Necroptosis inhibitor necrostatin-1 promotes cell protection and physiological function in traumatic spinal cord injury

Wang, Y.; Wang, Hongrong; Tao, Yajun; Zhang, S.; Wang, J.; Feng, Xinmin

doi:10.1016/j.neuroscience.2014.02.007

Cited by 115 publications

(95 citation statements)

References 31 publications

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“…Nec-1 mediates neuroprotective effects in rodent models of acute and chronic neurological conditions, including adult stroke (146), neonatal hypoxia/ischemia (H/I) (147, 148), retinal ischemia (149), retinal detachment (150–152), subarachnoid hemorrhage (153, 154), traumatic brain injury (155), spinal cord injury (156–159), and amyotrophic lateral sclerosis (160). The ability of Nec-1 to counteract manifestations of amyotrophic lateral sclerosis in mice was backed up by the knockdown of RIPK1 as well as by data obtained using human cells treated with necrosulfonamide (NSA, a chemical that inhibits human MLKL) (160).…”

Section: Pathophysiological Relevance Of Necroptosismentioning

confidence: 99%

Necroptosis: Mechanisms and Relevance to Disease

Galluzzi

Kepp

Chan

2017

Annu. Rev. Pathol. Mech. Dis.

532

398

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Necroptosis is a form of regulated cell death that critically depends on receptor-interacting serine-threonine kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) and generally manifests with morphological features of necrosis. The molecular mechanisms that underlie distinct instances of necroptosis have just begun to emerge. Nonetheless, it has already been shown that necroptosis contributes to cellular demise in various pathophysiological conditions, including viral infection, acute kidney injury, and cardiac ischemia/reperfusion. Moreover, human tumors appear to obtain an advantage from the downregulation of key components of the molecular machinery for necroptosis. Although such an advantage may stem from an increased resistance to adverse microenvironmental conditions, accumulating evidence indicates that necroptosis-deficient cancer cells are poorly immunogenic and hence escape natural and therapy-elicited immunosurveillance. Here, we discuss the molecular mechanisms and relevance to disease of necroptosis.

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Section: Pathophysiological Relevance Of Necroptosismentioning

confidence: 99%

Necroptosis: Mechanisms and Relevance to Disease

Galluzzi

Kepp

Chan

2017

Annu. Rev. Pathol. Mech. Dis.

532

398

View full text Add to dashboard Cite

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“…The neuroprotective potential of Nec-1 and its analogs in cellular and animal models of ischemia is rather well supported (Chavez-Valdez et al 2012Degterev et al 2005;Li et al 2018;Ni et al 2018;Northington et al 2011;Xu et al 2010a;Yang et al 2017a;Yin et al 2015;Zhan et al 2019;Zhang et al 2016). Moreover, in an in vitro setting, Nec-1 attenuated the neuronal cell damage induced by various harmful agents, e.g., oaubain, glutamate (Glu), N-methyl-D-aspartate (NMDA), 6hydroxydopamine (6-OHDA), rotenone, 1-methyl-4phenylpyridinium ion (MPP+), methamphetamine, aluminum (Al), 24(S)-hydroxycholesterol, cholesterol, staurosporine, and doxorubicin (Funakoshi et al 2016;Ito et al 2017;Jantas et al 2014a;Li et al 2011;Wang et al 2014;Wu et al 2015;Xiong et al 2016;Xu et al 2007;Yamanaka et al 2011;Zhang et al 2013). It should be noted that the protective effect of Nec-1 in the above studies was only partial, suggesting the participation of other than necroptosis cell death programs which can vary depending on the type of neuronal injury as has already been shown by in vivo (ischemia, traumatic brain injury, spinal cord injury, retina injury) and in vitro studies (e.g., Al-, iron-, 6-OHDA-, or β-amyloidinduced neurotoxicity) (Askalan et al 2015;Chinskey et al 2014;Dai et al 2013;Dong et al 2012;Liu et al 2014;Rosenbaum et al 2010;Qinli et al 2013;Wu et al 2015;Xu et al 2010a;Zhang et al 2008).…”

Section: Introductionmentioning

confidence: 95%

Neuroprotective Effects of Necrostatin-1 Against Oxidative Stress–Induced Cell Damage: an Involvement of Cathepsin D Inhibition

et al. 2020

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Necroptosis, a recently discovered form of non-apoptotic programmed cell death, can be implicated in many pathological conditions including neuronal cell death. Moreover, an inhibition of this process by necrostatin-1 (Nec-1) has been shown to be neuroprotective in in vitro and in vivo models of cerebral ischemia. However, the involvement of this type of cell death in oxidative stress-induced neuronal cell damage is less recognized. Therefore, we tested the effects of Nec-1, an inhibitor of necroptosis, in the model of hydrogen peroxide (H 2 O 2)-induced cell damage in human neuroblastoma SH-SY5Y and murine hippocampal HT-22 cell lines. The data showed that Nec-1 (10-40 μM) attenuated the cell death induced by H 2 O 2 in undifferentiated (UN-) and neuronal differentiated (RA-) SH-SY5Y cells with a higher efficacy in the former cell type. Moreover, Nec-1 partially reduced cell damage induced by 6-hydroxydopamine in UN-and RASH -SY5Y cells. The protective effect of Nec-1 was of similar magnitude as the effect of a caspase-3 inhibitor in both cell phenotypes and this effect were not potentiated after combined treatment. Furthermore, the non-specific apoptosis and necroptosis inhibitor curcumin augmented the beneficial effect of Nec-1 against H 2 O 2-evoked cell damage albeit only in RASH -SY5Y cells. Next, it was found that the mechanisms of neuroprotective effect of Nec-1 against H 2 O 2induced cell damage in SH-SY5Y cells involved the inhibition of lysosomal protease, cathepsin D, but not caspase-3 or calpain activities. In HT-22 cells, Nec-1 was protective in two models of oxidative stress (H 2 O 2 and glutamate) and that effect was blocked by a caspase inhibitor. Our data showed neuroprotective effects of the necroptosis inhibitor, Nec-1, against oxidative stress-induced cell damage and pointed to involvement of cathepsin D inhibition in the mechanism of its action. Moreover, a cell type-specific interplay between necroptosis and apoptosis has been demonstrated.

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“…Our experiment demonstrated that cell model after EHP could accurately reflect the injury degree of RGCs. Moreover, Nec-1 has become one of the widely recognized inhibitors in necroptosis [31]. Based on our data, the necroptosis can be found after high pressure insult (100 mmHg), and the proportion was reflected by the fact that the necrosis rate decreased to about 5% after adding Nec-1.…”

Section: Discussionmentioning

confidence: 52%

“…Nec-1 is the specific inhibitor of necroptosis, as reported in other studies the cell number of necrosis decreased when using it [31,32]. In order to analyze necroptosis, we detected the PI-positive cells to analyze cellular necroptosis by flow cytometry with PI/Annexin V double staining using Nec-1.…”

Section: Resultsmentioning

confidence: 93%

Calpain: a molecule to induce AIF-mediated necroptosis in RGC-5 following elevated hydrostatic pressure

et al. 2014

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BackgroundRIP3 (Receptor-interacting protein 3) pathway was mainly described as the molecular mechanism of necroptosis (programmed necrosis). But recently, non-RIP3 pathways were found to mediate necroptosis. We deliberate to investigate the effect of calpain, a molecule to induce necroptosis as reported (Cell Death Differ 19:245–256, 2012), in RGC-5 following elevated hydrostatic pressure.ResultsFirst, we identified the existence of necroptosis of RGC-5 after insult by using necrostatin-1 (Nec-1, necroptosis inhibitor) detected by flow cytometry. Immunofluorescence staining and western blot were used to detect the expression of calpain. Western blot analysis was carried out to describe the truncated AIF (tAIF) expression with or without pretreatment of ALLN (calpain activity inhibitor). Following elevated hydrostatic pressure, necroptotic cells pretreated with or without ALLN was stained by Annexin V/PI, The activity of calpain was also examined to confirm the inhibition effect of ALLN. The results showed that after cell injury there was an upregulation of calpain expression. Upon adding ALLN, the calpain activity was inhibited, and tAIF production was reduced upon injury along with the decreased number of necroptosis cells.ConclusionOur study found that calpain may induce necroptosis via tAIF-modulation in RGC-5 following elevated hydrostatic pressure.

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Necroptosis inhibitor necrostatin-1 promotes cell protection and physiological function in traumatic spinal cord injury

Cited by 115 publications

References 31 publications

Necroptosis: Mechanisms and Relevance to Disease

Necroptosis: Mechanisms and Relevance to Disease

Neuroprotective Effects of Necrostatin-1 Against Oxidative Stress–Induced Cell Damage: an Involvement of Cathepsin D Inhibition

Calpain: a molecule to induce AIF-mediated necroptosis in RGC-5 following elevated hydrostatic pressure

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