Yuanyuan Deng

Icariside II, a novel phosphodiesterase-5 inhibitor, attenuates streptozotocin-induced cognitive deficits in rats.

Beta-amyloid (Aβ) deposition and neuroinflammation are involved in Alzheimers disease (AD)-type neurodegeneration with cognitive deficits. Phosphodiesterase-5 (PDE5) inhibitors have recently been studied as a potential target for cognitive enhancement by reducing inflammatory responses and Aβ levels. The present study was designed to investigate the effects of icariside II (ICS II), a novel PDE5 inhibitor derived from the traditional Chinese herb Epimedium brevicornum, on cognitive deficits, Aβ levels and neuroinflammation induced by intracerebroventricular-streptozotocin (ICV-STZ) in rats. The results demonstrated that ICV-STZ exhibited cognitive deficits and neuronal morphological damage, along with Aβ increase and neuroinflammation in the rat hippocampus. ICS II improved cognitive deficits, attenuated neuronal death, and decreased the levels of Aβ1-40, Aβ1-42 and PDE5 in the hippocampus of STZ rats. Furthermore, administration of ICS II at the dose of 10mg/kg for 21days significantly suppressed the expression of beta-amyloid precursor protein (APP), beta-secretase1 (BACE1) and increased the expressions of neprilysin (NEP) together with inhibited interleukin-1β (IL-1β), tumor necrosis factor (TNF)-α, cyclooxygenase-2 (COX-2) and transforming growth factor-β1 (TGF-β1) levels. In addition, ICS II exerted a beneficial effect on inhibition of IκB-α degradation and NF-κB activation induced by STZ. Taken together, the present study demonstrated that ICS II was a potential therapeutic agent for AD treatment.

Icariin attenuates cerebral ischemia-reperfusion injury through inhibition of inflammatory response mediated by NF-κB, PPARα and PPARγ in rats.

Icariin (ICA), an active flavonoid extracted from Chinese medicinal herb Epimedii, has been reported to exhibit many pharmacological effects including alleviating brain injury. However, little is known about the protection of ICA on ischemic stroke. Hence, this study was designed to investigate the neuroprotective effect of ICA and explore its underlying mechanisms on ischemic stroke induced by cerebral ischemia-reperfusion (I/R) injury in rats. The animals were pretreated with ICA at doses of 10, 30mg/kg twice per day for 3 consecutive days followed by cerebral I/R injury induced by middle cerebral artery occlusion (MCAO) for 2h and reperfusion for 24h. Neurological function and infarct volume were observed at 24h after reperfusion, the protein expression levels of interleukin-1β (IL-1β), transforming growth factor-β1 (TGF-β1), PPARα and PPARγ, inhibitory κB-α (IκB-α) degradation and nuclear factor κB (NF-κB) p65 phosphorylation were detected by Western blot, respectively. It was found that pretreatment with ICA could decrease neurological deficit score, diminish the infarct volume, and reduce the protein levels of IL-1β and TGF-β1. Moreover, ICA suppressed IκB-α degradation and NF-κB activation induced by I/R. Furthermore, the present study also showed that ICA up-regulated PPARα and PPARγ protein levels. These findings suggest that ICA has neuroprotective effect on ischemic stroke in rats through inhibition of inflammatory responses mediated by NF-κB and PPARα and PPARγ.

Icariin, a major constituent of flavonoids from Epimedium brevicornum, protects against cognitive deficits induced by chronic brain hypoperfusion via its anti-amyloidogenic effect in rats.

Chronic cerebral hypoperfusion is considered to be a pivotal contributing factor of cognitive impairments that occur in vascular dementia and Alzheimers disease, and ideal drug treatment for these diseases is unavailable. Hence, this study was designed to investigate the protective effects of icariin, a major constituent of flavonoids from the Chinese medicinal herb Epimedium brevicornum, on cognitive impairments and neuronal morphological damage induced by permanent occlusion of bilateral common carotid arteries (BCCAO) in rats, and further explore the potential mechanisms. This study found that BCCAO could induce cognitive deficits and neuronal morphological damage, along with deposition of beta-amyloid (Aβ) in rat hippocampus. However, oral administration of icariin twice per day for 23days might attenuate cognitive deficits and neuronal morphological damage induced by BCCAO. Subsequently, icariin decreased the level of Aβ in rat hippocampus subjected to BCCAO. Administration of icariin reduced the expressions of amyloid precursor protein (APP), beta-secretase 1 (BACE1), and increased the expressions of insulin-degrading enzyme (IDE) and a disintegrin and metalloproteinase domain 10 (ADAM10) in rat hippocampus. Furthermore, icariin afforded beneficial actions in suppressing transforming growth factor-β1 (TGF-β1) signaling via inhibition of Smad2/3 phosphorylation. In summary, icariin is effective in improving cognitive deficits and hippocampus morphological alterations subjected to BCCAO. This protection appears to be due to the decreased expressions of both APP and BACE1, and the increased expressions of both IDE and ADAM10, resulting in a decrease in the level of insoluble Aβ fragments in rat hippocampus. Inhibitions of TGF-β1 signaling and Smad2/3 phosphorylation are involved in the course.

Hydrogen sulfide ameliorates learning memory impairment in APP/PS1 transgenic mice: A novel mechanism mediated by the activation of Nrf2

Beta-amyloid (Aβ) plaques and oxidative stress are associated with the pathogenesis of Alzheimers disease (AD). Hydrogen sulfide (H2S) has been recognized as a cytoprotectant, which improves learning memory impairment and exerts antioxidant effects in neurodegenerative disorders, including AD. The experiment was projected to explore the effects of H2S on cognitive deficits, Aβ levels and possible antioxidant mechanisms. Here, APP/PS1 transgenic mice were injected sodium hydrosulfide (NaHS, a H2S donor, 2.8mg/kg) once a day for three months. It was found that APP/PS1 transgenic mice exhibited cognitive deficits and a large number of senile plaques, along with neurons decrease and Aβ increase. However, intraperitoneal (i.p.) injection of NaHS improved learning memory deficits, decreased the number of senile plaques, Aβ1-40 and Aβ1-42 levels, suppressed neurons loss, together with up-regulated the levels of cystathionine-β-synthase (CBS) and 3-mercaptopyruvate-sulfurtransferase (3MST). Furthermore, the protein levels of beta-amyloid precursor (APP) and beta-secretase 1 (BACE1) were dramatically restrained after administration of H2S. In addition, H2S exerted antioxidant effects via up-regulation nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase-1(HO-1) and glutathione S-transferase (GST). Taken together, these findings suggest that H2S ameliorates learning memory impairment, decreases the number of senile plaques in APP/PS1 mice possibly through inhibition of Aβ production and activation of Nrf2/antioxidant response element (ARE) pathway.

Icariside II, a novel phosphodiesterase 5 inhibitor, protects against H2O2-induced PC12 cells death by inhibiting mitochondria-mediated autophagy

Oxidative stress is a major cause of cellular injury in a variety of human diseases including neurodegenerative disorders. Thus, removal of excessive reactive oxygen species (ROS) or suppression of ROS generation may be effective in preventing oxidative stress‐induced cell death. This study was designed to investigate the effect of icariside II (ICS II), a novel phosphodiesterase 5 inhibitor, on hydrogen peroxide (H2O2)‐induced death of highly differentiated rat neuronal PC12 cells, and to further examine the underlying mechanisms. We found that ICS II pre‐treatment significantly abrogated H2O2‐induced PC12 cell death as demonstrated by the increase of the number of metabolically active cells and decrease of intracellular lactate dehydrogenase (LDH) release. Furthermore, ICS II inhibited H2O2‐induced cell death through attenuating intracellular ROS production, mitochondrial impairment, and activating glycogen synthase kinase‐3β (GSK‐3β) as demonstrated by reduced intracellular and mitochondrial ROS levels, restored mitochondrial membrane potential (MMP), decreased p‐tyr216‐GSK‐3β level and increased p‐ser9‐GSK‐3β level respectively. The GSK‐3β inhibitor SB216763 abrogated H2O2‐induced cell death. Moreover, ICS II significantly inhibited H2O2‐induced autophagy by the reducing autophagosomes number and the LC3‐II/LC3‐I ratio, down‐regulating Beclin‐1 expression, and up‐regulating p62/SQSTM1 and HSP60 expression. The autophagy inhibitor 3‐methyl adenine (3‐MA) blocked H2O2‐induced cell death. Altogether, this study demonstrated that ICS II may alleviate oxidative stress‐induced autophagy in PC12 cells, and the underlying mechanisms are related to its antioxidant activity functioning via ROS/GSK‐3β/mitochondrial signalling pathways.

Neuroprotective effects of sodium hydrosulfide against β-amyloid-induced neurotoxicity

Alzheimers disease (AD) is known to be caused by the accumulation of amyloid-β peptide (Aβ). The accumulation of Aβ has been shown to cause learning and memory impairment in rats, and it has been shown that hydrogen sulfide donors, such as sodium hydrosulfide (NaHS) can attenuate these effects. However, the underlying mechanisms have not yet been fully eludicated. This study was designed to investigate whether NaHS attenuates the inflammation and apoptosis induced by Aβ. We demonstrated that NaHS attenuated Aβ25–35-induced neuronal reduction and apoptosis, and inhibited the activation of pro-caspase-3. It also decreased the protein expresion of phosphodiesterase 5 (PDE5) in the hippocampus of the rats. In addition, NaHS upregulated the expression of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ, but it did not affect the expression of PPAR-β. Moreover, the Aβ25–35-exposed rats exhibited a decrease in IκB-α degradation and an increase in nuclear factor-κB (NF-κB) p65 phosphorylation levels, whereas these effects were attenuated by NaHS. Our data suggest that NaHS prevents Aβ-induced neurotoxicity via the upregulation of PPAR-α and PPAR-γ and the inhibition of PDE5. Hence NaHS may prove to be beneficial in the treatment of AD.

Icariside II Effectively Reduces Spatial Learning and Memory Impairments in Alzheimer’s Disease Model Mice Targeting Beta-Amyloid Production

Icariside II (ICS II) is a broad-spectrum anti-cancer natural compound extracted from Herba Epimedii Maxim. Recently, the role of ICS II has been investigated in central nervous system, especially have a neuroprotective effect in Alzheimer’s disease (AD). In this study, we attempted to investigate the effects of ICS II, on cognitive deficits and beta-amyloid (Aβ) production in APPswe/PS1dE9 (APP/PS1) double transgenic mice. It was found that chronic ICS II administrated not only effectively ameliorated cognitive function deficits, but also inhibited neuronal degeneration and reduced the formation of plaque burden. ICS II significantly suppressed Aβ production via promoting non-amyloidogenic APP cleavage process by up-regulating a disintegrin and metalloproteinase domain 10 (ADAM10) expression, inhibited amyloidogenic APP processing pathway by down-regulating amyloid precursor protein (APP) and β-site amyloid precursor protein cleavage enzyme 1 (BACE1) expression in APP/PS1 transgenic mice. Meanwhile, ICS II attenuated peroxisome proliferator-activated receptor-γ (PPARγ) degradation as well as inhibition of eukaryotic initiation factor α phosphorylation (p-eIF2α) and PKR endoplasmic reticulum regulating kinase phosphorylation (p-PERK). Moreover, phosphodiesterase type 5 inhibitors (PDE5-Is) have recently emerged as a possible therapeutic target for cognitive enhancement via inhibiting Aβ levels, and we also found that ICS II markedly decreased phosphodiesterase-5A (PDE5A) expression. In conclusion, the present study demonstrates that ICS II could attenuate spatial learning and memory impairments in APP/PS1 transgenic mice. This protection appears to be due to the increased ADAM10 expression and decreased expression of both APP and BACE1, resulting in inhibition of Aβ production in the hippocampus and cortex. Inhibition of PPARγ degradation and PERK/eIF2α phosphorylation are involved in the course, therefore suggesting that ICS II might be a promising potential compound for the treatment of AD.

Gastrodin ameliorates subacute phase cerebral ischemia‑reperfusion injury by inhibiting inflammation and apoptosis in rats

Gastrodin (GAS), which is extracted from the Chinese herbal medicine Gastrodia elata Blume, has long been used to improve stroke, epilepsy, dizziness and dementia. However, the effects and underlying mechanisms of GAS on subacute phase cerebral ischemia-reperfusion (I/R) injury remain unknown. The aim of the present study was to investigate the effects and mechanisms of GAS on cerebral I/R injury in rats. The rats were pretreated with GAS by gavage for 7 days followed by I/R surgery, and were then treated with GAS for 7 days after I/R surgery. Neurological deficits were assessed on days 1, 3 and 7 post-cerebral I/R injury. 2,3,5-Triphenyltetrazolium chloride staining was using to measure the infarct volume; morphological alterations were observed by hematoxylin and eosin staining under an optical microscope; apoptosis in the hippocampus and cortex was observed by terminal deoxynucleotidyl transferase dUTP nick end labeling staining; and the level of mRNA and protein expression was tested by reverse transcription-quantitative polymerase chain reation and western blot analysis, respectively. GAS markedly attenuated I/R-induced disability and histological damage, alleviated neuronal apoptosis, and reduced the mRNA and protein expression levels of inflammatory and proapoptotic factors, including interleukin-1β, cyclooxygenase-2, inducible nitric oxide synthase and cleaved caspase-3. These findings suggested that GAS may ameliorate subacute phase cerebral I/R injury by inhibiting inflammation and apoptosis in rats; therefore, GAS may be considered a potential candidate for the treatment of cerebral ischemia.

Icariin, a major constituent from Epimedium brevicornum, attenuates ibotenic acid-induced excitotoxicity in rat hippocampus

Excitotoxicity is one of the most extensively studied causes of neuronal death and plays an important role in Alzheimers disease (AD). Icariin is a flavonoid component of a traditional Chinese medicine reported to possess a broad spectrum of pharmacological effects. The present study was designed to investigate the effects of icariin against learning and memory impairment induced by excitotoxicity. Here, we demonstrated that rats receiving intracerebroventricular injection of excitatory neurotoxin ibotenic acid exhibited impaired learning and memory. Oral administration of icariin at doses of 20 and 40mg/kg rescued behavioral performance and protected against neurotoxicity in rat hippocampus by suppressing ibotenic acid induced pro-apoptosis. Furthermore, Western blott of hippocampal specimens revealed that icariin up-regulated the expression of calbindin-D28k protein following ibotenic acid administration. Additionally, icariin inhibited mitogen-activated protein kinase (MAPK) family phosphorylation and nuclear factor kappa B (NF-κB) signaling, implicating the MAPK signaling and NF-κB signaling pathways were involved in the mechanism underlying icariin-mediated neuroprotection against ibotenic acid-induced excitotoxicity. These data suggested that icariin could be a potential agent for treatment of excitotoxicity-related diseases, including AD.

Icariside II Ameliorates Cognitive Impairments Induced by Chronic Cerebral Hypoperfusion by Inhibiting the Amyloidogenic Pathway: Involvement of BDNF/TrkB/CREB Signaling and Up-Regulation of PPARα and PPARγ in Rats

Chronic cerebral hypoperfusion (CCH) is regarded as a high-risk factor for cognitive decline of vascular dementia (VD) as it is conducive to induce beta-amyloid (Aβ) aggregation. Icariside II (ICS II), a plant-derived flavonoid compound, has showed neuroprotective effect on animal models of Alzheimer’s disease (AD) by decreasing Aβ levels. Here, we assessed the effect of ICS II on CCH-induced cognitive deficits and Aβ levels in rats, and the possible underlying mechanisms were also explored. It was disclosed that CCH induced by bilateral common carotid artery occlusion (BCCAO) caused cognitive deficits, neuronal injury and increase of Aβ1-40 and Aβ1-42 levels in the rat hippocampus, while oral administration of ICS II for 28 days abolished the above deficits in the hippocampus of BCCAO rats. Meanwhile, ICS II significantly decreased the expression of beta-amyloid precursor protein (APP) and β-site amyloid precursor protein cleavage enzyme 1 (BACE1), as well as increased the expression of a disintegrin and metalloproteinase domain 10 (ADAM10) and insulin-degrading enzyme (IDE). ICS II also activated peroxisome proliferator-activated receptor (PPAR)α and PPARγ, enhanced the expression of brain-derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TrkB), levels of Akt and cAMP response element binding protein (CREB) phosphorylation. Together, these findings suggested that ICS II attenuates CCH-induced cognitive deficits by inhibiting the amyloidogenic pathway via involvement of BDNF/TrkB/CREB signaling and up-regulation of PPARα and PPARγ in rats.