The ATP-sensitive potassium (K(ATP)) channels which extensively distribute in diverse tissues (e.g. vascular smooth muscle, cardiac cells, and pancreas) are well-established for characteristics like vasodilatation, myocardial protection against ischemia, and insulin secretion. The aim of this review is to get insight into the novel roles of K(ATP) channels in Parkinson's disease (PD), with consideration of the specificities K(ATP) channels in the central nervous system (CNS), such as the control of neuronal excitability, action potential, mitochondrial function and neurotransmitter release.
Humans ; KATP Channels ; drug effects ; physiology ; Mitochondria ; metabolism ; Parkinson Disease ; metabolism ; therapy

Animals ; Dynorphins ; metabolism ; Parkinson Disease ; drug therapy ; metabolism ; Peptides ; pharmacology ; Rats ; Scorpion Venoms ; pharmacology

To study the effects of 6-hydroxydopamine (6-OHDA) and reduced glutathione (GSH) on the nigral dopaminergic neurons in brain slices in vitro, immolunohistochemical technique was used to observe the changes of TH-stained neurons, including cell bodies and the dendrites, in the substantia nigra (SN) of midbrain slices of rats after incubation for 1 h in the presence of GSH 15 min before and during the period of incubation with 6-OHDA. The results showed that cell bodies remained intact but dendrites were fragmented and truncated after treatment with 6-OHDA. The antioxidant GSH alone did not significantly affect the dendrites of SN neurons but prevented 6-O-HDA-induced damage of dendrites. It was concluded that glutathione may prevent 6-OHDA-induced dopaminergic neurodegeneration and play a protective role in dopaminergic neurons.
Glutathione/*therapeutic use ; Neurons/pathology ; Oxidopamine ; Parkinson Disease, Secondary/chemically induced ; Parkinson Disease, Secondary/*drug therapy ; Random Allocation ; Rats, Sprague-Dawley ; Substantia Nigra/pathology ; Tyrosine 3-Monooxygenase/metabolism

Under the guidance of the traditional Chinese medicine(TCM) theory of "Zangfu-organs of spleen and stomach" and the modern theory of "microbiota-gut-brain axis", this study explored the effects of Nardostachys jatamansi on the gut microbiota of rats with Parkinson's disease(PD). The 40 SD rats were randomly divided into the control group, PD model group, levodopa group, and Nardostachys jatamansi ethanol extract group. The PD model was established by subcutaneous injection of rotenone in the neck and back area. After 14 days of intragastric administration, the PD rats' behaviors were analyzed through open field test, inclined plane test, and pole test. After the behavioral tests, the striatum, colon, and colon contents of rats in each group were collected. Western blot was employed to detect the protein expression of tyrosine hydroxylase(TH) and α-synuclein(α-syn) in striatum and that of α-syn in colon. Enzyme linked immunosorbent assay(ELISA) was used to detect the levels of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), and nuclear factor-kappa B(NF-κB) in striatum and colon. High-throughput sequencing of 16 S rRNA gene was conducted to detect the differences in microbial diversity, abundance, differential phyla, and dominant bacteria of rats between groups. The results indicated that Nar. ethanol extract could relieve dyskinesia, reverse the increased levels of α-syn, TNF-α, IL-1β, and NF-κB in striatum, and improve the protein expression of TH in striatum of PD rats. The α diversity analysis indicated a significant decrease in diversity and abundance of gut microbiota in the PD model. The results of linear discriminant analysis effect size(LEfSe) of dominant bacteria indicated that Nardostachys jatamansi ethanol extract increased the relative abundance of Clotridiaceae, Lachnospiraceae, and Anaerostipes, and reversed the increased relative abundance of Proteobacteria, Gammaproteobacteria, Enterobacteriaceae, and Escherichia-Shigella in PD model group to exhibit the neuroprotective effect. In summary, the results indicated that Nar. ethanol extract exert the therapeutic effect on PD rats. Specifically, the extract may regulate gut microbiota, decrease the levels of proinflammatory cytokines, and reduce the protein aggregation of α-syn in the colon and striatum to alleviate intestinal inflammation and neuroinflammation. This study provides a basis for combining the theory of "Zangfu-organs of spleen and stomach" with the theory of "microbiota-gut-brain axis" to treat PD.
Animals ; Gastrointestinal Microbiome ; NF-kappa B/metabolism* ; Nardostachys/metabolism* ; Parkinson Disease/drug therapy* ; Rats ; Rats, Sprague-Dawley

Baicalein, a flavonoid compound extracted from dried roots of traditional Chinese medicine Scutellaria baicalensis, has been widely applied as an antioxidant and anti-inflammatory agent. With continuous studies on its mechanisms, recent findings suggest that baicalein has some effect on neuroprotection and improvement of clinical symptoms in neurodegenerative diseases such as Parkinson's disease. Recent studies showed that its neuroprotective efficacy is closely related to such functions as antiinflammatory, antioxidative stress, protecting chondriosome, inhibiting glutamate neurotoxicity, promoting nerve growth and inhibiting alpha-synuclein protein-aggregate activities. The aim of this article is to summarize the neuroprotective effects of baicalein in Parkinson's disease.
Flavanones ; pharmacology ; therapeutic use ; Humans ; Mitochondria ; drug effects ; metabolism ; Nerve Growth Factor ; metabolism ; Neuroprotective Agents ; pharmacology ; therapeutic use ; Oxidative Stress ; drug effects ; Parkinson Disease ; drug therapy ; metabolism ; pathology

OBJECTIVETo explore the mechanism underlying the therapeutic effect of Bushen Huoxue Decoction (BHD), a traditional Chinese medicinal preparation, on dopamine D2 receptor (DRD2) in the brain of rat models of Parkinson's disease (PD).

METHODSA total of 120 SD rats were randomized into normal control group, saline model group and BHD-treated group. In the latter two groups, PD rat models were established by direct injection of 6-OHDA to destruct the substantia nigra compact part (SNC) with corresponding treatments. The behavioral changes of the rats were observed. Radioimmunoassay was employed to determine the changes in the equilibrium dissociation constant (Kd) and maximal binding capacity (B(max)) of DRD2, and immunohistochemistry was used to observe the number of the DRD2-positive cells in the brain of the rats.

RESULTSBHD can markedly improve the behavioral abnormalities of PD model rats. Compared with those in the saline model group, the B(max) of DRD2 in the damaged hemisphere increased while the Kd of BHD decreased significantly after BHD treatment (P<0.01). The number of DRD2-positive cells in BHD-treated group was significantly higher than that in the model group (80.9∓13.59 vs 11.15∓6.78, P<0.01), but showed no significant difference from that in the normal control group (P>0.05).

CONCLUSIONBHD can improve the behavioral abnormalities and increase the cerebral expression and affinity of DRD2 in PD rat models.

Animals ; Brain ; metabolism ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Parkinson Disease ; drug therapy ; metabolism ; Phytotherapy ; Rats ; Receptors, Dopamine D2 ; drug effects ; metabolism

Mammalian cells remove misfolded proteins using various proteolytic systems, including the ubiquitin (Ub)-proteasome system (UPS), chaperone mediated autophagy (CMA) and macroautophagy. The majority of misfolded proteins are degraded by the UPS, in which Ub-conjugated substrates are deubiquitinated, unfolded and cleaved into small peptides when passing through the narrow chamber of the proteasome. The substrates that expose a specific degradation signal, the KFERQ sequence motif, can be delivered to and degraded in lysosomes via the CMA. Aggregation-prone substrates resistant to both the UPS and the CMA can be degraded by macroautophagy, in which cargoes are segregated into autophagosomes before degradation by lysosomal hydrolases. Although most misfolded and aggregated proteins in the human proteome can be degraded by cellular protein quality control, some native and mutant proteins prone to aggregation into beta-sheet-enriched oligomers are resistant to all known proteolytic pathways and can thus grow into inclusion bodies or extracellular plaques. The accumulation of protease-resistant misfolded and aggregated proteins is a common mechanism underlying protein misfolding disorders, including neurodegenerative diseases such as Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), prion diseases and Amyotrophic Lateral Sclerosis (ALS). In this review, we provide an overview of the proteolytic pathways in neurons, with an emphasis on the UPS, CMA and macroautophagy, and discuss the role of protein quality control in the degradation of pathogenic proteins in neurodegenerative diseases. Additionally, we examine existing putative therapeutic strategies to efficiently remove cytotoxic proteins from degenerating neurons.
Alzheimer Disease/drug therapy/metabolism ; Amyloid beta-Peptides/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; Autophagy/drug effects ; DNA-Binding Proteins/metabolism ; Humans ; Huntington Disease/drug therapy/genetics/metabolism ; Lysosomes/metabolism ; Molecular Targeted Therapy ; Mutation ; Nerve Tissue Proteins/genetics/metabolism ; Neurodegenerative Diseases/drug therapy/*metabolism ; Parkinson Disease/drug therapy/metabolism ; PrPSc Proteins/metabolism ; Prion Diseases/drug therapy/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Proteolysis ; Proteostasis Deficiencies/metabolism ; Superoxide Dismutase/metabolism ; Ubiquitin/metabolism ; alpha-Synuclein/metabolism ; tau Proteins/metabolism

OBJECTIVETo observe the effect of Bushen Huoxue Granule (BHG) on dopamine (DA) neurotransmitter and dopamine transporter (DAT) in the brain of patients with Parkinson's disease (PD) as an adjunctive therapy.

METHODSNinety-four PD patients were randomly assigned to two groups, 47 in each group. Madopar was given to all as the basic treatment group. The placebo was given to those in the control group while BHG was given to those in the treatment. The therapeutic course for all was three months. Before and after treatment DA levels in the brain of patients were detected by encephalofluctuograph (EFG) technique. Changes of DAT in the striatum of patients in the treatment group were detected by positron emission tomography (PET) and region of interest (ROI) analysis.

RESULTS(1) Before treatment the DA level was lower in the two groups than the normal value, showing significant difference (P < 0.01), but with no significant difference between the two groups (P > 0.05). After treatment the DA level obviously increased in the two groups, showing significant difference from that before treatment (P < 0.01). No significant difference existed in the DA level in the two groups when compared with the normal value (P > 0.05), but with significant difference between the two groups (P < 0.05). Better results were obtained in the treatment group than in the control group. (2) The DAT radioactive accumulation inside the striatum increased obviously in the treatment group after treatment. ROI analysis showed the total ratio of striatum/cerebellum before and after treatment was 1.86 +/- 0.32 and 2.61 +/- 0.53 respectively, showing statistical difference (P < 0.05).

CONCLUSIONBHG could improve the DA level of PD patients, and increasing DAT contents in the striatum, thus playing a role in effectively treating PD.

Aged ; Brain ; metabolism ; Dopamine ; metabolism ; Dopamine Plasma Membrane Transport Proteins ; metabolism ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Parkinson Disease ; drug therapy ; metabolism ; Phytotherapy

OBJECTIVETo examine the protective effect of nicotinamide on 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) in mouse model and its mechanisms.

METHODSParkinson's disease was induced by injection of MPTP in adult male C57BL/6 mice, nicotinamide (500 mg/kg,i.p.) was given prior to subacute (30 mg/kg/d × 5 d,i.p.) MPTP administration. Locomotor activities, striatal dopamine levels, lactate dehydrogenase (LDH) and NO synthase (NOS) activities of whole brains and striatum were analyzed at d5 after last MPTP injections.

RESULTSPretreatment with nicotinamide significantly improved the locomotor activity in the open-field test (P<0.01), but not in the swimming test and grip & climbing test. Nicotinamide administration resulted in sparing striatal dopamine levels from MPTP-induced dopamine depletion. There was no significant difference in LDH and NOS activities in the whole brains among the groups; but the activities in the striatum were drastically elevated after MPTP treatment. Nicotinamide pretreatment markedly inhibited MPTP-induced LDH and NOS activities (P<0.01) and showed no significant difference compared to controls (P>0.05).

CONCLUSIONNicotinamide protects dopaminergic neurons against MPTP-induced neurodegeneration,which suggests that the neuroprotective effects be associated with the inhibition of cell injuries and NOS activities.

Animals ; Corpus Striatum ; drug effects ; metabolism ; Disease Models, Animal ; Dopamine ; metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Motor Activity ; drug effects ; physiology ; Neurons ; drug effects ; metabolism ; Niacinamide ; pharmacology ; Parkinson Disease ; drug therapy ; metabolism

AIM: To evaluate the effect of Ocimum sanctum leaf extract on the dietary supplementation in the transgenic Drosophila model of Parkinson's disease. METHOD: The effect of Ocimum sanctum leaf extract was studied on the transgenic Drosophila model of flies expressing normal human alpha synuclein (h-αs) in the neurons. O. sanctum extract at final concentrations of 0.042 8 × 10(-4), 0.87 × 10(-4), and 1.85 × 10(-4) g·mL(-1) of diet were established and the flies were allowed to feed for 21 days. The climbing assay and lipid peroxidation were taken as parameters for the study. RESULTS: The supplementation of O. sanctum extract showed a dose-dependent significant delay in the loss of climbing ability and reduction in oxidative stress in the brain of PD model flies. CONCLUSION The results of the present study showed that the O. sanctum extract is potent in reducing the PD symptoms in transgenic Drosophila model.
Animals ; Brain ; drug effects ; metabolism ; Dietary Supplements ; analysis ; Disease Models, Animal ; Drosophila ; drug effects ; genetics ; metabolism ; Humans ; Lipid Peroxidation ; drug effects ; Ocimum ; chemistry ; Oxidative Stress ; drug effects ; Parkinson Disease ; drug therapy ; metabolism ; Plant Extracts ; administration & dosage ; Plant Leaves ; chemistry