Fuhua Peng

Artemisinin attenuates lipopolysaccharide-stimulated proinflammatory responses by inhibiting NF-κB pathway in microglia cells.

Microglial activation plays an important role in neuroinflammation, which contributes to neuronal damage, and inhibition of microglial activation may have therapeutic benefits that could alleviate the progression of neurodegeneration. Recent studies have indicated that the antimalarial agent artemisinin has the ability to inhibit NF-κB activation. In this study, the inhibitory effects of artemisinin on the production of proinflammatory mediators were investigated in lipopolysaccharide (LPS)-stimulated primary microglia. Our results show that artemisinin significantly inhibited LPS-induced production of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1) and nitric oxide (NO). Artemisinin significantly decreased both the mRNA and the protein levels of these pro-inflammatory cytokines and inducible nitric oxide synthase (iNOS) and increased the protein levels of IκB-α, which forms a cytoplasmic inactive complex with the p65-p50 heterodimeric complex. Artemisinin treatment significantly inhibited basal and LPS-induced migration of BV-2 microglia. Electrophoretic mobility shift assays revealed increased NF-κB binding activity in LPS-stimulated primary microglia, and this increase could be prevented by artemisinin. The inhibitory effects of artemisinin on LPS-stimulated microglia were blocked after IκB-α was silenced with IκB-α siRNA. Our results suggest that artemisinin is able to inhibit neuroinflammation by interfering with NF-κB signaling. The data provide direct evidence of the potential application of artemisinin for the treatment of neuroinflammatory diseases.

Helicobacter pylori infection in Neuromyelitis Optica and Multiple Sclerosis.

Objective: To determine the Helicobacter pylori infection status in patients with multiple sclerosis (MS) and neuromyelitis optica (NMO) spectrum. Methods:H. pylori infection was certified by indirect immunofluorescence assay. Aquaporin-4 (AQP4) antibody was detected by cell-based assay. H. pylori seroprevalence was measured in 118 patients with NMO (n = 52), high-risk NMO (hrNMO, longitudinally extensive transverse myelitis, n = 17 and recurrent optic neuritis, n = 7), MS (n = 42) and healthy controls (n = 27). Logistic regression analysis was used to determine associations between H. pylori infection and NMO and MS. Results:H. pylori antibodies were present in 119 serum samples (82.1%, 119/145), with antibody positivity in 90.4% (47/52) of the patients with NMO, 95.8% (23/24) of the patients with hrNMO, 73.8% (31/42) of the patients with MS and 59.3% (16/27) of the controls. NMO spectrum patients had greater positivity for H. pylori than MS patients (p < 0.05) and controls (p < 0.05). The frequency of H. pylori seropositivity did not significantly differ between MS patients and controls (p = 0.726). H. pylori seropositivity was significantly higher in AQP4 antibody-positive patients (54/58, 93.1%; p = 0.038) than in AQP4 antibody-negative patients (48/60, 80%). Logistic regression analysis showed that H. pylori seropositivity was significantly associated with hrNMO [odds ratio (OR) = 9.311, p = 0.005] or hrNMO + NMO (OR = 6.350, p = 0.028). Conclusion:H. pylori infection was present in most Chinese patients with NMO and hrNMO, and may be a risk factor for the NMO spectrum.

Effect of high-dose methylprednisolone treatment on Th17 cells in patients with multiple sclerosis in relapse.

Objectives –  Growing evidences have suggested that Th17 cells are involved in the pathogenic mechanisms of multiple sclerosis (MS). Treatment with high‐dose intravenous methylprednisolone (IVMP) has beneficial effects on functional recovery in patients with MS during relapse. The present study was designed to analyze the influences of IVMP on Th17 cells in patients with MS after a 5‐day high‐dose IVMP treatment.

The anti-inflammatory effect of donepezil on experimental autoimmune encephalomyelitis in C57 BL/6 mice.

Donepezil is a potent and selective acetylcholinesterase inhibitor. It has been reported to restore cognitive performance in multiple sclerosis (MS) patients and experimental autoimmune encephalomyelitis (EAE) mice, an established model of MS. However, there are no reports about the anti-inflammatory effects of donepezil on EAE. In this study, the donepezil treatments on EAE mice were initiated at day 7 post immunization (7 p.i., subclinical periods, early donepezil treatment) and day 13 p.i. (clinical periods, late donepezil treatment) with the dosage of 1, 2 and 4 mg/kg/d respectively and the treatments persisted throughout the experiments. Blood-brain barrier (BBB) permeability was detected by Evans blue content, the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9, Akt and phosphorylated Akt (p-Akt) as well as nerve growth factor (NGF) and its precursor form (proNGF) in the brains of EAE mice were detected by Western blot, and the levels of interferon-γ and interleukin-4 in the splenocytes culture supernatants and brains of EAE mice were evaluated by ELISA. The results showed that the 2 mg/kg/d late donepezil treatment was the optimal dosage and could ameliorate clinical and pathological parameters, improve magnetic resonance imaging outcomes, reduce the permeability of BBB, inhibit the production of MMP-2 and MMP-9, modulate the expression of NGF and proNGF, increase Th2 bias and the phosphorylation of Akt in the brains of EAE mice. Our data suggested that the anti-inflammatory effects of donepezil may be a novel mechanism on treating EAE and provided further insights to understand the donepezils neuroprotective activities in MS.

Clinical, radiographic characteristics and immunomodulating changes in neuromyelitis optica with extensive brain lesions

BackgroundNeuromyelitis optica (NMO) shows various brain magnetic resonance imaging (MRI) abnormalities with recurrent central nervous system (CNS) attacks, although predominantly affecting the spinal cord and optic nerve. However, NMO with extensive involvement of the brain has infrequently been studied. We investigated the clinical, radiographic features and immunomodulating changes of NMO patients with extensive brain lesions (EBLs) in China.MethodsNMO patients (including 16 NMO patients with EBLs and 53 NMO patients without EBLs) hospitalized during January 2006 and February 2010 were recruited and analyzed retrospectively. Data of clinical characteristics, magnetic resonance imaging (MRI) features, laboratory abnormalities, treatment details and outcomes were analyzed. All the patients received the follow-up visits for two years.ResultsEBLs in NMO were classified into four categories according to their respective MRI characteristics: 1) Tumefactive-like lesions (n=4, 25%); 2) Acute disseminated encephalomyelitis (ADEM)-like lesions (n=6, 37.5%); 3) Multiple sclerosis (MS)-like lesions (n=5, 31.25%); 4) Posterior reversible encephalopathy syndrome (PRES)-like lesions (n=1, 6.25%). NMO patients with EBLs had higher rates of encephalopathy symptoms (37.5% vs. 5.6%, p = 0.004), homonymous hemianopia (18.8% vs. 0%, p = 0.011) and AQP4 seropositivity (100% vs. 69.8%, p = 0.008) than NMO patients without EBLs (NEBLs). Immunomodulating changes (including the levels of C3, C4, ESR and CRP) were significantly higher in patients with EBLs than those without EBLs. The relapse times in EBLs during the follow-up period were more frequent than those happened in NEBLs (1.88 ± 0.30 vs. 1.23 ± 0.14, p = 0.04). The EDSS scores in EBLs patients were also much higher than those in NEBLs throughout all the whole visits of follow-up.ConclusionsThe presence of EBLs in NMO may indicate a higher diseases activity and portend a worse prognosis. CRP is a useful marker in monitoring diseases activity. Systemic inflammation may be crucial to the formation of EBLs in NMO.

Serum bilirubin concentrations and multiple sclerosis

Bilirubin is the end product of heme catabolism by heme oxygenases. Although bilirubin has long been considered as a toxic waste product, it is now recognized as an endogenous antioxidant. It has been reported that bilirubin is an effective treatment in both acute and chronic experimental autoimmune encephalomyelitis (EAE) disease models. However, the relationship between bilirubin and multiple sclerosis (MS) has not been fully explored. The serum bilirubin concentrations were measured in 340 individuals comprising 88 healthy subjects, 133 patients with MS and 119 patients with cerebral infarction. Serum total bilirubin (Tbil), direct bilirubin (Dbil) and indirect bilirubin (Ibil) concentrations were significantly lower in patients with MS than in either patients with cerebral infarction or healthy controls (p<0.001). The correlation identified between bilirubin and MS was still highly significant when the effect of gender was eliminated. Among patients with MS, Tbil, Dbil and Ibil concentrations were lower in patients with MS with longer duration (>2 years), less disabling disease (Expanded Disability Status Scale score<3), and inactive MRI appearance, although the differences did not reach statistical significance. Our results suggest that there are reduced serum bilirubin concentrations in patients with MS.

Minocycline up-regulates the expression of brain-derived neurotrophic factor and nerve growth factor in experimental autoimmune encephalomyelitis

Previous evidence demonstrated that minocycline could ameliorate clinical severity of experimental autoimmune encephalomyelitis and exhibit several anti-inflammatory and neuroprotective activities. However, few studies have been carried out to assess its effects on the expression of neurotrophins in experimental autoimmune encephalomyelitis or multiple sclerosis. Here we investigated the alteration of brain-derived neurotrophic factor and nerve growth factor in the sera, cerebral cortex, and lumbar spinal cord of experimental autoimmune encephalomyelitis C57 BL/6 mice in vivo as well as the splenocytes culture supernatants in vitro after minocycline administration. Our results demonstrated that minocycline could up-regulate the expression of brain-derived neurotrophic factor and nerve growth factor both in peripheral (sera and splenocytes culture supernatants) and target organs (cerebral cortex and lumber spinal cord) of mice with experimental autoimmune encephalomyelitis. These data suggest that up-regulation of neurotrophins in experimental autoimmune encephalomyelitis may be a novel neuroprotective mechanism of minocycline.

Anti-aquaporin-4 antibody in Chinese patients with central nervous system inflammatory demyelinating disorders.

OBJECTIVE To determine seroprevalence of aquaporin-4 (AQP4) antibody in Chinese patients with central nervous system (CNS) inflammatory demyelinating disorders. METHODS AQP4 antibody was detected by anti-AQP4 antibody assay. We measured seroprevalence in 200 patients with neuromyelitis optica (NMO, n=44), multiple sclerosis (MS, n=46), transverse myelitis (TM, n=44), optic neuritis (ON, n=13), acute disseminated encephalomyelitis (ADEM, n=2), and other neurological diseases (OND, n=51). RESULTS AQP4 antibody seropositivity was 88.6% in patients with NMO, 4.3% in patients with MS, 30.8% in patients with ON and 51.7% in patients with LETM (longitudinally extensive TM). No patients with acute partial TM, ADEM, OND were positive for AQP4 antibody. Sensitivity of the test was 88.6% (95% CI 80-95) in patients with NMO. Specificity is 97.9% (95% CI 95.1-100) in 46 MS patients, with 51 OND patients as the control group. If the patients with recurrent ON, LETM were considered high risk for NMO (n=37) and the remaining patients (n=119) were considered controls, the sensitivity of this assay would be 48.6% (95% CI 33.4-64.1) and the specificity 97.5% (95% CI 94.7-100). CONCLUSION This study confirms that AQP4 antibody is a sensitive and specific biomarker for discrimination between NMO and other CNS autoimmune diseases.

Preliminary study on the association of AQP4 promoter polymorphism with anti-aquaporin-4 antibody positivity in Southern Han Chinese patients with idiopathic demyelinating disorders of central nervous system

OBJECTIVES To identify the association of aquaporin-4 (AQP4) promoter polymorphism with the presence of anti-aquaporin-4 antibody (AQP4-Ab) in Southern Han Chinese patients with idiopathic demyelinating disorders of central nervous system. METHODS Eighteen neuromyelitis optica (NMO), thirty-eight conventional MS (CMS), thirteen recurrent myelitis (RM), six recurrent optic neuritis (RON) patients and thirty-nine matched controls were enrolled. Polymorphisms of AQP4 promoters 0 and 1 were determined by sequencing-based typing. RESULTS Fourteen polymorphism loci were observed in AQP4-promoter 0, while the six ones were observed in AQP4-promoter 1. Among them, the frequency of polymorphism at position -1003bp (A-G) of AQP4-promoter 0 in AQP4-Ab-positive patients was significantly higher than that in AQP4-Ab-negative patients and controls (former: 13/18 vs 20/45, P=0.046; latter: 13/18 vs 10/39, P=.001). The frequency of polymorphism at position between -401bp and -400bp (C inserted) of AQP4-promoter 1 in AQP4-Ab-positive and -negative patients was significantly higher than that in controls (former: 5/16 vs 0/28, P=0.008; latter: 8/38 vs 0/28, P=0.027). CONCLUSIONS Polymorphism at position -1003bp (A-G) of AQP4-promoter 0 is associated with the presence of anti-AQP4 antibody. Genetic variation in AQP4 may account for the susceptibility to AQP4-Ab-positive NMO and NMO spectrum disorders in Southern Han Chinese population.

The Usefulness of Toluidine Red Unheated Serum Test in the Diagnosis of Hiv-negative Neurosyphilis

We retrospectively analyzed the Venereal Disease Research Laboratory test, Treponema pallidum particle agglutination test, and toluidine red unheated serum test (TRUST) in 41 cases of HIV-negative neurosyphilis and 34 non-neurologic syphilitic patient and found that serum-TRUST titers could be the indication of lumbar puncture in syphilitic patients and a reactive cerebrospinal fluid-TRUST is considered diagnostic to neurosyphilis.