Skip to main content

Advertisement

SpringerLink
Log in

Necrostatin-1s Suppresses RIPK1-driven Necroptosis and Inflammation in Periventricular Leukomalacia Neonatal Mice

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

A Correction to this article was published on 13 September 2023

This article has been updated

Abstract

Periventricular leukomalacia (PVL), a predominant form of brain injury in preterm survivors, is characterized by hypomyelination and microgliosis and is also the major cause of long-term neurobehavioral abnormalities in premature infants. Receptor-interacting protein kinase 1 (RIPK1) plays a pivotal role in mediating cell death and inflammatory signaling cascade. However, very little is known about the potential effect of RIPK1 in PVL and the underlying mechanism. Herein, we found that the expression level of RIPK1 was drastically increased in the brain of PVL neonatal mice models, and treatment of PVL neonatal mice with Necrostatin-1s (Nec-1s), an inhibitor of RIPK1, greatly ameliorated cerebral ischemic injury, exhibiting an increase of body weights, reduction of cerebral infarct size, neuronal loss, and occurrence of necrosis-like cells, and significantly improved the long-term abnormal neurobehaviors of PVL. In addition, Nec-1s significantly suppressed hypomyelination and promoted the differentiation of oligodendrocyte precursor cells (OPCs), as demonstrated by the increased expression levels of MBP and Olig2, the decreased expression level of GPR17, a significant increase in the number of CC-1-positive cells, and suppression of myelin ultrastructure impairment. Moreover, the mechanism of neuroprotective effects of Nec-1s against PVL is closely associated with its suppression of the RIPK1-mediated necrosis signaling molecules, RIPK1, PIPK3, and MLKL. More importantly, inhibition of RIPK1 could reduce microglial inflammatory injury by triggering the M1 to M2 microglial phenotype, appreciably decreasing the levels of M1 marker CD86 and increasing the levels of M2 markers Arg1 or CD206 in PVL mice. Taken together, inhibition of RIPK1 markedly ameliorates the brain injury and long-term neurobehavioral abnormalities of PVL mice through the reduction of neural cell necroptosis and reversing neuroinflammation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Change history

References

  1. Litt J, Taylor HG, Klein N, Hack M (2005) Learning disabilities in children with very low birthweight: prevalence, neuropsychological correlates, and educational interventions. J Learn Disabil 38:130–141. https://doi.org/10.1177/00222194050380020301

    Article  PubMed  Google Scholar 

  2. Soria-Pastor S, Gimenez M, Narberhaus A, Falcon C, Botet F, Bargallo N, Mercader JM, Junque C (2008) Patterns of cerebral white matter damage and cognitive impairment in adolescents born very preterm. Int J Dev Neurosci 26:647–654. https://doi.org/10.1016/j.ijdevneu.2008.08.001

    Article  PubMed  Google Scholar 

  3. Vanes LD, Murray RM, Nosarti C (2022) Adult outcome of preterm birth: implications for neurodevelopmental theories of psychosis. Schizophr Res 247:41–54. https://doi.org/10.1016/j.schres.2021.04.007

    Article  PubMed  Google Scholar 

  4. Back SA (2017) White matter injury in the preterm infant: pathology and mechanisms. Acta Neuropathol 134:331–349. https://doi.org/10.1007/s00401-017-1718-6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Galinsky R, Lear CA, Dean JM, Wassink G, Dhillon SK, Fraser M, Davidson JO, Bennet L, Gunn AJ (2018) Complex interactions between hypoxia-ischemia and inflammation in preterm brain injury. Dev Med Child Neurol 60:126–133. https://doi.org/10.1111/dmcn.13629

    Article  PubMed  Google Scholar 

  6. Zaghloul N, Ahmed M (2017) Pathophysiology of periventricular leukomalacia: what we learned from animal models. Neural Regen Res 12:1795–1796. https://doi.org/10.4103/1673-5374.219034

    Article  PubMed  PubMed Central  Google Scholar 

  7. Yuan J, Amin P, Ofengeim D (2019) Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat Rev Neurosci 20:19–33. https://doi.org/10.1038/s41583-018-0093-1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Zelic M, Pontarelli F, Woodworth L, Zhu C, Mahan A, Ren Y, Lamorte M, Gruber R, Keane A, Loring P, Guo L, Xia TH, Zhang B, Orning P, Lien E, Degterev A, Hammond T, Ofengeim D (2021) RIPK1 activation mediates neuroinflammation and disease progression in multiple sclerosis. Cell Rep 35:109112. https://doi.org/10.1016/j.celrep.2021.109112

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Ito Y, Ofengeim D, Najafov A, Das S, Saberi S, Li Y, Hitomi J, Zhu H, Chen H, Mayo L, Geng J, Amin P, Dewitt JP, Mookhtiar AK, Florez M, Ouchida AT, Fan JB, Pasparakis M, Kelliher MA, Ravits J, Yuan J (2016) RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science 353:603–608. https://doi.org/10.1126/science.aaf6803

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Deng X, Li S, Sun F (2019) Necrostatin-1 prevents necroptosis in brains after ischemic stroke via inhibition of RIPK1-Mediated RIPK3/MLKL signaling. Aging Dis 10:807. https://doi.org/10.14336/AD.2018.0728

    Article  PubMed  PubMed Central  Google Scholar 

  11. Liu J, Hu H, Wu B (2021) RIPK1 inhibitor ameliorates the MPP(+)/MPTP-induced Parkinson’s disease through the ASK1/JNK signalling pathway. Brain Res 1757:147310. https://doi.org/10.1016/j.brainres.2021.147310

    Article  PubMed  CAS  Google Scholar 

  12. Li S, Qu L, Wang X, Kong L (2022) Novel insights into RIPK1 as a promising target for future Alzheimer’s disease treatment. Pharmacol Ther 231:107979. https://doi.org/10.1016/j.pharmthera.2021.107979

    Article  PubMed  CAS  Google Scholar 

  13. Back SA, Luo NL, Borenstein NS, Volpe JJ, Kinney HC (2002) Arrested oligodendrocyte lineage progression during human cerebral white matter development: dissociation between the timing of progenitor differentiation and myelinogenesis. J Neuropathol Exp Neurol 61:197–211. https://doi.org/10.1093/jnen/61.2.197

    Article  PubMed  Google Scholar 

  14. Back SA, Han BH, Luo NL, Chricton CA, Xanthoudakis S, Tam J, Arvin KL, Holtzman DM (2002) Selective vulnerability of late oligodendrocyte progenitors to hypoxia-ischemia. J Neurosci 22:455–463. https://doi.org/10.1523/JNEUROSCI.22-02-00455.2002

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Qu Y, Tang J, Wang H, Li S, Zhao F, Zhang L, Richard LQ, Mu D (2017) RIPK3 interactions with MLKL and CaMKII mediate oligodendrocytes death in the developing brain. Cell Death Dis 8:e2629. https://doi.org/10.1038/cddis.2017.54

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Northington FJ, Chavez-Valdez R, Graham EM, Razdan S, Gauda EB, Martin LJ (2011) Necrostatin decreases oxidative damage, inflammation, and injury after neonatal HI. J Cereb Blood Flow Metab 31:178–189. https://doi.org/10.1038/jcbfm.2010.72

    Article  PubMed  CAS  Google Scholar 

  17. Wang J, Wang D, Zheng X, Li Y, Li Y, Ma T, Li J, Sun J, Wang Y, Ma Q (2022) A2B adenosine receptor inhibition ameliorates hypoxic-ischemic injury in neonatal mice via PKC/Erk/Creb/HIF-1alpha signaling pathway. Brain Res 1782:147837. https://doi.org/10.1016/j.brainres.2022.147837

    Article  PubMed  CAS  Google Scholar 

  18. Reddy N, Doyle M, Hanagandi P, Taranath A, Dahmoush H, Krishnan P, Oztekin O, Boltshauser E, Shroff M, Mankad K (2022) Neuroradiological mimics of Periventricular Leukomalacia. J Child Neurol 37:151–167. https://doi.org/10.1177/08830738211026052

    Article  PubMed  Google Scholar 

  19. Khurana R, Shyamsundar K, Taank P, Singh A (2021) Periventricular leukomalacia: an ophthalmic perspective. Med J Armed Forces India 77:147–153. https://doi.org/10.1016/j.mjafi.2020.05.013

    Article  PubMed  Google Scholar 

  20. Martinez-Biarge M, Groenendaal F, Kersbergen KJ, Benders M, Foti F, van Haastert IC, Cowan FM, de Vries LS (2019) Neurodevelopmental outcomes in Preterm Infants with White Matter Injury using a new MRI classification. Neonatology 116:227–235. https://doi.org/10.1159/000499346

    Article  PubMed  Google Scholar 

  21. Lecca D, Raffaele S, Abbracchio MP, Fumagalli M (2020) Regulation and signaling of the GPR17 receptor in oligodendroglial cells. Glia 68:1957–1967. https://doi.org/10.1002/glia.23807

    Article  PubMed  Google Scholar 

  22. Wang J, He X, Meng H, Li Y, Dmitriev P, Tian F, Page JC, Lu QR, He Z (2020) Robust myelination of regenerated axons Induced by Combined Manipulations of GPR17 and Microglia. Neuron 108:876–886. https://doi.org/10.1016/j.neuron.2020.09.016

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Merten N, Fischer J, Simon K, Zhang L, Schroder R, Peters L, Letombe AG, Hennen S, Schrage R, Bodefeld T, Vermeiren C, Gillard M, Mohr K, Lu QR, Brustle O, Gomeza J, Kostenis E (2018) Repurposing HAMI3379 to Block GPR17 and promote rodent and human oligodendrocyte differentiation. Cell Chem Biol 25:775–786. https://doi.org/10.1016/j.chembiol.2018.03.012

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Wang J, Yang L, Jiang M, Zhao C, Liu X, Berry K, Waisman A, Langseth AJ, Novitch BG, Bergles DE, Nishiyama A, Lu QR (2022) Olig2 ablation in immature oligodendrocytes does not enhance CNS myelination and remyelination. J Neurosci 42:8542–8555. https://doi.org/10.1523/JNEUROSCI.0237-22.2022

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Hammond TR, Robinton D, Stevens B (2018) Microglia and the brain: complementary partners in Development and Disease. Annu Rev Cell Dev Biol 34:523–544. https://doi.org/10.1146/annurev-cellbio-100616-060509

    Article  PubMed  CAS  Google Scholar 

  26. Shao R, Sun D, Hu Y, Cui D (2021) White matter injury in the neonatal hypoxic-ischemic brain and potential therapies targeting microglia. J Neurosci Res 99:991–1008. https://doi.org/10.1002/jnr.24761

    Article  PubMed  CAS  Google Scholar 

  27. Volpe JJ (2019) Microglia: newly discovered complexity could lead to targeted therapy for neonatal white matter injury and dysmaturation. J Neonatal Perinatal Med 12:239–242. https://doi.org/10.3233/NPM-190303

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Fan LW, Pang Y, Lin S, Rhodes PG, Cai Z (2005) Minocycline attenuates lipopolysaccharide-induced white matter injury in the neonatal rat brain. Neuroscience 133:159–168. https://doi.org/10.1016/j.neuroscience.2005.02.016

    Article  PubMed  CAS  Google Scholar 

  29. Pang Y, Fan LW, Tien LT, Dai X, Zheng B, Cai Z, Lin RC, Bhatt A (2013) Differential roles of astrocyte and microglia in supporting oligodendrocyte development and myelination in vitro. Brain Behav 3:503–514. https://doi.org/10.1002/brb3.152

    Article  PubMed  PubMed Central  Google Scholar 

  30. Pang Y, Cai Z, Rhodes PG (2003) Disturbance of oligodendrocyte development, hypomyelination and white matter injury in the neonatal rat brain after intracerebral injection of lipopolysaccharide. Brain Res Dev Brain Res 140:205–214. https://doi.org/10.1016/s0165-3806(02)00606-5

    Article  PubMed  CAS  Google Scholar 

  31. Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, van Wijngaarden P, Wagers AJ, Williams A, Franklin R, Ffrench-Constant C (2013) M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 16:1211–1218. https://doi.org/10.1038/nn.3469

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Sherwin C, Fern R (2005) Acute lipopolysaccharide-mediated injury in neonatal white matter glia: role of TNF-alpha, IL-1beta, and calcium. J Immunol 175:155–161. https://doi.org/10.4049/jimmunol.175.1.155

    Article  PubMed  CAS  Google Scholar 

  33. Anderson PJ, De Luca CR, Hutchinson E, Spencer-Smith MM, Roberts G, Doyle LW (2011) Attention problems in a representative sample of extremely preterm/extremely low birth weight children. Dev Neuropsychol 36:57–73. https://doi.org/10.1080/87565641.2011.540538

    Article  PubMed  Google Scholar 

  34. Liu J, Li J, Qin GL, Chen YH, Wang Q (2008) Periventricular leukomalacia in premature infants in mainland China. Am J Perinatol 25:535–540. https://doi.org/10.1055/s-0028-1083841

    Article  PubMed  Google Scholar 

  35. Jacobson LK, Dutton GN (2000) Periventricular leukomalacia: an important cause of visual and ocular motility dysfunction in children. Surv Ophthalmol 45:1–13. https://doi.org/10.1016/s0039-6257(00)00134-x

    Article  PubMed  CAS  Google Scholar 

  36. Chen Y, Zhang L, Yu H, Song K, Shi J, Chen L, Cheng J (2018) Necrostatin-1 improves long-term functional recovery through protecting oligodendrocyte precursor cells after transient focal cerebral ischemia in mice. Neuroscience 371:229–241. https://doi.org/10.1016/j.neuroscience.2017.12.007

    Article  PubMed  CAS  Google Scholar 

  37. Gao X, Zhang P, Chen J, Zhang L, Shang N, Chen J, Fan R, Wang Y, Huang T, Niu Q, Zhang Q (2022) Necrostatin-1 relieves learning and memory deficits in a zebrafish model of Alzheimer’s Disease Induced by Aluminum. Neurotox Res 40:198–214. https://doi.org/10.1007/s12640-021-00463-6

    Article  PubMed  CAS  Google Scholar 

Download references

Funding

This work was funded by the National Natural Science Foundation of China (grant nos.82060223, 32160192), the Natural Science Foundation of Ningxia (grant nos.2022AAC03607, 2023AAC02037, 2023AAC03162), the Key Research and Development Plan of Ningxia (grant no. 2021BEG03097).

Author information

Authors and Affiliations

  1. School of Basic Medicine, Ningxia Medical University, Yinchuan, 750004, Ningxia, P.R. China

    Jinping Sun, Quanrui Ma, Junyan Wang, Yong Han, Yunhong Li & Yin Wang

  2. Department of Pathology, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, P.R. China

    Jinping Sun, Xiaoli Pan & Hualiang Zhai

  3. Department of Neurosurgery, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, P.R. China

    Wei Wang

Authors
  1. Jinping Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Quanrui Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaoli Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hualiang Zhai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Junyan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yong Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yunhong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Jinping Sun contributed to the acquisition, analysis, and interpretation of data, the original manuscript. Jinping Sun, Xiaoli Pan, and Hualiang Zhai performed the experiments. Junyan Wang participated in the conception of the study and supervised the graduate students. Yong Han participated in the data analysis and chart making. Quanrui Ma contributed to the project design and the manuscript revision. Yunhong Li, Wei Wang, and Yin Wang contributed to the funding support, project design, and supervision, the manuscript revision. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Yunhong Li or Yin Wang.

Ethics declarations

Competing Interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Jinping Sun and Wei Wang contributed equally.

The original online version of this article was revised: due to missing equal contributor information.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sun, J., Wang, W., Ma, Q. et al. Necrostatin-1s Suppresses RIPK1-driven Necroptosis and Inflammation in Periventricular Leukomalacia Neonatal Mice. Neurochem Res 49, 129–141 (2024). https://doi.org/10.1007/s11064-023-04013-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-023-04013-8

Keywords

Search

Navigation