ABSTRACT
BACKGROUND: Neuroinflammation plays an important role in the pathogenesis of Parkinson's disease (PD), inducing and accelerating dopaminergic (DA) neuron loss. Autophagy, a critical mechanism for clearing misfolded or aggregated proteins such as α-synuclein (α-SYN), may affect DA neuron survival in the midbrain. However, whether autophagy contributes to neuroinflammation-induced toxicity in DA neurons remains unknown. RESULTS: Intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg) into young (3-month-old) and aged (16-month-old) male C57BL/6J mice was observed to cause persistent neuroinflammation that was associated with a delayed and progressive loss of DA neurons and accumulation of α-SYN in the midbrain. The autophagic substrate-p62 (SQSTM1) persistently increased, whereas LC3-II and HDAC6 exhibited early increases followed by a decline. In vitro studies further demonstrated that TNF-α induced cell death in PC12 cells. Moreover, a sublethal dose of TNF-α (50 ng/ml) increased the expression of LC3-II, p62, and α-SYN, implying that TNF-α triggered autophagic impairment in cells. CONCLUSION: Neuroinflammation may cause autophagic impairment, which could in turn result in DA neuron degeneration in midbrain.
Subject(s)
Autophagy , Dopaminergic Neurons/pathology , Inflammation/pathology , Mesencephalon/pathology , Animals , Autophagy/drug effects , Cell Count , Dopaminergic Neurons/metabolism , Inflammation/chemically induced , Lipopolysaccharides/pharmacology , Male , Mice , Mice, Inbred C57BL , PC12 Cells , Parkinson Disease/pathology , Rats , Tumor Necrosis Factor-alpha/pharmacology , alpha-Synuclein/metabolismABSTRACT
OBJECTIVE: To identify the association between fatigue and depression in Parkinson's disease (PD). METHODS: 56 PD patients were enrolled in this study. The degree of fatigue was measured by Fatigue Severity Scale (FSS). Hamilton Depression Scale (24 items) was used to evaluate the degree of depression. PD Quality of Life Questionnaire (PDQL) were tested to evaluate the quality of life in PD patients. While other clinical information such as Unified Parkinson's Disease Rating Scale (UPDRS) III, Hoehn-Yahr Scale and modified Webster Scale were investigated. RESULTS: The incidence of fatigue in this group is 71.4% (40/56). Score of HAMD and PDQL exhibited a significant correlation to patients' fatigue, coefficient of partial correlation was 0.451 (P < 0.01), -0.346 (P < 0.05). The incidence of fatigue in non-depressive patients was low, 27.3%. While in depressive patients, the incidence of fatigue is relatively high, for mild depression 75%, moderate depression 100%, severe depression 100% respectively. CONCLUSIONS: Fatigue is a prominent symptom of depression in PD patients, sometimes independent of depression also influencing the patients' quality of life.
Subject(s)
Depression/etiology , Fatigue/etiology , Parkinson Disease/complications , Quality of Life , Aged , Female , Humans , Male , Middle Aged , Surveys and QuestionnairesABSTRACT
Hydrogen sulfide (H2S), mainly produced by cystathionine γ-lyase (CSE) in vascular system, emerges as a novel gasotransmitter exerting anti-inflammatory and anti-atherosclerotic effects. Alterations of CSE/H2S pathway may thus be involved in atherosclerosis pathogenesis. However, the underlying mechanisms are poorly understood. The present study showed that the levels of CSE mRNA and protein expression, as well as H2S production were decreased in ox-LDL-treated macrophage. CSE overexpression reduced the ox-LDL-stimulated tumor necrosis factor-α (TNF-α) generation in Raw264.7 and primary macrophage while CSE knockdown enhanced it. Exogenous supplementation of H2S with NaHS and Na2S also decreased the production of TNF-α and intercellular adhesion molecule-1 (ICAM-1) in ox-LDL-stimulated macrophage, and alleviated the adhesion of macrophage to endothelial monolayer. Cysteine, a CSE preferential substrate for H2S biosynthesis, produced similar effects on the pro-inflammatory cytokine generation, which were reversed by CSE inhibitors PAG and BCA, respectively. Moreover, NaHS and Na2S attenuated the phosphorylation and degradation of IκBα and p65 nuclear translocation, as well as JNK activation caused by ox-LDL. The JNK inhibitor suppressed the NF-κB transcription activity in ox-LDL-treated cells. Furthermore, inhibitors of NF-κB (PDTC), ERK (U0126 and PD98059) and JNK (SP600125) partially blocked the suppression by ox-LDL on the CSE mRNA levels. Taken together, the findings demonstrate that ox-LDL may down-regulate the CSE/H2S pathway, which plays an anti-inflammatory role in ox-LDL-stimulated macrophage by suppressing JNK/NF-κB signaling. The study reveals new therapeutic strategies for atherosclerosis, based on modulating CSE/H2S pathway.
