Secondary prostaglandin metabolites produced by activation of cyclooxygenase 2 (COX2) after ischemia such as the cyclopentenone prostaglandins (CyPGs) may produce neuronal cell death. In preliminary studies, the concentrations of the CyPGs 15-deoxy-D12,14-PGD2, 15-deoxy-D12,14-PGJ2, and 12-PGJ2 were dramatically increased in brain after temporary focal ischemia. CyPGs injure primary cultured neurons, increase accumulation of ubiquitinated proteins (Ub-proteins), and exacerbate hypoxic injury in vitro at concentrations similar to those found in vivo. CyPGs covalently modify the cysteine C220 of UCH-L1, the key deubiquitinating enzyme in brain, and inhibit its activity. The susceptibility of neurons to hypoxia is reduced by transduction of neurons with a TAT-HA-UCH-L1 fusion protein. Based on these and other data we hypothesize that concentrations of CyPGs are increased in brain after ischemia and that CyPGs exacerbate hypoxic ischemic injury by disrupting the neuronal ubiquitin proteosome pathway (UPP), including covalent bonding and inhibition of UCH-L1. The following specific aims are proposed: 1. Characterize the production and metabolism of CyPGs after cerebral ischemia in vivo. 2. Determine if CyPGs exacerbate hypoxic injury and disrupt the UPP in primary neuronal culture in vitro. 3. Determine the role of inhibition of UCH-L1 activity and other components of the UPP by CyPGs in hypoxic ischemic injury. Accumulation of Ub-proteins and protein aggregation are important etiologies of delayed neuronal death in ischemia and neurodegenerative diseases. These studies aim to elucidate a new understanding of an important mechanism that results in accumulation of Ub-proteins and ER stress induced after ischemia. These findings may be relevant to the pathogenesis of stroke and neurodegenerative diseases such as Parkinson's and Alzheimer's disease.
The development of selective cyclooxygenase 2 (COX2) inhibitors as non-steroidal anti-inflammatory drugs raised hopes that these drugs could be useful in the treatment of stroke;however, chronic treatment with selective COX2 inhibitors such as Vioxx increased the incidence of myocardial ischemia and stroke in human trials. These undesirable effects of COX2 inhibitors have resulted in many of the drugs being withdrawn from the US market and tempered enthusiasm for any trials of these agents for acute stroke treatment. The current project aims to identify a downstream mechanism by which COX2 activity injures neurons which could lead to new treatments for stroke and neurodegenerative diseases.
|Tecuatl, Carolina; Herrrera-López, Gabriel; Martín-Ávila, Alejandro et al. (2018) TrkB-mediated activation of the phosphatidylinositol-3-kinase/Akt cascade reduces the damage inflicted by oxygen-glucose deprivation in area CA3 of the rat hippocampus. Eur J Neurosci 47:1096-1109|
|Liu, Hao; Rose, Marie E; Ma, Xiecheng et al. (2017) In vivo transduction of neurons with TAT-UCH-L1 protects brain against controlled cortical impact injury. PLoS One 12:e0178049|
|Graham, Steven H; Liu, Hao (2017) Life and death in the trash heap: The ubiquitin proteasome pathway and UCHL1 in brain aging, neurodegenerative disease and cerebral Ischemia. Ageing Res Rev 34:30-38|
|Graham, Steven H (2016) Modification of ubiquitin C-terminal hydrolase L1 by reactive lipid species: role in neural regeneration and diseases of aging. Neural Regen Res 11:908-9|
|Liu, H; Li, W; Rose, M E et al. (2015) The point mutation UCH-L1 C152A protects primary neurons against cyclopentenone prostaglandin-induced cytotoxicity: implications for post-ischemic neuronal injury. Cell Death Dis 6:e1966|
|Liu, Hao; Chen, Jie; Li, Wenjin et al. (2015) Protein disulfide isomerase as a novel target for cyclopentenone prostaglandins: implications for hypoxic ischemic injury. FEBS J 282:2045-59|
|Ahmad, Muzamil; Dar, Nawab J; Bhat, Zubair S et al. (2014) Inflammation in ischemic stroke: mechanisms, consequences and possible drug targets. CNS Neurol Disord Drug Targets 13:1378-96|
|Shaik, Jafar Sadik B; Miller, Tricia M; Graham, Steven H et al. (2014) Rapid and simultaneous quantitation of prostanoids by UPLC-MS/MS in rat brain. J Chromatogr B Analyt Technol Biomed Life Sci 945-946:207-16|
|Liu, Hao; Rose, Marie E; Miller, Tricia M et al. (2013) COX2-derived primary and cyclopentenone prostaglandins are increased after asphyxial cardiac arrest. Brain Res 1519:71-7|
|Liu, Hao; Li, Wenjin; Ahmad, Muzamil et al. (2013) Increased generation of cyclopentenone prostaglandins after brain ischemia and their role in aggregation of ubiquitinated proteins in neurons. Neurotox Res 24:191-204|
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