Beneficial effects of cornel iridoid glycoside on behavioral impairment and senescence status in SAMP8 mice at different ages

Ma, Denglei; Zhu, Yanqiu; Li, Yanzheng; Zhang, Li; Li, Yali; Li, Lin; Zhang, Lan

doi:10.1016/j.bbr.2016.06.008

Cited by 17 publications

(13 citation statements)

References 59 publications

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“…Previous studies in our laboratory indicated that CIG effectively improved memory ability and promoted neuronal survival through increasing the expression of synaptophysin and neurotrophic factors in cholinergic deficit AD-like model rats induced by fimbria-fornix transection ( Zhao et al, 2010 ). Our resent study found that CIG treatment ameliorated the cognitive impairment and inhibited tau hyperphosphorylation in the hippocampus and striatum of senescence-accelerated mouse prone 8 (SAMP8) model ( Ma et al, 2016 ). Our previous work also demonstrated that CIG attenuated tau hyperphosphorylation partially by enhancing PP2A activity in an AD-like cell model ( Yang et al, 2013 ), and inhibited the demethylation of PP2A catalytic subunit C in the hippocampus of rat model induced by intracerebroventricular injection with OA (data not shown).…”

Section: Introductionmentioning

confidence: 91%

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

Gao

Wang

et al. 2018

Front. Pharmacol.

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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.

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Section: Introductionmentioning

confidence: 91%

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

Gao

Wang

et al. 2018

Front. Pharmacol.

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“…The object recognition test (ORT) was performed to evaluate non-spatial memory as described previously 15,16. Briefly, the test lasted for three days: habituation day, training day, and testing day.…”

Section: Methodsmentioning

confidence: 99%

<p>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</p>

Wang¹,

Hua²,

Niu³

et al. 2019

NDT

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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.

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“…As aging is one of the key risk factors of AD, we studied the pharmacological effects of CIG using SAMP8 mice. In our previous article, we found SAMP8 mice showed cognitive impairments and senescent status, and CIG treatment reversed these changes at different ages (Ma et al, 2016). However, the effects and mechanisms of CIG on the AD pathologies on SAMP8 mice remains unclear.…”

Section: Introductionmentioning

confidence: 93%

“…Two different ages of SAMR1/SAMP8 mice were applied and allocated to two experiment tranches as previously reported (Ma et al, 2016). (1) Young SAMP8 mice at 4-month-old received treatments of three doses CIG (50, 100, 200 mg/kg/d), saline (as model group) or oxiracetam (as positive control drug, 360 mg/kg/d) for 2 months; same age SAMR1 mice were treated with saline or 100 mg/kg/d CIG; n = 15 per group.…”

Section: Animal Grouping and Treatmentmentioning

confidence: 99%

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Cornel iridoid glycoside ameliorated Alzheimer's disease-like pathologies and necroptosis through RIPK1/MLKL pathway in young and aged SAMP8 mice

Zhu

et al. 2021

Preprint

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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 researches. 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 Nissl and immunohistochemical staining was applied to detect NeuN-labeled neurons and myelin basic protein-labeled 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 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 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 a 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-associated neurodegenerative diseases such as AD.

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Beneficial effects of cornel iridoid glycoside on behavioral impairment and senescence status in SAMP8 mice at different ages

Cited by 17 publications

References 59 publications

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

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

<p>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</p>

Cornel iridoid glycoside ameliorated Alzheimer's disease-like pathologies and necroptosis through RIPK1/MLKL pathway in young and aged SAMP8 mice

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