Siva Sundara Kumar Durairajan

Salvianolic acid B inhibits hydrogen peroxide-induced endothelial cell apoptosis through regulating PI3K/Akt signaling.

Background Salvianolic acid B (Sal B) is one of the most bioactive components of Salvia miltiorrhiza, a traditional Chinese herbal medicine that has been commonly used for prevention and treatment of cerebrovascular disorders. However, the mechanism responsible for such protective effects remains largely unknown. It has been considered that cerebral endothelium apoptosis caused by reactive oxygen species including hydrogen peroxide (H2O2) is implicated in the pathogenesis of cerebrovascular disorders. Methodology and Principal Findings By examining the effect of Sal B on H2O2-induced apoptosis in rat cerebral microvascular endothelial cells (rCMECs), we found that Sal B pretreatment significantly attenuated H2O2-induced apoptosis in rCMECs. We next examined the signaling cascade(s) involved in Sal B-mediated anti-apoptotic effects. We showed that H2O2 induces rCMECs apoptosis mainly through the PI3K/ERK pathway, since a PI3K inhibitor (LY294002) blocked ERK activation caused by H2O2 and a specific inhibitor of MEK (U0126) protected cells from apoptosis. On the other hand, blockage of the PI3K/Akt pathway abrogated the protective effect conferred by Sal B and potentated H2O2-induced apoptosis, suggesting that Sal B prevents H2O2-induced apoptosis predominantly through the PI3K/Akt (upstream of ERK) pathway. Significance Our findings provide the first evidence that H2O2 induces rCMECs apoptosis via the PI3K/MEK/ERK pathway and that Sal B protects rCMECs against H2O2-induced apoptosis through the PI3K/Akt/Raf/MEK/ERK pathway.

Berberine ameliorates β-amyloid pathology, gliosis, and cognitive impairment in an Alzheimer's disease transgenic mouse model.

The accumulation of β-amyloid (Aβ) peptide derived from abnormal processing of amyloid precursor protein (APP) is a common pathological hallmark of Alzheimers disease (AD) brains. In this study, we evaluated the therapeutic effect of berberine (BBR) extracted from Coptis chinensis Franch, a Chinese medicinal herb, on the neuropathology and cognitive impairment in TgCRND8 mice, a well established transgenic mouse model of AD. Two-month-old TgCRND8 mice received a low (25 mg/kg per day) or a high dose of BBR (100 mg/kg per day) by oral gavage until 6 months old. BBR treatment significantly ameliorated learning deficits, long-term spatial memory retention, as well as plaque load compared with vehicle control treatment. In addition, enzyme-linked immunosorbent assay (ELISA) measurement showed that there was a profound reduction in levels of detergent-soluble and -insoluble β-amyloid in brain homogenates of BBR-treated mice. Glycogen synthase kinase (GSK)3, a major kinase involved in APP and tau phosphorylation, was significantly inhibited by BBR treatment. We also found that BBR significantly decreased the levels of C-terminal fragments of APP and the hyperphosphorylation of APP and tau via the Akt/glycogen synthase kinase 3 signaling pathway in N2a mouse neuroblastoma cells stably expressing human Swedish mutant APP695 (N2a-SwedAPP). Our results suggest that BBR provides neuroprotective effects in TgCRND8 mice through regulating APP processing and that further investigation of the BBR for therapeutic use in treating AD is warranted.

Isorhynchophylline, a natural alkaloid, promotes the degradation of alpha-synuclein in neuronal cells via inducing autophagy

Accumulation of α-synuclein (α-syn) in the brain is a pathogenic feature and also a causative factor of Parkinson disease. Isorhynchophylline (IsoRhy) is a major tetracyclic oxindole alkaloid isolated from the Chinese herbal medicine Uncaria rhynchophylla (Miq.)Jacks (Gouteng in Chinese), which has been used for the treatment of neurological diseases in East Asia for centuries. Here we report a novel function of IsoRhy as a neuronal autophagy inducer. IsoRhy induced autophagy in different neuronal cell lines, including N2a, SH-SY5Y and PC12 cells, and also in primary cortical neurons. Furthermore, IsoRhy induced autophagy in the fat bodies of Drosophila. IsoRhy promoted clearance of wild-type, A53T and A30P α-syn monomers, α-syn oligomers and α-syn/synphilin-1 aggresomes in neuronal cells via the autophagy-lysosome pathway. More importantly, IsoRhy was able to decrease the expression levels of wild-type and A53T α-syn protein in differentiated human dopaminergic neurons. Notably, IsoRhy-induced autophagy was independent of the mTOR pathway but dependent on the function of Beclin 1. Taken together, data from this study raise the possibility that oxindole alkaloid derivatives may serve as a means to stimulate autophagy in neuronal cells, thereby exerting preventive and therapeutic values against neurodegenerative diseases such as Parkinson disease by reducing pathogenic protein aggregates in neurons.

Baicalein inhibits formation of α-Synuclein oligomers within living cells and prevents Aβ peptide fibrillation and oligomerisation

Abnormal protein aggregation in the brain is linked to the pathogenesis of neurodegenerative diseases, including Alzheimers disease (AD) and Parkinsons disease (PD). Recent studies revealed that the oligomeric form of aggregates is most likely the toxic species, and thus could be a good therapeutic target. To screen for potent inhibitors that can inhibit both oligomerisation and fibrillation of α‐synuclein (α‐syn), we systematically compared the antioligomeric and antifibrillar activities of eight compounds that were extracted from Chinese herbal medicines through three platforms that can monitor the formation of α‐syn fibrils and oligomers in cell‐free or cellular systems. Our results revealed that baicalein, a flavonoid extracted from the Chinese herbal medicine Scutellaria baicalensis Georgi (“huang qin” in Chinese), is a potent inhibitor of α‐syn oligomerisation both in cell‐free and cellular systems, and is also an effective inhibitor of α‐syn fibrillation in cell‐free systems. We further tested the protective effect of baicalein against α‐syn‐oligomer‐induced toxicity in neuronal cells. Our data showed that baicalein inhibited the formation of α‐syn oligomers in SH‐SY5Y and Hela cells, and protected SH‐SY5Y cells from α‐syn‐oligomer‐induced toxicity. We also explored the effect of baicalein on amyloid‐β peptide (Aβ) aggregation and toxicity. We found that baicalein can also inhibit Aβ fibrillation and oligomerisation, disaggregate pre‐formed Aβ amyloid fibrils and prevent Aβ fibril‐induced toxicity in PC12 cells. Our study indicates that baicalein is a good inhibitor of amyloid protein aggregation and toxicity. Given the role of these processes in neurodegenerative diseases such as AD and PD, our results suggest that baicalein has potential as a therapeutic agent for the treatment of these devastating disorders.

Neuroprotective effects of Astragaloside IV in 6-hydroxydopamine-treated primary nigral cell culture

Parkinsons disease (PD) is caused by a progressive degeneration of dopaminergic neurons in the substantia nigra. Oxidative stress and neural degeneration are suggested to be involved in the pathogenesis of Parkinsons disease. In the present study, Astragaloside IV (AS-IV) extracted from the dried root of Astragalus membranaceus, a well-known Chinese medicine used for the treatment of neurodegenerative diseases, was investigated for its capacity to protect dopaminergic neurons in experimental Parkinsons disease. By examining the effect of AS-IV on 6-hydroxydopamine (6-OHDA)-induced loss of dopaminergic neurons in primary nigral culture, we found that AS-IV pretreatment significantly and dose-dependently attenuated 6-OHDA-induced loss of dopaminergic neurons. Neuronal fiber length studies showed that massive neuronal cell death with degenerated neurons was observed in those cultures incubated with 6-OHDA, whereas in AS-IV co-treatments most dopaminergic neurons were seen to be intact and sprouting. In flow cytometric analysis, AS-IV resulted in a marked and dose-dependent rescue in tyrosine hydrolase (TH)-immunopositive cells from 6-OHDA-induced degeneration of dopaminergic neurons. Double immunofluorescence revealed that AS-IV treatment alone at concentrations of 100 and 200 microM increased the level of TH and NOS (nitrite oxide synthase) immunoreactivities; however, the protective effect of AS-IV on TH and NOS immunopositive cells in 6-OHDA treated nigral cell cultures was only seen at a concentration of 100 microM. These findings show that AS-IV can protect dopaminergic neurons against 6-OHDA-induced degeneration. Besides the neuroprotective effect, AS-IV alone promoted neurite outgrowth and increased TH and NOS immunoreactive of dopaminergic neurons. The neuroprotective and neurosprouting effects of AS-IV are specific for dopaminergic neurons and it has therapeutic potential in the treatment of PD.

Efficacy and safety of acupuncture for idiopathic Parkinson's disease: a systematic review.

OBJECTIVES To assess the efficacy and safety of acupuncture therapy (monotherapy or adjuvant therapy), compared with placebo, conventional interventions, or no treatment in treating patients with idiopathic Parkinsons disease (IPD). DATA SOURCES International electronic database: (1) The Cochrane Controlled Trials Register, (2) Academic Search Premier, (3) ACP Medicine, Alternative Medicine, (4) CINAHL, (5) EBM Reviews, (6) EMBASE, (7) MEDLINE, (8) OLD MEDLINE, (9) ProQuest Medical Library. Chinese electronic databases searched included: (1) VIP, (2) CJN, (3) CBM disk, (4) China Medical Academic Conference. Hand searching was conducted on all appropriate journals. Reference lists of relevant trials and reviews were also searched to identify additional studies. SELECTION CRITERIA All randomized controlled trials (RCTs) of any duration comparing monotherapy and adjuvant acupuncture therapy with placebo or no intervention were included. DATA COLLECTION AND ANALYSIS Data were abstracted independently by Y. C. Lam and S. C. Man onto standardized forms, and disagreements were resolved by discussion. MAIN RESULTS Ten (10) trials were included, each using a different set of acupoints and manipulation of needles. None of them reported the concealment of allocation. Only two mentioned the number of dropouts. Two (2) used a nonblind method while others did not mention their blinding methods. Nine (9) studies claimed a statistically significant positive effect from acupuncture as compared with their control; only one indicated that there were no statistically significant differences for all variables measured. Only 2 studies described details about adverse events. CONCLUSIONS There is evidence indicating the potential effectiveness of acupuncture for treating IPD. The results were limited by the methodological flaws, unknowns in concealment of allocation, number of dropouts, and blinding methods in the studies. Large, well-designed, placebo-controlled RCTs with rigorous methods of randomization and adequately concealed allocation, as well as intention-to-treat data analysis are needed.

HMGB1 is involved in autophagy inhibition caused by SNCA/α-synuclein overexpression: A process modulated by the natural autophagy inducer corynoxine B

SNCA/α-synuclein and its rare mutations are considered as the culprit proteins in Parkinson disease (PD). Wild-type (WT) SNCA has been shown to impair macroautophagy in mammalian cells and in transgenic mice. In this study, we monitored the dynamic changes in autophagy process and confirmed that overexpression of both WT and SNCAA53T inhibits autophagy in PC12 cells in a time-dependent manner. Furthermore, we showed that SNCA binds to both cytosolic and nuclear high mobility group box 1 (HMGB1), impairs the cytosolic translocation of HMGB1, blocks HMGB1-BECN1 binding, and strengthens BECN1-BCL2 binding. Deregulation of these molecular events by SNCA overexpression leads to autophagy inhibition. Overexpression of BECN1 restores autophagy and promotes the clearance of SNCA. siRNA knockdown of Hmgb1 inhibits basal autophagy and abolishes the inhibitory effect of SNCA on autophagy while overexpression of HMGB1 restores autophagy. Corynoxine B, a natural autophagy inducer, restores the deficient cytosolic translocation of HMGB1 and autophagy in cells overexpressing SNCA, which may be attributed to its ability to block SNCA-HMGB1 interaction. Based on these findings, we propose that SNCA-induced impairment of autophagy occurs, in part, through HMGB1, which may provide a potential therapeutic target for PD.

HMGB1 is involved in autophagy inhibition caused by SNCA/α-synuclein overexpression

SNCA/α-synuclein and its rare mutations are considered as the culprit proteins in Parkinson disease (PD). Wild-type (WT) SNCA has been shown to impair macroautophagy in mammalian cells and in transgenic mice. In this study, we monitored the dynamic changes in autophagy process and confirmed that overexpression of both WT and SNCAA53T inhibits autophagy in PC12 cells in a time-dependent manner. Furthermore, we showed that SNCA binds to both cytosolic and nuclear high mobility group box 1 (HMGB1), impairs the cytosolic translocation of HMGB1, blocks HMGB1-BECN1 binding, and strengthens BECN1-BCL2 binding. Deregulation of these molecular events by SNCA overexpression leads to autophagy inhibition. Overexpression of BECN1 restores autophagy and promotes the clearance of SNCA. siRNA knockdown of Hmgb1 inhibits basal autophagy and abolishes the inhibitory effect of SNCA on autophagy while overexpression of HMGB1 restores autophagy. Corynoxine B, a natural autophagy inducer, restores the deficient cytosolic translocation of HMGB1 and autophagy in cells overexpressing SNCA, which may be attributed to its ability to block SNCA-HMGB1 interaction. Based on these findings, we propose that SNCA-induced impairment of autophagy occurs, in part, through HMGB1, which may provide a potential therapeutic target for PD.

Systematic Review on the Efficacy and Safety of Herbal Medicines for Alzheimer's Disease

A systematic review was conducted to assess the efficacy and safety of herbal medications (HM), as either monotherapy or adjunct to orthodox medications (cholinesterase inhibitors and nootropic agents, OM) for Alzheimers disease (AD). Sixteen studies testing different HM were included. Out of the 15 HM monotherapy studies, 13 reported HM to be significantly better than OM or placebo; one reported similar efficacy between HM and OM. Only the HM adjuvant study reported significant efficacy. No major adverse events for HM were reported and HMs were found to reduce the adverse effects arising from OM. Imbalance in ethnicity among participants was observed; gender distribution was unclear. Heterogeneity in diagnostic criteria, interventions and outcome measures hindered comprehensive data analysis. Studies comparing HM with OM suggest that HM can be a safe, effective treatment for AD, either alone or in conjunction with OM. Methodological flaws in the design of the studies, however, limited the extent to which the results could be interpreted. Among various HMs, the safety and tolerability of EGb761 was best established. Further multi-center trials with large sample size, high methodological qualities and standardized HM ingredients are necessary for clinical recommendations on the use of HM in treating AD.

Treatment of Idiopathic Parkinson's Disease with Traditional Chinese Herbal Medicine: A Randomized Placebo-Controlled Pilot Clinical Study

The objective of this clinical study is to examine the effects of a Chinese herbal medicine formula (Jia Wei Liu Jun Zi Tang: JWLJZT) on motor and non-motor symptoms, and on complications of conventional therapy in idiopathic Parkinsons disease (PD), using an add-on design. Fifty-five patients with PD were randomly allocated to receive either Chinese herbal medicine or placebo for 24 weeks. Primary outcome measure was the 39-item Parkinsons Disease Questionnaire (PDQ-39). Secondary outcome measures included the Unified Parkinsons Disease Rating Scale (UPDRS), Short-Form-36 Health Survey (SF-36), Geriatric Depression Scale (GDS), home diaries, and a range of category rating scales. JWLJZT resulted in a significant improvement in the UPDRS IVC when compared with placebo at 12 weeks (P = .039) and 24 weeks (P = .034). In addition, patients in the Chinese herbal medicine group also showed significant improvement in PDQ-39 communication scores at 12 weeks (P = .024) and 24 weeks (P = .047) when compared with the placebo group. There were no significant differences between treatment and control groups for SF-36 variables, GDS score or the mean daily “on-off” time. One case of mild diarrhea was noted in the treatment group. The findings suggest that JWLJZT can relieve some non-motor complications of conventional therapy and improve the communication ability in patients with PD. The results of this pilot study warrant larger multi-center clinical studies to assess long-term efficacy and tolerability of JWLJZT, and to elucidate the mechanisms by which it affects PD function.