calycosin-7-o-beta-d-glucopyranoside and Disease-Models--Animal

Ononin is a flavonoid compound found in several medicinal plants, including Astragalus membranaceus, Sophora flavescens, and Ononis spinosa. These plants have been traditionally used in various parts of the world for their medicinal properties, including anti-inflammatory, antioxidant, and antitumor effects. Major depression is a common, long-lasting, and recurrent psychiatric disorder with a high suicide rate. Naturally occurring flavonoids treat depression via poorly understood mechanisms.. The present study aimed to determine whether ononin conferred an antidepressant-like effect in PC12 cell models and chronic mild stress (CMS)-induced depressive rat models and to explore its possible mechanisms.. Depression-related behaviors were measured using sucrose preference, tail suspension and open-field tests. Furthermore, to explore these mechanisms, we employed in vitro and in vivo assay methods, including neurite outgrowth, western blotting, quantitative RT-PCR, and staining methods.. Treatment with ononin or BDNF significantly increased PC12 cells' neuronal growth and differentiation. Furthermore, ononin promotes the activation of TrkB and growth factors and upregulates the PI3K/Akt and BDNF/TrkB/CREB signaling pathways. The in vitro results were consistent with CMS-induced depressive rat models, in which ononin treatment significantly decreased depression-like behaviors and activated TrkB, growth factors, and BDNF/TrkB/CREB signaling pathways in the frontal cortex and hippocampus. Depression-induced microscopic alterations in the frontal cortex and hippocampus of rats with CMS-induced depression were also mitigated following ononin treatment.. Based on these findings, we suggest that ononin is a promising antidepressant candidate for treating depression.

Topics: Animals; Antidepressive Agents; Brain-Derived Neurotrophic Factor; Depression; Disease Models, Animal; Flavonoids; Hippocampus; Humans; Phosphatidylinositol 3-Kinases; Rats; Stress, Psychological

Earlier studies show that endogenous sphingolipids can induce pain hypersensitivity, activation of spinal astrocytes, release of proinflammatory cytokines and activation of TRPM3 channel. Here we studied whether the development of pain hypersensitivity induced by sphingolipids in the spinal cord can be prevented by pharmacological inhibition of potential downstream mechanisms that we hypothesized to include TRPM3, σ. Experiments were performed in adult male rats with a chronic intrathecal catheter for spinal drug administrations. Mechanical nociception was assessed with monofilaments and heat nociception with radiant heat. N,N-dimethylsphingosine (DMS) was administered to induce pain hypersensitivity. Ononetin, isosakuranetin, naringenin (TRPM3 antagonists), BD-1047 (σ. DMS alone produced within 15 min a dose-related mechanical hypersensitivity that lasted at least 24 h, without effect on heat nociception. Preemptive treatments with ononetin, isosakuranetin, naringenin, BD-1047, carbenoxolone, MK-801 or AS-057278 attenuated the development of the DMS-induced hypersensitivity, but had no effects when administered alone. Pregnenolone sulphate (TRPM3 agonist) alone induced a dose-related mechanical hypersensitivity that was prevented by ononetin, isosakuranetin and naringenin.. Among spinal pronociceptive mechanisms activated by DMS are TRPM3, gap junction coupling, the σ

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Flavanones; Flavonoids; Glucosides; Hyperalgesia; Isoflavones; Male; Rats; Rats, Wistar; Sphingolipids; Sphingosine; Spinal Cord

Astragali Radix (AR) has been used for thousands years to treat ischemic stroke. Calycosin and its glycoside form calycosin-7-O-β-D-glucoside (CG) are two representative isoflavones in Astragali Radix. However, its neurological effects and related molecular mechanisms are largely unknown. The present study aims to evaluate the neuroprotective effects of CG on blood-brain barrier (BBB) integrity of ischemic brain tissue and explore the relevant signaling mechanisms.. Male adult Sprague-Daweley rats were subjected to 2 h of middle cerebral artery occlusion (MCAO) plus 24 h or 14 days of reperfusion. CG (26.8 mg/kg) was intraperitoneally administered into the rats at 15 min before onset of ischemia. The neuroprotective effects of CG were evaluated by measuring infarct volume, histological damage and BBB permeability. Furthermore, the effects of CG on scavenging nitric oxide (NO), and modulating matrix metalloproteinases (MMPs) and caveolin-1 (cav-1) were investigated with in vitro cultured brain microvascular endothelial cells treated with NO donor or oxygen-glucose deprivation (OGD) and/or in vivo rat model of MCAO cerebral ischemia-reperfusion injury.. CG treatment significantly reduced infarct volume, histological damage and BBB permeability in the in vivo MCAO ischemia-reperfusion rat model. CG treatment remarkably inhibited the expression and activities of MMPs, and secured the expression of cav-1 and tight junction proteins in the microvessels isolated from ischemic rat cortex. Furthermore, CG was revealed to scavenge NO, inhibit the activities of MMP-2 and MMP-9, and attenuate cell death in the in vitro cultured brain microvascular endothelial cells under OGD condition.. CG could protect BBB integrity in experimental cerebral ischemia-reperfusion injury via regulating NO/cav-1/MMPs pathway.

Topics: Animals; Astragalus Plant; Blood-Brain Barrier; Brain Ischemia; Caveolin 1; Disease Models, Animal; Glucosides; Isoflavones; Male; Matrix Metalloproteinases; Microvessels; Neuroprotective Agents; Nitric Oxide; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tight Junction Proteins; Time Factors