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
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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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DOI: https://doi.org/10.1007/978-3-030-71519-9_210-1
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