of prematurely aged patients. Conclusion: Considering that the AKT-3 and Parkin markers showed a significantly increased, a high proliferative activity of GM and a possibility of protection against an ischemic insult is suggested. However, both NF-kB and its pro-cursor VEGFR-1 were significantly reduced compared to the survival time, proposing an insufficient time for the transcription and expression of VEGFR-1 in the plasmatic membrane, leading to a decreased protective activity. Therefore, this study is ongoing to identify a possible clinical marker in serum level to signal the ischemic hypoxic insult during the postpartum procedure, treating it as soon as possible.

Palavras Chave

Germinative matrix, NF-kB, VEGFR-1, prematurity CNS, hypoxic-ischemic lesion.

Declaração de conflito de interesses de TODOS os autores

Todos os autores declaram não haver nenhum conflito de interesses.

Fonte de Fomento (se houver)

CNPQ (304356/2018-2)

Referências (se houver)

1.
Vargas NS. Marcadores prognósticos de evolução neonatal de recém-nascidos de termo portadores de asfixia perinatal [dissertation]. São Paulo: Faculdade de Medicina, Universidade de São Paulo; 2012.
2.
Veloso FC, Kassar LM, Oliveira MJ, Lima TH, Bueno NB, Gurgel RQ, et al. Analysis of neonatal mortality risk factors in Brazil: a systematic review and meta-analysis of observational studies. J Pediatr (Rio J). 2019;95:519-30. https://doi.org/10.1016/j.jped.2018.12.014
» https://doi.org/10.1016/j.jped.2018.12.014
3.
Lansky S, Friche AA, Silva AA, Campos D, Bittencourt SD, Carvalho ML, et al. Pesquisa nascer no Brasil: perfil da mortalidade neonatal e avaliação da assistência à gestante e ao recém-nascido. Cad Saúde Pública. 2014;30(suppl 1):S192-207. https://doi.org/10.1590/0102-311X00133213
» https://doi.org/10.1590/0102-311X00133213
4.
Pedrosa LD, Sarinho SW, Ordonha MA. Óbitos neonatais: por que e como informar? Rev Bras Saude Matern Infant. 2005;5:411-8. https://doi.org/10.1590/S1519-38292005000400004
» https://doi.org/10.1590/S1519-38292005000400004
5.
Morales P, Bustamante D, Espina-Marchant P, Neira-Peña T, Gutiérrez-Hernández MA, Allende-Castro C, et al. Pathophysiology of perinatal asphyxia: can we predict and improve individual outcomes? EPMAJ. 2011;2:211-30. https://doi.org/10.1007%2Fs13167-011-0100-3
» https://doi.org/10.1007%2Fs13167-011-0100-3
6.
Higginbotham H, Yokota Y, Anton ES. Strategies for analyzing neuronal progenitor development and neuronal migration in the developing cerebral cortex. Cereb Cortex. 2011;21:1465-74. https://doi.org/10.1093/cercor/bhq197
» https://doi.org/10.1093/cercor/bhq197
7.
Ballabh P, Vries LS. White matter injury in infants with intraventricular haemorrhage: mechanisms and therapies. Nat Rev Neurol. 2021;17:199-214. https://doi.org/10.1038/s41582-020-00447-8
» https://doi.org/10.1038/s41582-020-00447-8
8.
Ballabh P, Braun A, Nedergaard M. Anatomic analysis of blood vessels in germinal matrix, cerebral cortex, and white matter in developing infants. Pediatr Res. 2004;56:117-24. https://doi.org/10.1203/01.PDR.0000130472.30874.FF
» https://doi.org/10.1203/01.PDR.0000130472.30874.FF
9.
Raets MM, Dudink J, Govaert P. Neonatal disorders of germinal matrix. J Matern Neonatal Med. 2015;28 Suppl 1:2286-90. https://doi.org/10.3109/14767058.2013.796169
» https://doi.org/10.3109/14767058.2013.796169
10.
Jossin Y. Neuronal migration and the role of reelin during early development of the cerebral cortex. Mol Neurobiol. 2004;30:225-51. https://doi.org/10.1385/MN:30:3:225
» https://doi.org/10.1385/MN:30:3:225
11.
Kandel ER. Príncípios de neurociências. 5a ed. Porto Alegre: McHill; 2014.
12.
Matsuo FS. Estudo da via de sinalização PI3K-Akt e GSK3β em carcinomas epidermoides metastáticos e não metastáticos de cavidade bucal [dissertation]. Uberlândia: Universidade Federal de Uberlândia; 2015.
13.
Osaki M, Oshimura M, Ito H. PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis. 2004;9:667-76. https://doi.org/10.1023/B:APPT.0000045801.15585.dd
» https://doi.org/10.1023/B:APPT.0000045801.15585.dd
14.
Wang Y, Shan B, Liang Y, Wei H, Yuan J. Parkin regulates NF-κB by mediating site-specific ubiquitination of RIPK1. Cell Death Dis. 2018;9:732. https://doi.org/10.1038/s41419-018-0770-z
» https://doi.org/10.1038/s41419-018-0770-z
15.
Franco DG. Fator de transcrição nuclear kappa B no sistema nervoso central: do fisiológico ao patológico. Rev Biol. 2010;4:35-9. https://doi.org/10.7594/revbio.04.07
» https://doi.org/10.7594/revbio.04.07
16.
van Uden P, Kenneth NS, Rocha S. Regulation of hypoxia-inducible factor-1alpha by NF-kappaB. Biochem J. 2008;412:477-84. https://doi.org/10.1042/BJ20080476
» https://doi.org/10.1042/BJ20080476
17.
Wenger RH. Cellular adaptation to hypoxia: O2 -sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2 -regulated gene expression. FASEB J. 2002;16:1151-62. https://doi.org/10.1096/fj.01-0944rev
» https://doi.org/10.1096/fj.01-0944rev
18.
Kaur C, Hao AJ, Wu CH, Ling EA. Origin of microglia. Microsc Res Tech. 2001;54:2-9. https://doi.org/10.1002/jemt.1114
» https://doi.org/10.1002/jemt.1114
19.
Santos NK. Avaliação da inflamação por mensuração de IL-1β em modelo animal de hemorragia da matriz germinativa/intraventricular perinatal [TCC]. Porto Alegre: Universidade Federal do Rio Grande do Sul; 2013.
20.
Supramaniam V, Vontell R, Srinivasan L, Wyatt-Ashmead J, Hagberg H, Rutherford M. Microglia activation in the extremely preterm human brain. Pediatr Res. 2013;73:301-9. https://doi.org/10.1038/pr.2012.186
» https://doi.org/10.1038/pr.2012.186
21.
Hayden MS, Ghosh S. Regulation of NF-κB by TNF family cytokines. Semin Immunol. 2014;26:253-66. https://doi.org/10.1016/j.smim.2014.05.004
» https://doi.org/10.1016/j.smim.2014.05.004
22.
Mulero MC, Huxford T, Ghosh G. NF-κB, IκB, and IKK: integral components of immune system signaling. Adv Exp Med Biol. 2019;1172:207-26. https://doi.org/10.1007/978-981-13-9367-9_10
» https://doi.org/10.1007/978-981-13-9367-9_10
23.
Minet E, Ernest I, Michel G, Roland I, Remacle J, Raes M, et al. HIF1A gene transcription is dependent on a core promoter sequence encompassing activating and inhibiting sequences located upstream from the transcription initiation site and cis-elements located within the 5’UTR. Biochem Biophys Res Commun. 1999;261:534-40. https://doi.org/10.1006/bbrc.1999.0995
» https://doi.org/10.1006/bbrc.1999.0995
24.
Jiang BH, Zheng JZ, Aoki M, Vogt PK. Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factors in endothelial cells. Proc Natl Acad Sci U S A. 2000;97:1749-53. https://doi.org/10.1073/pnas.040560897
» https://doi.org/10.1073/pnas.040560897
25.
Chen EY, Mazure NM, Cooper JA, Giaccia AJ. Hypoxia activates a platelet-derived growth factor receptor/phosphatidylinositol 3-kinase/Akt pathway that results in glycogen synthase kinase-3 inactivation. Cancer Res. 2001;61:2429-33. PMID: 11289110