t-0070907 and Disease-Models--Animal

The 3-hydroxyquinone derivative of the non-psychotrophic phytocannabinoid cannabigerol, so-called VCE-003.2, and some other derivatives have been recently investigated for neuroprotective properties in experimental models of Parkinson's disease (PD) in mice. The pharmacological effects in those models were related to the activity on the peroxisome proliferator-activated receptor-γ (PPAR-γ) and possibly other pathways. In the present study, we investigated VCE-004.8 (formulated as EHP-101 for oral administration), the 3-hydroxyquinone derivative of cannabidiol (CBD), with agonist activity at the cannabinoid receptor type-2 (CB

Topics: Administration, Oral; Animals; Benzamides; Camphanes; Cannabidiol; Cannabinoids; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Neurons; Neuroprotection; Oxidopamine; Parkinson Disease; PPAR gamma; Pyrazoles; Pyridines; Quinones; Tyrosine 3-Monooxygenase

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Reduced expression of peroxisome proliferator-activated receptor γ (PPARγ) in the placenta was found in women with severe preeclampsia. Aspirin is currently used as the only recommended intervention in pregnancies for prevention of preeclampsia. In this study, we aimed to investigate whether aspirin could attenuate PPARγ inhibitor (T0070907)-induced preeclampsia and its impact on expression of PPARγ. Sixty Sprague-Dawley rats were used and treated with different doses of aspirin (0, 1, and 1.5 mg/kg) in presence or absence of PPARγ antagonist, T0070907. We found that mean arterial blood pressure was significantly reduced by aspirin treatment in T0070907-exposed rats. T0070907 exposure also led to significant decrease in fetal weight and increase in placental weights. However, 1.5 mg/kg of aspirin reversed these effects of T0070907. Additionally, aspirin also reversed T0070907-induced changes in the levels of thromboxane B2, vascular endothelial growth factor, soluble fms-like tyrosine kinase, and matrix metalloproteinase 2 in both maternal blood and placental tissue. The increased messenger RNA and protein levels of Cox1 and Cox2 induced by T0070907 were markedly reduced by aspirin treatment. Importantly, T0070907 repressed both transcriptional and translational levels of PPARγ, which were reversed by aspirin. In conclusion, this study suggests that aspirin prevented the occurrence of preeclampsia, which is possibly through enhancing both transcriptional and translational levels of PPARγ.

Topics: Animals; Aspirin; Benzamides; Blood Pressure; Cyclooxygenase Inhibitors; Disease Models, Animal; Female; Gene Expression Regulation; PPAR gamma; Pre-Eclampsia; Pregnancy; Pyridines; Rats; Rats, Sprague-Dawley; Treatment Outcome

Alcoholic liver disease (ALD) is one of the predominant causes of liver-related morbidity and mortality worldwide. However, effective therapy for ALD is still lacking. Wogonin, a major flavonoid compound, is found in Scutellaria baicalensis Georgi. Accumulating studies have revealed that wogonin possesses anti-inflammatory and anti-tumour activities in various models. However, the hepatoprotective activity of wogonin in ALD is still obscure. In this study, we found that wogonin significantly attenuated inflammatory response in EtOH-fed mice, and reduced the expression of inflammatory cytokines such as TNF-α and IL-6 in EtOH-induced RAW264.7 cells. Furthermore, our findings showed that wogonin remarkably induced the expression of PPAR-γ in vivo and in vitro. Compared with the wogonin-treated group, blockade of PPAR-γ with inhibitor (T0070907) or PPAR-γ small interfering (si)-RNA were applied in RAW264.7 cells to evaluate the involvement of wogonin in alleviating EtOH-induced inflammation. Moreover, forced expression of PPAR-γ further suppressed the expression of TNF-α and IL-6 when treated with wogonin on EtOH-induced RAW264.7 cells. In addition, it was demonstrated that wogonin remarkably suppressed PPAR-γ-meditated phosphorylation and activation of NF-κB-P65. In conclusion, our results indicated that wogonin may serve as an effective modulator of PPAR-γ by down-regulating NF-κB pathway, thereby attenuated inflammatory response in ALD.

Topics: Animals; Anti-Inflammatory Agents; Benzamides; Disease Models, Animal; Ethanol; Flavanones; Humans; Immunomodulation; Inflammation Mediators; Interleukin-6; Liver Diseases, Alcoholic; Male; Mice; Mice, Inbred C57BL; PPAR gamma; Pyridines; RAW 264.7 Cells; RNA, Small Interfering; Scutellaria baicalensis; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Activation of microglia plays a crucial role in immune and inflammatory processes after ischemic stroke. Microglia is reported with two opposing activated phenotypes, namely, classic phenotype (M1) and the alternative phenotype (M2). Inhibiting M1 while stimulating M2 has been suggested as a potential therapeutic approach in the treatment of stroke.. In this study, we indicated that a novel natural anti-oxidant extracted from the Chinese plant Hopea hainanensis, malibatol A (MA), decreased the infarct size and alleviated the brain injury after mice middle cerebral artery occlusion (MCAO). MA inhibited expression inflammatory cytokines in not only MCAO mice but also lipopolysaccharide (LPS)-stimulated microglia. Moreover, treatment of MA decreased M1 markers (CD16, CD32, and CD86) and increased M2 markers (CD206, YM-1) while promoting the activation of nuclear receptor PPARγ.. MA has anti-inflammatory effects in MCAO mice in a PPARγ-dependent manner, making it a potential candidate for stroke treatment.

Topics: Animals; Benzamides; Brain Infarction; Calcium-Binding Proteins; Cell Polarity; Cells, Cultured; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Infarction, Middle Cerebral Artery; Lipopolysaccharides; Mice; Microfilament Proteins; Microglia; Neuroprotective Agents; Nitric Oxide Synthase Type II; PPAR gamma; Pyridines; Stilbenes; Time Factors

Epilepsy is commonly associated with cognitive impairment. Astrocyte activation and oxidative stress occur following seizures, and play a role in the pathological injury of epilepsy with cognitive impairment. The peroxisome proliferator-activated receptor gamma (PPARγ) has been shown to exhibit neuroprotective and antioxidative effects in CNS diseases. Thus, we hypothesized that rosiglitazone, a PPARγ agonist, would prevent cognitive impairment by inhibiting astrocyte activation and regulating glutathione (GSH) homeostasis after status epilepticus (SE). Using a lithium pilocarpine-induced SE model, we found that rosiglitazone significantly prevented cognitive impairment induced by SE, and potently inhibited astrocyte activation with maintenance of GSH homeostasis in the hippocampus after SE. These protective effects were significantly reversed by co-treatment with the PPARγ antagonist T0070907. These data suggest that rosiglitazone can improve cognitive impairment, and inhibit astrocyte activation and oxidative damage following SE. Rosiglitazone may be a promising agent for treatment of epilepsy involving SE-induced cognitive impairment.

Topics: Analysis of Variance; Animals; Astrocytes; Benzamides; Cell Count; Cognition Disorders; Disease Models, Animal; Glial Fibrillary Acidic Protein; Glutathione; Glutathione Disulfide; Hippocampus; Lithium Chloride; Male; Maze Learning; Oxidative Stress; Pilocarpine; PPAR gamma; Pyridines; Rats; Rats, Sprague-Dawley; Rosiglitazone; Status Epilepticus; Systole; Thiazolidinediones

Peroxisome proliferator-activated receptor α (PPAR-α) is a ligand-activated transcription factor that exerts strong effects on metabolic pathways. Our aim was to elucidate the effect of clofibrate, a PPAR-α agonist, on the longitudinal muscle of the mouse distal colon. We initially found that clofibrate induced a relaxation response in this muscle. Notably, the PPAR-α antagonists GW9662 and T0070907 did not attenuate this clofibrate-induced relaxation. The structurally related PPAR-α agonists fenofibrate and bezafibrate induced relaxation in the distal colon as effectively as clofibrate. In contrast, wy-14643, which activates PPAR-α more selectively than clofibrate, had no effect. Furthermore, clofibrate-induced relaxation was not affected by N-nitro-L-arginine, an NO synthase inhibitor, 1H-[1,2,4]-oxadiazolo-[4,3- a]quinoxaline-1-one, a soluble guanylate cyclase inhibitor, or H89, a protein kinase A inhibitor. Tetrodotoxin, an Na⁺ channel blocker, and glibenclamide, apamin, charybdotoxin and XE991, various K⁺ channel blockers, had no effect on clofibrate-induced relaxation. Importantly, clofibrate induced a relaxation response that was not accompanied by any alteration in the cytoplasmic Ca²⁺ concentration in the longitudinal muscle of the mouse distal colon. Moreover, calyculin A, a myosin light-chain phosphatase (MLCP) inhibitor, attenuated clofibrate-induced relaxation. Our findings indicate that clofibrate relaxes the longitudinal smooth muscle of the mouse distal colon by regulating MLCP activity.

Topics: Anilides; Animals; Anticholesteremic Agents; Benzamides; Calcium; Clofibrate; Colon; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Drug Evaluation, Preclinical; Guanylate Cyclase; Male; Marine Toxins; Mice; Mice, Inbred C57BL; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Myosin-Light-Chain Phosphatase; Nitric Oxide Synthase; Oxazoles; Potassium Channel Blockers; PPAR alpha; Pyridines; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Sodium Channel Blockers; Soluble Guanylyl Cyclase

Status epilepticus (SE) can cause severe neuronal loss and oxidative damage. As peroxisome proliferator-activated receptor gamma (PPARgamma) agonists possess antioxidative activity, we hypothesize that rosiglitazone, a PPARgamma agonist, might protect the central nervous system (CNS) from oxidative damage in epileptic rats. Using a lithium-pilocarpine-induced SE model, we found that rosiglitazone significantly reduced hippocampal neuronal loss 1 week after SE, potently suppressed the production of reactive oxygen species (ROS) and lipid peroxidation. We also found that treatment with rosiglitazone enhanced antioxidative activity of superoxide dismutase (SOD) and glutathione hormone (GSH), together with decreased expression of heme oxygenase-1 (HO-1) in the hippocampus. The above effects of rosiglitazone can be blocked by co-treatment with PPARgamma antagonist T0070907. The current data suggest that rosiglitazone exerts a neuroprotective effect on oxidative stress-mediated neuronal damage followed by SE. Our data also support the idea that PPARgamma agonist might be a potential neuroprotective agent for epilepsy.

Topics: Animals; Benzamides; Cell Death; Convulsants; Disease Models, Animal; Glutathione; Heme Oxygenase (Decyclizing); Hippocampus; Lipid Peroxidation; Lithium; Male; Muscarinic Agonists; Nerve Degeneration; Neuroprotective Agents; Oxidative Stress; Pilocarpine; PPAR gamma; Pyridines; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Rosiglitazone; Status Epilepticus; Superoxide Dismutase; Superoxide Dismutase-1; Thiazolidinediones