Therapeutic Role of a Cysteine Precursor, OTC, in Ischemic Stroke Is Mediated by Improved Proteostasis in Mice.

Abstract

Oxidative stress aggravates brain injury following ischemia/reperfusion (I/R). We previously showed that ubiquilin-1 (Ubqln1), a ubiquitin-like protein, improves proteostasis and protects brains against oxidative stress and I/R-induced brain injury. Here, we demonstrate that a small molecule compound, L-2-oxothiazolidine-4-carboxylic acid (OTC) that functions as a precursor of cysteine, upregulated Ubqln1 and protected cells against oxygen-glucose deprivation-induced cell death in neuronal cultures. Further, the administration of OTC either at 1 h prior to ischemia or 3 h after the reperfusion significantly reduced brain infarct injury and improved behavioral outcomes in a stroke model. Administration of OTC also increased glutathione (GSH) level and decreased superoxide production, oxidized protein, and neuroinflammation levels in the penumbral cortex after I/R in the stroke mice. Furthermore, I/R reduced both Ubqln1 and the glutathione S-transferase protein levels, whereas OTC treatment restored both protein levels, which was associated with reduced ubiquitin-conjugated protein level. Interestingly, in the Ubqln1 knockout (KO) mice, OTC treatment showed reduced neuroprotection and increased ubiquitin-conjugated protein level when compared to the similarly treated non-KO mice following I/R, suggesting that OTC-medicated neuroprotection is, at least partially, Ubqln1-dependent. Thus, OTC is a potential therapeutic agent for stroke and possibly for other neurological disorders and its neuroprotection involves enhanced proteostasis.

• Authors: Yanying Liu, Jia-Wei Min, Shelley Feng, Kalpana Subedi, Fangfang Qiao, Emily Mammenga, Eduardo Callegari, Hongmin Wang
• Journal: Translational stroke research (Transl Stroke Res) Vol. 11 Issue 1 Pg. 147-160 (02 2020) ISSN: 1868-601X [Electronic] United States
• PMID: 31049841 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adaptor Proteins, Signal Transducing
• Autophagy-Related Proteins
• Thiazolidines
• UBQLN1 protein, mouse
• Cysteine
• Pyrrolidonecarboxylic Acid
• 2-oxothiazolidine-4-carboxylic acid

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Animals
• Autophagy-Related Proteins (metabolism)
• Brain Ischemia (drug therapy, metabolism)
• Cells, Cultured
• Cysteine (metabolism)
• Ischemic Stroke (drug therapy, metabolism)
• Male
• Mice, Inbred C57BL
• Neurons (drug effects, metabolism)
• Oxidative Stress (drug effects)
• Proteostasis (drug effects)
• Pyrrolidonecarboxylic Acid (administration & dosage)
• Thiazolidines (administration & dosage)