Faculty Opinions recommendation of Elevated aggrecanase activity in a rat model of joint injury is attenuated by an aggrecanase specific inhibitor.

Abstract Background Several studies demonstrated that glioblastoma multiforme progression and recurrence is linked to epigenetic regulatory mechanisms. Sirtuin 1 (SIRT1) plays an important role in glioma progression, invasion, and treatment response and is a potential therapeutic target. The aim of this study is to test the feasibility of 2-[18F]BzAHA for quantitative imaging of SIRT1 expression–activity and monitoring pharmacologic inhibition in a rat model of intracerebral glioma. Methods Sprague Dawley rats bearing 9L (N = 12) intracerebral gliomas were injected with 2-[18F]BzAHA (300–500 µCi/animal i.v.) and dynamic positron-emission tomography (PET) imaging was performed for 60 min. Then, SIRT1 expression in 9L tumors (N = 6) was studied by immunofluorescence microscopy (IF). Two days later, rats with 9L gliomas were treated either with SIRT1 specific inhibitor EX-527 (5 mg/kg, i.p.; N = 3) or with histone deacetylases class IIa specific inhibitor MC1568 (30 mg/kg, i.p.; N = 3) and 30 min later were injected i.v. with 2-[18F]BzAHA. PET-computerized tomography-magnetic resonance (PET/CT/MR) images acquired after EX-527 and MC1568 treatments were co-registered with baseline images. Results Standard uptake values (SUVs) of 2-[18F]BzAHA in 9L tumors measured at 20 min post-radiotracer administration were 1.11 ± 0.058 and had a tumor-to-brainstem SUV ratio of 2.73 ± 0.141. IF of 9L gliomas revealed heterogeneous upregulation of SIRT1, especially in hypoxic and peri-necrotic regions. Significant reduction in 2-[18F]BzAHA SUV and distribution volume in 9L tumors was observed after administration of EX-527, but not MC1568. Conclusions PET/CT/MRI with 2-[18F]BzAHA can facilitate studies to elucidate the roles of SIRT1 in gliomagenesis and progression, as well as to optimize therapeutic doses of novel SIRT1 inhibitors.

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The Effect of Phosphodiesterase-4-Specific Inhibitor in the Rat Model of Spinal Nerve Ligation

Journal of Korean Neurosurgical Society ◽

10.3340/jkns.2011.50.2.109 ◽

2011 ◽

Vol 50 (2) ◽

pp. 109 ◽

Cited By ~ 2

Author(s):

Sung Hoon Kim ◽

Bit-Na-Ri Park ◽

Seok Won Kim

Keyword(s):

Rat Model ◽

Specific Inhibitor ◽

Spinal Nerve ◽

Spinal Nerve Ligation ◽

Phosphodiesterase 4

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Omi inhibition ameliorates neuron apoptosis and neurological deficit after subarachnoid hemorrhage in rats

Genes & Genomics ◽

10.1007/s13258-021-01176-y ◽

2021 ◽

Author(s):

Yuanfeng Du ◽

Dingbo Yang ◽

Xiaoqiao Dong ◽

Quan Du ◽

Ding Wang ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Rat Model ◽

Neurological Deficit ◽

Cell Apoptosis ◽

Caspase 3 ◽

Specific Inhibitor ◽

Nerve Cells ◽

Tunel Staining ◽

Apoptotic Cells ◽

Related Proteins

Abstract Background Subarachnoid hemorrhage (SAH) is a severe neurological emergency, resulting in cognitive impairments and threatening human's health. Currently, SAH has no effective treatment. It is urgent to search for an effective therapy for SAH. Objective To explore the expression of Omi protein after subarachnoid hemorrhage in rats. Methods SAH rat model was established by injecting blood into the prechiasmatic cistern. Neurological deficit was assessed by detecting neurological deficit scores and brain tissue water contents. Apoptotic cells were evaluated by TUNEL staining and IHC staining. Omi and Cleaved caspase 3 expressions in nerve cells were determined by double staining using IF. Apoptosis-related proteins were measured by Western blotting assay. Results SAH rat model was successfully established, showing more apoptotic cells and high neurological deficit scores in SAH rat. In SAH rat model, Omi expression in nerve cells was elevated and the upregulation of Omi mainly occurred in cytoplasm, accompanied by the degradation of XIAP and the increased cleaved caspase 3/9 and cleaved PARP. Once treated with UCF-101, a specific inhibitor of Omi, the increased cell apoptosis, left/right brain moisture contents and neurological deficits were notably reversed in SAH rat brain. Of note, SAH-induced the increases of apoptosis-related protein in nerve cells were also rescued by the administration of UCF-101. Conclusions UCF-101-mediated Omi inhibition decreased the degradation of XIAP and subsequently inhibited the activation of apoptosis-related proteins, decreased nerve cell apoptosis, leading to the improvement on early brain injury in SAH rat. UCF-101-based Omi inhibition may be used to treat SAH with great potential application.

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504: Y -27362, a Specific Inhibitor of Rho-Kinase, Improves Bladder Function in a Rat Model of Hyperactivity

The Journal of Urology ◽

10.1016/s0022-5347(18)37766-8 ◽

2004 ◽

Vol 171 (4S) ◽

pp. 134-135

Author(s):

Mahadevan Rajasekaran ◽

Steven Kuntz ◽

Nathan Wilkes ◽

Michael Albo

Keyword(s):

Rat Model ◽

Rho Kinase ◽

Specific Inhibitor ◽

Bladder Function

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BIO alleviates inflammation through inhibition of GSK-3β in a rat model of intracerebral hemorrhage

Journal of Neurosurgery ◽

10.3171/2019.4.jns183501 ◽

2020 ◽

Vol 133 (2) ◽

pp. 383-391 ◽

Cited By ~ 2

Author(s):

Sha Zhao ◽

Zhen Liu ◽

Zihan Yu ◽

Xinran Wu ◽

Rui Li ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Western Blotting ◽

Rat Model ◽

Glycogen Synthase ◽

Specific Inhibitor ◽

Microglia Activation ◽

Enzyme Linked Immunosorbent Assay ◽

Optimal Dosage ◽

Autologous Whole Blood ◽

Gsk 3Β

OBJECTIVEInflammation plays a key role in secondary brain damage following intracerebral hemorrhage (ICH). Glycogen synthase kinase–3β (GSK-3β) plays a strong proinflammatory role in many CNS diseases, including stroke. The present study was undertaken to examine the effects of 6-bromoindirubin-3ʹ-oxime (BIO), a specific inhibitor of GSK-3β, on inflammation in ICH rats.METHODSAn ICH rat model was induced by autologous whole-blood injection into the striatum. First, 10, 20, 40, 60, 80, or 100 μg/kg BIO was applied to ICH animals to determine an optimal dosage for producing sufficient GSK-3β inhibition in rat ipsilateral hippocampus by Western blotting. Second, 40 μg/kg BIO was applied to ICH rats for 1, 3, 7, or 14 days, respectively, to determine a suitable intervention time course of BIO by Western blotting analysis on GSK-3β. Third, Western blotting and enzyme-linked immunosorbent assay were used for quantification of inflammation-related factors upstream or downstream of GSK-3β in rat ipsilateral hippocampus. Then, immunohistochemical staining was applied to detect activated microglia and apoptotic cells in rat ipsilateral hippocampus. Last, neurobehavioral tests were performed to assess the sensorimotor impairments in the ICH rats.RESULTSThe results show that BIO 1) blocked GSK-3βTyr216 phosphorylation/activation, thus stabilizing β-catenin, increasing upstream brain-derived neurotrophic factor and downstream heat shock protein 70 levels, and decreasing the levels of nuclear factor–κB p65 and cyclooxygenase 2; 2) decreased the levels of the proinflammatory cytokines tumor necrosis factor–α and interleukin (IL)–1β and IL-6 and elevated the level of antiinflammatory cytokine IL-10; 3) inhibited microglia activation and cell apoptosis; and 4) improved the sensorimotor deficits of ICH rats.CONCLUSIONSBIO posttreatment inhibited microglia activation, prevented inflammation and hippocampal cell death, and ameliorated functional and morphological outcomes in a rat ICH model through inactivation of GSK-3β.

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Neuroprotective Effects of a Novel Inhibitor of c-Jun N-Terminal Kinase in the Rat Model of Transient Focal Cerebral Ischemia

Cells ◽

10.3390/cells9081860 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1860 ◽

Cited By ~ 1

Author(s):

Mark B. Plotnikov ◽

Galina A. Chernysheva ◽

Vera I. Smolyakova ◽

Oleg I. Aliev ◽

Eugene S. Trofimova ◽

...

Keyword(s):

Cerebral Ischemia ◽

Infarct Size ◽

Rat Model ◽

Focal Cerebral Ischemia ◽

Neuroprotective Effect ◽

Specific Inhibitor ◽

Fold Increase ◽

Neuroprotective Activity ◽

Prophylactic Regimen ◽

Neuroprotective Effects

A novel specific inhibitor of c-Jun N-terminal kinase, 11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt (IQ-1S), has a high affinity to JNK3 compared to JNK1/JNK2. The aim of this work was to study the mechanisms of neuroprotective activity of IQ-1S in the models of reversible focal cerebral ischemia (FCI) in Wistar rats. The animals were administered with an intraperitoneal injection of IQ-1S (5 and 25 mg/kg) or citicoline (500 mg/kg). Administration of IQ-1S exerted a pronounced dose-dependent neuroprotective effect, not inferior to the effects of citicoline. Administration of IQ-1S at doses of 5 and 25 mg/kg reduced the infarct size by 20% and 50%, respectively, 48 h after FCI, whereas administration of citicoline reduced the infarct size by 34%. The administration of IQ-1S was associated with a faster amelioration of neurological status. Control rats showed a 2.0-fold increase in phospho-c-Jun levels in the hippocampus compared to the corresponding values in sham-operated rats 4 h after FCI. Administration of IQ-1S at a dose of 25 mg/kg reduced JNK-dependent phosphorylation of c-Jun by 20%. Our findings suggest that IQ-1S inhibits JNK enzymatic activity in the hippocampus and protects against stroke injury when administered in the therapeutic and prophylactic regimen in the rat model of FCI.

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