Light therapy: a new option for neurodegenerative diseases.

ABSTRACT: Given the increasing incidence of neurodegenerative disease (ND), recent research efforts have intensified the search for curative treatments. Despite significant research, however, existing therapeutic options for ND can only slow down the progression of the disease, but not provide a cure. Light therapy (LT) has been used to treat some mental and sleep disorders. This review illustrates recent studies of the use of LT in patients with ND and highlights its potential for clinical applications. The literature was collected from PubMed through June 2020. Selected studies were primarily English articles or articles that could be obtained with English abstracts and Chinese main text. Articles were not limited by type. Additional potential publications were also identified from the bibliographies of identified articles and the authors' reference libraries. The identified literature suggests that LT is a safe and convenient physical method of treatment. It may alleviate sleep disorders, depression, cognitive function, and other clinical symptoms. However, some studies have reported limited or no effects. Therefore, LT represents an attractive therapeutic approach for further investigation in ND. LT is an effective physical form of therapy and a new direction for research into treatments for ND. However, it requires further animal experiments to elucidate mechanisms of action and large, double-blind, randomized, and controlled trials to explore true efficacy in patients with ND.

Relationship between 25-Hydroxyvitamin D, bone density, and Parkinson's disease symptoms.

OBJECTIVES: Vitamin D deficiency is widespread in patients with Parkinson's disease (PD). Our aim was to determine whether serum vitamin D levels correlated with bone mineral density (BMD) and non-motor symptoms in patients with PD. MATERIALS & METHODS: A consecutive series of 182 patients with PD and 185 healthy controls were included. Serum 25-hydroxyvitamin D (25[OH]D) levels were measured by immunoassay, while BMD of the lumbar spine and femoral neck was measured by dual-energy X-ray absorptiometry. Associations between serum vitamin D levels and clinical data were evaluated using partial correlation analysis. RESULTS: Patients with PD had significantly lower serum 25(OH)D levels relative to healthy controls (49.75 ± 14.11 vs 43.40 ± 16.51, P < 0.001). Furthermore, PD patients with lower vitamin D levels had a significantly higher frequency of falls (P = 0.033) and insomnia (P = 0.015). They also had significantly higher scores for the Pittsburgh Sleep Quality Index (PSQI; P = 0.014), depression (P = 0.020), and anxiety (P = 0.009). Finally, patients with PD also had a significantly lower mean BMD of the lumbar spine (P = 0.011) and femoral neck (P < 0.001). After adjusting for age, sex, and body mass index, vitamin D levels significantly correlated with falls, insomnia, and scores for the PSQI, depression, and anxiety. CONCLUSIONS: In patients with PD, vitamin D levels significantly correlated with falls and some non-motor symptoms. However, no associations were found between BMD and the serum 25(OH)D levels in patients with PD. Thus, vitamin D supplementation is a potential therapeutic for non-motor PD symptoms.

Different Techniques of Minimally Invasive Craniopuncture for the Treatment of Hypertensive Intracerebral Hemorrhage.

OBJECTIVE: Efficacy of minimally invasive craniopuncture with the YL-1 puncture needle (hard-channel) and soft drainage tube (soft-channel) in treating hypertensive intracerebral hemorrhage (HICH). MATERIALS AND METHODS: A total of 150 patients with HICH were randomly assigned into 3 groups: conservative group (n = 50), hard-channel group (n = 50), and soft-channel group (n = 50). Computed tomography, National Institutes of Health Stroke Scale (NIHSS) and the levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), superoxide dismutase (SOD), and malondialdehyde (MDA) in serum and in drainage fluid were examined on days 2, 4, and 6 after operation. RESULTS: Compared with the conservative group, the serum levels of IL-6, TNF-α, and MDA were decreased and SOD was increased (P < 0.05); volumes of hematoma and perihematomal edema as well as NIHSS were reduced (P < 0.05) in minimally invasive groups on days 7, 14, and 28 after operation. Compared with the hard-channel group, the serum levels of IL-6, TNF-α, MDA, and SOD showed the same trend as above in the soft-channel group. In the soft-channel group, MDA was reduced and SOD was increased in brain drainage fluid on days 2, 4, and 6 (P < 0.05); volumes of hematoma and perihematomal edema on days 14 and 28 were found to be reduced compared with the hard-channel group (P < 0.05). There was no significant difference of volumes of hematoma and perihematomal edema on day 7 between minimally invasive groups. NIHSS of the soft-channel group appeared to be significantly reduced on days 7, 14, and 28 after operation (P < 0.05). CONCLUSIONS: Soft-channel minimally invasive craniopuncture is an ideal technique for treating HICH, with advantages of alleviating cerebral edema, reducing oxidative stress, and inhibiting inflammatory response.

Chinese guidelines for the assessment and provision of nutrition support therapy in critically ill children.

BACKGROUND: This document represents the first evidence-based guidelines to describe best practices in nutrition therapy in critically ill children (> 1 month and < 18 years), who are expected to require a length of stay more than 2 or 3 days in a Pediatric Intensive Care Unit admitting medical patients domain. METHODS: A total of 25,673 articles were scanned for relevance. After careful review, 88 studies appeared to answer the pre-identified questions for the guidelines. We used the grading of recommendations, assessment, development and evaluation criteria to adjust the evidence grade based on the quality of design and execution of each study. RESULTS: The guidelines emphasise the importance of nutritional assessment, particularly the detection of malnourished patients. Indirect calorimetry (IC) is recommended to estimate energy expenditure and there is a creative value in energy expenditure, 50 kcal/kg/day for children aged 1-8 years during acute phase if IC is unfeasible. Enteral nutrition (EN) and early enteral nutrition remain the preferred routes for nutrient delivery. A minimum protein intake of 1.5 g/kg/day is suggested for this patient population. The role of supplemental parenteral nutrition (PN) has been highlighted in patients with low nutritional risk, and a delayed approach appears to be beneficial in this group of patients. Immune-enhancing cannot be currently recommended neither in EN nor PN. CONCLUSION: Overall, the pediatric critically ill population is heterogeneous, and an individualized nutrition support with the aim of improving clinical outcomes is necessary and important.

Ginkgo biloba Extract EGb 761 and Its Specific Components Elicit Protective Protein Clearance Through the Autophagy-Lysosomal Pathway in Tau-Transgenic Mice and Cultured Neurons.

Alzheimer's disease (AD) is a neurodegenerative disease pathologically characterized by extracellular amyloid-ß (Aß) deposits and intracellular neurofibrillary tangles (NFT) in many brain regions. NFT are primarily composed of hyperphosphorylated tau protein (p-Tau). Aß and p-Tau are two major pathogenic molecules with tau acting downstream to Aß to induce neuronal degeneration. In this study, we investigated whether Ginkgo biloba extract EGb 761 reduces cerebral p-Tau level and prevents AD pathogenesis. Human P301S tau mutant-transgenic mice were fed with EGb 761, added to the regular diet for 2 or 5 months. We observed that treatment with EGb 761 for 5 months significantly improved the cognitive function of mice, attenuated the loss of synaptophysin and recovered the phosphorylation of CREB in the mouse brain. Treatment with EGb 761 for 5 but not 2 months also decreased p-Tau protein amount and shifted microglial pro-inflammatory to anti-inflammatory activation in the brain. As potential therapeutic mechanisms, we demonstrated that treatment with EGb 761, especially the components of ginkgolide A, bilobalide, and flavonoids, but not with purified ginkgolide B or C, increased autophagic activity and degradation of p-Tau in lysosomes of neurons. Inhibiting ATG5 function or treating cells with Bafilomycin B1 abolished EGb 761-enhanced degradation of p-Tau in cultured neurons. Additionally, we observed that 5- instead of 2-month-treatment with EGb 761 inhibited the activity of p38-MAPK and GSK-3ß. Therefore, long-term treatment with Ginkgo biloba extract EGb 761, a clinically available and well-tolerated herbal medication, ameliorates AD pathology through mechanisms against multiple AD pathogenic processes.

Excessive Daytime Sleepiness in Parkinson's Disease: Clinical Implications and Management.

OBJECTIVE: Excessive daytime sleepiness (EDS) is one of the most common sleep abnormalities in patients with Parkinson's disease (PD), yet its multifactorial etiology complicates its treatment. This review summarized recent studies on the epidemiology, etiology, clinical implications, associated features, and evaluation of EDS in PD. The efficacy of pharmacologic and non-pharmacologic treatments for EDS in PD was also reviewed. DATA SOURCES: English language articles indexed in PubMed and Cochrane databases and Chinese-language papers indexed in Wanfang and National Knowledge Infrastructure databases that were published between January 1987 and November 2017 were located using the following search terms: "sleepiness", "sleep and Parkinson's disease", and "Parkinson's disease and treatment". STUDY SELECTION: Original research articles and critical reviews related to EDS in PD were selected. RESULTS: EDS is a major health hazard and is associated with many motor and nonmotor symptoms of PD. Its causes are multifactorial. There are few specific guidelines for the treatment of EDS in PD. It is first necessary to identify and treat any possible factors causing EDS. Recent studies showed that some nonpharmacologic (i.e., cognitive behavioral therapy, light therapy, and repetitive transcranial magnetic stimulation) and pharmacologic (i.e., modafinil, methylphenidate, caffeine, istradefylline, sodium oxybate, and atomoxetine) treatments may be effective in treating EDS in PD. CONCLUSIONS: EDS is common in the PD population and can have an immensely negative impact on quality of life. Its causes are multifactorial, which complicates its treatment. Further investigations are required to determine the safety and efficacy of potential therapies and to develop novel treatment approaches for EDS in PD.

EGb-761 Attenuates the Anti-proliferative Activity of Fluoride via DDK1 in PC-12 Cells.

EGb-761 is commonly used as a treatment for ischemic brain injury, neurodegenerative diseases and some types of tumors (Christen and Maixent, in Cell Mol Biol 48(6):601-611, 2002). However, it is unclear whether EGb-761 affects the proliferation of cells exposed to fluoride. In this study, the proliferation and apoptosis of PC-12 cells exposed to fluoride were investigated and EGb-761 was used to protect PC-12 cells against the effects of fluoride. We found that the canonical Wnt signaling pathway was involved in the anti-proliferation of PC-12 cells exposed to fluoride. Furthermore, the results also showed that EGb-761 could attenuate the anti-proliferative activity of fluoride via DDK1 in PC-12 cells. This study may provide a new method for protecting against the inhibition of cell proliferation induced by fluoride.

Neuroprotective Effects of Paeoniflorin on 6-OHDA-Lesioned Rat Model of Parkinson's Disease.

Paeoniflorin (PF) is the main active component extracted from the roots of Paeonialactiflora, a traditional Chinese medicine used for the treatment of neurodegenerative disorders, especially Parkinson's disease (PD). The degeneration of dopaminergic (DA-) neurons in PD may be caused by pathological activation of acid-sensing ion channels (ASICs). Thus, we designed a series of experiments to evaluate the therapeutic effects of PF and to test whether its effects are related to its inhibitory effect on ASIC1a. We found that systemic administration of PF or ASICs blockers (psalmotoxin-1 and amiloride) improved behavioral symptoms, delayed DA-neuronal loss and attenuated the reduction of dopamine (DA) and its metabolites in a rat model of 6-hydroxydopamine (6-OHDA)-induced PD. In addition, our data showed that PF, like ASICs blockers, regulated the expression of ASIC1a, decreased the level of α-synuclein (α-SYN), and improved autophagic dysfunction. Further experiments showed that ASIC1a knockdown down-regulated the α-SYN level and alleviated the autophagic injury in the 6-OHDA-treated ASIC1a-silenced PC12 cells. In summary, these findings indicate that PF enhanced the autophagic degradation of α-SYN and, thus, protected DA-neurons against the neurotoxicity caused by 6-OHDA. These findings also provide experimental evidence that PF may be a neuroprotectant for PD by acting on ASIC1a and that ASIC1a may be involved in the pathogenesis of PD.

[Sleep disorders associated with essential tremor and Parkinson's disease].

OBJECTIVE: To evaluate the sleep quality and explore the manifestations of sleep disorders for 62 essential tremor (ET) patients, 60 normal controls and 62 Parkinson's disease (PD) patients. METHODS: A total of 62 ET patients, 60 normal controls and 62 PD patients from June 2009 to December 2013 were recruited. All of them were outpatients at Second Affiliated Hospital, Soochow University and Hospital of Changshu Hospital of Traditional Chinese Medicine. Sleep was assessed with Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). RESULTS: The global PSQI score was 4.7 ± 2.5 in controls, 6.0 ± 4.0 in ET cases and 7.4 ± 3. 7 in PD cases. PD cases had the highest PSQI score, followed by ET (intermediate) and lowest scores in controls (F = 9.022, P = 0.000). A poor quality of sleep was observed in normal controls (23/62, 38.3%) compared to ET cases (34/62, 54.8%) and PD cases (40/62, 64.5%) (χ² = 8.555, P = 0.014 when comparing all three groups and χ² = 1.206, P = 0.272 when ET vs PD). The ESS score increased from normal controls (4.4 ± 2.5) to ET cases (6.3 ± 4.8) and PD cases (8.2 ± 4.2). An ESS score ≥ 10 (an indicator of greater than normal levels of daytime sleepiness) was observed in 6 (10.0%) normal controls, compared to ET cases (16, 25.8%) and PD cases (20, 32.3%) (χ² = 9.047, P = 0.011 when comparing all three groups and χ² = 0.626, P = 0.429 when ET vs PD). For normal controls, ET and PD patients, the factor scores of subjective sleep were 0.6 ± 0.7, 0.8 ± 0.8 and 1.1 ± 0.7; the factor scores of quality sleep latency 0.6 ± 0.7, 0.9 ± 0.9 and 1.1 ± 1.0; the factor scores of sleep duration 0.6 ± 0.8, 0.7 ± 1.0 and 1.0 ± 0.9; the factor scores of sleep efficiency 0.6 ± 0.8, 0.9 ± 0.9 and 1.0 ± 1.0; the factor scores of sleep disturbances 1.2 ± 0.6, 1.2 ± 0.5 and 1.7 ± 0.7; the factor scores of daytime dysfunction 1.2 ± 1.0, 1.3 ± 1.0 and 2.0 ± 1.1 respectively. There were inter-group statistical differences in subjective sleep (F = 7.709, P = 0.001), quality sleep latency (F = 4.414, P = 0.013), sleep duration (F = 4.464, P = 0.013), sleep efficiency (F = 3.201, P = 0.043), sleep disturbances (F = 12.594, P = 0.000) and daytime dysfunction (F = 9.022, P = 0.000) . However, no inter-group statistical differences existed in use of sleeping medication (F = 1.200, P = 0.304). There were statistical differences in subjective sleep (P < 0.05), sleep efficiency (P < 0.05) and daytime dysfunction (P < 0.05) between ET and PD patients. CONCLUSION: Some sleep scores in ET are intermediate between those of PD cases and normal controls. And it suggests that a mild form of sleep dysregulation may be present in ET.

Antidepressant-like effects of auraptenol in mice.

Depression is a major psychiatric disorder affecting nearly 21% of the world population and imposes a substantial health burden on society. Current available antidepressants are not adequate to meet the clinical needs. Here we report that auraptenol, an active component of the traditional Chinese medicine, angelicae dahuricae radix, had antidepressant-like effects in mice models of depression. In mouse forced swimming test and tail suspension test, two validated models of depression, auraptenol dose-dependently decreased the immobility duration within the dose range of 0.05-0.4 mg/kg. In addition, the antidepressant-like effects of auraptenol was significantly averted by a selective serotonin 5-HT1A receptor antagonist WAY100635 (1 mg/kg). These doses that affected the immobile response did not affect locomotor activity. In summary, this study for the first time identified an active component from the herbal medicine angelicae dahuricae radix that possesses robust antidepressant-like efficacy in mice. These data support further exploration for the possibility of developing auraptenol as a novel antidepressant agent in the treatment of major depression disorders.

Dysregulation of cystathionine γ-lyase (CSE)/hydrogen sulfide pathway contributes to ox-LDL-induced inflammation in macrophage.

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.

Paeoniflorin, a potent natural compound, protects PC12 cells from MPP+ and acidic damage via autophagic pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Paeoniflorin (PF) is the principal bioactive component of Radix Paeoniae alba, which is widely used in Traditional Chinese Medicine for the treatment of neurodegenerative disorders such as Parkinson's disease (PD). AIM OF THE STUDY: To evaluate the neuroprotective effects of PF on MPP(+)- or acid- (pH 5.0) induced injury in cultured PC12 cells and to investigate the activity of autophagy-lysosome pathway (ALP). Amiloride (Ami), a non-selective blocker of acid-sensing ion channels (ASICs), as a positive control drug, since it is neuroprotective in rodent models of PD. MATERIALS AND METHODS: The cell viability was analyzed with MTT assay. The cell injury was assessed by lactate dehydrogenase (LDH) assay. Flow cytometry and Western blot analysis were used to study the apoptotic, calcium influx and autophagic mechanisms. RESULTS: Ami (100 microM) and PF (50 microM) both protected PC12 cells against MPP(+)- or acid-induced injury as assessed by MTT assay, lactate dehydrogenase release, and apoptosis rate. The concentrations of cytosolic free Ca(2+) were raised after exposure to MPP(+) or acidosis, while Ami and PF both reduced the influx of Ca(2+). More importantly, we found that the mechanisms of neuroprotective effects of Ami and PF were closely associated with the upregulation of LC3-II protein, which is specifically associated with autophagic vacuole membranes. Furthermore, application of MPP(+) or acid induced the overexpression of LAMP2a, which is directly correlated with the activity of the chaperone-mediated autophagy pathway. However, Ami and PF inhibited the overexpression of LAMP2a. CONCLUSIONS: Our data provide the first experimental evidence that PF modulates autophagy in models of neuron injury, as well as providing the first indication of a relationship between ASICs and ALP.