Graded brain fMRI response to somatic and visual acupuncture stimulation.

Increased stimulation can enhance acupuncture clinical response; however, the impact of acupuncture stimulation as "dosage" has rarely been studied. Furthermore, acupuncture can include both somatic and visual components. We assessed both somatic and visual acupuncture dosage effects on sensory ratings and brain response. Twenty-four healthy participants received somatic (needle inserted, manually stimulated) and visual (needle video, no manual stimulation) acupuncture over the leg at three different dosage levels (control, low-dose, and high-dose) during functional magnetic resonance imaging (fMRI). Participants reported the perceived deqi sensation for each acupuncture dose level. Blood-oxygen-level dependent imaging data were analyzed by general linear model and multivariate pattern analysis. For both somatic and visual acupuncture, reported deqi sensation increased with increased dosage of acupuncture stimulation. Brain fMRI analysis demonstrated that higher dosage of somatic acupuncture produced greater brain responses in sensorimotor processing areas, including anterior and posterior insula and secondary somatosensory cortex. For visual acupuncture, higher dosage of stimulation produced greater brain responses in visual-processing areas, including the middle temporal visual areas (V5/MT+) and occipital cortex. Psychophysical and psychophysiological responses to both somatic and visual acupuncture were graded in response to higher doses. Our findings suggest that acupuncture response may be enhanced by the dosage of needling-specific and nonspecific components, represented by different neural mechanisms.

Chronic Gut Inflammation and Dysbiosis in IBS: Unraveling Their Contribution to Atopic Dermatitis Progression.

Emerging evidence suggests a link between atopic dermatitis (AD) and gastrointestinal disorders, particularly in relation to gut microbial dysbiosis. This study explored the potential exacerbation of AD by gut inflammation and microbial imbalances using an irritable bowel syndrome (IBS) mouse model. Chronic gut inflammation was induced in the model by intrarectal injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS), followed by a 4-week development period. We noted significant upregulation of proinflammatory cytokines in the colon and evident gut microbial dysbiosis in the IBS mice. Additionally, these mice exhibited impaired gut barrier function, increased permeability, and elevated systemic inflammation markers such as IL-6 and LPS. A subsequent MC903 challenge on the right cheek lasting for 7 days revealed more severe AD symptoms in IBS mice compared to controls. Further, fecal microbial transplantation (FMT) from IBS mice resulted in aggravated AD symptoms, a result similarly observed with FMT from an IBS patient. Notably, an increased abundance of Alistipes in the feces of IBS mice correlated with heightened systemic and localized inflammation in both the gut and skin. These findings collectively indicate that chronic gut inflammation and microbial dysbiosis in IBS are critical factors exacerbating AD, highlighting the integral relationship between gut and skin health.

TSLP up-regulates inflammatory responses through induction of autophagy in T cells.

Thymic stromal lymphopoietin (TSLP), a type I cytokine belonging to the IL-2 cytokine family, promotes Th2-mediated inflammatory responses. The aim of this study is to investigate whether TSLP increases inflammatory responses via induction of autophagy using a murine T cell lymphoma cell line, EL4 cells, and lipopolysaccharide (LPS)-injected mice. TSLP increased expression levels of autophagy-related factors, such as Beclin-1, LC3-II, p62, Atg5, and lysosome associated membrane protein 1/2, whereas these factors increased by TSLP disappeared by neutralization of TSLP in EL4 cells. TSLP activated JAK1/JAK2/STAT5/JNK/PI3K, while the blockade of JAK1/JAK2/STAT5/JNK/PI3K signaling pathways reduced the expression levels of Beclin-1, LC3-II, and p62 in TSLP-stimulated EL4 cells. In addition, TSLP simultaneously increased levels of inflammatory cytokines via induction of autophagy by activation of JAK1/JAK2/STAT5/JNK/PI3K signaling pathways. In an LPS-induced acute liver injury (ALI) mouse model, exogenous TSLP increased expression levels of Beclin-1 and LC3-II, whereas functional deficiency of TSLP by TSLP siRNA resulted in lower expression of Beclin-1, LC3-II, and inflammatory cytokines, impairing their ability to form autophagosomes in ALI mice. Thus, our findings show a new role of TSLP between autophagy and inflammatory responses. In conclusion, regulating TSLP-induced autophagy may be a potential therapeutic strategy for inflammatory responses.

The west meets the east - A need for a renaissance in brain, behavior, and immunity research.

Psychoneuroimmunology (PNI)-the burgeoning concept in recent years, can potentially contribute to developing effective treatments for mental health disorders. Despite the advancement in the modern pharmacological approach for mental disorders, especially Western medicine attributed explicitly to interacting with a specific target has given rise to unmet needs, and treatment failure has led to the proliferation and exploration of traditional and alternative therapies. As research into these exciting under-explored traditional treatment approaches continues to evolve at an unprecedented pace, the need to gain vital insights into the potentiality and mechanism of action in neuropsychiatric disorders has resulted in the current Special Issue. This Special Issue is devoted to psychoneuroimmunology, focusing on introducing the recent advances with traditional and alternative medications in East Asia at the interface of immunology, neurosciences, molecular psychiatry and behavioural medicine neurosciences.

Correction: Han et al. Dexamethasone Attenuates Oncostatin M Production via Suppressing of PI3K/Akt/NF-κB Signaling in Neutrophil-like Differentiated HL-60 Cells. Molecules 2022, 27, 129.

In the original article [...].

Resveratrol Downregulates Granulocyte-Macrophage Colony-Stimulating Factor-Induced Oncostatin M Production through Blocking of PI3K/Akt/NF-κB Signal Cascade in Neutrophil-like Differentiated HL-60 Cells.

Oncostatin M (OSM) is essential in a wide range of inflammatory responses, and most OSM is produced by neutrophils in respiratory diseases. While resveratrol (RES) is regarded as an anti-inflammatory agent in a variety of conditions, the mechanism of OSM inhibition by RES in neutrophils remains to be elucidated. In this study, we investigated whether RES could inhibit OSM production in neutrophil-like differentiated (d)HL-60 cells. The effects of RES were measured by means of an enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and Western blotting. Increases in production and mRNA expression of OSM resulted from the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) in neutrophil-like dHL-60 cells; however, these increases were downregulated by RES treatment. Exposure to GM-CSF led to elevations of phosphorylation of phosphatidylinositol 3-kinase (PI3K), Akt, and nuclear factor (NF)-kB. Treatment with RES induced downregulation of the phosphorylated levels of PI3K, Akt, and NF-κB in neutrophil-like dHL-60 cells. These results suggest that RES could be applicable to prevent and/or treat inflammatory disorders through blockade of OSM.

Acupuncture attenuates comorbid anxiety- and depressive-like behaviors of atopic dermatitis through modulating neuroadaptation in the brain reward circuit in mice.

Atopic dermatitis (AD) is highly comorbid with negative emotions such as anxiety and depression. Although acupuncture has demonstrated efficacy in AD, its influence on comorbid anxiety and depression remains unclear. We sought to explore the impact and mechanisms of action of acupuncture on comorbid anxiety and depression of AD. AD-like skin lesions were induced by the topical application of MC903 to the mouse cheek. Acupuncture was performed at Gok-Ji (LI11) acupoints. AD-like phenotypes were quantified by lesion scores, scratching behavior, and histopathological changes. The effects of acupuncture on comorbid anxiety and depression-like behaviors were assessed using the elevated plus-maze (EPM), open-field tests (OFT), and tail-suspension test (TST). In addition, biochemical changes in the brain reward regions were investigated by immunoblotting for the expression of tyrosine hydroxylase (TH), dopamine D1 receptor (D1R), phospho-dopamine and cAMP-regulated phosphoprotein-32 kDa (pDARPP-32), phospho-cAMP response element binding protein (pCREB), ΔFosB, and brain-derived neurotrophic factor (BDNF) in the nucleus accumbens, dorsolateral striatum, and ventral tegmental area. Acupuncture effectively improved the chronic itching and robust AD-like skin lesions with epidermal thickening. Additionally, it considerably reduced comorbid anxiety- and depression-like symptoms, as indicated by more time spent in the open arms of the EPM and in the center of the open field and less time spent immobile in the TST. Higher pCREB, ΔFosB, BDNF, and pDARPP-32 levels, and reduced TH and D1R protein expression in the brain reward regions of AD mice were reversed by acupuncture treatment. The beneficial effects of acupuncture on clinical symptoms (scratching behavior) and comorbid psychological distress in AD strongly correlated with dorsal striatal ΔFosB levels. Collectively, these data indicate that acupuncture had a significant, positive impact on comorbid anxiety- and depression-like behaviors by modulating neuroadaptation in the brain reward circuit in mice with AD, providing a novel perspective for the non-pharmacological management of psychiatric comorbidities of AD.

Acupuncture ameliorates not only atopic dermatitis-like skin inflammation but also acute and chronic serotonergic itch possibly through blockade of 5-HT2 and 5-HT7 receptors in mice.

Acupuncture has been known to be effective for atopic dermatitis, especially ameliorating itch; however, its mechanisms are still unclear. The aim of this study was to test the anti-itch effects of acupuncture and to investigate its possible mechanisms. Acupuncture was performed at Gok-Ji (LI11) acupoints just before the injection of pruritogens in the mouse cheek model of acute itch and of MC903-induced atopic dermatitis displaying serotonergic chronic itch. Acupuncture significantly reduced acute itch triggered by compound 48/80, chloroquine, or especially serotonin. It also markedly reduced scratching behaviors evoked by the serotonin 5-HT2 receptor agonist α-methylserotonin and selective 5-HT7 receptor agonist LP 44. In addition, acupuncture treatment at LI11 had the preventive and therapeutic effects on persistent itch as well as the robust skin inflammation with epidermal thickening in mice with MC903-induced atopic dermatitis. It also considerably reduced the increased expression of 5-HT2A, 5-HT2B and 5-HT7 receptors in atopic dermatitis-like skin lesions in mice treated with MC903. Taken together, these findings highlight that acupuncture significantly ameliorates not only skin inflammation, but also acute and chronic serotonergic itch, possibly through blockade of serotonin 5-HT2 and 5-HT7 receptors.

Comparative Analysis of the Microbiome across the Gut-Skin Axis in Atopic Dermatitis.

Atopic dermatitis (AD) is a refractory and relapsing skin disease with a complex and multifactorial etiology. Various congenital malformations and environmental factors are thought to be involved in the onset of the disease. The etiology of the disease has been investigated, with respect to clinical skin symptoms and systemic immune response factors. A gut microbiome-mediated connection between emotional disorders such as depression and anxiety, and dermatologic conditions such as acne, based on the comorbidities of these two seemingly unrelated disorders, has long been hypothesized. Many aspects of this gut-brain-skin integration theory have recently been revalidated to identify treatment options for AD with the recent advances in metagenomic analysis involving powerful sequencing techniques and bioinformatics that overcome the need for isolation and cultivation of individual microbial strains from the skin or gut. Comparative analysis of microbial clusters across the gut-skin axis can provide new information regarding AD research. Herein, we provide a historical perspective on the modern investigation and clinical implications of gut-skin connections in AD in terms of the integration between the two microbial clusters.

Dexamethasone Attenuates Oncostatin M Production via Suppressing of PI3K/Akt/NF-κB Signaling in Neutrophil-like Differentiated HL-60 Cells.

Oncostatin M (OSM) plays a role in various inflammatory reactions, and neutrophils are the main source of OSM in pulmonary diseases. However, there is no evidence showing the mechanism of OSM production in neutrophils. While dexamethasone (Dex) has been known to exert anti-inflammatory activity in various fields, the precise mechanisms of OSM downregulation by Dex in neutrophils remain to be determined. Here, we examined how OSM is produced in neutrophil-like differentiated HL-60 cells. Enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and Western blot analysis were utilized to assess the potential of Dex. Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation resulted in OSM elevation in neutrophil-like dHL-60 cells. OSM elevation induced by GM-CSF is regulated by phosphatidylinositol 3-kinase (PI3K)/Akt/nuclear factor (NF)-kB signal cascades. GM-CSF stimulation upregulated phosphorylated levels of PI3K or Akt or NF-κB in neutrophil-like dHL-60 cells. Treatment with Dex decreased OSM levels as well as the phosphorylated levels of PI3K or Akt or NF-κB in neutrophil-like dHL-60 cells. Our findings show the potential of Dex in the treatment of inflammatory diseases via blocking of OSM.

Acupuncture inhibits neuroinflammation and gut microbial dysbiosis in a mouse model of Parkinson's disease.

Growing evidences show that gut microbiota is associated with the pathogenesis of Parkinson's disease (PD) and the gut-brain axis can be promising target for the development of the therapeutic strategies for PD. Acupuncture has been used to improve brain functions and inflammation in neurological disorders such as PD, and to recover the gastrointestinal dysfunctions in various gastrointestinal disorders. Thus, we investigated whether acupuncture could improve Parkinsonism and gut microbial dysbiosis induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. First, we observed that acupuncture treatment at acupoints GB34 and ST36 could improve motor functions and comorbid anxiety in PD mice. Next, we found that acupuncture increased the levels of dopaminergic fibers and neurons in the striatum and the substantia nigra, respectively. Acupuncture also restored the overexpression of microglia and astrocyte as well as conversion of Bax and Bcl-2 expression in both the striatum and the substantia nigra, indicating that inflammatory responses and apoptosis were blocked by acupuncture. Additionally, via 16S rRNA sequence analysis, we observed that the relative abundance of 18 genera were changed in acupuncture-treated mice compared to the PD mice. Of them, Butyricimonas, Holdemania, Frisingicoccus, Gracilibacter, Phocea, and Aestuariispira showed significant correlations with anxiety as well as motor functions. Furthermore, the predicted functional analyses showed that acupuncture restored the physiology functions such as glutathione metabolism, methane metabolism, and PD pathway. In conclusion, we suggest that the effects of acupuncture on the enhanced motor function and the protection of the dopaminergic neurons may be associated with the regulation of the gut microbial dysbiosis and thus the inhibition of the neuroinflammation in the PD mice.

Spatial Information of Somatosensory Stimuli in the Brain: Multivariate Pattern Analysis of Functional Magnetic Resonance Imaging Data.

Background: Multivoxel pattern analysis has provided new evidence on somatotopic representation in the human brain. However, the effects of stimulus modality (e.g., penetrating needle versus non-penetrating touch) and level of classification (e.g., multiclass versus binary classification) on patterns of brain activity encoding spatial information of body parts have not yet been studied. We hypothesized that performance of brain-based prediction models may vary across the types of stimuli, and neural patterns of voxels in the SI and parietal cortex would significantly contribute to the prediction of stimulated locations. Objective: We aimed to (1) test whether brain responses to tactile stimuli could distinguish among stimulated locations on the body surface, (2) investigate whether the stimulus modality and number of classes affect classification performance, and (3) localize brain regions encoding the spatial information of somatosensory stimuli. Methods: Fifteen healthy participants completed two functional magnetic resonance imaging (MRI) scans and were stimulated via the insertion of acupuncture needles or by non-invasive touch stimuli (5.46-sized von Frey filament). Participants received the stimuli at four different locations on the upper and lower limbs (two sites each) for 5 min while blood-oxygen-level-dependent activity (BOLD) was measured using 3-Tesla MRI. We performed multivariate pattern analysis (MVPA) using parameter estimate images of each trial for each participant and the support vector classifier (SVC) function, and the prediction accuracy and other MVPA outcomes were evaluated using stratified five-fold cross validation. We estimated the significance of the classification accuracy using a permutation test with randomly labeled training data (n = 10,000). Searchlight analysis was conducted to identify brain regions associated with significantly higher accuracy compared to predictions based on chance as obtained from a random classifier. Results: For the four-class classification (classifying four stimulated points on the body), SVC analysis of whole-brain beta values in response to acupuncture stimulation was able to discriminate among stimulated locations (mean accuracy, 0.31; q < 0.01). The searchlight analysis found that values related to the right primary somatosensory cortex (SI) and intraparietal sulcus were significantly more accurate than those due to chance (p < 0.01). On the other hand, the same classifier did not predict stimulated locations accurately for touch stimulation (mean accuracy, 0.25; q = 0.66). For binary classification (discriminating between two stimulated body parts, i.e., the arm or leg), the SVC algorithm successfully predicted the stimulated body parts for both acupuncture (mean accuracy, 0.63; q < 0.001) and touch stimulation (mean accuracy, 0.60; q < 0.01). Searchlight analysis revealed that predictions based on the right SI, primary motor cortex (MI), paracentral gyrus, and superior frontal gyrus were significantly more accurate compared to predictions based on chance (p < 0.05). Conclusion: Our findings suggest that the SI, as well as the MI, intraparietal sulcus, paracentral gyrus, and superior frontal gyrus, is responsible for the somatotopic representation of body parts stimulated by tactile stimuli. The MVPA approach for identifying neural patterns encoding spatial information of somatosensory stimuli may be affected by the stimulus type (penetrating needle versus non-invasive touch) and the number of classes (classification of four small points on the body versus two large body parts). Future studies with larger samples will identify stimulus-specific neural patterns representing stimulated locations, independent of subjective tactile perception and emotional responses. Identification of distinct neural patterns of body surfaces will help in improving neural biomarkers for pain and other sensory percepts in the future.

Continentalic Acid Rather Than Kaurenoic Acid Is Responsible for the Anti-Arthritic Activity of Manchurian Spikenard In Vitro and In Vivo.

The aim of this study was to identify the active compound responsible for the pharmacological activities of Manchurian spikenard (Aralia continentalis Kitag.). Interleukin (IL)-1ß-stimulated human chondrocytes and monoiodoacetate (MIA)-induced osteoarthritic rats were treated with the 50% ethanolic extract of spikenard or its major components, such as continentalic acid (ent-pimara-8(14),15-diene-19-oic acid) and kaurenoic acid (ent-kaura-16-en-19-oic acid). The spikenard extract significantly inhibited IL-1ß-stimulated production of IL-6, IL-8, metalloproteinase (MMP)-1, MMP-13, cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) and prostaglandin(PG)E2 in a dose-dependent manner but not MMP-3 production. The extract also inhibited the IL-1ß-induced translocation of NF-κB/p65 into the nucleus and dose-dependent phosphorylation levels of extracellular signal-regulated kinase (ERK), Jun amino-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase. Continentalic acid exhibited significant anti-arthritic activity corresponding exactly to that of the extract containing an equivalent amount of continentalic acid. On the other hand, kaurenoic acid exhibited a compatible activity at about a 10-times higher molar concentration than that of continentalic acid. In vitro anti-arthritic activities of the spikenard extract and continentalic acid were also confirmed in MIA-induced osteoarthritic rats. The 50% ethanolic extract of Manchurian spikenard exhibited promising anti-arthritic activities in the in vitro and in vivo osteoarthritis models, and continentalic acid, not kaurenoic acid, was most probably responsible for those activities.

Salusin-ß mediate neuroprotective effects for Parkinson's disease.

Neuropeptides, small peptides found in many mammalian brain, play key roles in communicating with each other to modulate neuronal activity. Here, we reported that endogenous neuropeptide salusin-ß has neuroprotective effects on the midbrain dopamine neurons and can be used as an effective therapeutic treatment for Parkinson's disease (PD). We found that the MrgprA1 receptor mediates the neuroprotective effects of salusin-ß on the midbrain dopamine neurons. Importantly, intranasal administration of salusin-ß in a PD mouse model show the neuroprotection of dopaminergic neurons and increased the survival of midbrain dopamine neurons. Furthermore, inhibition of the salusin-ß receptor, MrgprA1, abolished the neuroprotective effects induced by salusin-ß. Taken together, these results demonstrate the novel role of salusin-ß in the central nervous system and salusin-ß can be used as a novel therapeutic to effectively treat PD.

Does different information disclosure on placebo control affect blinding and trial outcomes? A case study of participant information leaflets of randomized placebo-controlled trials of acupuncture.

BACKGROUND: While full disclosure of information on placebo control in participant information leaflets (PILs) in a clinical trial is ethically required during informed consent, there have been concerning voices such complete disclosures may increase unnecessary nocebo responses, breach double-blind designs, and/or affect direction of trial outcomes. Taking an example of acupuncture studies, we aimed to examine what participants are told about placebo controls in randomized, placebo-controlled trials, and how it may affect blinding and trial outcomes. METHODS: Authors of published randomized, placebo-controlled trials of acupuncture were identified from PubMed search and invited to provide PILs for their trials. The collected PILs were subjected to content analysis and categorized based on degree of information disclosure on placebo. Blinding index (BI) as a chance-corrected measurement of blinding was calculated and its association with different information disclosure was examined. The impact of different information disclosure from PILs on primary outcomes was estimated using a random effects model. RESULTS: In 65 collected PILs, approximately 57% of trials fully informed the participants of placebo control, i.e. full disclosure, while the rest gave deceitful or no information on placebo, i.e. no disclosure. Placebo groups in the studies with no disclosure tended to make more opposite guesses on the type of received intervention than those with disclosure, which may reflect wishful thinking (BI -0.21 vs. -0.16; p = 0.38). In outcome analysis, studies with no disclosure significantly favored acupuncture than those with full disclosure (standardized mean difference - 0.43 vs. -0.12; p = 0.03), probably due to enhanced expectations. CONCLUSIONS: How participants are told about placebos can be another potential factor that may influence participant blinding and study outcomes by possibly modulating patient expectation. As we have few empirical findings on this issue, future studies are needed to determine whether the present findings are relevant to other medical disciplines and at the same time a routine practice of fully disclosing placebo information in PILs calls for reevaluation.

Coarse needle surface potentiates analgesic effect elicited by acupuncture with twirling manipulation in rats with nociceptive pain.

BACKGROUND: Biomechanical phenomenon called "needle grasp" through the winding of connective tissue has been proposed as an action mechanism of acupuncture manipulation. The aim of the present study is to verify whether the needle grasp force affects the pain-relieving activity of acupuncture in the tail-flick latency (TFL) and the rat paw formalin tests. METHODS: In order to make different roughness on the acupuncture needle surface, the needles with 0.2 mm-diameter were scratched using silicon carbide sandpapers with the grit numbers of 600 (mild coarse) and 200 (extra coarse). The surface roughness and rotation-induced torque of the scratched needles were then measured by atomic force microscope and Acusensor®, respectively. Rat abdominal wall tissues including insertion site of acupuncture needle were excised after 5 unidirectional rotations of the needles having various degrees of roughness, and the morphological changes of connective tissues were analyzed using hematoxylin and eosin (H-E) staining. Finally, the effects of coarse needle surface on anti-nociception induced by twirling manipulation were tested in rat TFL and formalin test. RESULTS: It was observed that the rougher the needle surface, the stronger the needle grasp force and thickness of subcutaneous connective tissue while rotating. TFL increased in proportion to surface roughness of the ground needles 10 min after acupuncture into the Zusanli acupoint (ST36) on rat's legs. In the rat formalin test, the rougher needle also significantly exerted the larger analgesic effect during both early and late phases compared to non-ground normal needle. CONCLUSION: Surface roughness of the acupuncture needle enhanced an anti-nociceptive activity of acupuncture therapy in rats, which partially supports the mechanical signaling theory through connective tissues in acupuncture manipulation.

What intrinsic factors influence responsiveness to acupuncture in pain?: a review of pre-clinical studies that used responder analysis.

BACKGROUND: Not many studies have investigated individual sensitivity to acupuncture. To explore the intrinsic factors related to individual responses to acupuncture, we reviewed published pre-clinical studies using responder analysis on pain. METHODS: We searched the PubMed and EMBASE databases to June 2015. We included pre-clinical reports describing responders and non-responders to anti-nociceptive and analgesic effects of acupuncture in animal study. We identified the potential intrinsic factors which might be related with the response to acupuncture. RESULTS: Totally, 216 potentially relevant articles were retrieved and 14 studies met our inclusion criteria. Rat (n = 1348) and rabbit (n = 56) were used, and only electroacupuncture (EA) was applied as an intervention. Results showed that high levels of cholecystokinin-8 and receptors were associated with poor responsiveness to EA. Endogenous opioids including ß-endorphin and met-enkephalin, descending inhibitory norepinephrine and serotonin system, and hypothalamic 5'-AMP-activated protein kinase seemed to be associated with high-level responses. Spinal levels of neurotransmitters and pro-inflammatory cytokines were also differentially expressed depending on the EA sensitiveness. In the central nervous system, hypothalamus, periaqueductal grey, pituitary gland, and spinal cord were suggested to be involved in the EA responsiveness. Identified individual variations did not seem to be accidental, as the responsiveness to EA was replicated over time. However, methodological issues such as reproducibility, cut-off criteria, and clinical relevance need to be further elaborated. CONCLUSION: Our study suggests that the identification of the biological factors differentiating responders from non-responders is necessary and it may aid in understanding how acupuncture modulates pain.

Effects of a combination treatment of KD5040 and L-dopa in a mouse model of Parkinson's disease.

BACKGROUND: Although the dopamine precursor L-3, 4-dihydroxyphenylalanine ( l -dopa) remains the gold standard pharmacological therapy for patients with Parkinson's disease (PD), long-term treatment with this drug has been known to result in several adverse effects, including l -dopa-induced dyskinesia (LID). Recently, our group reported that KD5040, a modified herbal remedy, had neuroprotective effects in both in vitro and in vivo models of PD. Thus, the present study investigated whether KD5040 would have synergistic effects with l -dopa and antidyskinetic effects caused by l -dopa as well. METHODS: The effects of KD5040 and l -dopa on motor function, expression levels of substance P (SP) and enkephalin (ENK) in the basal ganglia, and glutamate content in the motor cortex were assessed using behavioral assays, immunohistochemistry, Western blot analyses, and liquid chromatography tandem mass spectrometry in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In addition, the antidyskinetic effects of KD5040 on pathological movements triggered by l -dopa were investigated by testing abnormal involuntary movements (AIMs) and measuring the activations of FosB, cAMP-dependent phosphor protein of 32 kDa (DARPP-32), extracellular signal-regulated kinases (ERK), and cAMP response element-binding (CREB) protein in the striatum. RESULTS: KD5040 synergistically improved the motor function when low-dose l -dopa (LL) was co-administered. In addition, it significantly reversed MPTP-induced lowering of SP, improved ENK levels in the basal ganglia, and ameliorated abnormal reduction in glutamate content in the motor cortex. Furthermore, KD5040 significantly lowered AIMs and controlled abnormal levels of striatal FosB, pDARPP-32, pERK, and pCREB induced by high-dose l -dopa. CONCLUSIONS: KD5040 lowered the effective dose of l -dopa and alleviated LID. These findings suggest that KD5040 may be used as an adjunct therapy to enhance the efficacy of l -dopa and alleviate its adverse effects in patients with PD.

MPTP-induced vulnerability of dopamine neurons in A53T α-synuclein overexpressed mice with the potential involvement of DJ-1 downregulation.

Familial Parkinson's disease (PD) has been linked to point mutations and duplication of the α-synuclein (α-syn) gene. Mutant α-syn expression increases the vulnerability of neurons to exogenous insults. In this study, we developed a new PD model in the transgenic mice expressing mutant hemizygous (hemi) or homozygous (homo) A53T α-synuclein (α-syn Tg) and their wildtype (WT) littermates by treatment with sub-toxic (10 mg/kg, i.p., daily for 5 days) or toxic (30 mg/kg, i.p., daily for 5 days) dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Tyrosine hydroxylase and Bcl-2 levels were reduced in the α-syn Tg but not WT mice by sub-toxic MPTP injection. In the adhesive removal test, time to remove paper was significantly increased only in the homo α-syn Tg mice. In the challenging beam test, the hemi and homo α-syn Tg mice spent significantly longer time to traverse as compared to that of WT group. In order to find out responsible proteins related with vulnerability of mutant α-syn expressed neurons, DJ-1 and ubiquitin enzyme expressions were examined. In the SN, DJ-1 and ubiquitin conjugating enzyme, UBE2N, levels were significantly decreased in the α-syn Tg mice. Moreover, A53T α-syn overexpression decreased DJ-1 expression in SH-SY5Y cells. These findings suggest that the vulnerability to oxidative injury such as MPTP of A53T α-syn mice can be explained by downregulation of DJ-1.