TSG-6 alleviates cerebral ischemia/reperfusion injury and blood-brain barrier disruption by suppressing ER stress-mediated inflammation.

Tumor necrosis factor-stimulated gene-6 (TSG-6) exhibits promising neuroprotective activity, but how it influences cerebral ischemia/reperfusion (CIR) injury remains to be established. Here, the impact of TSG-6 on the CIR-induced disturbance in the blood-brain barrier (BBB) and associated neurological degeneration was assessed, and the related molecular processes were explored. In this study, TSG-6 markedly reduced CIR-mediated increases in neurological deficit scores, decreased infarct volume, and protected against the apoptotic death of neurons in MCAO/R model rats. Similarly, TSG-6 pretreatment protected cultured neurons against OGD/R-associated neuronal death. TSG-6 also restored BBB integrity, suppressing PERK-eIF2α and IRE1α-TRAF2 pathway activation in CIR model systems, thereby inhibiting NF-κB, TNF-α, IL-1ß, and IL-6. The further use of specific inhibitors of ER stress, 4-phenyl butyric acid (4-PBA), PERK (GSK2656157), and IRE1α (STF083010) demonstrated the ability of ER stress to drive inflammatory activity in the context of CIR injury i the PERK-eIF2α-NF-κB and IRE1α-TRAF2-NF-κB pathways. Consistently, the activation of ER stress using tunicamycin resulted in reversing the beneficial effects of TSG-6 on CIR-associated BBB disruption and neurological damage in vitro and in vivo. Treatment with TSG-6 can protect against CIR injury via the inhibition of ER stress-related inflammatory activity induced through the PERK-eIF2α-NF-κB and IRE1α-TRAF2-NF-κB pathways.

TSG-6 inhibits hypertrophic scar fibroblast proliferation by regulating IRE1α/TRAF2/NF-κB signalling.

TNF-stimulated gene (TSG-6) was reported to suppress hypertrophic scar (HS) formation in a rabbit ear model, and the overexpression of TSG-6 in human HS fibroblasts (HSFs) was found to induce their apoptotic death. The molecular basis for these findings, however, remains to be clarified. HSFs were subjected to TSG-6 treatment. Treatment with TSG-6 significantly suppressed HSF proliferation and induced them to undergo apoptosis. Moreover, TSG-6 exposure led to reductions in collagen I, collagen III, and α-SMA mRNA and protein levels, with a corresponding drop in proliferating cell nuclear antigen (PCNA) expression indicative of impaired proliferative activity. Endoplasmic reticulum (ER) stress was also suppressed in these HSFs as demonstrated by decreases in Bip and p-IRE1α expression, downstream inositol requiring enzyme 1 alpha (IRE1α) -Tumor necrosis factor receptor associated factor 2 (TRAF2) pathway signalling was inhibited and treated cells failed to induce NF-κB, TNF-α, IL-1ß, and IL-6 expression. Overall, ER stress was found to trigger inflammatory activity in HSFs via the IRE1α-TRAF2 axis, as confirmed with the specific inhibitor of IRE1α STF083010. Additionally, the effects of TSG-6 on apoptosis, collagen I, collagen III, α-SMA, and PCNA of HSFs were reversed by the IRE1α activator thapsigargin (TG). These data suggest that TSG-6 administration can effectively suppress the proliferation of HSFs in part via the inhibition of IRE1α-mediated ER stress-induced inflammation (IRE1α/TRAF2/NF-κB signalling).

Connectivity-Based Brain Parcellation for Parkinson's Disease.

Connectivity-based parcellation (CBP) studies for exploring cerebral topographic organization have emerged rapidly, likely due to the joint developments of non-invasive imaging technologies and advances in computing science. CBP studies have extended our understanding of human brain development and many brain-related disorders such as Parkinson's Disease (PD), and have provided promising approaches to guide electrode placement during the planning of deep brain stimulation (DBS) surgery. This work reviews prevalent CBP methods, summarizing the methodological advantages and limitations of each. As PD is the second most common neurodegenerative disorder, we particularly focus on data-driven parcellation studies in this disease, providing researchers with a comprehensive overview of PD-specific atlases and their applications. We show that, while many advances have been achieved, heterogeneity in the PD population still provides an ongoing challenge to find a robust consensus on regional representation. Although some parcellation-driven studies exhibit encouraging achievements, these PD-specific parcellations are still limited and most approaches depend on a single modality. We discuss the future directions of parcellation-driven PD exploration and surgical planning, with the aim to inspire future investigation into connectivity-based parcellation for PD.

Combined dimercaptosuccinic acid and zinc treatment in neurological Wilson's disease patients with penicillamine-induced allergy or early neurological deterioration.

The clinical data of safety and efficacy of a combined treatment with dimercaptosuccinic acid (DMSA) and Zinc with 2 years' follow-up in 60 neurological Wilson's disease (WD) patients was retrospectively analyzed. All the patients included in the present study were newly diagnosed and initialized with D-penicillamine (DPA) treatment but were found to have either neurological deterioration or allergy, and their treatment was switched to a combined treatment of DMSA and Zinc. Fifty-one patients (85%) had the neurological symptoms improved 1 and 2 years after treatment, 7 (11.67%) experienced a stable neurological condition, and 2 (3.33%) suffered deterioration of neurological symptoms. No early neurological deterioration was observed in all patients. Twenty-five percent patients experienced mild adverse reactions which did not require a discontinuation of the DMSA and Zinc treatment. Our study confirmed the safety and efficacy of the combined DMSA and Zinc therapy as an initial and probably long-term treatment in neurological WD patients.

Wilson disease patient with rare heterozygous mutations in ATP7B accompanied by distinctive nocturnal enuresis: A case report.

INTRODUCTION: Wilson disease (WD) is an autosomal-recessive disorder of copper metabolism, which exhibits various symptoms due to the combination of environmental and genetic factors. Here, we report a WD patient who displayed distinctive symptom of nocturnal enuresis. PATIENT CONCERNS: The patient was a 31-year old woman, who recently developed nocturnal enuresis, combined with hand tremors, trouble speaking, and panic disorder at night. DIAGNOSIS: The patient had been diagnosed with WD by Kayser-Fleischer rings, abnormal copper metabolism, neuropsychiatric symptoms, and magnetic resonance imaging when she was 17. The diagnosis was further confirmed by genetic analysis, which revealed a compound heterozygous mutations in ATP7B gene (c.2195T>C and c.3044T>C). The patient exhibited nocturnal enuresis, but the ambulatory electroencephalogram, routine urinalysis, residual urine detection, color doppler ultrasound of kidney, ureter, and bladder all displayed no abnormality. INTERVENTIONS: The patient was treated with sodium dimercaptosulphonate, supplemented with Glutathione and Encephalin-inosine. OUTCOMES: The urinary copper excretion level decreased gradually, and the nocturnal enuresis was alleviated along with the neuropsychiatric symptoms by copper chelation therapy. CONCLUSION: In this study, we proved that variants c.2195T>C and c.3044T>C is involved in pathogenesis of WD, and revealed that nocturnal enuresis may be a symptom of WD.

Gandouling Tablets Inhibit Excessive Mitophagy in Toxic Milk (TX) Model Mouse of Wilson Disease via Pink1/Parkin Pathway.

OBJECTIVE: Gandouling (GDL) tablet is a Chinese patent medicine approved by the National Medical Product Administration, which is used to treat Wilson disease (WD) in China. In this study, we aimed to investigate the effects of GDL on mitophagy in the hippocampus in the toxic milk (TX) mouse model of WD. METHODS: Mice were randomly divided into the following four groups: control, Wilson (model group), D-penicillamine (DPA), and GDL groups. The animal behaviors were evaluated by the water maze experiment, traction test, and pole test. Transmission electron microscopy was used for the detection of mitochondrion structure. An enzyme-linked immunosorbent assay (ELISA) was performed for the analysis of the changes in liver function. Colocalization of mitophagy-related proteins was detected by fluorescence microscopy. Western blotting (WB) and reverse transcription-polymerase chain reaction (RT-PCR) were conducted for the detection of protein expression and mRNA levels, respectively. RESULTS: Significant reduction in neurological impairments was observed in the WD model group. All of these results were significantly reversed by GDL intervention. Compared with the levels in the Wilson group, the levels of alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin (TBIL), and albumin (ALB) changed obviously. Colocalization between mitophagy-related proteins pink1, parkin, and mitochondria was changed significantly. The mitophagy-related mRNA (pink1, parkin, and LC3II) and protein expression levels (pink1, parkin, and the rate of LC3II/LC3I) were decreased significantly, while p62 was remarkably increased after GDL intervention. CONCLUSION: Our findings indicated that the neuroprotective mechanism of GDL may occur via the inhibition of excessive mitophagy through the regulation of the pink1/parkin pathway in the TX mouse brain of WD.

Acute onset neurological symptoms in Wilson disease after traumatic, surgical or emotional events: A cross-sectional study.

Acute onset neurological symptoms evoked by traumatic, surgical, or emotional events in Wilson disease (WD) have never been reported and its clinical characteristics are unclear.We aimed to summarize the clinical characteristics of a special WD whose neurological symptoms acutely developed after traumatic, surgical, or emotional events.Retrospective pilot study.Thirty-one patients who had acute onset neurological symptom as an initial presentation of WD or a new presentation of hepatic WD after mild trauma, surgery, or emotional events were retrospectively studied. All patients were followed for half to 1 year after regular anti-copper treatment.The averaged latency for neurological symptom presentation was 2.79 ±â€Š1.21 hours. The most frequent neurological symptoms were tremor (74%) and basal ganglia (BG) lesions were detected on magnetic resonance imaging in all patients. Lesions in other regions were much less frequently detected. Neurological symptom score and its recovery after treatment were correlated with lesion location: BG area and BG plus other brain areas. Neurological symptoms improved in 21 patients who received timely anti-copper treatment but continued to deteriorate in 6 patients who did not accept regular anti-copper treatment for delayed diagnosis.A diagnosis of WD should be considered when adolescents or adults experience acute presentation of extrapyramidal systems after traumatic, surgical, or emotional stimulation. Timely anti-copper therapy usually gives rise to an excellent prognosis.

Efficacy of neuromuscular electrical stimulation on Wilson's disease patients with dysphagia.

[Purpose] Dysphagia is a neurological symptom that is observed in more than half of patients with Wilson's disease. It is often associated with aspiration pneumonia, dehydration, and malnutrition, resulting in drastic reduction of the quality of life. Neuromuscular electrical stimulation could be an adjunct therapy for dysphagia treatment. However, there is limited data about the application of NMES for dysphagia in Wilson's disease. Thus, we explored the potential application of NMES for dysphagia treatment in Wilson's disease. [Participants and Methods] Sixty Wilson's disease patients who suffered from dysphagia were randomized into two groups. Swallowing function training was taught to the control group (n=30) while Neuromuscular electrical stimulation therapy was given to treatment group (n=30). Eight weeks post treatment, using the water swallow test and the Standardized Swallowing Assessment, the swallowing function was determined. [Results] None of the patients experienced discomfort before, during or after the intervention. After 8 weeks of therapy, when compared to the control, an increased improvement in swallowing function was noted for the treatment group. [Conclusion] Neuromuscular electrical stimulation treatment can improve swallowing function in Wilson's disease patients afflicted with dysphagia. Therefore, it has the potential to be a form of therapy in clinical practice.

Successful Treatment of Hypersplenism in Wilson's Disease by Partial Splenic Embolization.

AIM: Hypersplenism can occur in patients with Wilson's disease (WD). Surgical splenectomy is a conventional treatment for this condition; however, emotional and neurological deterioration may follow splenectomy. In recent years, partial splenic embolization (PSE) has been increasingly performed as a nonsurgical alternative treatment for hypersplenism. The aim of this study was to evaluate the effectiveness and safety of PSE compared with splenectomy in the treatment of hypersplenism in WD patients. METHODS: Fifty WD patients with hypersplenism were randomly divided into two groups (group A and group B), each including 25 patients. Patients in groups A and B were treated with PSE and splenectomy, respectively. Data were collected on the clinical efficacy of each procedure, adverse reactions, hematologic and blood chemistry test results, and abdominal computed tomography (CT) scan findings (group A only). RESULTS: Marked improvements in the platelet and leukocyte counts after PSE and splenectomy were observed in all patients. PSE was associated with improved liver function without severe complications, and no significant changes in emotional and neurological symptoms were observed. In contrast, seven WD patients suffered neurological deterioration after splenectomy. CONCLUSIONS: Hypersplenism in WD patients was successfully treated by PSE, which appears to be a safe and effective alternative treatment for WD-induced hypersplenism.

Clinical efficacy and safety of Gandouling plus low-dose D-penicillamine for treatment of Wilson's disease with neurological symptoms.

OBJECTIVE: To investigate the effect and safety of Gandouling plus low-dose D-penicillamine for treating patients with Wilson's disease (WD) who have neurological symptoms. METHODS: WD patients with neurological symptoms were divided into two groups: a treatment group (n = 53) and a control group (n = 50). The treatment group received anti-copper therapy with a combination of Gandouling and low-dose D-penicillamine (10 mg/kg), whereas the control group was with conventional dose D-penicillamine (20 mg/kg) monotherapy. The clinical efficacies, adverse reactions, and results of the various hematological and biochemical investigations were recorded and analyzed statistically. RESULTS: Overall, 98.11% of the WD patients treated with the combined therapy experienced alleviation of their neurological condition (paralleled by a significantly improved Global Assessment Scale score or remained stable). Their white blood cell and platelet counts stabilized, and their liver function was improved or remained stable. The combined therapy also obviously promoted improved 24-h urinary copper excretion. Only 15.09% of the WD patients with the combined therapy experienced adverse reactions, including neurological deterioration in one case (1.89%) and hepatic worsening in one case (1.89%), which was less frequent than that in the control group given conventional-dose D-penicillamine monotherapy. CONCLUSION: Treating WD patients with neurological symptoms using Gandouling plus low-dose D-penicillamine is effective and safe.

Evaluation of efficacy and safety of gandouling plus sodium dimercaptosulphonate in treatment of patients with neurological Wilson's disease from China.

OBJECTIVE: To evaluate the efficacy and safety of gandouling plus sodium dimercaptosulphonate (DMPS) on neurological Wilson's disease (WD) in patients. METHODS: We retrospectively evaluated the clinical records of 125 WD patients with neurological syndromes who were treated with gandouling plus sodium DMPS or DMPS used alone. All patients had a history of neurological deterioration during their diseases courses. The clinical efficacies, adverse reactions, and results of the various hematological and biochemical investigations were recorded for statistical analysis. RESULTS: 92.30% (60 patients) of the WD patients treated with the combined therapy experienced an improved or stable neurological condition paralleled by a significantly improved GAS score. Meanwhile, the WBC and PLT counts stabilized, liver function and renal function were improved or remained stable. The combined therapy also obviously promoted the 24-h urinary copper excretion. In particular, only 30.76% of the WD patients experienced mild adverse reactions, including neurological deterioration in 5 patients (7.69%), hepatic worsening in 1 subject (1.89%), which was less frequently than those in the control group treated with DMPS only. CONCLUSION: Our findings indicate that the safety and efficacy of gandou-ling plus DMPS is superior to those of DMPS used alone in the WD patients with neurological symptoms.

Successful Splenectomy for Hypersplenism in Wilson's Disease: A Single Center Experience from China.

Splenomegaly and pancytopenia are common in Wilson's disease (WD) and splenectomy is one of the conventional treatments for splenomegaly and the associated pancytopenia. However, splenectomy remained controversial for hypersplenism in WD as it was reported that splenectomy leaded to serious emotional and neurological deterioration in WD patients with hypersplenism. In the current study, we present our experiences in 70 WD patients with hypersplenism who had undergone splenectomy, outlining the safety and efficacy of splenectomy in WD. The clinical database of 70 WD patients with hypersplenism who had undergone splenectomy in our hospital between 2009 and 2013 were reviewed and followed-up regularly. Before splenectomy, all the patients accepted a short period of anti-copper treatment with intravenous sodium 2, 3-dimercapto-1-propane sulfonate (DMPS). All the patients demonstrated a marked improvement in platelet and leucocyte counts after splenectomy. No severe postoperative complication was observed. In particular, none of the 37 patients with mixed neurologic and hepatic presentations experienced neurological deterioration after splenectomy, and none of the patients with only hepatic presentations newly developed neurological symptoms. During the one year follow-up period, no patient presented hepatic failure or hepatic encephalopathy, no hepatic patient newly developed neurological presentations, and only 3 patients with mixed neurologic and hepatic presentations suffered neurological deterioration and these 3 patients had poor compliance of anti-copper treatment. Quantative analysis of the neurological symptoms in the 37 patients using the Unified Wilson's Disease Rating Scale (UWDRS) showed that the neurological symptoms were not changed in a short-term of one week after splenectomy but significantly improved in a long-term of one year after splenectomy. Additionally, compared to that before splenectomy, the esophageal gastric varices in most patients significantly improved one year after splenectomy. Thus, we may conclude that splenectomy is a safe and effective therapeutic measure for hypersplenism in WD patients who had been preoperatively treated with DMPS for powerful anti-copper therapy.

TGFß1 treatment reduces hippocampal damage, spontaneous recurrent seizures, and learning memory deficits in pilocarpine-treated rats.

Studies have demonstrated the neuroprotective activity of transforming growth factor beta-1 (TGFß1), protecting neurons against different kinds of insults. However, the role of exogenous TGFß1 in the neuronal damage following status epilepticus (SE) and the related spontaneous recurrent seizures (SRS) is unknown. The present study aimed to determine the effect of intranasal TGFß1 administration on SRS and cognitive function following lithium-pilocarpine-induced SE and associated hippocampal damage. We found that intranasal TGFß1 significantly attenuated the hippocampal insults marked by hematoxylin and eosin, terminal deoxynucleotidyl transferase dUTP nick end labeling, and Fluoro-Jade B staining by 24, 48, and 72 h after SE was induced. The expression of the apoptosis-suppressing protein, Bcl-2, was elevated, whereas the expression of the apoptosis-promoting proteins, Bax and Caspase-3, was suppressed in TGFß1-treated rats compared to rats without TGFß1 treatment by 24, 48, and 72 h following induction of SE. The seizure number, severity, and duration of SRS over a 1-month period of monitoring starting 15 days after SE induction as well as the cognitive deficits detected 45 days after SE induction were significantly reduced in TGFß1-treated rats compared to those without TGFß1 treatment. Our results indicate that intranasal delivery of TGFß1 immediately after SE induction not only protected against SRS but also improved cognitive function. The anti-epileptogenic properties of TGFß1 may be related to its effect of neuroprotection or to its effect of apoptosis pathway changes.

Hypothermia reduces brain edema, spontaneous recurrent seizure attack, and learning memory deficits in the kainic acid treated rats.

AIMS: It is unknown whether hypothermia can disrupt the progress of epileptogenesis. The present study aimed to determine the effect of hypothermia on brain edema and epileptogenesis and to establish whether brain edema is associated with epileptogenesis after severe status epilepticus (SE). METHODOLOGY: Rats were injected with a single dose of Kainic acid (KA) to produce either chronic epileptic rats (rats with spontaneous recurrent seizure, SRS) or rats without spontaneous recurrent seizure (no-SRS rats). A second KA injection was used to induce SE in SRS rats and in no-SRS rats. The number of SRS was counted and the brain edema induced by SE was assessed by brain water content measurement. The cognitive function was assessed by the radial-arm maze (RAM) test. RESULTS: A second KA injection resulted in brain edema that was more severe in SRS rats than in no-SRS rats. After second injection of KA, hypothermia treatment attenuated the KA induced brain edema and reduced the SRS attack in SRS rats. Additionally cognitive function was better in hypothermia-treated SRS rats than in nomothermia treated SRS rats 1 month after the second KA injection. CONCLUSIONS: Hypothermia treatment immediately after SE not only exhibited protective effects against the chronic spontaneous recurrent convulsant seizures but also improved cognitive function. These antiepileptogenic properties of hypothermia may be related to its attenuating effect on brain edema induced by SE. They therefore suggest that brain edema may be involved in the progress of epileptogenesis.