iridoids and Stroke

Topics: Animals; Apoptosis; Energy Metabolism; Iridoids; Male; Mice; Mice, Inbred C57BL; Mitochondria; Neuroprotective Agents; Oxidative Stress; Reactive Oxygen Species; Reperfusion Injury; Signal Transduction; Sirtuin 3; Stroke; Uncoupling Protein 2

Berberine, baicalin, and jasminoidin were major active ingredients of Huang-Lian-Jie-Du-Decoction (HLJDD), a famous prescription of traditional Chinese medicine (TCM), which has been used for the treatment of ischemic stroke. The aim of the present study was to classify their roles in the treatment effects of ischemic stroke. A rat model of middle cerebral artery occlusion (MCAO) was constructed to mimic ischemic stroke and treatment effects of berberine, baicalin, and jasminoidin, and HLJDD was assessed by neurologic deficit scoring, infarct volume, histopathology, immunohistochemistry, biochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting. In addition, the

Topics: Berberine; Brain Ischemia; Drugs, Chinese Herbal; Flavonoids; Humans; Iridoids; Medicine, Chinese Traditional; Metabolomics; Stroke

Intracerebral haemorrhage (ICH) as a devastating form of stroke has remained a public health threat due to lack of FDA-approved therapy. Oxidative stress originated from blood cell degradation products plays a crucial role in the ICH pathogenesis. In this study we evaluated oleuropein, a potent natural antioxidant from olive, in a well-established rat ICH model from overall symptoms to detailed molecular mechanism.. ICH model was established by collagenase injection to the brain of rats, which were randomly divided into groups with vehicle mock treatment, followed by treatment with different doses of oleuropein via daily intraperitoneal injection post-ICH for 3days. The overall neurological deficit, brain edema level and blood-brain barrier (BBB) integrity were then measured in different treatment groups. To understand the protection mechanism of oleuropein in ICH, BBB structural components ZO-1 and occludin, oxidative stress and MAPK signalling pathways were also examined.. Oleuropein treatment showed overall alleviation of ICH-associated neurological deficit and brain edema in a dose dependent manner. Consistently, it could preserve the BBB structure and attenuate oxidative stress as well as ICH-induced MAPK activation in brain tissue.. Our study suggests oleuropein could be used as a promising therapeutic agent for ICH.

Topics: Animals; Antioxidants; Blood-Brain Barrier; Brain Edema; Cerebral Hemorrhage; Disease Models, Animal; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Iridoid Glucosides; Iridoids; Male; MAP Kinase Signaling System; Oxidative Stress; Rats; Rats, Sprague-Dawley; Stroke

Xingnaojing microemulsion (XNJ-M) administered intranasally is used for stroke treatment. In order to decrease the XNJ-M-induced mucosal irritation, XNJ-M modified by mPEG2000-PLA (XNJ-MM) were prepared in a previous work. The present work aimed to assess the impact of mPEG2000-PLA on pharmacokinetic features and brain-targeting ability of XNJ-M. The bioavailability and brain-target effects of borneol and geniposide in XNJ-M and XNJ-MM were compared in mice after intravenous (i.v.) and intranasal (i.n.) administrations. Gas chromatography, high-performance liquid chromatography, and ultra-performance liquid chromatography/tandem mass spectrometry methods were developed for the quantification of borneol and geniposide. Blood and brain samples were collected from mice at different time points after i.v. and i.n. treatments with borneol at 8.0 mg/kg, geniposide at 4.12 mg/kg. In addition, near-infrared fluorescence dye, 1,1'-dioctadecyl-3,3,3',3'-tetramethyl indotricarbocyanine iodide was loaded into microemulsions to evaluate the brain-targeting ability of XNJ-M and XNJ-MM by near-infrared fluorescence imaging in vivo and ex vivo. For XNJ-M and XNJ-MM, the relative brain targeted coefficients (Re) were 134.59% and 198.09% (borneol), 89.70% and 188.33% (geniposide), respectively. Besides, significant near-infrared fluorescent signal was detected in the brain after i.n. administration of microemulsions, compared with that of groups for i.v. administration. These findings indicated that mPEG2000-PLA modified microemulsion improved drug entry into blood and brain compared with normal microemulsion: the introduction of mPEG2000-PLA in microemulsion resulted in brain-targeting enhancement of both fat-soluble and water-soluble drugs. These findings provide a basis for the significance of mPEG2000-PLA addition in microemulsion, defining its effects on the drugs in microemulsion.

Topics: Administration, Intranasal; Animals; Biological Availability; Brain; Camphanes; Drug Delivery Systems; Drugs, Chinese Herbal; Emulsions; Iridoids; Male; Mice; Mice, Inbred ICR; Nasal Cavity; Polyesters; Polyethylene Glycols; Stroke

Huang-Lian-Jie-Du-Decoction (HLJDD) is a Traditional Chinese Medicine (TCM) clinical prescription noted for its neuroprotective effects. The total alkaloids, flavonoids, and iridoids are the main active components of HLJDD. In the present study we explored the possible effects of the total alkaloids, flavonoids, and iridoids from HLJDD on behavioral recovery and cortical neurogenesis after stroke.. The stroke model was induced by permanent middle cerebral artery occlusion (pMACO). The total alkaloids (44 mg/kg), flavonoids (50 mg/kg), and iridoids (80 mg/kg) from HLJDD were orally administered for 2h after stroke and daily thereafter. Neurological function was assessed and then rats were sacrificed 7 days after pMACO. Following repeated intraperitoneal injections of the cell proliferation - specific marker 5-bromodeoxyuridine (BrdU) after stroke induction, precursor cell proliferation and differentiation was monitored by immunofluorescent staining. The levels of relevant proteins were determined by western blotting and the mRNA expressions were assessed by quantitative real time-polymerase chain reaction (qRT-PCR).. Total alkaloids, flavonoids and iridoids from HLJDD showed improved functional outcome after brain ischemia. The total alkaloids and iridoids increased number of BrdU-positive cells and enhanced neuronal differentiation in the cortex. Alkaloids-enhanced neurogenesis might be associated with increased VEGF, Ang-1, and Ang-2 protein expression. And the neuroproliferative effect of alkaloids was partially correlated with increased phosphorylation of AKT, and GSK-3β. Flavonoids treatment was found to promote differentiation of cortical precursor cells into neuronal but not glial cells, which may be at least attributable to the regulation of AKT, GSK-3β mRNA and Ang-1 protein levels.. Total alkaloids, iridoids and flavonoids from HLJDD promoted functional recovery likely via enhancing cortical neurogenesis and thus have potential as a treatment for ischemic brain injury.

Topics: Alkaloids; Animals; Brain Ischemia; Bromodeoxyuridine; Cell Differentiation; Cell Proliferation; Drugs, Chinese Herbal; Flavonoids; Infarction, Middle Cerebral Artery; Iridoids; Male; Medicine, Chinese Traditional; Neurogenesis; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Stroke

Renal damage precedes occurrence of stroke in high-sodium/low-potassium-fed stroke-prone spontaneously hypertensive rat (SHRSP). We previously reported a marked suppression of uncoupling protein-2 (UCP2) upon high-salt Japanese-style diet in SHRSP kidneys. Vegetable compounds are known to exert protective effects in cardiovascular diseases. We aimed at evaluating the impact of Brassica oleracea sprouts juice toward renal damage in Japanese diet-fed SHRSP and exploring the role of 5'-adenosine monophosphate-activated protein kinase (AMPK)/NAD-dependent deacetylase sirtuin-1 (SIRT1)/peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α)/peroxisome proliferator-activated receptor-α (PPARα)/UCP2 axis.. SHRSP received Japanese diet for 4 weeks. A group of SHRSP received Japanese diet and B. oleracea. A third group received Japanese diet, B. oleracea, and PPARα inhibitor (GW6471). A group of SHRSP fed with regular diet served as control.. Japanese diet induced marked increases of oxidative stress, inflammation, and proteinuria, along with glomerular and tubular damage, as compared with regular diet. A significant suppression of AMPK/UCP2 pathway was observed. Despite Japanese diet feeding, concomitant administration of B. oleracea prevented oxidative stress accumulation, inflammation, renal damage, and proteinuria. All components of the UCP2 regulatory pathway were significantly increased by B. oleracea. Superoxide dismutase 2 and phosphoendothelial nitric oxide synthase were also stimulated. Addition of PPARα inhibitor to B. oleracea and Japanese diet significantly reduced the B. oleracea beneficial effects. SBP levels were comparable among the different groups of rats.In vitro, UCP2 inhibition by genipin offset the antioxidant effect of B. oleracea in renal mesangial and proximal tubular cells.. B. oleracea administration prevented renal damage in salt-loaded SHRSP, independently from SBP, with parallel stimulation of AMPK/SIRT1/PGC1α/PPARα/UCP2 axis. Stimulation of the latter mechanism may provide relevant renal protective effect and play a therapeutic role in target organ damage progression in hypertension.

Topics: AMP-Activated Protein Kinases; Animals; Antioxidants; Blood Pressure; Brassica; Diet; Glomerular Mesangium; Hypertension; Ion Channels; Iridoids; Kidney Diseases; Kidney Glomerulus; Kidney Tubules, Proximal; Mitochondrial Proteins; Oxidative Stress; Plant Extracts; PPAR alpha; Proteinuria; Rats; Rats, Inbred SHR; Seedlings; Sodium Chloride, Dietary; Stroke; Uncoupling Protein 2

Ischemic stroke causes extensive cellular loss that impairs brain functions, resulting in severe disabilities. No effective treatments are currently available for brain tissue regeneration. The need to develop effective therapeutic approaches for treating stroke is compelling. A tissue engineering approach employing a hydrogel carrying both cells and neurotrophic cytokines to damaged regions is an encouraging alternative for neuronal repair. However, this approach is often challenged by low in vivo cell survival rate, and low encapsulation efficiency and loss of cytokines. To address these limitations, we propose to develop a biomaterial that can form a matrix capable of improving in vivo survival of transplanted cells and reducing in vivo loss of cytokines. Here, we report that using sericin, a natural protein from silk, we have fabricated a genipin-cross-linked sericin hydrogel (GSH) with porous structure and mild swelling ratio. The GSH supports the effective attachment and growth of neurons in vitro. Strikingly, our data reveal that sericin protein is intrinsically neurotrophic and neuroprotective, promoting axon extension and branching as well as preventing primary neurons from hypoxia-induced cell death. Notably, these functions are inherited by the GSH's degradation products, which might spare a need of incorporating costly cytokines. We further demonstrate that this neurotrophic effect is dependent on the Lkb1-Nuak1 pathway, while the neuroprotective effect is realized through regulating the Bcl-2/Bax protein ratio. Importantly, when transplanted in vivo, the GSH gives a high cell survival rate and allows the cells to continuously proliferate. Together, this work unmasks the neurotrophic and neuroprotective functions for sericin and provides strong evidence justifying the GSH's suitability as a potential neuronal cell delivery vehicle for ischemic stroke repair.

Topics: Animals; Biocompatible Materials; Bombyx; Brain Ischemia; Cell Hypoxia; Cell Line; Cell Proliferation; Cell Survival; Cross-Linking Reagents; Cytokines; Glutathione Transferase; Green Fluorescent Proteins; Humans; Hydrogels; Iridoids; Mice; Mice, Inbred C57BL; Mice, Nude; Neurons; Neuroprotective Agents; Porosity; Regeneration; Sericins; Silk; Sincalide; Spectroscopy, Fourier Transform Infrared; Stroke; Tissue Engineering

Geniposide is a bioactive substance derived from gardenia, which has been used in traditional Chinese preparation, such as "Xing-Nao-Jing" (XNJ) for stroke treatment. Stroke and the ingredients of herbal preparation affect the pharmacokinetics of geniposide. A comparative pharmacokinetic study of geniposide in stroke and sham-operated rats after administration of XNJ and geniposide was proceeded to evaluate the effect of stroke on pharmacokinetics of geniposide, while the influence of other components in XNJ was determined by using gardenia extract and geniposide-borneol compounds in rats with stroke to compare.. Stroke was induced by middle cerebral artery occlusion followed by reperfusion 2h later. Plasma concentration of geniposide was determined by HPLC. Various pharmacokinetic parameters were estimated from the plasma concentration versus time data using non-compartmental methods.. The maximum plasma concentration (Cmax) and area under the curve (AUC0-t) in stroke after administration of XNJ were 5.97±3.82 μg/mL, and 570.06±274.32 μg·min/mL, respectively, which were 5 times compared with sham-operated rats or the stroke-afflicted rats given geniposide. In stroke, the Cmax and AUC(0-t) of geniposide-borneol group and gardenia extraction group were close to XNJ group and geniposide group, respectively. The geniposide-borneol group had a higher value.. Stroke improved the absorption of geniposide in XNJ. Borneol may be the key ingredient in XNJ improving the absorption of geniposide.

Topics: Animals; Area Under Curve; Camphanes; Chromatography, High Pressure Liquid; Disease Models, Animal; Drugs, Chinese Herbal; Gardenia; Iridoids; Male; Models, Biological; Rats; Rats, Sprague-Dawley; Stroke

Composed of Ginsenoside Rg1 and Geniposide, the herbal medicine TongLuoJiuNao (TLJN) injection liquid has anti-inflammatory properties and can improve learning and memory in mice. Recently, TLJN has been used to treat the patients with cerebral ischemic stroke and vascular dementia, which significantly increase the risk of developing Alzheimer's disease (AD) in the early human beings. Although beneficial effects of TLJN have been reported in the vascular-associated brain disorders, the roles of TLJN in AD brains are still not clear. In this study, we chronically administered TLJN in amyloid precursor protein (APP) Swedish mutant transgenic mice (APP23) from 6 months old of age, which is at the onset of Aβ plaques, to 12 months old. We found that TLJN significantly decreased Aβ production and deposition in the brain of APP23 mice. Furthermore, we observed that TLJN down-regulated the levels and activity of β-secretase 1 (BACE1) protein as well as the expression levels of γ-secretase complex components: PS1, nicastrin and anterior pharynx-defective 1 (APH1) but not presenilin enhancer 2 (PEN2). The results suggest an inhibitory effect of TLJN on amyloidogenic APP processing by down-regulating the cleavage enzymes BACE1 and γ-secretase.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Central Nervous System Agents; Drug Combinations; Drugs, Chinese Herbal; Endopeptidases; Ginsenosides; Humans; Iridoids; Male; Membrane Glycoproteins; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Presenilin-1; Stroke

Jasminoidin and ursodeoxycholic acid are 2 bioactive compounds extracted from Chinese medicine that have been proven to exert a synergistic effect as a combined administration for the treatment of stroke. The aim of this study was to reveal the pharmacogenomic mechanism of this synergistic effect of jasminoidin and ursodeoxycholic acid.. One hundred and fifteen mice with brain damage, induced by focal cerebral ischemia/reperfusion, were divided into 5 groups: jasminoidin-treated, ursodeoxycholic acid-treated, combination-treated, vehicle group, and sham-operated group. Comparative analysis of stroke-related gene expression profiles and Kyoto Encyclopedia of Genes and Genomes pathways among the 3 treatment groups were performed to reveal the mechanism of this synergistic effect.. This study demonstrated that (1) treatment with jasminoidin alone caused similar changes in the pattern of gene expression as those treated with the combination; (2) jasminoidin treatment and the combination treatment had more overlapping changes in gene expression and activated pathways than the ursodeoxycholic acid treatment; (3) Hspa1a and Ppm1e were only up-regulated in the combination-treated group; (4) the nonoverlapping genes Fgf12, Rarα, Map3k4, paxillin (PXN) in the combination-treated group were markedly expressed, and P53 pathway was obviously activated in the combination-treated group.. These findings may suggest that jasminoidin is the major component of the combination, and the combination plays an important role of the synergistic effect in up-regulating expression of gene Hspa1a, genes Fgf12, Rarα, Map3k4 and down-regulating gene PXN, as well as activating P53 pathway.

Topics: Animals; Cluster Analysis; Coloring Agents; Databases, Genetic; DNA, Complementary; Drug Synergism; Gene Expression; Gene Expression Profiling; Iridoids; Mice; Microarray Analysis; Principal Component Analysis; Real-Time Polymerase Chain Reaction; Reperfusion Injury; RNA; Signal Transduction; Stroke; Ursodeoxycholic Acid

Refined Qing-Kai-Ling (QKL), a modified Chinese medicine, consists of three main ingredients (Baicalin, Jasminoidin and Desoxycholic acid), plays a synergistic effect on the treatment of the acute stage of ischemic stroke. However, the rules of the combination and synergism are still unknown. Based on the ischemic stroke mice model, all different kinds of combination of Baicalin, Jasminoidin, and Desoxycholic acid were investigated by the methods of neurological examination, microarray, and genomics analysis. As a result, it confirmed that the combination of three drugs offered a better therapeutical effect on ischemic stroke than monotherapy of each drug. Additionally, we used Ingenuity pathway Analysis (IPA) and principal component analysis (PCA) to extract the dominant information of expression changes in 373 ischemia-related genes. The results suggested that 5 principal components (PC1-5) could account for more than 95% energy in the gene data. Moreover, 3 clusters (PC1, PC2+PC5, and PC3+PC4) were addressed with cluster analysis. Furthermore, we matched PCs on the drug-target networks, the findings demonstrated that Baicalin related with PC1 that played the leading role in the combination; Jasminoidin related with PC2+PC5 that played a compensatory role; while Desoxycholic acid had the least performance alone which could relate with PC3+PC4 that played a compatible role. These manifestations were accorded with the principle of herbal formulae of Traditional Chinese Medicine (TCM), emperor-minister-adjuvant-courier. In conclusion, we firstly provided scientific evidence to the classic theory of TCM formulae, an initiating holistic viewpoint of combination therapy of TCM. This study also illustrated that PCA might be an applicable method to analyze the complicated data of drug combination.

Topics: Animals; Cluster Analysis; Computational Biology; Deoxycholic Acid; Disease Models, Animal; Drug Combinations; Drugs, Chinese Herbal; Enzyme Inhibitors; Flavonoids; Gene Expression Profiling; Gene Expression Regulation; Iridoids; Ischemia; Male; Mice; Models, Statistical; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction; Principal Component Analysis; Stroke