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

• Published in: Translational stroke research Vol. 11; no. 1; pp. 147 - 160
• Main Authors: Liu, Yanying, Min, Jia-Wei, Feng, Shelley, Subedi, Kalpana, Qiao, Fangfang, Mammenga, Emily, Callegari, Eduardo, Wang, Hongmin
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2020; Springer Nature B.V
• Subjects: Antioxidants; Biomedical and Life Sciences; Biomedicine; Brain research; Cardiology; Cell death; Experiments; FDA approval; Glucose; Ischemia; Laboratory animals; Neurology; Neurosciences; Neurosurgery; Original Article; Oxidative stress; Penicillin; Proteins; Software; Stroke; Vascular Surgery; United States > US; Ubiquilin-1; Oxidative stress; Stroke; Proteostasis; Cysteine precursor
• ISSN: 1868-4483; 1868-601X
• DOI: 10.1007/s12975-019-00707-w

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.