Salidroside protects dopaminergic neurons by regulating the mitochondrial MEF2D-ND6 pathway in the MPTP/MPP+ -induced model of Parkinson's disease.

Mitochondrial complex I damage and oxidative stress play critical roles in the degeneration of dopaminergic (DA) neurons during the progression of Parkinson's disease (PD). Our previous study showed that NADH dehydrogenase 6 (ND6), exclusively regulated by mitochondrial myocyte enhancer factor 2D (MEF2D), was critical for mitochondrial complex I assembly. Recently, we found that Salidroside (Sal), isolated from Rhodiola rosea L., protected DA neurons by regulating oxidative stress-related mitochondrial pathways. Here, we investigated whether the mitochondrial MEF2D-ND6 pathway was involved in the neuroprotective effects of Sal. Our results showed that in 1-methyl-4-phenylpyridinium (MPP+ )-injured SN4741 cells, Sal pretreatment improved cellular viability, inhibited apoptosis, and restored both the mitochondrial membrane potential and complex I activity. Similarly, the protective effects of Sal on mitochondrial complex I activity, DA neurons, and behavior were also confirmed in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-lesioned mice. Besides, Sal pretreatment restored the expression of mitochondrial MEF2D and ND6 in MPP+ -injured SN4741 cells and MPTP-lesioned mice. Finally and interestingly, the protective effects of Sal were not observed in cells transfected with Mt2Ddn, a specific blocker of mitochondrial MEF2D function, suggesting that Sal protects DA neurons primarily by regulating the mitochondrial MEF2D-ND6 pathway. Our study sheds light upon the protective role of Sal through targeting the mitochondrial MEF2D-ND6 pathway in regulations of mitochondrial function and DA neuronal viability, providing novel mechanistic insights into the neuroprotective effects of Sal against PD.

Salidroside Protects Dopaminergic Neurons by Enhancing PINK1/Parkin-Mediated Mitophagy.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by the degeneration of nigrostriatal dopaminergic (DA) neurons. Our previous studies have suggested that salidroside (Sal) might play neuroprotective effects against PD by preserving mitochondrial Complex I activity. However, the exact mechanism of the neuroprotective effect of Sal remains unclear. Growing evidence indicates that PINK1/Parkin-mediated mitophagy is involved in the development of PD. In this study, we investigated whether Sal exerts a neuroprotective effect by modulating PINK1/Parkin-mediated mitophagy. Results showed that Sal alleviated MPTP-induced motor deficits in pole test. Moreover, Sal diminished MPTP-induced degeneration of nigrostriatal DA neurons as evidenced by upregulated TH-positive neurons in the substantia nigra, increased DAT expression, and high dopamine and metabolite levels in the striatum. Furthermore, in comparison with the MPP+/MPTP group, Sal considerably increased the mitophagosome and mitophagy flux. Moreover, in comparison with the MPP+/MPTP group, Sal evidently enhanced the mitochondrial expression of PINK1 and Parkin, accompanied by an increase in the colocalization of mitochondria with Parkin. However, transfection of MN9D cells with PINK1 siRNA reversed Sal-induced activated mitophagy and cytoprotective effect. In conclusion, Sal may confer neuroprotective effects by enhancing PINK1/Parkin-mediated mitophagy in MPP+/MPTP-induced PD models.

Triptolide Inhibits Preformed Fibril-Induced Microglial Activation by Targeting the MicroRNA155-5p/SHIP1 Pathway.

Evidence suggests that various forms of α-synuclein- (αSyn-) mediated microglial activation are associated with the progression of Parkinson's disease. MicroRNA-155-5p (miR155-5p) is one of the most important microRNAs and enables a robust inflammatory response. Triptolide (T10) is a natural anti-inflammatory component, isolated from a traditional Chinese herb. The objective of the current study was to identify the role and potential regulatory mechanism of T10 in αSyn-induced microglial activation via the miR155-5p mediated SHIP1 signaling pathway. Mouse primary microglia were exposed to monomers, oligomers, and preformed fibrils (PFFs) of human wild-type αSyn, respectively. The expressions of TNFα and IL-1ß, measured by enzyme-linked immunosorbent assay (ELISA) and qPCR, demonstrated that PFFs initiated the strongest immunogenicity in microglia. Application of inhibitors of toll-like receptor (TLR) 1/2, TLR4, and TLR9 indicated that PFFs activated microglia mainly via the NF-κB pathway by binding TLR1/2 and TLR4. Treatment with T10 significantly suppressed PFF-induced microglial activation and attenuated the release of proinflammatory cytokines including TNFα and IL-1ß. Levels of IRAK1, TRAF6, IKKα/ß, p-IKKα/ß, NF-κB, p-NF-κB, PI3K, p-PI3K, t-Akt, p-Akt and SHIP1 were measured via Western blot. Levels of miR155-5p were measured by qPCR. The results demonstrated that SHIP1 acted as a downstream target molecule of miR155-5p. Treatment with T10 did not alter the expression of IRAK1 and TRAF6, but significantly decreased the expression of miR155-5p, resulting in upregulation of SHIP1 and repression of NF-κB activity, suggesting inhibition of inflammation and microglial activation. The protective effects of T10 were abolished by the use of SHIP1 siRNA and its inhibitor, 3AC, and miR155-5p mimics. In conclusion, our results demonstrated that treatment with T10 suppressed microglial activation and attenuated the release of proinflammatory cytokines by suppressing NF-κB activity via targeting the miR155-5p/SHIP1 pathway in PFFs-induced microglial activation.

Salidroside Protects Dopaminergic Neurons by Preserving Complex I Activity via DJ-1/Nrf2-Mediated Antioxidant Pathway.

The pathogenic mechanism of Parkinson's disease (PD) remains to be elucidated; however, mitochondrial dysfunction at the level of complex I and oxidative stress is suggestively involved in the development of PD. In our previous work, salidroside (Sal), an active component extracted from the medicinal plant Rhodiola rosea L., might protect dopaminergic (DA) neurons through modulating ROS-NO-related pathway. However, the mechanism of Sal-induced neuroprotective effects against PD remains poorly understood. Therefore, we further investigated whether Sal plays neuroprotective effects by activating complex I via DJ-1/Nrf2-mediated antioxidant pathway. The results showed that Sal remarkably attenuated MPP+/MPTP-induced decline in cell viability, accompanied by decreases in reactive oxygen species (ROS), malondialdehyde (MDA), and 8-hydroxy-deoxyguanosine (8-OHdG) contents and increases in the superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), as well as glutathione (GSH) levels. Furthermore, Sal greatly improved the behavioral performance and prevented the severe reduction of TH-positive neuron numbers in the substantia nigra (SN). Moreover, in comparison with the MPP+/MPTP group, Sal increased the nuclear translocation of DJ-1 and Nrf2 and the mitochondrial translocation of DJ-1, accompanied by activating complex I. Furthermore, silencing of DJ-1/Nrf2 inhibited the increase of complex I activity and cell viability elicited by Sal. Together, these results support the neuroprotective effect of Sal against MPP+/MPTP-induced DA neurons damage.

Biological Effects of Tetrahydroxystilbene Glucoside: An Active Component of a Rhizome Extracted from Polygonum multiflorum.

Polygonum multiflorum Thunb. (PM), a traditional Chinese medicinal herb, has been widely used in the Orient as a tonic and antiaging agent. 2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside (TSG, C20H22O9, FW = 406.38928) is one of the active components extracted from PM. TSG is an antioxidant agent, which exhibits remarkable antioxidative activities in vivo and in vitro. The antioxidant effect of TSG is achieved by its radical-scavenging effects. TSG can inhibit apoptosis and protect neuronal cells against injury through multifunctional cytoprotective pathways. TSG performs prophylactic and therapeutic activities against Alzheimer's disease, Parkinson's disease, and cerebral ischemia/reperfusion injury. It is also antiatherosclerotic and anti-inflammatory. However, the mechanisms underlying these pharmacological activities are unclear. This study aimed at reviewing experimental studies and describing the effectiveness and possible mechanisms of TSG.

Salidroside Promotes the Pathological α-Synuclein Clearance Through Ubiquitin-Proteasome System in SH-SY5Y Cells.

Parkinson's disease (PD) is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and the presence of Lewy bodies (LBs) in the surviving SNc neurons. LBs formation is caused by the accumulation of α-synuclein (α-syn) or phosphorylated α-syn at serine-129 (pSer129-α-syn), which is implicated in the pathological progression of PD. Salidroside (Sal), the main active ingredient of the root of Rhodiola rosea L., has been reported to have potent neuroprotective properties in our previous investigations. Here, we investigated the effects of Sal on 6-OHDA and overexpresssion of WT/A30P-α-syn-induced pathological α-syn increase and the mechanism behind it in SH-SY5Y cells. We found Sal displays neuroprotective effects against 6-hydroxydopamine (6-OHDA)-induced cytotoxicity. Sal decreased the pSer129-α-syn level mainly by maintaining the normal function of ubiquitin-proteasome system (UPS). Furthermore, Sal promoted the clearance of α-syn and protected the cell viability mainly through recovered the 20S proteasome activity in WT/A30P-α-syn-transfected cells. These data provide new mechanistic insights into the neuroprotective effects of Sal and Sal may be a promising therapy to slow neurodegeneration in PD. Highlights: Sal protects cells and decreases the pSer129-α-syn protein level in 6-OHDA-induced impairmental and dysfunctional SH-SY5Y cells. Sal promotes the clearance of α-syn and protects the cell viability mainly through recovering the 20S proteasome activity in WT/A30P-α-syn plasmids transfected cells. Maintaining the normal function of the UPS may be one of the important mechanisms of Sal in neuroprotective effects.

Ultra Performance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry-Based Metabonomics Reveal Protective Effect of Terminalia chebula Extract on Ischemic Stroke Rats.

Terminalia chebula (TC), a kind of Combretaceae, is a widely used herb in India and East Asia to treat cerebrovascular diseases. However, the potential mechanism of the neuroprotective effects of TC at the metabonomics level is still not clear. The present study focused on the effects of TC on metabonomics in a stroke model. Rats were divided randomly into sham, model, and TC groups. Rats in the TC group were intragastrically administered with TC for 7 days after a middle cerebral artery occlusion (MCAO) operation. The sham and the model groups received vehicle for the same length of time. Subsequently, the neuroprotective effects of TC were examined by evaluation of neurological defects, assessment of infarct volume, and identification of biochemical indicators for antioxidant and anti-inflammatory activities. Further, metabonomics technology was employed to evaluate the endogenous metabolites profiling systematically. Consist with the results of biochemical and histopathological assays, pattern recognition analysis showed a clear separation of the model group and the sham group, indicating the recovery impact of TC on the MCAO rats. Moreover, 12 potential biomarkers were identified in the MCAO model group, involving energy (lactic acid, succinic acid, and fumarate), amino acids (leucine, alanine, and phenylalanine), and glycerophospholipid (PC [16:0/20:4], PC [20:4/20:4], LysoPC [18:0], and LysoPC [16:0]) metabolism, as well as other types of metabolism (arachidonic acid and palmitoylcarnitine). Notably, it was found that metabolite levels of TC group were partially reversed to normal. In conclusion, TC could ameliorate MCAO in rats by affecting energy metabolism (glycolysis and the TCA cycle), amino acid metabolism, glycerophospholipid metabolism, and other types of metabolism.

Salidroside Protects against MPP+-Induced Neuronal Injury through DJ-1-Nrf2 Antioxidant Pathway.

Parkinson's disease (PD) is the second most common neurodegenerative disorder. We have found that salidroside (Sal) exhibited neuroprotective effects against MPP+ toxicity. However, the molecular mechanism is not fully understood. In this study, we found that Sal significantly prevented MPP+-induced decrease of mRNA and protein expression of Nrf2, GCLc, SOD1, and SOD2 in SH-SY5Y cells. Moreover, silencing of Nrf2 significantly inhibited Sal-induced increase in mRNA and protein expression of GCLc, SOD1, and SOD2. But Nrf2 silence did not significantly impact Sal-exhibited effects on DJ-1 expression. Silencing of Nrf2 significantly suppressed the decrease of apoptosis induced by Sal in MPP+-treated SH-SY5Y cells. Sal significantly prevented MPP+-induced decrease of the mRNA and protein expression of DJ-1 in SH-SY5Y cells. Moreover, silencing of DJ-1 significantly inhibited Sal-induced increase in mRNA and protein expression of Nrf2, GCLc, SOD1, and SOD2 in MPP+-treated SH-SY5Y cells. These results indicated that DJ-1 was an upstream regulator of Nrf2 in the neuroprotective effects of Sal. Furthermore, silencing of DJ-1 significantly suppressed the decrease of apoptosis induced by Sal in MPP+-treated SH-SY5Y cells. In conclusion, Sal prevented MPP+-induced neurotoxicity through upregulation of DJ-1-Nrf2-antioxidant pathway. Our findings provide novel insights into the neuroprotective effects of Sal against PD.

JinqiJiangtang tablets for pre-diabetes: A randomized, double-blind and placebo-controlled clinical trial.

This study observed the efficacy and safety of JinqiJiangtang tablets (JQJT tablets, a traditional Chinese patent medicine) for pre-diabetes. Four hundred patients with pre-diabetes at five centres were treated for 12months and followed for an additional 12months to investigate the preventative effects of JQJT tablets (Registration ID: ChiCTR-PRC-09000401). The incidence rate of diabetes mellitus was the primary endpoint. The risk of converting from pre-diabetes to diabetes was 0.58-fold less in the JQJT tablets group than in the placebo group [HR (95% CI): 0.58 (0.384, 0.876), P = 0.010]. Furthermore, the probability of achieving normalized blood glucose was 1.41-fold greater in the JQJT tablets group than in the placebo group [HR (95% CI): 1.41 (1.002, 1.996), P = 0.0049]. ITT analysis revealed that the incidence of diabetes upon treatment completion was 16.5% in the JQJT tablets group compared with 28.9% in the control group. The percentage of patients with normalized blood glucose upon 12-month intervention was 41.8% in the JQJT tablets group compared with 27.8% in the control group. JQJT tablets could be an effective intervention for preventative treatment of Type 2 diabetes mellitus.

Potential molecular mechanisms mediating the protective effects of tetrahydroxystilbene glucoside on MPP+-induced PC12 cell apoptosis.

Our previous work demonstrated that tetrahydroxystilbene glucoside (TSG) was able to effectively attenuate 1-methyl-4-phenylpyridinium (MPP+)-induced apoptosis in PC12 cells partially via inhibiting reactive oxygen species (ROS) generation. However, the precise molecular mechanisms of TSG responsible for suppressing neuronal apoptosis have not been fully elucidated. To investigate the possible mechanism, we studied the neuroprotective effects of TSG on MPP+-induced PC12 cells apoptosis and explored the molecular mechanisms that mediated the effects of TSG. Our results showed that treatment with TSG prior to MPP+ exposure effectively attenuated the cell viability decrease in PC12 cells, reversed the cell apoptosis, and further restored the mitochondria membrane potential (MMP). In addition, TSG remarkably enhanced the anti-oxidant enzyme activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), and efficiently reduced the malondialdehyde (MDA) content in the PC12 cells. Meanwhile, TSG markedly upregulated the Bcl-2/Bax ratio, reversed release of Cytochrome c, and inhibited the activation of caspase-3 induced by MPP+. Furthermore, TSG significantly inhibited the activation of p38 mitogen-activated protein kinase (p38MAPK) signaling pathway, while extracellular signal-regulated protein kinases (ERK) phosphorylation was not affected. Together, these findings provide the basis for TSG clinical application as a new therapeutic strategy in the treatment of neurodegenerative diseases.

Neuroprotective Effects of Salidroside in the MPTP Mouse Model of Parkinson's Disease: Involvement of the PI3K/Akt/GSK3ß Pathway.

The degenerative loss through apoptosis of dopaminergic neurons in the substantia nigra pars compacta plays a primary role in the progression of Parkinson's disease (PD). Our in vitro experiments suggested that salidroside (Sal) could protect against 1-methyl-4-phenylpyridine-induced cell apoptosis in part by regulating the PI3K/Akt/GSK3ß pathway. The current study aims to increase our understanding of the protective mechanisms of Sal in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine- (MPTP-) induced PD mouse model. We found that pretreatment with Sal could protect against MPTP-induced increase of the time of turning downwards and climbing down to the floor. Sal also prevented MPTP-induced decrease of locomotion frequency and the increase of the immobile time. Sal provided a protection of in MPTP-induced loss of tyrosine hydroxylase-positive neurons in SNpc and the level of DA, DOPAC, and HVA in the striatum. Furthermore, Sal could increase the phosphorylation level of Akt and GSK3ß, upregulate the ratio of Bcl-2/Bax, and inhibit the activation of caspase-3, caspase-6, and caspase-9. These results show that Sal prevents the loss of dopaminergic neurons and the PI3K/Akt/GSK3ß pathway signaling pathway may have mediated the protection of Sal against MPTP, suggesting that Sal may be a potential candidate in neuroprotective treatment for PD.

Anxiolytic effect of essential oils of Salvia miltiorrhiza in rats.

This study aims to investigate the anxiolytic effects of essential oil from S. miltiorrhiza in rats. The elevated plus maze test and the social interaction test were performed to evaluate the anxiolytic effects of essential oil. The levels of noradrenaline (NE), dopamine (DA) and serotonin (5-HT) in cerebral cortex of rats as well as the plasma corticosterone (CORT) level were examined in the rats with the treatment of essential oil. The rota-rod test was carried out to exclude any false positive results in experimental procedures related to anxiety disorders. The catalepsy test was carried out to investigate whether essential oil induces the catalepsy. Our results showed that oral administration of essential oil increased the percentage of time spent in the open arms and increased the number of entries to the open arms in the elevated plus maze test. Oral administration of essential oil also increased the time for social interaction in rats. No apparent extrapyramidal symptom (EPS) was observed in the animals with essential oil treatment. The effect of essential oil in the intracellular chloride (Cl(-)) concentration in the cultured human neuroblastoma cells was assessed. Treatment with essential oil (50-100 mg/kg) increased intracellular Cl(-) concentration in the cell culture in a dose-dependent manner, suggesting the involvement of GABAA receptor-Cl(-) ion channel. Together, our data indicate an anxiolytic effect induced by the essential oil from S. miltiorrhiza.

Protective effects of 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside in the MPTP-induced mouse model of Parkinson's disease: Involvement of reactive oxygen species-mediated JNK, P38 and mitochondrial pathways.

Parkinson's disease (PD) is characterized by the selective death of dopaminergic neurons in the substantia nigra pars compacta. Oxidative stress-induced neuron loss is thought to play a crucial role in the pathogenesis of PD. Previous work from our group suggests that 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (TSG), an active component extracted from a traditional Chinese herb, Polygonum multiflorum thunb, can attenuate 1-methyl-4-phenyl pyridium-induced apoptosis in the neuronal cell line PC12, by inhibiting reactive oxygen species generation and modulating c-Jun N-terminal kinases (JNK) activation. Here, we investigated the protective effects of TSG against 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine (MPTP)-induced loss of tyrosine hydroxylase positive cells in mice and the underlying mechanisms. The results showed that MPTP-induced loss of tyrosine hydroxylase positive cells and reactive oxygen species generation were prevented by TSG in a dose-dependent manner. The reactive oxygen species scavenger N-acetylcysteine could also mitigate reactive oxygen species generation. Moreover, JNK and P38 were activated by MPTP, but extracellular signal-regulated protein kinases phosphorylation did not change after MPTP treatment. TSG at different doses blocked the activation of JNK and P38. The protective effect of TSG was also associated with downregulation of the bax/bcl-2 ratio, reversed the release of cytochrome c and smac, and inhibited the activation of caspase-3, -6, and -9 induced by MPTP. In conclusion, our studies demonstrated that the protective effects of TSG in the MPTP-induced mouse model of PD are involved, at least in part, in controlling reactive oxygen species-mediated JNK, P38, and mitochondrial pathways.

As2O3 induces apoptosis in human hepatocellular carcinoma HepG2 cells through a ROS-mediated mitochondrial pathway and activation of caspases.

Arsenic trioxide (As2O3) has been shown to induce apoptosis in hepatocellular carcinoma cells. However, the molecular mechanism of As2O3-induced apoptosis in the hepatocellular carcinoma cells remains poorly understood. Here, we investigated the impact of As2O3 exposure on the human hepatocellular carcinoma cell line HepG2 and examined the underlying mechanism of cell death. As2O3 induced apoptosis of HepG2 cells in a dose- and time-dependent manner and caused a massive production of reactive oxygen species (ROS). The antioxidant N-acetylcysteine (NAC) was able to prevent As2O3-induced cell death, implying an involvement of ROS in the induction of As2O3-triggered apoptosis. Furthermore, As2O3 initiated apoptosis by triggering of the mitochondria apoptotic pathway as indicated by inhibited Bcl-2 expression, a collapse of the mitochondrial membrane potential (MMP), release of cytochrome c and activation of the caspase cascade. However, these As2O3-induced events can be prevented by NAC. Taken together, these findings suggest that the As2O3 induced apoptosis through a ROS-mediated mitochondrial pathway and activation of caspases.

Three New Dimers and Two Monomers of Phenolic Amides from the Fruits of Lycium barbarum and Their Antioxidant Activities.

The aims of this study were to complement the current knowledge on the antioxidative composition of alcohol extracts from the fruits of Lycium barbarum and to evaluate their antioxidant activities. Three new dimers of phenolic amides, named lyciumamides A (3), B (4), and C (5), together with two monomers, N-E-coumaroyl tyramine (1) and N-E-feruloyl tyramine (2), were isolated from the fruits for the first time with the help of activity-guided chromatography. Compounds 1-5 were evaluated for their antioxidant activities in scavenging 2,2-diphenyl-1-picrylhydrazyl free radical and inhibiting lipid peroxidation in rat liver microsomes induced by ascorbate/Fe2+, cumine hydroperoxide, or CCl4/reduced form of nicotinamide-adenine dinucleotide phosphate, and the results showed that all of them exhibited strong activities, whereas compounds 1 and 2 were more potent than the reference tert-butyl-4-hydroxyanisole.

Analysis of clinical evaluation of response to treatment of Parkinson's disease with integrated Chinese and Western medicine therapy.

OBJECTIVE: To analyze the clinical evaluation of Parkinson's disease (PD) patients receiving integrated Chinese and Western medicine therapy. METHODS: One hundred and twenty patients were enrolled and randomly allocated to a control group or treatment group. Patients in the two groups received placebo and Bushen Huoxue Granule (, BHG), respectively. Both groups received baseline levodopa and benserazide (Madopar). The effects of treatment were assessed monthly during the 9-month treatment. Means of evaluation included Unified PD Rating Scale (UPDRS) scores (II and III), sleep scale score, 10 m turn back test (getting up time, 10 m×2 times, and turning time), timing motor test (TMT)-left and TMT-right, which were treated as the dependent variables; and age, sex, duration of PD, Hoehn and Yahr (H-Y) stage and Madopar dosage of admitted PD patients were as the independent variables. Multiple linear regression was used to analyze these factors. RESULTS: H-Y stage significantly affected UPDRS II score, UPDRS III score, and getting up time (P<0.01). Madopar dosage and H-Y stage significantly affected the 10 m×2 times (P<0.05 or <0.01). Madopar dosage significantly affected the sleep scale score (P<0.05). There were also significant correlations between age and TMT-left or TMT-right (P<0.01), and duration of PD and TMT-right (P<0.05). CONCLUSIONS: The six assessed means of clinical evaluation (including UPDRS II and UPDRS III scores, sleep scale score, getting up time, 10 m×2 times, and turning time) are sensitive indexes in all PD patients. H-Y stage and Madopar dosage are the major factors influencing means of clinical assessment of PD treatment.

Protective effects of salidroside in the MPTP/MPP(+)-induced model of Parkinson's disease through ROS-NO-related mitochondrion pathway.

Parkinson's disease is a progressive neurodegenerative disease causing tremor, rigidity, bradykinesia, and gait impairment. Oxidative stress and mitochondrial dysfunction play important roles in the development of Parkinson disease. Salidroside (Sal), a phenylpropanoid glycoside isolated from Rhodiola rosea L., has potent antioxidant properties. Previous work from our group suggests that Sal might protect dopaminergic neurons through inhibition of reactive oxygen species (ROS) and nitric oxide (NO) generation. In the present study, we investigated the protective effects of Sal in MPTP/MPP(+) models of Parkinson's disease in an attempt to elucidate the underlying mechanism of protection. We found that Sal pretreatment protected dopaminergic neurons against MPTP/MPP(+)-induced toxicity in a dose-dependent manner by: (1) reducing the production of ROS-NO, (2) regulating the ratio of Bcl-2/Bax, (3) decreasing cytochrome-c and Smac release, and inhibiting caspase-3, caspas-6, and caspas-9 activation, and (4) reducing α-synuclein aggregation. The present study supports the hypothesis that Sal may act as an effective neuroprotective agent through modulation of the ROS-NO-related mitochondrial pathway in vitro and in vivo.

Neuroprotection by tetrahydroxystilbene glucoside in the MPTP mouse model of Parkinson's disease.

Our in vitro experiments suggested that tetrahydroxystilbene glucoside (TSG) affords a significant neuroprotective effect against MPP⁺-induced damage and apoptosis in PC12 cells though activation of the PI3K/Akt pathway. This study was aimed to investigate the potential neuroprotective effect of TSG in 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine (MPTP)-treated mouse model of Parkinson's disease (PD). We found that treatment of TSG protected dopaminergic neurons by preventing MPTP-induced decreases in substantia nigra tyrosine hydroxylase (TH)-positive cells and striatal dopaminergic transporter (DAT) protein levels. Furthermore, it was also associated with increasing striatal Akt and GSK3ß phosphorylation, up-regulation of the Bcl-2/BAD ratio, and inhibition of the activation of caspase-9 and caspase-3. These results showed that TSG promoted dopamine neuron survival in vivo, the PI3K/Akt signaling pathway may have mediated the protection of TSG against MPTP, suggesting that TSG treatment might represent a neuroprotective treatment for PD.

Protection by salidroside against bone loss via inhibition of oxidative stress and bone-resorbing mediators.

Oxidative stress is a pivotal pathogenic factor for bone loss in mouse model. Salidroside, a phenylpropanoid glycoside extracted from Rhodiola rosea L, exhibits potent antioxidative effects. In the present study, we used an in vitro oxidative stress model induced by hydrogen peroxide (H(2)O(2)) in MC3T3-E1 cells and a murine ovariectomized (OVX) osteoporosis model to investigate the protective effects of salidroside on bone loss and the related mechanisms. We demonstrated that salidroside caused a significant (P<0.05) elevation of cell survival, alkaline phosphatase (ALP) staining and activity, calcium deposition, and the transcriptional expression of Alp, Col1a1 and Osteocalcin (Ocn) in the presence of H(2)O(2). Moreover, salidroside decreased the production of intracellular reactive oxygen species (ROS), and osteoclast differentiation inducing factors such as receptor activator of nuclear factor-kB ligand (RANKL) and IL-6 induced by H(2)O(2). In vivo studies further demonstrated that salidroside supplementation for 3 months caused a decrease in malondialdehyde (MDA) and an increase in reduced glutathione (GSH) concentration in blood of ovariectomized mouse (P<0.05), it also improved trabecular bone microarchitecture and bone mineral density in the fourth lumbar vertebra and distal femur. Our study indicated that the protection provided by salidroside in alleviating bone loss was mediated, at least in part, via inhibition of the release of bone-resorbing mediators and oxidative damage to bone-forming cells, suggesting that salidroside can be used as an effective remedy in the treatment or prevention of osteoporosis.

Therapeutic properties of quercetin on monosodium urate crystal-induced inflammation in rat.

OBJECTIVES: Gouty arthritis is characterized by intense, acute inflammatory reactions that occur in response to articular deposits of monosodium urate crystals. In this study we have assessed the effects of the flavonoid, quercetin, on monosodium urate crystal-induced inflammation in rats, an experimental model for gouty arthritis. METHODS: Gouty arthritis was induced by intra-articular injection of monosodium urate crystal suspension inside the ankle joint of the rat right hind limb. Circumference was assessed at 2, 4, 8, 12, 24, and 48 h after monosodium urate crystal injection. Histopathological analysis of joint synovial tissue, inflammatory mediator levels, lipid peroxidation, and antioxidant status in serum, liver and joint synovial tissue were determined in control and monosodium urate crystal-treated rats at the end of experiment. KEY FINDINGS: Quercetin treatment attenuated oedema in a dose-dependent manner and decreased histological signs of acute inflammation in the treated animals. In addition, quercetin treatment suppressed leucocyte recruitment, decreased chemokine levels, decreased levels of the lipid peroxidation end-product malondialdehyde, and increased antioxidant enzyme activity in treated rats. CONCLUSIONS: These results indicated that quercetin exerted a strong anti-inflammatory effect that may be useful for the treatment of acute gouty arthritis.