Mangiferin, a natural glucoxilxanthone, inhibits mitochondrial dynamin-related protein 1 and relieves aberrant mitophagic proteins in mice model of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease featured to mitochondrial dysfunction in neuronal cells. Dynamin-related protein 1 (Drp1) is an important regulator of mitochondrial fission and subsequent mitophagy. Mangiferin (MGF) is a glucosyl xanthone mainly derived from Mangifera indica L., possessing multifaceted properties, e.g., antioxidant, anti-inflammatory, and enhancement of cognitive ability. Besides, it can cross the blood-brain barrier, thereby exerting a neuroprotective effect. However, so far, MGF's effect in balancing mitochondrial homeostasis via regulation of Drp1 level and mitophagic pathway in PD remains rarely reported. PURPOSE: We aimed to investigate the neuroprotective effect of MGF against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and examine the possible mechanisms. METHODS: We utilized C57BL/6 mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); Behavioral parameters, containing the open field test, balance beam, pole test, and rotarod test, assessed the locomotor activity; immunohistochemistry assessed the number of TH-positive neurons; transmission electron microscopy detected ultrastructural mitochondrial morphology in the dopaminergic neuron; complex I enzymatic activity microplate assay kit measured the mitochondrial complex I activity; ATP determination kit measured ATP levels in mitochondria isolated from cells or striatal tissues; western blot measured the levels of Drp1 and mitophagic proteins. RESULTS: We observed that MGF could mitigate motor deficiency and improve the expression of tyrosine hydroxylase in the substantia nigra of MPTP-induced PD mice. Furthermore, MGF not only ameliorated mitochondrial ultrastructure, but also improved mitochondrial ATP content. Within mitochondria, MGF could reduce Drp1 expression and reverse the expressions of mitophagic proteins, including PINK1, Parkin, NIX, BNIP3, FUNDC1, and p62. CONCLUSION: Present study indicates that MGF benefits mitochondrial networks by recovering mitochondrial ultrastructure and ATP contents, reducing mitochondrial Drp1, and modulating mitophagic proteins in the MPTP-induced PD mice model, which revealed a novel acting mechanism of MGF in PD's treatment.

Efficacy of Traditional Chinese Medicine Combined with Selective Serotonin Reuptake Inhibitors on the Treatment for Parkinson's Disease with Depression: A Systematic Review and Meta-Analysis.

Depression is a common neuropsychiatric symptom of Parkinson's disease (PD), resulting in a lower quality of life and cognitive impairment in PD patients. Traditional Chinese medicine (TCM) formulas have been widely used in neurodegenerative disease and neuropsychic disorders to improve life quality of patients in ethnomedicine. TCM formulas combined with selective serotonin reuptake inhibitors (SSRIs) also have a positive effect on depressed PD compared with SSRIs as reported by several clinical studies. However, the results are discordant and failed to be conclusive. We aim to evaluate the efficacy of TCM formulas combined with SSRIs for depressed PD in this systematic review. We searched literatures from PubMed, Web of Science, Medline, Embase, Google Scholar, Chinese National Knowledge Infrastructure, Wanfang Database, and VIP Information Database before July 2020. We included randomized controlled trials investigating the efficacy of TCM formulas combined with SSRIs on depressed PD patients. This analysis was according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. Eleven randomized clinical trials involving 861 subjects were enrolled in this analysis. The overall results showed that TCM formulas combined with SSRIs significantly improved the depression score [weighted mean difference (WMD): -4.920, 95% confidence interval (CI): (-5.999, -3.840); [Formula: see text]¡ 0.001] and had a statistical significance on Unified Parkinson's Disease Rating Scale II score [WMD: -1.209, 95% CI: (-1.561, -0.857); [Formula: see text] < 0.001]. Furthermore, we observed that Chai-Hu-Shu-Gan Powder combined with SSRIs had a significant improvement on the depressive symptom in PD compared to the SSRIs alone [WMD: -5.390, 95% CI: (-7.66, -3.11); [Formula: see text] < 0.001]. No severe side events were reported in these included trials. This systematic review provided the evidences that TCM formulas combined with SSRIs might be helpful and safe in the treatment of depression of PD, including Chai-Hu-Shu-Gan Powder. Also, more randomized double-blinded trials with reliable design are required in the future.

Bioactive flavonoid dimers from Chinese dragon's blood, the red resin of Dracaena cochinchinensis.

Seven flavonoid dimers, biflavocochins A-G, together with six known compounds were isolated from the red resins of Dracaena cochinchinensis (Chinese dragon's blood). Their structures were elucidated based on extensive spectroscopic analysis. The absolute configurations of 1-7 was assigned by experimental and quantum chemical calculated ECD spectra, and that of 4 was further established by X-ray diffraction analysis using Cu Kα radiation. Compounds 1-3 are novel dimers of homoisoflavonoid and dihydrochalcone with a unique dibenzopyran ring. Compounds 2, 6, 7 exhibited moderate PTP1B inhibitory activities in an enzyme assay. Compound 1 showed neuroprotective effect on serum deficiency-induced cellular damage in PC12 cells.

The therapeutic role of cannabinoid receptors and its agonists or antagonists in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease and its characteristic is the progressive degeneration of dopaminergic neurons within the substantia nigra (SN) of the midbrain. There is hardly any clinically proven efficient therapeutics for its cure in several recent preclinical advances proposed to treat PD. Recent studies have found that the endocannabinoid signaling system in particular the comprised two receptors, CB1 and CB2 receptors, has a significant regulatory function in basal ganglia and is involved in the pathogenesis of PD. Therefore, adding new insights into the biochemical interactions between cannabinoids and other signaling pathways may help develop new pharmacological strategies. Factors of the endocannabinoid system (ECS) are abundantly expressed in the neural circuits of basal ganglia, where they interact interactively with glutamatergic, γ-aminobutyric acid-ergic (GABAergic), and dopaminergic signaling systems. Although preclinical studies on PD are promising, the use of cannabinoids at the clinical level has not been thoroughly studied. In this review, we evaluated the available evidence and reviewed the involvement of ECS in etiologies, symptoms and treatments related to PD. Since CB1 and CB2 receptors are the two main receptors of endocannabinoids, we primarily put the focus on the therapeutic role of CB1 and CB2 receptors in PD. We will try to determine future research clues that will help understand the potential therapeutic benefits of the ECS in the treatment of PD, aiming to open up new strategies and ideas for the treatment of PD.

Ginsenoside Rg1 attenuates okadaic acid induced spatial memory impairment by the GSK3ß/tau signaling pathway and the Aß formation prevention in rats.

Ginsenoside Rg1, one of the major active ingredients isolated from Panax Ginseng, has been shown notable neuroprotective effects in memory impairment animals. However, the role of ginsenoside Rg1 on cognition capacity damaged by neurofibrillary tangles (NFTs) is still poorly understood, and the underlying mechanism remain to be fully elucidated. Okadaic acid (OKA), a potent phosphatase inhibitor, often apply to imitate Alzheimer's disease-like symptom damaged by neurofibrillary tangles, was used to investigate the effects of ginsenoside Rg1 on memory impairment and the related mechanisms in Sprague Dawley (SD) rats. The anti-dementic drug donepezil was used as a positive contrast. The results showed that OKA intracerebroventricular (i.c.v.) injection induced memory impairment, including changes in the ability of orientation navigate, spatial probe and relearning memory in behavioral test of Morris water maze (MWM). However, treatment with Rg1 and donepezil remarkably alleviated these changes. Also OKA treated rats showed memory impairment including increasing of phospho-tau, decreasing of phospho-GSK3ß and the formation of ß-amyloid in special brain regions, which were reversed by Rg1 (20 mg/kg) and donepezil (1 mg/kg) administration. All these indicating that ginsenoside Rg1 protects rats against OKA-induced neurotoxicity. The possible neuroprotective mechanism may be that Rg1 decreases OKA-induced memory impairment through GSK3ß/tau signaling pathway and/or attenuating Aß formation. Thus, these studies indicate that ginsenoside Rg1 might be a potential preventive drug for Alzheimer's disease.

Coumarin glycosides and iridoid glucosides with neuroprotective effects from Hydrangea paniculata.

Five new coumarin glycosides, umbelliferone 7-O-sophoroside (1), umbelliferone 7-O-ß-D-glucopyranosyl(1 → 3)-ß-D-glucopyranoside (2), umbelliferone 7-O-ß-D-glucopyranosyl(1 → 3)-[ß-D-apiofuranosyl(1 → 6)]-ß-D-glucopyranoside (3), umbelliferone 7-O-ß-D-glucopyranosyl(1 → 2)-ß-D-apiofuranosyl(1 → 6)-ß-D-glucopyranoside (4), and umbelliferone 7-O-ß-D-glucopyranosyl(1 → 5)-ß-D-apiofuranosyl(1 → 6)-ß-D-glucopyranoside (5), and two new iridoid glucosides, 7-O-E-isoferuloyl loganic acid (6) and 7-O-ß-D-glucopyranosyl loganin (7), together with eight known compounds (8-15) were isolated from the stems of Hydrangea paniculata. Their structures were established by spectroscopic analysis and chemical methods. At 10 µM, compounds 1, 3, 5, 6, 8, 9, and 13 showed neuroprotective effects against serum deprivation-induced PC12 cell damage.

Protective effect of Bu-7, a flavonoid extracted from Clausena lansium, against rotenone injury in PC12 cells.

AIM: To investigate the protective effect and underlying mechanisms of Bu-7, a flavonoid isolated from the leaves of Clausena lansium, against rotenone-induced injury in PC12 cells. METHODS: The cell viability was evaluated using MTT assay. The cell apoptosis rate was analyzed using flow cytometry. JC-1 staining was used to detect the mitochondrial membrane potential (MMP). Western blotting analysis was used to determine the phosphorylation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38), tumor protein 53 (p53), Bcl-2-associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), and caspase 3. RESULTS: Treatment of PC12 cells with rotenone (1-20 µmol/L) significantly reduced the cell viability in a concentration-dependent manner. Pretreatment with Bu-7 (0.1 and 10 µmol/L) prevented PC12 cells from rotenone injury, whereas Bu-7 (1 µmol/L) had no significant effect. Pretreatment with Bu-7 (0.1 and 10 µmol/L) decreased rotenone-induced apoptosis, attenuated rotenone-induced mitochondrial potential reduction and suppressed rotenone-induced protein phosphorylation and expression, whereas Bu-7 (1 µmol/L) did not cause similar effects. Bu-7 showed inverted bell-shaped dose-response relationship in all the effects. CONCLUSION: Bu-7 protects PC12 cells against rotenone injury, which may be attributed to MAP kinase cascade (JNK and p38) signaling pathway. Thus, Bu-7 may be a potential bioactive compound for the treatment of Parkinson's disease.

Inhibitory effect of ginsenoside Rg1 on lipopolysaccharide-induced microglial activation in mice.

Microglial activation plays a pivotal role in the pathogenesis of neurodegenerative diseases by producing various pro-inflammatory cytokines and nitric oxide (NO). In the paper, the anti-inflammatory effect of ginsenoside Rg1 was investigated in mice intracerebroventricular injected of lipopolysaccharide (LPS). NO and tumor necrosis factor (TNF)-α production in both cerebral cortex and hippocampus decreased at dose-dependent manner by oral administration with Rg1. And the expression of ionized calcium binding adaptor molecule 1 (Iba-1) increased in both cerebral cortex and hippocampus in LPS-injected group compared to that in control group. However, Rg1 inhibited microglial activation by suppressing Iba-1 expression. In addition, the expression of inducible nitric oxide synthase (iNOS) was inhibited by Rg1. Moreover, Rg1 suppressed the phosphorylation level of IκB, nuclear translocation of p65 subunit of NFκB, and phosphorylation level of p38, ERK1/2, JNK mitogen-activated protein kinase (MAPK) induced by LPS. Concluding, Rg1 inhibited the inflammation mediated by LPS by suppressing NFκB and MAPK pathway, which provided the explanation for its therapeutic effect on neurodegenerative diseases.