peoniflorin and Alzheimer-Disease

Alzheimer's disease (AD) is a neurodegenerative disease, associated with progressive cognitive impairment and memory loss. In the present study, we examined the protective effects of paeoniflorin against memory loss and cognitive decline in lipopolysaccharide (LPS)-induced mice. Treatment with paeoniflorin alleviated LPS-induced neurobehavioral dysfunction, as confirmed by behavioral tests, including the T-maze test, novel-object recognition test, and Morris water maze test. LPS stimulated the amyloidogenic pathway-related proteins (amyloid precursor protein, APP; β-site APP cleavage enzyme, BACE; presenilin1, PS1; presenilin2, PS2) expression in the brain. However, paeoniflorin decreased APP, BACE, PS1, and PS2 protein levels. Therefore, paeoniflorin reverses LPS-induced cognitive impairment via inhibition of the amyloidogenic pathway in mice, which suggests that paeoniflorin may be useful in the prevention of neuroinflammation related to AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cognitive Dysfunction; Disease Models, Animal; Glucosides; Lipopolysaccharides; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Monoterpenes

The traditional Chinese medicine formula Danggui-Shaoyao-San (DSS) has been reported to have estrogen-like effects and therapeutic effects on the symptoms of Alzheimer's disease (AD).. To explore whether the central oxytocin and neuroendocrine system is involved in the modulating effects of DSS on the cognition and neuropsychiatric hebaviors in female AD rats, and to investigate the pharmacokinetics of paeoniflorin and ferulic acid in female AD rats with DSS treatment.. DSS (1.2, 3.2, 8.6 g/kg/day) was orally administered to ovariectomized (OVX) rats, and saline was orally administered to sham operation rats as control group. The Morris water maze test, novel object recognition test, and passive avoidance test were conducted for evaluation of learning and memory abilities, while elevated plus maze test and forced swim test were performed to assess anxiety- and depressive-like behaviors. ELISA kits were used to detect the levels of estrogen (E), estrogen receptor α (ERα), oxytocin (OT), oxytocin receptor (OTR), acetylcholine (Ach), acetylcholin esterase (AchE), and choline acetyl transferase (ChAT) in the cortex. The concentrations of Ach, glutamate (Glu), γ-aminobutyric acid (GABA), 5-hydroxytryptamine (5-HT), norepinephrine (NE) and dopamine (DA) in the hippocampus were assessed by HPLC-MS. The changes of neuronal morphology in the hippocampus were observed by Nissl staining. The pharmacokinetics of paeoniflorin and ferulic acid in OVX rats with DSS treatment were studied by HPLC.. In the Morris water maze test, novel object recognition test, and passive avoidance test, OVX rats showed cognitive impairment. In the elevated plus maze test and forced swim test, the anxiety- and depressive-like behaviors of OVX rats were significant as compared to the control group. Treatment of DSS significantly imporved the cognitive deficits, and ameliorated anxiety- and depressive-like behaviors of OVX rats. The expression of E, ERα, OT, OTR, AchE and ChAT in the cortex of model group were significantly decreased, and DSS significantly reversed these changes. The concentrations of Ach, Glu, GABA, 5-HT and NE in the hippocampus of OVX rats were significantly decreased, whereas DSS significantly increased the levels of Ach, Glu, GABA, 5-HT and NE. There was no significant difference in the concentration of DA in the hippocampus among groups. Degenerating neurons in the hippocampal CA3 region were observed in OVX rats, and the number of neurons was decreased. DSS treatment reduced the degenerating neurons, and incresed the number of neurons. The MRT (0 - ∞), AUC (0 - ∞), Cmax and t1/2z values of paeoniflorin, and the AUC. DSS improves the learning and memory ability, and attenuates anxiety- and depressive-like behaviors of OVX rats. The mechanism may be through increasing estrogen, reducing cholinergic damage, and modulating neurotransmitters. The increase in absorption and elimination time of paeoniflorin and ferulic acid in OVX rats may enhance the efficacy of DSS.

Topics: Alzheimer Disease; Animals; Dopamine; Estrogen Receptor alpha; Estrogens; Female; Hippocampus; Humans; Norepinephrine; Ovariectomy; Oxytocin; Rats; Serotonin

Aim of this research was to examine the impact of paeoniflorin (Pae) in suppressing the occurrence of ferroptosis in individuals with Alzheimer's disease (AD). The study utilized APP/PS1 mice with AD as the experimental subjects. Following the administration of Pae, the cognitive behaviors of mice were evaluated and the key indexes of ferroptosis were measured, as well as levels of oxidative stress (OS). For in-vitro experiments, Erastin was adopted for inducing the ferroptosis of PC12 cells, and the level of cell ferroptosis was detected after Pae treatment. Pae improved the cognitive ability of AD mice, reduced the level of ferroptosis, decreased the iron ion and MAD levels in brain tissues, and increased SOD expression. In PC12 cells, Pae suppressed the Erastin-induced ferroptosis, mitigated oxidative damage, and reduced the level of ROS. Based on the findings from our research, it was observed that Pae exhibited a specific binding affinity to P53, leading to the suppression of ferroptosis. This mechanism ultimately resulted in the improvement of nerve injury in mice with AD.

Topics: Alzheimer Disease; Animals; Cognition; Ferroptosis; Glucosides; Humans; Mice; Rats

Alzheimer's disease (AD) is the most common cause of dementia, characterised by advanced cognitive and memory deterioration with no effective treatments available. Previous in vitro and in vivo studies suggest that paeoniflorin (PF), a major bioactive constituent of Radix Paeoniae, might possess anti-dementia properties; however, the underlying mechanism remains unclear. The aim of the current study was to determine the therapeutic effects of PF in a transgenic mouse model of AD and to identify its mechanism. Transgenic mice with five familial AD mutations (5XFAD) were used in this study. We showed that 28 days of PF (5 mg/kg, ip) treatment significantly decreased the escape latency and path length in the Morris water maze test and increased the alternation rate in the T-maze test, compared to the vehicle treatment group. In addition, PF treatment significantly alleviated amyloid β plaque burden, inhibited astrocyte activation, and decreased IL-1β and TNF-α expression in the brain of 5XFAD mice. However, the anti-cognitive deficits, anti-amyloidogenic, and anti-inflammatory effects of PF were abolished by 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 0.3 mg/kg), an adenosine A

Topics: Adenosine; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Glucosides; Memory; Mice, Transgenic; Monoterpenes; Neuroprotective Agents; Receptor, Adenosine A1

Abnormal phosphorylation of tau, one of the most common symptoms of dementia, has become increasingly important in the study of the etiology and development of Alzheimer's disease. Paeoniflorin, the main bioactive component of herbaceous peony, is a monoterpene glycoside, which has been reported to exert beneficial effects on neurodegenerative disease. However, the effect of paeoniflorin on tauopathies remains ambiguous. SH-SY5Y cells were treated with okadaic acid (OA) for 8 h to induce tau phosphorylation and no cell death was observed. Optical microscopy results showed that paeoniflorin ameliorated okadaic acid induced morphological changes, including cell swelling and synapsis shortening. Western blotting data illustrated that paeoniflorin reversed okadaic acid induced tau hyperphosphorylation, which was enhanced by inhibiting the activities of calpain, Akt and GSK-3β. Transmission electron microscopy results showed that paeoniflorin alone can reduce the number of autophagosomes and stabilize the microtubule structure. In addition, calpastain and paeoniflorin enhance the effect of paeoniflorin on stabilizing microtubules. In addition, calpastain markedly enhanced the effect of paeoniflorin on reversing okadaic acid-lowered fluorescence intensity of both MAP-2 and β III-tubulin, two microtubule-associated proteins. This study shows that paeoniflorin protected SH-SY5Y cells against okadaic acid assault by interfering with the calpain/Akt/GSK-3β-related pathways, in which autophagy might be involved. Besides, paeoniflorin is found to relieve the stress response of the microtubule structure system caused by okadaic acid treatment. The results presented in this study suggest that paeoniflorin potentially plays an important role in tauopathies.

Topics: Alzheimer Disease; Autophagy; Calpain; Cell Line, Tumor; Glucosides; Glycogen Synthase Kinase 3 beta; Humans; Microtubules; Monoterpenes; Neurons; Neuroprotective Agents; Okadaic Acid; Phosphorylation; Proto-Oncogene Proteins c-akt; tau Proteins

Paeoniflorin, the main active component of the peony plant, exerts various pharmacological effects. Recently, research on the effect of paeoniflorin on the nervous system has gained more attention. The aim of the present study was to determine whether paeoniflorin exerts a protective effect that improves Alzheimer's disease (AD) via inflammation and apoptosis in the cerebral cortex of a transgenic mouse model of AD. Transgenic mice were used to construct the model of AD and were treated with paeoniflorin. The Morris water maze test was used to analyze cognitive function in AD mice. The protein expression levels of nuclear factor‑κB, tumor necrosis factor‑α, interleukin (IL)‑1β, IL‑6 and caspase‑3 were examined with commercial kits. Expression levels of B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein (Bax), phosphorylated (p)‑Akt and p‑p38 mitogen‑activated protein kinase (p‑p38 MAPK) in AD were evaluated by western blotting. The neuroprotective effects of paeoniflorin significantly improved cognitive function and ameliorated patterns of escape distance and escape latency in AD mice. Furthermore, the effects of paeoniflorin decreased inflammation and caspase‑3 activity, and inhibited cell death via increasing the Bcl‑2/Bax ratio and p‑Akt expression levels, and downregulating p‑p38 MAPK expression in AD mice.

Topics: Alzheimer Disease; Animals; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Cerebral Cortex; Cognition; Disease Models, Animal; Glucosides; Inflammation; Mice, Transgenic; Monoterpenes; Neuroprotective Agents; Phosphorylation; Proto-Oncogene Proteins c-akt

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Benzyl Alcohols; Brain; Disease Models, Animal; Glucosides; Hippocampus; Memory; Mice; Mice, Transgenic; Monoterpenes; Plaque, Amyloid; Random Allocation; Saponins; Triterpenes

Alzheimer's disease (AD) is associated with the inflammatory response in response to amyloid β-peptide (Aβ). Previous studies have suggested that paeoniflorin (PF) shows anti-inflammatory and neuroprotective effects in inflammation-related diseases. However, the impacts of PF on AD have not been investigated. In the present study, we showed that a 4-week treatment with PF could significantly inhibit Aβ burden, Aβ-induced over activation of astrocytes and microglia, downregulation of proinflammatory cytokines, and upregulation of anti-inflammatory cytokines in the brain. In addition, we demonstrated that chronic treatment with PF inhibited the activation of glycogen synthase kinase 3β (GSK-3β) and reversed neuroinflammtory-induced activation of nuclear factor-kappa B (NF-κB) signaling pathways. Moreover, PF exerted inhibitory effects on NALP3 inflammasome, caspase-1, and IL-1β. Collectively, in the present study, we demonstrated that PF exhibits neuroprotective effects in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (APP/PS1) mice via inhibiting neuroinflammation mediated by the GSK-3β and NF-κB signaling pathways and nucleotide-binding domain-like receptor protein 3 inflammasome. Thus, these results suggest that PF might be useful to intervene in development or progression of neurodegeneration in AD through its anti-inflammatory and anti-amyloidogenic effects.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Glucosides; Inflammation; Inflammation Mediators; Male; Memory Disorders; Mice; Mice, Transgenic; Monoterpenes; Paeonia; Plaque, Amyloid; Presenilin-1

The pathogenic mechanism of neurodegenerative brain disorder such as Alzheimer's disease (AD) has been still far from clearly understood. Previous research has identified that mitochondrial dysfunction induced by Aβ has been recognized as a hallmark in AD. Therefore, the effective agents targeting β-amyloid (Aβ)-induced mitochondrial dysfunction may be useful for the treatment or prevention of AD. In the present study, the neuroprotective effect of paeoniflorin (PF), one monoterpene glycoside isolated from the Chinese herb Radix Paeoniae alba, on Aβ25-35-induced toxicity in PC12 cells was investigated for the first time. The results showed that PF could attenuate or restore the cell injury induced by Aβ25-35 in PC12 cells through preventing mitochondrial dysfunction, including decreased mitochondrial membrane potential, increased cytochrome c release as well as activity of caspase-3 and caspase-9. Therefore, our data provide the evidence that PF could protect PC12 cells against Aβ25-35-induced neurotoxicity and might be a potentially therapeutic approach for AD in the future.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Cell Survival; Disease Models, Animal; Glucosides; Membrane Potential, Mitochondrial; Mitochondria; Monoterpenes; Neurons; Neuroprotective Agents; PC12 Cells; Peptide Fragments; Rats

To study the role of PI3K/Akt pathway in the neuroprotective effect of paeoniflorin on PC12 cells.. The paeoniflorin group (5, 10, 20 μmol · L(-1)) was pretreated for 30 min, and then added with Aβ25-35 (20 μmol · L(-1)) for interaction for 24 h. Inhibitor LY294002 (10 μmol · L(-1)) was pretreated for 30 min before the action of paeoniflorin (10 μmol · L(-1)). The MTT colorimetric method was used to detect the cell viability. The apoptosis rate was tested by the FITC-Annexin V/PI staining. The protein expression of p-AKT, Bax, Bcl-2 and cleaved caspase-3 protein were detected by Western blot analysis.. Paeoniflorin could significantly inhibit the Aβ25-35-induced PC12 cell toxicity and apoptosis. Its protection effect may be achieved by up- regulating AKT phosphorylation level, increasing Bcl-2 protein expression, reducing Bax protein expression, inhibiting the activation of caspase-3. Inhibitor LY294002 could weaken the above protective effects of paeoniflorin.. Paeoniflorin could activate PI3K/Akt signaling pathway to protect the PC12 cell injury induced by Aβ25-35.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Cell Survival; Drugs, Chinese Herbal; Glucosides; Humans; Monoterpenes; Neurons; Neuroprotective Agents; PC12 Cells; Peptide Fragments; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Rats; Signal Transduction

This study was to investigate the effect of peoniflorin on the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream signal molecules in the hippocampus of Alzheimer's disease (AD) rats for exploring the mechanism of peoniflorin protecting hippocampal neurons. AD model rats were established by bilateral intrahippocampal injection of beta-amyloid(1-42) (Abeta(1-42)) and divided randomly into 3 groups: AD model group, peoniflorin low-dose (15 mg x kg(-1)) group and peoniflorin high-dose (30 mg x kg(-1)) group. The vehicle control rats were given bilateral intrahippocampal injection of solvent with the same volume. After peoniflorin or saline was administered (ip) once daily for 14 days, the hippocampuses of all animals were taken out for measuring the expressions of Nrf2, heme oxygenase-1 (HO-1) and gamma-glutamylcysteine synthethase (gamma-GCS) mRNA by reverse transcription PCR, determining the contents of glutathione (GSH), malondialdehyde (MDA) and carbonyl protein (CP) using colorimetric method, and for assaying the expressions of neuronal apoptosis inhibitory protein (NAIP) and Caspase-3 by immunohistochemical staining method. The results showed that peoniflorin markedly increased the expressions of Nrf2, HO-1 and gamma-GCS mRNA, enhanced the level of GSH and decreased the contents of MDA and CP in the hippocampus, as compared with the model group. Peoniflorin also improved the NAIP expression and reduced the Caspase-3 expression in the hippocampus neurons. In conclusion, peoniflorin protects against the Abeta(1-42)-mediated oxidative stress and hippocampal neuron injury in AD rats by activating the Nrf2/ARE pathway.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Caspase 3; Glucosides; Glutamate-Cysteine Ligase; Glutathione; Heme Oxygenase (Decyclizing); Hippocampus; Male; Malondialdehyde; Monoterpenes; Neuronal Apoptosis-Inhibitory Protein; Neurons; NF-E2-Related Factor 2; Oxidative Stress; Peptide Fragments; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger

A method based on high performance liquid chromatography (HPLC) was developed for the quantitative determination of six components in an anti-Alzheimer medicine, Xiao-Xu-Ming Decoction, which is an effective prescription in treating stroke and the sequela of stroke by herbalist doctors for thousands years. The effective component group (ECG) was made according to the results of high-throughput screening, and the curative effect of ECG was validated on aging rats. In this method an ODS column was used. The mobile phase consisted of water-formic acid-ethylenediamine (A; 100: 0.1: 0.1, v/v) and methanol-formic acid (B; 100 : 0.05, v/v), eluted with gradient (0 - 5 min, 20% B; 5 - 100 min, 20% B - 40% B; 100 - 140 min, 40% B - 70% B). The flow rate was 1 mL/min. The detection wavelength was set at 240 nm. Under the above separation conditions, six components belonged to two different categories, indicans and alkaloids, were determined simultaneously. The relationships between the concentrations and the peak areas of these six components were all linear. The recoveries of the six components were 99.1% for paeoniflorin, 99.6% for prim-O-glucosylcimifugin, 98.4% for baicalin, 99.9% for 4'-O-beta-D-glucosyl-5-O-methylvisamminol, 99.6% for fangchinoline, and 102.0% for tetrandrine. The relative standard deviations (RSD) were 1.3%, 1.4%, 0.4%, 0.8%, 0.2%, and 1.4%, respectively. This method is simple and reproducible and it can be used for the quality control of the effective component group of Xiao-Xu-Ming Decoction.

Topics: Alzheimer Disease; Animals; Benzoates; Benzylisoquinolines; Bridged-Ring Compounds; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Flavonoids; Glucosides; Monosaccharides; Monoterpenes; Xanthenes