Cornel Iridoid Glycoside Research Articles

The cornel Iridoid glycoside attenuated brain edema of the cerebral ischemia/reperfusion rats by modulating the polarized aquaporin 4

Brain edema after ischemic stroke could worsen cerebral injury in patients who received intravenous thrombolysis. Cornus officinalis Sieb. et Zucc., a long-established traditional Chinese medicine, is beneficial to the treatment of neurodegenerative diseases including ischemic stroke. In particular, its major component, cornel iridoid glycoside (CIG), was evidenced to exhibit neuroprotective effects against cerebral ischemic/reperfusion injury (CIR/I). Aimed to explore the effects of the CIG on brain edema of the CIR/I rats, the CIG was analyzed with the main constituents by using HPLC. The molecular docking analysis was performed between the CIG constituents and AQP4-M23. TGN-020, an AQP4 inhibitor, was used as a comparison. In the in vivo experiments, the rats were pre-treated with the CIG and were injured by performing middle cerebral artery occlusion/reperfusion (MCAO/R). After 24 h, the rats were examined for neurological function, pathological changes, brain edema, and polarized Aqp4 expressions in the brain. The HPLC analysis indicated that the CIG was composed of morroniside and loganin. The molecular docking analysis showed that both morroniside and loganin displayed lower binding energies to AQP4-M23 than TGN-020. The CIG pre-treated rats exhibited fewer neurological function deficits, minimized brain swelling, and reduced lesion volumes compared to the MCAO/R rats. In the peri-infarct and infarct regions, the CIG pre-treatment restored the polarized Aqp4 expression which was lost in the MCAO/R rats. The results suggested that the CIG could attenuate brain edema of the cerebral ischemia/reperfusion rats by modulating the polarized Aqp4 through the interaction of AQP4-M23 with morroniside and loganin.

Cornuside improves murine autoimmune hepatitis through inhibition of inflammatory responses.

Autoimmune hepatitis (AIH) poses an important public health concern worldwide, with few therapeutic options available. Cornuside, a primary cornel iridoid glycoside present in Cornus officinalis Sieb. et Zucc., is a well-known traditional Chinese medicine that possesses anti-inflammatory, antioxidant and anti-apoptotic properties. However, the effects of cornuside on autoimmune diseases including AIH is still not defined, neither is clear on the mechanisms of cornuside in the suppression of inflammatory responses. The study was aimed to investigate the therapeutic effects of cornuside on AIH using murine models. A murine model of AIH induced by concanavalin A (Con A) was used to examine the pharmacological activity of cornuside in suppressing the inflammatory responses in vivo. C57BL/6J mice were intravenously with different doses of cornuside and challenged with 18mg/kg Con A 3h later. Network pharmacological analysis was performed to identify the potential target genes and signaling pathways by cornuside in AIH. Next serum and liver tissues were collected 12h after Con A injection to analyze the levels of markers for hepatic injury, apoptosis, oxidative stress, immune responses, and inflammation. Network pharmacological analysis revealed that cornuside may modulate oxidative stress and apoptosis in AIH. Compared with the Con A group, cornuside pretreatment significantly reduced the serum levels of alanine aminotransferase and aspartate aminotransferase, improving histopathological damage and apoptosis in the livers. In addition, cornuside decreased the levels of malondialdehyde, myeloperoxidase, but increased superoxide dismutase levels, suggesting the relieving of oxidative stress. Furthermore, cornuside suppressed the activation of T and natural killer T cells, whereas the proportion of myeloid-derived suppressor cells was significantly increased. The production of proinflammatory cytokines, including interleukin (IL)-6, IL-12, IL-1β, and tumor necrosis factor-alpha (TNF-α), was also clearly decreased. Finally, western blot analysis displayed that cornuside inhibited the phosphorylation of extracellular receptor kinase (ERK) and c-Jun N-terminal kinase (JNK). We demonstrated that cornuside has protective effects for Con A-induced immune-mediated hepatitis by suppressing the oxidative stress, apoptosis, and the inflammatory responses through the ERK and JNK signaling pathways, as well as by modulating the activation and recruitment of immune cells.

Cornel Iridoid Glycoside Alleviates Microglia-Mediated Inflammatory Response via the NLRP3/Calpain Pathway.

Vascular dementia (VaD) is associated with cerebral hypoperfusion, which results in long-term cognitive impairment and memory loss. Cornel iridoid glycoside (CIG) is the major active constituent isolated from the ripe fruit of Cornus officinalis. Previous studies have shown that CIG enhances neurological function in VaD rats. In the present research, we attempted to clarify the molecular processes underlying the role of CIG in neuroinflammation in VaD. We created a chronic cerebral ischemia rat model by ligation of the bilateral common carotid arteries (2VO) and then treated rats with different concentrations of CIG. Comprehensive analyses revealed that CIG ameliorated myelin integrity and neuronal loss. Furthermore, we also found that CIG inhibited polarized microglia activation and attenuated inflammasome-mediated production of proinflammatory cytokines in BV2 microglia cells induced by LPS/IFN-γ and in the brains of 2VO rats. To further elucidate the role of CIG in microglia-mediated inflammatory response, we investigated the expression and activity of calpain. CIG inhibited the expression and activity of calpain 1/2, which was characterized by decreased calpastatin and spectrin αII expression. In particular, intra- and extracellular calpain 1 levels were reduced by CIG. However, CIG showed weak interaction with calpain 1. In addition, we found that CG administration significantly repressed the assembly of the NOD-like receptor protein 3 (NLRP3) inflammasome, including NLRP3, ASC, and caspase-1. In conclusion, our knowledge of the mechanisms by which CIG regulates NLRP3/calpain signaling to influence inflammatory responses offers further insights into potential therapeutic strategies to treat VaD.

Cornel Iridoid Glycoside and Its Effective Component Regulate ATPase Vps4A/JNK to Alleviate Autophagy Deficit with Autophagosome Accumulation.

Improving autophagy-lysosome fusion has been considered a key method in the treatment of Alzheimer's disease (AD). Cornel iridoid glycoside (CIG) is extracted from Cornus officinalis and has been shown to promote the clearance of tau oligomers via the autophagy pathway. However, the mechanisms of CIG on autophagy deficits are not understood. Here, we found autophagy deficit and tau aggregation in the brains of P301S tau transgenic mice and MAPT cells edited using CRISPR-Cas9 technology. CIG decreased tau aggregation and alleviated autophagic markers involving the JNK/Beclin-1 signaling pathway which demonstrated CIG that might enhance lysosome formation by upregulating ATPase Vps4A expression. Knocking down VPS4A increased autophagosome accumulation and attenuated the effect of CIG on p62. In addition, CIG had no effect on tau oligomers but still inhibited the level of tau monomer in VPS4A knockout cells. The effective component (Sweroside, SWE) of CIG attenuated tau oligomers accumulation and increased Vps4A level but not CHMP2B. SWE could not change the level of tau oligomers in VPS4A knockout cells. In conclusion, CIG suppressed autophagosome accumulation by regulating the ATPase Vps4A/JNK. SWE is a core of active factors of CIG in Vps4A regulation. These findings suggest CIG may be a potential drug in AD treatment.

Cornel iridoid glycoside protects against STAT1‐dependent synapse and memory deficits by increasing NMDA receptor expression in tau transgenic mice

AbstractBackgroundP301S transgenic mice is an animal model of tauopathy and Alzheimer’s disease (AD), exhibiting tau pathology and synaptic dysfunction. Cornel iridoid glycoside (CIG) is an active ingredient extracted from Cornus officinalis, a traditional Chinese herb. The purpose of the present study was to investigate the effects and mechanisms of CIG on tau pathology and synaptic dysfunction using P301S mice.MethodIntragastric administration of CIG for 3.5 months was applied to P301S mice from 9‐month‐old to 12.5‐month‐old of age. Objective recognition test and Y maze task were used to test the cognitive impairments of P301S mice. Electrophysiological recording was applied to record long‐term potential. Transmission electron microscopy was used to investigate the the ultrastructure and number of synapse. Immunohistochemical staining was applied to detect tau phosphorylation. Western blotting was used to detect the expression levels of related proteins.ResultsIntragastric administration of CIG for 3.5 months improved learning and memory abilities, increased the survival rate of P301S mice. Electrophysiological recordings and transmission Electron microscopy study showed that CIG improved synaptic plasticity, increased the ultrastructure and number of synapse. Moreover, CIG increased the expression of N‐methyl‐D‐aspartate receptors (NMDARs) subunits GluN1, GluN2A and GluN2B, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptor (AMPAR) subunit GluA1. The major mechanism of CIG involved in the regulation of synaptic dysfunction was to inhibited the activation of Janus kinase‐2 (JAK2) /signal transducer and activator of transcription 1 (STAT1) signaling pathway and STAT1‐induced suppression of NMDAR expression.ConclusionBased on our findings, CIG might be a promising candidate for the prevention of tauopathy such as AD.

Cornel Iridoid Glycoside Ameliorated Alzheimer's Disease-Like Pathologies and Necroptosis through RIPK1/MLKL Pathway in Young and Aged SAMP8 Mice.

Background Aging is an important risk factor for sporadic Alzheimer's disease (AD) and other neurodegenerative diseases. Senescence-accelerated mouse-prone 8 (SAMP8) is used as an animal model for brain aging and sporadic AD research studies. The aim of the current study was to investigate the pharmacological effects of cornel iridoid glycoside (CIG), an active ingredient of Cornus officinalis, on AD-type pathological changes in young and aged SAMP8 mice. Methods Locomotor activity test was used to detect the aging process of SAMP8 mice. Nissl staining and immunohistochemical staining were applied to detect neurons and myelin basic protein-labelled myelin sheath. Western blotting was used to detect the expression levels of related proteins of synapse, APP processing, and necroptosis. Results The results showed that SAMP8 mice at the age of 6 and 14 months exhibited lower locomotor activity, age-related neuronal loss, demyelination, synaptic damage, and APP amyloidogenic processing. In addition, the increased levels of receptor-interacting protein kinase-1 (RIPK1), mixed lineage kinase domain-like protein (MLKL), and p-MLKL indicating necroptosis were found in the brain of SAMP8 mice. Intragastric administration of CIG for 2 months improved locomotor activity; alleviated neuronal loss and demyelination; increased the expression of synaptophysin, postsynaptic density protein 95, and AMPA receptor subunit 1; elevated the levels of soluble APPα fragment and disintegrin and metalloproteinase 10 (ADAM10); and decreased the levels of RIPK1, p-MLKL, and MLKL in the brain of young and aged SAMP8 mice. Conclusion This study denoted that CIG might be a potential drug for aging-related neurodegenerative diseases such as AD.

Cornel Iridoid Glycoside Protects Against STAT1-Dependent Synapse and Memory Deficits by Increasing N-Methyl-D-aspartate Receptor Expression in a Tau Transgenic Mice.

P301S transgenic mice are an animal model of tauopathy and Alzheimer’s disease (AD), exhibiting tau pathology and synaptic dysfunction. Cornel iridoid glycoside (CIG) is an active ingredient extracted from Cornus officinalis, a traditional Chinese herb. In the present study, the purpose was to investigate the effects and mechanisms of CIG on tau pathology and synaptic dysfunction using P301S transgenic mice. The results showed that intragastric administration of CIG for 3.5 months improved cognitive impairments and the survival rate of P301S mice. Electrophysiological recordings and transmission electron microscopy study showed that CIG improved synaptic plasticity and increased the ultrastructure and number of synapse. Moreover, CIG increased the expression levels of N-methyl-D-aspartate receptors (NMDAR) subunits GluN1, GluN2A, and GluN2B, and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunit GluA1. We inferred that the major mechanism of CIG involving in the regulation of synaptic dysfunctions was inhibiting the activation of Janus kinase-2 (JAK2)/signal transducer and activator of transcription 1 (STAT1) signaling pathway and alleviating STAT1-induced suppression of NMDAR expressions. Based on our findings, we thought CIG might be a promising candidate for the therapy of tauopathy such as AD.

An iridoid glycoside from Cornus officinalis balances intestinal microbiome disorder and alleviates alcohol-induced liver injury

Abstract The intestinal microbiota plays an important role in the occurrence and development of alcoholic liver disease (ALD). The aim of this study was to investigate whether the cornel iridoid glycoside (CIG) of Cornus officinalis Sieb. et Zucc. could protect against ALD through the gut-liver axis. The results showed that, compared to an alcohol treated group, CIG could inhibit the activities of AST, ALT and MDA, promote the activities of SOD, CAT and GSH, and reduce oxidative damage to the liver. CIG could significantly alter intestinal microbial diversity, reduce the presence of serum LPS and levels of TNF-α, IL-1β and IL-6 in the liver. In addition, CIG supplementation reduced the imbalance of intestinal microbiota caused by alcohol and improved intestinal barrier function. Therefore, CIG may have a beneficial effect in alcoholic liver disease by maintaining the stability of the intestinal microbiota. We propose CIG as a potential therapeutic and prophylactic compound in clinical treatment of ALD.

Cornel Iridoid Glycoside Regulates Modification of Tau and Alleviates Synaptic Abnormalities in Aged P301S Mice

Alzheimer's disease (AD), also defined as a tauopathology, is a common neurodegenerative disease. Hyper-phosphorylation, cleavage or truncation, and aggregation of tau contribute to AD. Thus, targeting the post-translational modifications on tau may be a therapeutic strategy to treat AD. This study understood how cornel iridoid glycoside (CIG) affects tau post-translational modifications and synaptic abnormalities. The 10-month old P301S tau transgenic mice were given CIG at 100 and 200 mg/kg every day orally for 1 month. Hyperphosphorylated and truncated tau, synapse-associated proteins and glutamatergic receptors were all detected using Western blotting. The interactions between Morroniside (MOR) or Loganin (LOG) and tau were detected using Autodock and Surface Plasmon Resonance (SPR). The effects of CIG on the aggregation of tau were investigated using a cell-free system. CIG attenuated tau hyperphosphorylation at Thr205, Ser212, Ser262, Thr231 and Ser235 (AT180), but had no effect on tau truncation in the brains of 10-month old P301S mice. Binding free energies and interactions revealed that MOR and LOG bound with tau. We also found that CIG upregulated synapse-associated proteins such as PSD-95, syntaxin1A and synaptotagmin. In addition, CIG restored N-methyl-D-aspartic acid receptor and glutamate receptor levels. CIG improves post-translational modification of tau as well as synaptic abnormalities. The data presented here reveal that CIG may be used in the treatment of AD.

Cornel iridoid glycoside ameliorates cognitive deficits in APP/PS1/tau triple transgenic mice by attenuating amyloid‐beta, tau, and neurotrophic dysfunction

AbstractBackgroundTargeting proteinopathies is involved in the protective effects of pharmacologic agents to treat Alzheimer’s disease (AD). Cornel iridoid glycoside (CIG) are the effective component from Cornus officinalis. The aim of the present research was to explore the potential effects of CIG on β‐amyloid (Aβ) and tau pathology and its underlying mechanisms in APP/PS1/Tau triple transgenic (3×Tg) mice.MethodWe intragastrically administered 16‐month‐old 3×Tg mice with CIG (100 and 200 mg/kg) for 2 months. Morris water maze and object recognition tests were used to detect learning and memory abilities. Thioflavin‐S staining and immunohistochemistry were used to detect amyloid plaques and Aβ40/42. Western blotting assay was performed to determine the expression of related proteins in the cerebral cortex and hippocampus of mice.ResultThe results showed that CIG treatment improved learning and memory impairment in 3×Tg mice. CIG decreased amyloid plaque deposition, Aβ40/42 and the expression of full‐length amyloid precursor protein; and increased the levels of ADAM‐10 (a‐secretase), neprilysin (NEP) and insulin degrading enzyme (IDE) in the brain of 3×Tg mice. Moreover, CIG reduced tau hyperphosphorylation, and elevated phosphorylation level of GSK‐3β at Ser9 and methylation of PP2A catalytic subunit C in the model mice. CIG increased the expression of nerve growth factor (NGF), brain‐derived neurotrophic factor (BDNF) and phosphorylated cAMP‐responsive element binding protein (p‐CREB) in the brain of 3×Tg mice.ConclusionCIG ameliorated learning and memory deficit via reducing Aβ content and, tau hyperphosphorylation and increasing neurotrophic factors in the brain of 3×Tg mice. These results suggest that CIG may be beneficial for AD therapy.

Cornel Iridoid Glycoside Suppresses Hyperactivity Phenotype in rTg4510 Mice through Reducing Tau Pathology and Improving Synaptic Dysfunction.

rTg4510 mice are transgenic mice expressing P301L mutant tau and have been developed as an animal model of tauopathies including Alzheimer's disease (AD). Besides cognitive impairments, rTg4510 mice also show abnormal hyperactivity behavior. Cornel iridoid glycoside (CIG) is an active ingredient extracted from Cornus officinalis, a traditional Chinese herb. The purpose of the present study was to investigate the effects of CIG on the emotional disorders such as hyperactivity, and related mechanisms. The emotional hyperactivity was detected by locomotor activity test and Y maze test. Immunofluorescent and immunohistochemical analyses were conducted to measure neuron loss and phosphorylated tau. Western blotting was used to detect the expression of related proteins. The results showed that intragastric administration of CIG for 3 months decreased the hyperactivity phenotype, prevented neuronal loss, reduced tau hyperphosphorylation and aggregation in the amygdala of rTg4510 mice. Meanwhile, CIG alleviated the synaptic dysfunction by increasing the expression of N-methyl-D-aspartate receptors (NMDARs) subunits GluN1 and GluN2A and αamino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunits GluA1 and GluA2, and increased the level of phosphorylated Ca2+/calmodulin dependent protein kinase II α (p-CaMK IIα) in the brain of rTg4510 mice. In conclusion, CIG may have potential to treat the emotional disorders in tauopathies such as AD through reducing tau pathology and improving synaptic dysfunction.

Cornel iridoid glycoside ameliorates cognitive deficits in APP/PS1/tau triple transgenic mice by attenuating amyloid-beta, tau hyperphosphorylation and neurotrophic dysfunction.

BackgroundTargeted proteinopathy is involved in creating pharmacological agents that protect against Alzheimer disease (AD). Cornel iridoid glycoside (CIG) is an effective component derived from Cornus officinalis. The present study aimed to determine the effects of CIG on β-amyloid (Aβ) and tau pathology and the underlying mechanisms in APP/PS1/tau triple transgenic (3×Tg) model mice.MethodsWe intragastrically administered 16-month-old 3×Tg mice with CIG (100 and 200 mg/kg) daily for two months. Learning and memory abilities were determined using the Morris water maze (MWM) and object recognition tests (ORT). Amyloid plaques and Aβ40/42 and the expression of related proteins in the cerebral cortex and hippocampus of mice was determined by western blottingResultsCIG improved learning and memory impairment in 3×Tg model mice, decreased amyloid plaque deposition, Aβ40/42 and the expression of full-length amyloid precursor protein, and increased levels of ADAM-10 (α-secretase), neprilysin (NEP), and insulin degrading enzyme (IDE) in the brains of the model mice. CIG also reduced tau hyperphosphorylation, and elevated phosphorylation level of GSK-3β at Ser9 and methylation of PP2A catalytic subunit C in the model mice. Moreover, CIG increased the expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP-responsive element binding protein (p-CREB) in the brain of 3×Tg mice.ConclusionsCIG ameliorated learning and memory deficit via reducing Aβ content and, tau hyperphosphorylation and increasing neurotrophic factors in the brain of 3×Tg mice. These results suggest that CIG may be beneficial for AD therapy.

Cornel Iridoid Glycoside Suppresses Tau Hyperphosphorylation and Aggregation in a Mouse Model of Tauopathy through Increasing Activity of PP2A

rTg4510 mice are transgenic mice expressing P301L mutant tau and have been developed as an animal model of tauopathy including Alzheimer's Disease (AD). Cornel Iridoid Glycoside (CIG) is an active ingredient extracted from Cornus officinalis, a traditional Chinese herb. The purpose of the present study was to investigate the effects of CIG on tau pathology and underlying mechanisms using rTg4510 mice. The cognitive functions were detected by Morris water maze and objective recognition tests. Western blotting and immunofluorescence were conducted to measure the levels of phosphorylated tau and related proteins. Serine/threonine phosphatase assay was applied to detect the activity of protein phosphatase 2A (PP2A). Intragastric administration of CIG for 3 months improved learning and memory abilities, prevented neuronal and synapse loss, halted brain atrophy, elevated levels of synaptic proteins, protected cytoskeleton, reduced tau hyperphosphorylation and aggregation in the brain of rTg4510 mice. In the mechanism studies, CIG increased the activity of PP2A, elevated the methylation of PP2A catalytic C (PP2Ac) at leucine 309, decreased the phosphorylation of PP2Ac at tyrosine 307, and increased protein expression of leucine carboxyl methyltransferase 1 (LCMT-1), protein tyrosine phosphatase 1B (PTP1B), and protein phosphatase 2A phosphatase activator (PTPA) in the brain of rTg4510 mice. CIG might have the potential to treat tauopathy such as AD via activating PP2A.

Cornel Iridoid Glycoside Protects Against White Matter Lesions Induced by Cerebral Ischemia in Rats via Activation of the Brain-Derived Neurotrophic Factor/Neuregulin-1 Pathway.

BackgroundIschemic stroke often induces profound white matter lesions, resulting in poor neurological outcomes and impaired post-stroke recovery. The present study aimed to investigate the effects of cornel iridoid glycoside (CIG), a major active component extracted from Cornus officinalis, on the white matter injury induced by ischemic stroke and further investigate its neuroprotective mechanisms.MethodsAdult male Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO) surgery for 2 h, followed by reperfusion. Rats were intragastrically administered CIG (60 mg/kg and 120 mg/kg) beginning 6 h afters reperfusion, once daily for seven days. A series of behavioral tests (modified neurological severity scores test, object recognition test, adhesive removal test, and beam walking test) were performed to evaluate the neurological functioning in MCAO rats. Histology of the white matter was studied using luxol fast blue staining and transmission electron microscopy. Immunohistochemical staining was performed to assess myelin loss, oligodendrocyte maturation, and glial activation. Activation of the brain-derived neurotrophic factor (BDNF)/neuregulin-1 (NRG1) pathway was evaluated by Western blotting.ResultsCIG treatment remarkably decreased the neurological deficit score, accelerated the recovery of somatosensory and motor functions, and ameliorated the memory deficit in MCAO rats. Furthermore, CIG alleviated white matter lesions and demyelination, increased myelin basic protein expression and the number of mature oligodendrocytes, and decreased the number of activated microglia and astrocytes in the corpus callosum of MCAO rats. In addition, Western blot analysis indicated that CIG increased the expression of BDNF/p-TrkB, NRG1/ErbB4 proteins, which further elevated PI3K p110α/p-Akt/p-mTOR signaling in the corpus callosum of MCAO rats.ConclusionWe demonstrated that CIG protects against white matter lesions induced by cerebral ischemia partially by decreasing the number of activated microglia and astrocytes, increasing BDNF level, and activating NRG1/ErbB4 and its downstream PI3K/Akt/mTOR pathways in the white matter. CIG might be used as a potential neuroprotective agent for the treatment of ischemic stroke.

Cornel iridoid glycoside improves cognitive impairment induced by chronic cerebral hypoperfusion via activating PI3K/Akt/GSK-3β/CREB pathway in rats

Chronic cerebral hypoperfusion is an important risk factor for vascular dementia (VaD) and other brain dysfunctions, for which there are currently no effective medications available. In the present study, we investigated the potential therapeutic effects of cornel iridoid glycoside (CIG) on VaD in rats modeled by permanent bilateral common carotid artery ligation (2-vessel occlusion, 2VO). The object recognition test (ORT) and Morris water maze (MWM) test were conducted to evaluate the learning and memory function. Western blot analysis and immunohistochemical staining were used to detect the expression of related proteins. Results showed that intragastric administration of CIG (30, 60, and 120 mg/kg) for 3 months significantly increased the discrimination index in ORT and decreased the escape latency in MWM test, ameliorating the learning and memory deficit in 2VO rats. Further data indicated that CIG increased the expression of neurotrophic factors (NGF and BDNF) and their receptors (TrkA and TrkB), glutamate receptor subunits (NMDAR1 and GluR2) in the cerebral cortex and hippocampus of 2VO rats. In addition, CIG elevated the expression of PI3K subunits p110α and p85, further upregulated the phosphorylation of Akt, GSK3β-ser9 and CREB in the cerebral cortex and hippocampus at 3 months after 2VO surgery. Collectively, CIG treatment improved learning and memory deficit induced by chronic cerebral hypoperfusion via increasing neurotrophic factors thus protecting glutamate receptors and activating PI3K/Akt/GSK3β/CREB signaling pathway in rats. These results suggest that CIG may be beneficial to VaD therapy.

Cornel iridoid glycoside induces autophagy to protect against tau oligomer neurotoxicity induced by the activation of glycogen synthase kinase-3β.

Tau oligomers are the etiologic molecules of Alzheimer's disease, and correlate strongly with neuronal loss and exhibit neurotoxicity. Recent evidence indicates that small tau oligomers are the most relevant toxic aggregate species. The aim of the present study was to investigate the mechanisms of cornel iridoid glycoside (CIG) on tau oligomers and cognitive functions. We injected wortmannin and GF-109203X (WM/GFX, 200μM each) into the lateral ventricles to induce tau oligomer and memory impairment in rats. When orally administered with CIG at 60 and 120mg/kg/day for 14days, CIG decreased the escape latency in the Morris water maze test. We also found that CIG restored the expression of presynaptic p-synapsin, synaptophysin, and postsynaptic density-95 (PSD-95) decreased by WM/GFX in rat cortex. CIG reduced the accumulation of tau oligomers in the brain of WM/GFX rats and in cells transfected with wild type glycogen synthase kinase-3β (wtGSK-3β). In addition, CIG up-regulated the levels of ATG7, ATG12, Beclin-1, and LC3II in vivo and in vitro, suggesting the restoration of autophagy function. These results suggest that CIG could ameliorate memory deficits and regulate memory-associated synaptic proteins through the clearance of tau oligomers accumulation. Moreover, CIG clears tau oligomers by restoring autophagy function.

Cornel iridoid glycoside exerts a neuroprotective effect on neuroinflammation in rats with brain injury by inhibiting NF-κB and STAT3.

Traumatic brain injury leads to problems with movement and cognitive deficits and has a high mortality rate. Cornel iridoid glycoside, the active ingredient of Cornus officinalis, has been reported to ameliorate apoptosis and inflammation in rats. We investigated the therapeutic effect of cornel iridoid glycoside on neuroinflammation in rats with brain injury. Rats were treated with cornel iridoid glycoside, and then measurements of antioxidant, proinflammatory marker, and NF-κB and STAT3 mRNA and protein levels, as well as a histopathologic analysis, were conducted. Cornel iridoid glycoside significantly reduced lipid peroxidation and TNF-α and IL-6 levels but increased the levels of antioxidants. In addition, cornel iridoid glycoside significantly decreased the expression of NF-κB and STAT3. Histopathological analyses showed that cornel iridoid glycoside reduced the severity of neuroinflammation and apoptosis. Therefore, cornel iridoid glycoside significantly ameliorated neuroinflammation by reducing lipid peroxidation and proinflammatory marker levels and increasing antioxidant levels in rats with brain injury.

Effect of cornel iridoid glycoside on microglia activation through suppression of the JAK/STAT signalling pathway

The effect of cornel iridoid glycoside (CIG), main component extracted from Cornus officinalis, on microglia activation has not been elucidated so far. We induced a mouse model of multiple sclerosis (MS), namely, the experimental autoimmune encephalomyelitis (EAE) model by immunization subcutaneously with the MOG35–55 peptide, which causes neuroinflammation and microglia activation. Our data demonstrated that CIG delayed the onset of the EAE, ameliorated the severity of the symptoms and inhibited the activation of microglia in different brain regions. In addition, we also found that CIG has therapeutic potential by modulating microglia polarization by reducing the expression and release of proinflammatory cytokines, chemokines and inhibiting phosphorylation in the JAK/STAT cell signalling pathway. Based on our findings, CIG might be a promising candidate for the prevention of neurological disorders such as multiple sclerosis (MS).

Cornel Iridoid Glycoside Inhibits Tau Hyperphosphorylation via Regulating Cross-Talk Between GSK-3β and PP2A Signaling.

Neurofibrillary pathology contributes to neuronal dysfunction and correlates with the clinical progression of Alzheimer’s disease (AD). Tau phosphorylation is mainly regulated by a balance of glycogen synthase kinase-3β (GSK-3β) and protein phosphatase 2A (PP2A) activities. Cornel iridoid glycoside (CIG) is a main component extracted from Cornus officinalis. The purpose of this study was to investigate the effects of CIG on GSK-3β and PP2A, thus to explore the mechanisms of CIG to inhibit tau hyperphosphorylation. The rat model of tau hyperphosphorylation was established by intraventricular injection of wortmannin and GF-109203X (GFX) to activate GSK-3β. The results showed that intragastrical administration of CIG inhibited tau hyperphosphorylation in the brain of rats induced by wortmannin/GFX. The results in vivo and in vitro exhibited that CIG inhibited tau hyperphosphorylation and GSK-3β over-activation. In the mechanism of action, CIG’s attenuating GSK-3β activity was found to be dependent on PI3K/AKT signaling pathway. PP2A catalytic C subunit (PP2Ac) siRNA abrogated the effect of CIG on PI3K/AKT/GSK-3β. Additionally and crucially, we also found that CIG inhibited the demethylation of PP2Ac at Leu309 in vivo and in vitro. It enhanced PP2A activity, decreased tau hyperphosphorylation, and protected cell morphology in okadaic acid (OA)-induced cell model in vitro. PP2Ac siRNA abated the inhibitory effect of CIG on tau hyperphosphorylation. Moreover, CIG inhibited protein phosphatase methylesterase-1 (PME-1) and demethylation of PP2Ac, enhanced PP2A activity, and decreased tau hyperphosphorylation in PME-1-transfectd cells. Taken together, CIG inhibited GSK-3β activity via promoting P13K/AKT and PP2A signaling pathways. In addition, CIG also elevated PP2A activity via inhibiting PME-1-induced PP2Ac demethylation to inhibit GSK-3β activity, thus regulated the cross-talk between GSK-3β and PP2A signaling and consequently inhibited tau hyperphosphorylation. These results suggest that CIG may be a promising agent for AD therapy.

Protective Effects of Cornel Iridoid Glycoside in Rats After Traumatic Brain Injury.

Cornel iridoid glycoside (CIG) is the active ingredient extracted from Cornus officinalis. Our previous studies showed that CIG had protective effects on several brain injury models. In the present study, we aimed to examine the effects and elucidate the mechanisms of CIG against traumatic brain injury (TBI). TBI was induced in the right cerebral cortex of male adult rats. The neurological and cognitive functions were evaluated by modified neurological severity score (mNSS) and object recognition test (ORT), respectively. The level of serum S100β was measured by an ELISA method. Nissl staining was used to estimate the neuron survival in the brain. The expression of proteins was determined by western blot and/or immunohistochemical staining. We found that intragastric administration of CIG in TBI rats ameliorated the neurological defects and cognitive impairment, and alleviated the neuronal loss in the injured brain. In the acute stage of TBI (24-72h), CIG decreased the level of S100β in the serum and brain, increased the ratio of Bcl-2/Bax and decreased the expression of caspase-3 in the injured cortex. Moreover, the treatment with CIG for 30 days increased the levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), enhanced the expression of synapsin I, synaptophysin and postsynaptic density protein 95 (PSD-95), and inhibited the apoptosis-regulating factors in the chronic stage of TBI. The present study demonstrated that CIG had neuroprotective effects against TBI through inhibiting apoptosis in the acute stage and promoting neurorestoration in the chronic stage. The results suggest that CIG may be beneficial to TBI therapy.