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Necrostatin-1 as a Neuroprotectant

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Handbook of Neurotoxicity

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Abstract

Necrostatin-1 (Nec-1) is an inhibitor of necroptosis, a form of regulated nonapoptotic cell death pathway. It acts via allosteric blockade of receptor-interacting protein 1 (RIP1) kinase, thereby preventing the formation of the necrosome complex and execution of necroptotic program. Apart from serving a crucial physiological role during development and adulthood, necroptosis has been implicated in the pathogenesis of various human pathologies including acute and chronic neurodegenerative conditions. This chapter summarizes experimental data on neuroprotective effects of Nec-1 and current views on its molecular mechanisms of action. It also highlights advantages and limitations of Nec-1 as a potential neuroprotectant. Nec-1 showed marked neuroprotective properties in a wide range of in vivo experimental models of brain ischemia, neonatal hypoxia-ischemia, retinal ischemia, subarachnoid hemorrhage, traumatic brain and spinal cord injuries, neuropathies, and some neurodegenerative diseases. However, as a candidate for a clinically useful neuroprotectant, Nec-1 shows also some shortcomings. Its solubility in water is limited and its half-time after systemic administration is relatively short. Nevertheless, Nec-1 proved to be a highly valuable tool in studying the relationships between various cell death pathways enabling researchers to get more insight into severe CNS pathologies, and in this way this compound may contribute to further development of the long-desired clinically approved neuroprotectant.

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Abbreviations

6-OHDA:

6-hydroxydopamine

AD:

Alzhemier’s disease

AIF:

Apoptosis inducing factor

ALS:

Amyotrophic lateral sclerosis

CNS:

Central nervous system

DRP1:

Dynamin-related protein 1

GSH:

Glutathione

HD:

Huntington’s disease

I/R:

Ischemia/Reperfusion

ICH:

Intracerebral hemorrhage

IDO:

Indoleamine 2,3-dioxygenase

MCAO:

Middle cerebral artery occlusion

MLKL:

Mixed lineage kinase like protein

MPTP:

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Nec-1 s:

Necrostatin-1 stable, 5-((7-chloro-1H-indol-3-yl)mevthyl)-3-methyl-2,4-imidazolidinedione

Nec-1:

Necrostatin-1, 5-(1H-Indol-3-ylmethyl)-(2-thio-3-methyl) hydantoin, methyl-thiohydantoin-tryptophan

Nec-1i:

Necrostatin-1 inactive, 5-(Indol-3-ylmethyl)-2-thiohydantoin

NHI:

Neonatal hypoxia-ischemia

PD:

Parkinson’s disease

RIP1:

Receptor-interacting serine/threonine-protein kinase 1

RIP3:

Receptor-interacting serine/threonine-protein kinase 3

ROS:

Reactive oxygen species

SAH:

Subarachnoid hemorrhage

SCI:

Spinal cord injury

SNpc:

Substantia nigra pars compacta

TBI:

Traumatic brain injury

TNFα:

Tumor necrosis factor alpha

References

  • Arrázola, M. S., Saquel, C., Catalán, R. J., Barrientos, S. A., Hernandez, D. E., Martínez, N. W., Catenaccio, A., & Court, F. A. (2019). Axonal degeneration is mediated by necroptosis activation. The Journal of Neuroscience, 39, 3832–3844.

    Article  PubMed  PubMed Central  Google Scholar 

  • Askalan, R., Gabarin, N., Armstrong, E. A., Fang, L. Y., Couchman, D., & Yager, J. Y. (2015). Mechanisms of neurodegeneration after severe hypoxic-ischemic injury in the neonatal rat brain. Brain Research, 1629, 94–103.

    Article  CAS  PubMed  Google Scholar 

  • Bao, Z., Fan, L., Zhao, L., Xu, X., Liu, Y., Chao, H., Liu, N., You, Y., Liu, Y., Wang, X., & Ji, J. (2019). Silencing of A20 aggravates neuronal death and inflammation after traumatic brain injury: A potential trigger of necroptosis. Frontiers in Molecular Neuroscience, 12, 222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caccamo, A., Branca, C., Piras, I. S., Ferreira, E., Huentelman, M. J., Liang, W. S., Readhead, B., Dudley, J. T., Spangenberg, E. E., Green, K. N., Belfiore, R., Winslow, W., & Oddo, S. (2017). Necroptosis activation in Alzheimer’s disease. Nature Neuroscience, 20, 1236–1246.

    Article  CAS  PubMed  Google Scholar 

  • Cao, L., & Mu, W. (2020). Necrostatin-1 and necroptosis inhibition: Pathophysiology and therapeutic implications. Pharmacological Research, 163, 105297.

    Article  PubMed  PubMed Central  Google Scholar 

  • Chang, P., Dong, W., Zhang, M., Wang, Z., Wang, Y., Wang, T., Gao, Y., Meng, H., Luo, B., Luo, C., Chen, X., & Tao, L. (2014). Anti-necroptosis chemical necrostatin-1 can also suppress apoptotic and autophagic pathway to exert neuroprotective effect in mice intracerebral hemorrhage model. Journal of Molecular Neuroscience, 52, 242–249.

    Article  CAS  PubMed  Google Scholar 

  • Chavez-Valdez, R., Flock, D. L., Martin, L. J., & Northington, F. J. (2016). Endoplasmic reticulum pathology and stress response in neurons precede programmed necrosis after neonatal hypoxia-ischemia. International Journal of Developmental Neuroscience, 48, 58–70.

    Article  PubMed  Google Scholar 

  • Chavez-Valdez, R., Martin, L. J., Flock, D. L., & Northington, F. J. (2012). Necrostatin-1 attenuates mitochondrial dysfunction in neurons and astrocytes following neonatal hypoxia-ischemia. Neuroscience, 219, 192–203.

    Article  CAS  PubMed  Google Scholar 

  • Chavez-Valdez, R., Martin, L. J., Razdan, S., Gauda, E. B., & Northington, F. J. (2014). Sexual dimorphism in BDNF signaling after neonatal hypoxia-ischemia and treatment with necrostatin-1. Neuroscience, 260, 106–119.

    Article  CAS  PubMed  Google Scholar 

  • Chen, F., Su, X., Lin, Z., Lin, Y., Yu, L., Cai, J., Kang, D., & Hu, L. (2017). Necrostatin-1 attenuates early brain injury after subarachnoid hemorrhage in rats by inhibiting necroptosis. Neuropsychiatric Disease and Treatment, 13, 1771–1782.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen, J., Jin, H., Xu, H., Peng, Y., Jie, L., Xu, D., Chen, L., Li, T., Fan, L., He, P., Ying, G., Gu, C., Wang, C., Wang, L., & Chen, G. (2019). The neuroprotective effects of necrostatin-1 on subarachnoid hemorrhage in rats are possibly mediated by preventing blood-brain barrier disruption and RIP3-mediated necroptosis. Cell Transplantation, 28, 1358–1372.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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, 2018(371), 229–241.

    Article  Google Scholar 

  • Conrad, M., Angeli, J. P., Vandenabeele, P., & Stockwell, B. R. (2016). Regulated necrosis: Disease relevance and therapeutic opportunities. Nature Reviews. Drug Discovery, 15, 348–366.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cougnoux, A., Cluzeau, C., Mitra, S., Li, R., Williams, I., Burkert, K., Xu, X., Wassif, C. A., Zheng, W., & Porter, F. D. (2016). Necroptosis in Niemann-Pick disease, type C1: A potential therapeutic target. Cell Death & Disease, 7, e2147.

    Article  CAS  Google Scholar 

  • Degterev, A., Hitomi, J., Germscheid, M., Ch’en, I. L., Korkina, O., Teng, X., Abbott, D., Cuny, G. D., Yuan, C., Wagner, G., Hedrick, S. M., Gerber, S. A., Lugovskoy, A., & Yuan, J. (2008). Identification of RIP1 kinase as a specific cellular target of necrostatins. Nature Chemical Biology, 4, 313–321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Degterev, A., Huang, Z., Boyce, M., Li, Y., Jagtap, P., Mizushima, N., Cuny, G. D., Mitchison, T. J., Moskowitz, M. A., & Yuan, J. (2005). Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nature Chemical Biology, 1, 112–119.

    Article  CAS  PubMed  Google Scholar 

  • Degterev, A., Ofengeim, D., & Yuan, J. (2019). Targeting RIPK1 for the treatment of human diseases. Proceedings of the National Academy of Sciences of the United States of America, 116, 9714–9722.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deng, X. X., Li, S. S., & Sun, F. Y. (2019). Necrostatin-1 prevents necroptosis in brains after ischemic stroke via inhibition of RIPK1-mediated RIPK3/MLKL signaling. Aging and Disease, 10, 807–817.

    Article  PubMed  PubMed Central  Google Scholar 

  • Dermentzaki, G., Politi, K.A., Lu, L., Mishra, V., Pérez-Torres, E.J., Sosunov, A.A., McKhann, G.M. 2nd., Lotti, F., Shneider, N.A., Przedborski, S. (2019). Deletion of Ripk3 prevents motor neuron death in vitro but not in vivo. eNeuro, 6(1), ENEURO.0308-18.2018.

    Google Scholar 

  • Dionísio, P. A., Oliveira, S. R., Gaspar, M. M., Gama, M. J., Castro-Caldas, M., Amaral, J. D., & Rodrigues, C. M. P. (2019). Ablation of RIP3 protects from dopaminergic neurodegeneration in experimental Parkinson’s disease. Cell Death & Disease, 10, 840.

    Article  Google Scholar 

  • Do, Y. J., Sul, J. W., Jang, K. H., Kang, N. S., Kim, Y. H., Kim, Y. G., & Kim, E. (2017). A novel RIPK1 inhibitor that prevents retinal degeneration in a rat glaucoma model. Experimental Cell Research, 359, 30–38.

    Article  CAS  PubMed  Google Scholar 

  • Dong, K., Zhu, H., Song, Z., Gong, Y., Wang, F., Wang, W., Zheng, Z., Yu, Z., Gu, Q., Xu, X., & Sun, X. (2012). Necrostatin-1 protects photoreceptors from cell death and improves functional outcome after experimental retinal detachment. The American Journal of Pathology, 181, 1634–1641.

    Article  CAS  PubMed  Google Scholar 

  • Dong, K., Zhu, Z. C., Wang, F. H., Ke, G. J., Yu, Z., & Xu, X. (2014). Activation of autophagy in photoreceptor necroptosis after experimental retinal detachment. International Journal of Ophthalmology, 7, 745–752.

    PubMed  PubMed Central  Google Scholar 

  • Duan, S., Wang, X., Chen, G., Quan, C., Qu, S., & Tong, J. (2018). Inhibiting RIPK1 limits neuroinflammation and alleviates postoperative cognitive impairments in D-Galactose-induced aged mice. Frontiers in Behavioral Neuroscience, 12, 138.

    Article  PubMed  PubMed Central  Google Scholar 

  • Dvoriantchikova, G., Degterev, A., & Ivanov, D. (2014). Retinal ganglion cell (RGC) programmed necrosis contributes to ischemia-reperfusion-induced retinal damage. Experimental Eye Research, 123, 1–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fan, H., Tang, H.-B., Kang, J., Shan, L., Song, H., Zhu, K., Wang, J., Ju, G., & Wang, Y.-Z. (2015). Involvement of endoplasmic reticulum stress in the necroptosis of microglia/macrophages after spinal cord injury. Neuroscience, 311, 362–373.

    Article  CAS  PubMed  Google Scholar 

  • Fan, J., Dawson, T. M., & Dawson, V. L. (2017). Cell death mechanisms of neurodegeneration. Advances in Neurobiology, 15, 403–425.

    Article  PubMed  Google Scholar 

  • Fang, Y., Gao, S., Wang, X., Cao, Y., Lu, J., Chen, S., Lenahan, C., Zhang, J. H., Shao, A., & Zhang, J. (2020). Programmed cell deaths and potential crosstalk with blood-brain barrier dysfunction after hemorrhagic stroke. Frontiers in Cellular Neuroscience, 14, 68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Geng, F., Yin, H., Li, Z., Li, Q., He, C., Wang, Z., & Yu, J. (2017). Quantitative analysis of necrostatin-1, a necroptosis inhibitor by LC-MS/MS and the study of its pharmacokinetics and bioavailability. Biomedicine & Pharmacotherapy, 95, 1479–1485.

    Article  CAS  Google Scholar 

  • Grievink, H. W., Heuberger, J. A. A. C., Huang, F., Chaudhary, R., Birkhoff, W. A. J., Tonn, G. R., Mosesova, S., Erickson, R., Moerland, M., Haddick, P. C. G., Scearce-Levie, K., Ho, C., & Groeneveld, G. J. (2020). DNL104, a centrally penetrant RIPK1 inhibitor, inhibits RIP1 kinase phosphorylation in a randomized phase I ascending dose study in healthy volunteers. Clinical Pharmacology and Therapeutics, 107, 406–414.

    Article  CAS  PubMed  Google Scholar 

  • Hao, Y. X., Li, M. Q., Zhang, J. S., Zhang, Q. L., Jiao, X., Ji, X. L., Li, H., & Niu, Q. (2020). Aluminum-induced “mixed” cell death in mice cerebral tissue and potential intervention. Neurotoxicity Research, 37, 835–846.

    Article  CAS  PubMed  Google Scholar 

  • Hu, Y. B., Zhang, Y. F., Wang, H., Ren, R. J., Cui, H. L., Huang, W. Y., Cheng, Q., Chen, H. Z., & Wang, G. (2019). miR-425 deficiency promotes necroptosis and dopaminergic neurodegeneration in Parkinson’s disease. Cell Death & Disease, 10, 589.

    Article  Google Scholar 

  • Iannielli, A., Bido, S., Folladori, L., Segnali, A., Cancellieri, C., Maresca, A., Massimino, L., Rubio, A., Morabito, G., Caporali, L., Tagliavini, F., Musumeci, O., Gregato, G., Bezard, E., Carelli, V., Tiranti, V., & Broccoli, V. (2018). Pharmacological inhibition of necroptosis protects from dopaminergic neuronal cell death in Parkinson’s disease models. Cell Reports, 22, 2066–2079.

    Article  CAS  PubMed  Google Scholar 

  • 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, J. P., Mookhtiar, A. K., Florez, M., Ouchida, A. T., Fan, J. B., Pasparakis, M., Kelliher, M. A., … Yuan, J. (2016). RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science, 353, 603–608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jang, K. H., Do, Y. J., Koo, T. S., Choi, J. S., Song, E. J., Hwang, Y., Bae, H. J., Lee, J. H., & Kim, E. (2019). Protective effect of RIPK1-inhibitory compound in in vivo models for retinal degenerative disease. Experimental Eye Research, 180, 8–17.

    Article  CAS  PubMed  Google Scholar 

  • Jantas, D., Chwastek, J., Grygier, B., & Lasoń, W. (2020). Neuroprotective effects of Necrostatin-1 against oxidative stress-induced cell damage: An involvement of cathepsin D inhibition. Neurotoxicity Research, 37, 525–542.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiao, Y., Wang, J., Zhang, H., Cao, Y., Qu, Y., Huang, S., Kong, X., Song, C., Li, J., Li, Q., Ma, H., Lu, X., & Wang, L. (2020). Inhibition of microglial receptor-interacting protein kinase 1 ameliorates neuroinflammation following cerebral ischaemic stroke. Journal of Cellular and Molecular Medicine, 24, 12585–12598.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jinawong, K., Apaijai, N., Wongsuchai, S., Pratchayasakul, W., Chattipakorn, N., & Chattipakorn, S. C. (2020). Necrostatin-1 mitigates cognitive dysfunction in prediabetic rats with no alteration in insulin sensitivity. Diabetes, 69, 1411–1423.

    Article  PubMed  Google Scholar 

  • Kim, C. R., Kim, J. H., Park, H. L., & Park, C. K. (2017). Ischemia reperfusion injury triggers TNFα induced-necroptosis in rat retina. Current Eye Research, 42, 771–779.

    Article  CAS  PubMed  Google Scholar 

  • King, M. D., Whitaker-Lea, W. A., Campbell, J. M., Alleyne, C. H., Jr., & Dhandapani, K. M. (2014). Necrostatin-1 reduces neurovascular injury after intracerebral hemorrhage. International Journal of Cell Biology, 2014, 495817.

    Article  PubMed  PubMed Central  Google Scholar 

  • Li, J., Zhang, J., Zhang, Y., Wang, Z., Song, Y., Wei, S., He, M., You, S., Jia, J., & Cheng, J. (2019). TRAF2 protects against cerebral ischemia-induced brain injury by suppressing necroptosis. Cell Death & Disease, 10, 328.

    Article  Google Scholar 

  • Li, W., Liu, J., Chen, J. R., Zhu, Y. M., Gao, X., Ni, Y., Lin, B., Li, H., Qiao, S. G., Wang, C., Zhang, H. L., & Ao, G. Z. (2018). Neuroprotective effects of DTIO, a novel analogue of Nec-1, in acute and chronic stages after ischemic stroke. Neuroscience, 390, 12–29.

    Article  CAS  PubMed  Google Scholar 

  • Liang, Y. X., Wang, N. N., Zhang, Z. Y., Juan, Z. D., & Zhang, C. (2019). Necrostatin-1 ameliorates peripheral nerve injury-induced neuropathic pain by inhibiting the RIP1/RIP3 pathway. Frontiers in Cellular Neuroscience, 13, 211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin, Q. S., Chen, P., Wang, W. X., Lin, C. C., Zhou, Y., Yu, L. H., Lin, Y. X., Xu, Y. F., & Kang, D. Z. (2020). RIP1/RIP3/MLKL mediates dopaminergic neuron necroptosis in a mouse model of Parkinson disease. Laboratory Investigation, 100, 503–511.

    Article  CAS  PubMed  Google Scholar 

  • Liu, M., Wu, W., Li, H., Li, S., Huang, L. T., Yang, Y. Q., Sun, Q., Wang, C. X., Yu, Z., & Hang, C. H. (2015). Necroptosis, a novel type of programmed cell death, contributes to early neural cells damage after spinal cord injury in adult mice. The Journal of Spinal Cord Medicine, 38, 745–753.

    Article  PubMed  PubMed Central  Google Scholar 

  • Mehta, S. L., Manhas, N., & Raghubir, R. (2007). Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Research Reviews, 54, 34–66.

    Article  CAS  PubMed  Google Scholar 

  • Mikuš, P., Pecher, D., Rauová, D., Horváth, C., Szobi, A., & Adameová, A. (2018). Determination of novel highly effective necrostatin Nec-1s in rat plasma by high performance liquid chromatography hyphenated with quadrupole-time-of-flight mass spectrometry. Molecules, 23, 1946.

    Article  PubMed Central  Google Scholar 

  • Mu, J., Weng, J., Yang, C., Guan, T., Deng, L., Li, M., Zhang, G., & Kong, J. (2021). Necrostatin-1 prevents the proapoptotic protein Bcl-2/adenovirus E1B 19-kDa interacting protein 3 from integration into mitochondria. Journal of Neurochemistry, 156, 929–942.

    Article  CAS  PubMed  Google Scholar 

  • Ni, Y., Gu, W. W., Liu, Z. H., Zhu, Y. M., Rong, J. G., Kent, T. A., Li, M., Qiao, S. G., An, J. Z., & Zhang, H. L. (2018). RIP1K contributes to neuronal and astrocytic cell death in ischemic stroke via activating autophagic-lysosomal pathway. Neuroscience, 371, 60–74.

    Article  CAS  PubMed  Google Scholar 

  • Nikseresht, S., Khodagholi, F., & Ahmadiani, A. (2019). Protective effects of ex-527 on cerebral ischemia-reperfusion injury through necroptosis signaling pathway attenuation. Journal of Cellular Physiology, 234, 1816–1826.

    Article  CAS  PubMed  Google Scholar 

  • Nikseresht, S., Khodagholi, F., Nategh, M., & Dargahi, L. (2015). RIP1 inhibition rescues from Lps-induced Rip3-mediated programmed cell death, distributed energy metabolism and spatial memory impairment. Journal of Molecular Neuroscience, 57, 219–230.

    Article  CAS  PubMed  Google Scholar 

  • Northington, F. J., Chavez-Valdez, R., Graham, E. M., Razdan, S., Gauda, E. B., & Martin, L. J. (2011). Necrostatin decreases oxidative damage, inflammation, and injury after neonatal HI. Journal of Cerebral Blood Flow and Metabolism, 31, 178–189.

    Article  CAS  PubMed  Google Scholar 

  • Oñate, M., Catenaccio, A., Salvadores, N., Saquel, C., Martinez, A., Moreno-Gonzalez, I., Gamez, N., Soto, P., Soto, C., Hetz, C., & Court, F. A. (2020). The necroptosis machinery mediates axonal degeneration in a model of Parkinson disease. Cell Death and Differentiation, 27, 1169–1185.

    Article  PubMed  Google Scholar 

  • Qinli, Z., Meiqing, L., Xia, J., Li, X., Weili, G., Xiuliang, J., Junwei, J., Hailan, Y., Ce, Z., & Qiao, N. (2013). Necrostatin-1 inhibits the degeneration of neural cells induced by aluminum exposure. Restorative Neurology and Neuroscience, 31, 543–555.

    Article  PubMed  Google Scholar 

  • Re, D. B., Le Verche, V., Yu, C., Amoroso, M. W., Politi, K. A., Phani, S., Ikiz, B., Hoffmann, L., Koolen, M., Nagata, T., Papadimitriou, D., Nagy, P., Mitsumoto, H., Kariya, S., Wichterle, H., Henderson, C. E., & Przedborski, S. (2014). Necroptosis drives motor neuron death in models of both sporadic and familial ALS. Neuron, 81, 1001–1008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosenbaum, D. M., Degterev, A., David, J., Rosenbaum, P. S., Roth, S., Grotta, J. C., Cuny, G. D., Yuan, J., & Savitz, S. I. (2010). Necroptosis, a novel form of caspase-independent cell death, contributes to neuronal damage in a retinal ischemia-reperfusion injury model. Journal of Neuroscience Research, 88, 1569–1576.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Savard, A., Brochu, M. E., Chevin, M., Guiraut, C., Grbic, D., & Sébire, G. (2015). Neuronal self-injury mediated by IL-1β and MMP-9 in a cerebral palsy model of severe neonatal encephalopathy induced by immune activation plus hypoxia-ischemia. Journal of Neuroinflammation, 12, 111.

    Article  PubMed  PubMed Central  Google Scholar 

  • Su, X., Wang, H., Kang, D., Zhu, J., Sun, Q., Li, T., & Ding, K. (2015). Necrostatin-1 ameliorates intracerebral hemorrhage-induced brain injury in mice through inhibiting RIP1/RIP3 pathway. Neurochemical Research, 40, 643–650.

    Article  CAS  PubMed  Google Scholar 

  • Takahashi, N., Duprez, L., Grootjans, S., Cauwels, A., Nerinckx, W., DuHadaway, J. B., Goossens, V., Roelandt, R., Van Hauwermeiren, F., Libert, C., Declercq, W., Callewaert, N., Prendergast, G. C., Degterev, A., Yuan, J., & Vandenabeele, P. (2012). Necrostatin-1 analogues: Critical issues on the specificity, activity and in vivo use in experimental disease models. Cell Death & Disease, 3, e437.

    Article  CAS  Google Scholar 

  • Teng, X., Degterev, A., Jagtap, P., Xing, X., Choi, S., Denu, R., Yuan, J., & Cuny, G. D. (2005). Structure-activity relationship study of novel necroptosis inhibitors. Bioorganic & Medicinal Chemistry Letters, 15, 5039–5044.

    Article  CAS  Google Scholar 

  • Thomas, C. N., Thompson, A. M., Ahmed, Z., & Blanch, R. J. (2019). Retinal ganglion cells die by necroptotic mechanisms in a site-specific manner in a rat blunt ocular injury model. Cell, 8, 1517.

    Article  CAS  Google Scholar 

  • Trichonas, G., Murakami, Y., Thanos, A., Morizane, Y., Kayama, M., Debouck, C. M., Hisatomi, T., Miller, J. W., & Vavvas, D. G. (2010). Receptor interacting protein kinases mediate retinal detachment-induced photoreceptor necrosis and compensate for inhibition of apoptosis. Proceedings of the National Academy of Sciences of the United States of America, 107, 21695–21700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vanden Berghe, T., Kaiser, W. J., Bertrand, M. J., & Vandenabeele, P. (2015). Molecular crosstalk between apoptosis, necroptosis, and survival signaling. Molecular & Cellular Oncology, 2, e975093.

    Article  Google Scholar 

  • Vandenabeele, P., Galluzzim, L., Vanden Berghem, T., & Kroemer, G. (2010). Molecular mechanisms of necroptosis: An ordered cellular explosion. Nature Reviews. Molecular Cell Biology, 11, 700–714.

    Article  CAS  PubMed  Google Scholar 

  • Viringipurampeer, I. A., Metcalfe, A. L., Bashar, A. E., Sivak, O., Yanai, A., Mohammadi, Z., Moritz, O. L., Gregory-Evans, C. Y., & Gregory-Evans, K. (2016). NLRP3 inflammasome activation drives bystander cone photoreceptor cell death in a P23H rhodopsin model of retinal degeneration. Human Molecular Genetics, 25, 1501–1516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, S., Wu, J., Zeng, Y. Z., Wu, S. S., Deng, G. R., Chen, Z. D., & Lin, B. (2017). Necrostatin-1 mitigates endoplasmic reticulum stress after spinal cord injury. Neurochemical Research, 42, 3548–3558.

    Article  CAS  PubMed  Google Scholar 

  • Wang, T., Perera, N. D., Chiam, M. D. F., Cuic, B., Wanniarachchillage, N., Tomas, D., Samson, A. L., Cawthorne, W., Valor, E. N., Murphy, J. M., & Turner, B. J. (2020). Necroptosis is dispensable for motor neuron degeneration in a mouse model of ALS. Cell Death and Differentiation, 27, 1728–1739.

    Article  CAS  PubMed  Google Scholar 

  • Wang, X., Mao, X., Liang, K., Chen, X., Yue, B., & Yang, Y. (2021). RIP3-mediated necroptosis was essential for spiral ganglion neuron damage. Neuroscience Letters, 744, 135565.

    Article  CAS  PubMed  Google Scholar 

  • Wang, X., Wang, Y., Ding, Z. J., Yue, B., Zhang, P. Z., Chen, X. D., Chen, X., Chen, J., Chen, F. Q., Chen, Y., Wang, R. F., Mi, W. J., Lin, Y., Wang, J., & Qiu, J. H. (2014b). The role of RIP3 mediated necroptosis in ouabain-induced spiral ganglion neurons injuries. Neuroscience Letters, 578, 111–116.

    Article  CAS  PubMed  Google Scholar 

  • Wang, Y., Guo, L., Wang, J., Shi, W., Xia, Z., & Li, B. (2019b). Necrostatin-1 ameliorates the pathogenesis of experimental autoimmune encephalomyelitis by suppressing apoptosis and necroptosis of oligodendrocyte precursor cells. Experimental and Therapeutic Medicine, 18, 4113–4119.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, Y., Jiao, J., Zhang, S., Zheng, C., & Wu, M. (2019a). RIP3 inhibition protects locomotion function through ameliorating mitochondrial antioxidative capacity after spinal cord injury. Biomedicine & Pharmacotherapy, 116, 109019.

    Article  CAS  Google Scholar 

  • Wang, Y., Wang, H., Tao, Y., Zhang, S., Wang, J., & Feng, X. (2014a). Necroptosis inhibitor necrostatin-1 promotes cell protection and physiological function in traumatic spinal cord injury. Neuroscience, 266, 91–101.

    Article  CAS  PubMed  Google Scholar 

  • Wang, Y., Wang, J., Yang, H., Zhou, J., Feng, X., Wang, H., & Tao, Y. (2015). Necrostatin-1 mitigates mitochondrial dysfunction post-spinal cord injury. Neuroscience, 289, 224–232.

    Article  CAS  PubMed  Google Scholar 

  • Wang, Y. Q., Wang, L., Zhang, M. Y., Wang, T., Bao, H. J., Liu, W. L., Dai, D. K., Zhang, L., Chang, P., Dong, W. W., Chen, X. P., & Tao, L. Y. (2012). Necrostatin-1 suppresses autophagy and apoptosis in mice traumatic brain injury model. Neurochemical Research, 37, 1849–1858.

    Article  CAS  PubMed  Google Scholar 

  • Xie, T., Peng, W., Liu, Y., Yan, C., Maki, J., Degterev, A., Yuan, J., & Shi, Y. (2013). Structural basis of RIP1 inhibition by necrostatins. Structure, 21, 493–499.

    Article  CAS  PubMed  Google Scholar 

  • Xu, X., Chua, K. W., Chua, C. C., Liu, C. F., Hamdy, R. C., & Chua, B. H. (2010). Synergistic protective effects of humanin and necrostatin-1 on hypoxia and ischemia/reperfusion injury. Brain Research, 1355, 189–194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang, C., Li, T., Xue, H., Wang, L., Deng, L., Xie, Y., Bai, X., Xin, D., Yuan, H., Qiu, J., Wang, Z., & Li, G. (2019a). Inhibition of necroptosis rescues SAH-induced synaptic impairments in hippocampus via CREB-BDNF pathway. Frontiers in Neuroscience, 12, 990.

    Article  PubMed  PubMed Central  Google Scholar 

  • Yang, R., Hu, K., Chen, J., Zhu, S., Li, L., Lu, H., Li, P., & Dong, R. (2017a). Necrostatin-1 protects hippocampal neurons against ischemia/reperfusion injury via the RIP3/DAXX signaling pathway in rats. Neuroscience Letters, 651, 207–215.

    Article  CAS  PubMed  Google Scholar 

  • Yang, S. H., Lee, D. K., Shin, J., Lee, S., Baek, S., Kim, J., Jung, H., Hah, J. M., & Kim, Y. (2017b). Nec-1 alleviates cognitive impairment with reduction of Abeta and tau abnormalities in APP/PS1 mice. EMBO Molecular Medicine, 9, 61–77.

    Article  CAS  PubMed  Google Scholar 

  • Yang, S. H., Shin, J., Shin, N. N., Hwang, J. H., Hong, S. C., Park, K., Lee, J. W., Lee, S., Baek, S., Kim, K., Cho, I., & Kim, Y. (2019b). A small molecule Nec-1 directly induces amyloid clearance in the brains of aged APP/PS1 mice. Scientific Reports, 9, 4183.

    Article  PubMed  PubMed Central  Google Scholar 

  • Yin, B., Xu, Y., Wei, R. L., He, F., Luo, B. Y., & Wang, J. Y. (2015). Inhibition of receptor-interacting protein 3 upregulation and nuclear translocation involved in Necrostatin-1 protection against hippocampal neuronal programmed necrosis induced by ischemia/reperfusion injury. Brain Research, 1609, 63–71.

    Article  CAS  PubMed  Google Scholar 

  • You, Z., Savitz, S. I., Yang, J., Degterev, A., Yuan, J., Cuny, G. D., Moskowitz, M. A., & Whalen, M. J. (2008). Necrostatin-1 reduces histopathology and improves functional outcome after controlled cortical impact in mice. Journal of Cerebral Blood Flow and Metabolism, 28, 1564–1573.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, S., Tang, M. B., Luo, H. Y., Shi, C. H., & Xu, Y. M. (2017). Necroptosis in neurodegenerative diseases: A potential therapeutic target. Cell Death & Disease, 8, e2905.

    Article  CAS  Google Scholar 

  • Zhao, H., Jaffer, T., Eguchi, S., Wang, Z., Linkermann, A., & Ma, D. (2015). Role of necroptosis in the pathogenesis of solid organ injury. Cell Death & Disease, 6, e1975.

    Article  CAS  Google Scholar 

  • Zhou, K., Shi, L., Wang, Z., Zhou, J., Manaenko, A., Reis, C., Chen, S., & Zhang, J. (2017). RIP1-RIP3-DRP1 pathway regulates NLRP3 inflammasome activation following subarachnoid hemorrhage. Experimental Neurology, 295, 116–124.

    Article  CAS  PubMed  Google Scholar 

  • Zhu, S., Zhang, Y., Bai, G., & Li, H. (2011). Necrostatin-1 ameliorates symptoms in R6/2 transgenic mouse model of Huntington’s disease. Cell Death & Disease, 2, e115.

    Article  CAS  Google Scholar 

  • Zhu, X., Park, J., Golinski, J., Qiu, J., Khuman, J., Lee, C. C., Lo, E. H., Degterev, A., Whalen, M., & J. (2014). Role of Akt and mammalian target of rapamycin in functional outcome after concussive brain injury in mice. Journal of Cerebral Blood Flow and Metabolism, 34, 1531–1539.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Maj Institute of Pharmacology Polish Academy of Sciences, Department of Experimental Neuroendocrinology, Krakow, Poland

    Danuta Jantas & Władysław Lasoń

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  1. Danuta Jantas
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  2. Władysław Lasoń
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Correspondence to Danuta Jantas .

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  1. Department of Biomedical Sciences, East Tennessee State University, Johnson City, TN, USA

    Richard M. Kostrzewa

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Jantas, D., Lasoń, W. (2021). Necrostatin-1 as a Neuroprotectant. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-030-71519-9_210-1

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