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RIP1 Inhibition Rescues from LPS-Induced RIP3-Mediated Programmed Cell Death, Distributed Energy Metabolism and Spatial Memory Impairment

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Abstract

Receptor interacting protein 1 (RIP1) has a critical role in initiation of programmed necrosis or necroptosis. RIP1 in a close collaboration with RIP3 not only mediates necroptosis but also is involved in apoptosis and inflammatory signaling. However, the interpretation of the distinct function of RIP1 and RIP3 is complicated. Herein, we demonstrated that RIP1 inhibition in the context of LPS-induced neuroinflammation decreases RIP3 expression. Concomitant administration of Nec-1, specific inhibitor of RIP1, with LPS also attenuated the activating effect of RIP3 on metabolic enzymes, glutamate-ammonia ligase and glutamate dehydrogenase as bioenergetic determinants, in hippocampal and cortical cells. RIP1 inhibition possessed an anti-inflammatory effect and improved the antioxidant capacity against LPS. Interestingly, and opposed to some reports that necroptosis inhibition sensitizes cells to apoptosis, our results showed that RIP1 inhibition attenuates apoptotic cell death in response to LPS. The survival of neuronal function was also confirmed by measuring spontaneous alternations of rats in Y-maze. In conclusion, effects of RIP1 inhibition on RIP3 and cell death provide new approaches to ameliorate neuroinflammation and relative disorders.

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Acknowledgments

This work was carried out as part of a PhD project and financially supported by the Neuroscience Research Center, Shahid Beheshti University of Medical Sciences.

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Authors and Affiliations

  1. Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Sara Nikseresht, Fariba Khodagholi & Mohsen Nategh

  2. NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Leila Dargahi

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  1. Sara Nikseresht
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  2. Fariba Khodagholi
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Correspondence to Leila Dargahi.

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Nikseresht, S., Khodagholi, F., Nategh, M. et al. RIP1 Inhibition Rescues from LPS-Induced RIP3-Mediated Programmed Cell Death, Distributed Energy Metabolism and Spatial Memory Impairment. J Mol Neurosci 57, 219–230 (2015). https://doi.org/10.1007/s12031-015-0609-3

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