ABSTRACT
Stroke is associated with over-production of misfolded and aggregating proteins. However, it remains largely unclear whether enhanced removal of protein aggregates following ischemic stroke is neuroprotective. Deubiquitinating enzymes (DUBs) are a large group of proteases that regulate protein degradation. The ubiquitin-specific protease 14 (USP14) is a DUB that is associated with the proteasome and negatively regulates proteasome activity. In this study, we examined the effect of 1-[1-(4-fluorophenyl)-2,5-dimethylpyrrol-3-yl]-2-pyrrolidin-1-ylethanone (IU1), a specific small molecule inhibitor of USP14, on mouse focal cerebral ischemic stroke-induced neuronal injury in mice. We found that IU1 treatment attenuated ischemic stroke-caused neuronal injury, which was reflected by increased survival rate, reduced infarct volume, as well as decreased neuronal loss in the IU1-treated mice compared to the control-treated mice. Additionally, IU1 treatment is associated with reduced protein aggregates and enhanced proteasome functionality. These data not only highlight the significance of protein homeostasis in cerebral ischemia/reperfusion-induced neuronal injury but also extend the therapeutic role of DUB inhibitors.
Subject(s)
Brain Ischemia/drug therapy , Neurons/pathology , Neuroprotective Agents/therapeutic use , Protease Inhibitors/therapeutic use , Pyrroles/therapeutic use , Pyrrolidines/therapeutic use , Reperfusion Injury/drug therapy , Ubiquitin Thiolesterase/antagonists & inhibitors , Animals , Behavior, Animal , Brain Ischemia/psychology , Infarction, Middle Cerebral Artery/pathology , Male , Mice , Mice, Inbred C57BL , Proteasome Endopeptidase Complex/drug effects , Recovery of Function , Reperfusion Injury/psychology , Survival AnalysisABSTRACT
OBJECTIVE: The development of arterial hypertension is sexually dimorphic. Venous tone is elevated in the spontaneously hypertensive rat model of hypertension. This study tested the hypothesis that endogenous androgens exacerbate venous tone in the developmental stages of spontaneous hypertension. METHODS: Male spontaneously hypertensive rats (SHRs) were subjected to sham operation, castration or castration + testosterone treatment. Ten-week-old SHR rats were instrumented for the measurement of arterial and venous pressure. A balloon catheter was advanced into the right atrium. Mean circulatory filling pressure (MCFP), an index of venous tone, was calculated. Mean arterial pressure (MAP) and MCFP were recorded from conscious rats. Postsynaptic adrenergic responsiveness was assessed by constructing cumulative dose-response curves to norepinephrine (NE). Baseline values and responsiveness to NE were obtained before and after autonomic blockade. RESULTS: MAP and MCFP were significantly reduced in castrated (MAP, 130 +/- 4 mmHg; MCFP, 5.5 +/- 0.2 mmHg) versus sham-operated SHRs (MAP, 149 +/- 5 mmHg; MCFP, 6.7 +/- 0.3 mmHg) or castrated + testosterone-treated SHRs (MAP, 145 +/- 6 mmHg; MCFP, 7.1 +/- 0.4 mmHg). Ganglion blockade abolished these differences in MAP and MCFP. Infusion of NE caused dose-dependent increases in MAP and MCFP. The MAP responses in castrated SHRs were displaced to the right of those for sham and castrated + testosterone-treated SHRs. This was not evident in the venous circulation, where there were no marked differences in the NE dose-MCFP response curves. CONCLUSION: Accordingly we conclude that endogenous male sex steroids contribute to the elevated arterial and venous pressures observed in the SHR.
