Necroptosis contributes to methamphetamine-induced cytotoxicity in rat cortical neurons

Liao

et al. 2018

Front. Cell. Neurosci.

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The purpose of the current study was to investigate whether peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) can interact with calpastatin (CAST) and regulate CAST/calpain2, under excessive glutamate conditions, and subsequently regulate necrosis in rat retinal neurons. Glutamate triggered CAST/calpain2-mediated necrosis regulation in primary cultured retinal neurons, as demonstrated by propidium iodide-staining and lactate dehydrogenase assay. Co-IP results and a computer simulation suggested that Pin1 could bind to CAST. Western blot, real-time quantitative polymerase chain reaction, immunofluorescence, and phosphorylation analysis results demonstrated that CAST was regulated by Pin1, as proven by the application of juglone (i.e., a Pin1 specific inhibitor). The retinal ganglion cell 5 cell line, combined with siRNA approach and flow cytometry, was then used to verify the regulatory pathway of Pin1 in CAST/calpain2-modulated neuronal necrosis that was induced by glutamate. Finally, in vivo studies further confirmed the role of Pin1 in CAST/calpain2-modulated necrosis following glutamate excitation, in the rat retinal ganglion cell and inner nuclear layers. In addition, a flash electroretinogram study provided evidence for the recovery of impaired visual function, which was induced by glutamate, with juglone treatment. Our work aims to investigate the involvement of the Pin1-CAST/calpain2 pathway in glutamate-mediated excitotoxicity.

Section: Methodsmentioning

confidence: 99%

Pin1 Promotes Regulated Necrosis Induced by Glutamate in Rat Retinal Neurons via CAST/Calpain2 Pathway

Liao

et al. 2018

Front. Cell. Neurosci.

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“…Agents such as inorganic metals, pesticides, and psychostimulants can induce neurotoxicity (Liu et al ; Xiong et al ; Zhang et al ; Sang et al ; Yang et al ; Gao et al ). Because of the significant impacts on human health caused by neurotoxic agents, there is considerable demand to characterize the biological signals and markers associated with exposure to these agents (Roberts et al ; Yang et al ).…”

Section: Circrnas In Neurological Disordersmentioning

confidence: 99%

Current status and potential role of circular RNAs in neurological disorders

Yang

Journal of Neurochemistry

et al. 2019

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Given the importance of non‐coding RNAs in modulating normal brain functions and their implications in the treatment of neurological disorders, non‐coding RNA‐based diagnostic and therapeutic strategies have shown great clinical potential. Circular RNAs (circRNAs) have emerged as potentially important players in this field. Recent studies have indicated that circRNAs might play vital roles in Alzheimer’s disease, Parkinson’s disease, ischemic brain injury, and neurotoxicity. However, the mechanisms of action of circRNAs have not been fully characterized. We aimed to review recent advances in circRNA research in the brain to provide new insights on the roles of circRNAs in neurological disorders.

“…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: 99%

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

et al. 2020

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.