Iguratimod suppresses plasma cell differentiation and ameliorates experimental Sjögren's syndrome in mice by promoting TEC kinase degradation.

Primary Sjögren's syndrome (pSS) is a chronic inflammatory autoimmune disease with an unclear pathogenesis, and there is currently no approved drug for the treatment of this disease. Iguratimod, as a novel clinical anti-rheumatic drug in China and Japan, has shown remarkable efficacy in improving the symptoms of patients with pSS in clinical studies. In this study we investigated the mechanisms underlying the therapeutic effect of iguratimod in the treatment of pSS. Experimental Sjögren's syndrome (ESS) model was established in female mice by immunizing with salivary gland protein. After immunization, ESS mice were orally treated with iguratimod (10, 30, 100 mg·kg-1·d-1) or hydroxychloroquine (50 mg·kg-1·d-1) for 70 days. We showed that iguratimod administration dose-dependently increased saliva secretion, and ameliorated ESS development by predominantly inhibiting B cells activation and plasma cell differentiation. Iguratimod (30 and 100 mg·kg-1·d-1) was more effective than hydroxychloroquine (50 mg·kg-1·d-1). When the potential target of iguratimod was searched, we found that iguratimod bound to TEC kinase and promoted its degradation through the autophagy-lysosome pathway in BAFF-activated B cells, thereby directly inhibiting TEC-regulated B cells function, suggesting that the action mode of iguratimod on TEC was different from that of conventional kinase inhibitors. In addition, we found a crucial role of TEC overexpression in plasma cells of patients with pSS. Together, we demonstrate that iguratimod effectively ameliorates ESS via its unique suppression of TEC function, which will be helpful for its clinical application. Targeting TEC kinase, a new regulatory factor for B cells, may be a promising therapeutic option.

Efficacy and safety of Y-2 sublingual tablet for patients with acute ischaemic stroke: protocol of a phase III randomised double-blind placebo-controlled multicentre trial.

BACKGROUND AND PURPOSE: Clinical studies have demonstrated that edaravone dexborneol can improve the functional outcomes in patients with acute ischaemic stroke (AIS). The present clinical trial aimed at testing the efficacy and safety of Y-2 sublingual tablet on 90-day functional outcome in patients with AIS. METHODS AND DESIGN: This is a randomised, double-blind, placebo-controlled, multicentre, parallel-group trial of Y-2 sublingual tablet on patients with AIS.An estimated 914 patients at age of 18-80 years with AIS within 48 hours after symptom onset from 40 hospitals will be randomly assigned to receive Y-2 sublingual tablet or placebo for 14 days. Patients are at score 6-20 points on National Institutes of Health Stroke Scale (NIHSS) and had a modified Rankin Scale (mRS) ≤1 before this stroke, except mechanical thrombectomy and neuroprotective agents treatment. STUDY OUTCOMES: The primary outcome is the proportion of patients with mRS ≤1 on day 90 after randomisation. Secondary efficacy outcomes include mRS score on day 90, the proportion of patients with mRS ≤2 on day 90; the change of NIHSS score from baseline to day 14 and the proportion of patients with NIHSS score ≤1 at the days 14, 30 and 90. DISCUSSION: This trial will provide valuable evidence for the efficacy and safety of Y-2 sublingual table for improving 90 days the functional outcomes in patients with AIS. TRIAL REGISTRATION NUMBER: NCT04950920.

Sublingual Edaravone Dexborneol for the Treatment of Acute Ischemic Stroke: The TASTE-SL Randomized Clinical Trial.

Importance: Sublingual edaravone dexborneol, which can rapidly diffuse and be absorbed through the oral mucosa after sublingual exposure, is a multitarget brain cytoprotection composed of antioxidant and anti-inflammatory ingredients edaravone and dexborneol. Objective: To investigate the efficacy and safety of sublingual edaravone dexborneol on 90-day functional outcome in patients with acute ischemic stroke (AIS). Design, Setting, and Participants: This was a double-blind, placebo-controlled, multicenter, parallel-group, phase 3 randomized clinical trial conducted from June 28, 2021, to August 10, 2022, with 90-day follow-up. Participants were recruited from 33 centers in China. Patients randomly assigned to treatment groups were aged 18 to 80 years and had a National Institutes of Health Stroke Scale score between 6 and 20, a total motor deficit score of the upper and lower limbs of 2 or greater, a clinically diagnosed AIS symptom within 48 hours, and a modified Rankin Scale (mRS) score of 1 or less before stroke. Patients who did not meet the eligibility criteria or declined to participate were excluded. Intervention: Patients were assigned, in a 1:1 ratio, to receive sublingual edaravone dexborneol (edaravone, 30 mg; dexborneol, 6 mg) or placebo (edaravone, 0 mg; dexborneol, 60 µg) twice daily for 14 days and were followed up until 90 days. Main Outcomes and Measures: The primary efficacy outcome was the proportion of patients with mRS score of 1 or less on day 90 after randomization. Results: Of 956 patients, 42 were excluded. A total of 914 patients (median [IQR] age, 64.0 [56.0-70.0] years; 608 male [66.5%]) were randomly allocated to the edaravone dexborneol group (450 [49.2%]) or placebo group (464 [50.8%]). The edaravone dexborneol group showed a significantly higher proportion of patients experiencing good functional outcomes on day 90 after randomization compared with the placebo group (290 [64.4%] vs 254 [54.7%]; risk difference, 9.70%; 95% CI, 3.37%-16.03%; odds ratio, 1.50; 95% CI, 1.15-1.95, P = .003). The rate of adverse events was similar between the 2 groups (89.8% [405 of 450] vs 90.1% [418 of 464]). Conclusion and Relevance: Among patients with AIS within 48 hours, sublingual edaravone dexborneol could improve the proportion of those achieving a favorable functional outcome at 90 days compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04950920.

A novel form of docetaxel polymeric micelles demonstrates anti-tumor and ascites-inhibitory activities in animal models as monotherapy or in combination with anti-angiogenic agents.

Malignant ascites (MA) is caused by intraperitoneal spread of solid tumor cells and results in a poor quality of life. Chemotherapy is a common first-line treatment for patients with MA. Taxotere ® (DTX) is widely used in solid tumor therapies. However, the low water solubility and side effects caused by additives in the formulation restrict the clinical application of docetaxel. HT001 is a clinical stage docetaxel micelle developed to overcome the solubility issue with improved safety profiles. To support clinical development and expand clinical application of HT001, this study used in vitro and in vivo approaches to investigate the anti-tumor effects of HT001 when applied as monotherapy or in combination with anti-angiogenic agents. HT001 demonstrated comparable anti-proliferative activities as docetaxel in a broad range of cancer cell lines in vitro. Furthermore, HT001 suppressed tumor growth in a dose-dependent manner in A549, MCF-7, and SKOV-3 xenograft tumor mouse models in vivo. In a hepatocellular carcinoma H22 malignant ascites-bearing mouse model, HT001 presented a dose-dependent inhibition of ascites production, prolonged animal survival, and reduced VEGF levels. When dosed at 20 mg/kg, the HT001-treated group exhibited curative results, with no ascites formation in 80% of mice at the end of the study while all the mice in the vehicle control group succumbed. Similar results were obtained in HT001 treatment of mice bearing malignant ascites produced by human ovarian cancer ES-2 cells. Notably, the combination of HT001 with Endostar not only significantly reduced ascites production but also prolonged survival of H22 ascites-bearing mice. HT001 showed similar PK and tissue distribution profiles as DTX in non-rodent hosts. Collectively, these results demonstrate potent anti-tumor activity of HT001 in multiple solid tumor models or malignant ascites models, and reveal synergistic effects with anti-angiogenic agents, supporting the clinical development and clinical expansion plans for HT001.

A Novel 4H-SiC MESFET with a Heavily Doped Region, a Lightly Doped Region and an Insulated Region.

A novel 4H-SiC MESFET was presented, and its direct current (DC), alternating current (AC) characteristics and power added efficiency (PAE) were studied. The novel structure improves the saturation current (Idsat) and transconductance (gm) by adding a heavily doped region, reduces the gate-source capacitance (Cgs) by adding a lightly doped region and improves the breakdown voltage (Vb) by embedding an insulated region (Si3N4). Compared to the double-recessed (DR) structure, the saturation current, the transconductance, the breakdown voltage, the maximum oscillation frequency (fmax), the maximum power added efficiency and the maximum theoretical output power density (Pmax) of the novel structure is increased by 24%, 21%, 9%, 11%, 14% and 34%, respectively. Therefore, the novel structure has excellent performance and has a broader application prospect than the double recessed structure.

An Improved P-Type Doped Barrier Surface AlGaN/GaN High Electron Mobility Transistor with High Power-Added Efficiency.

An improved P-type doped barrier surface AlGaN/GaN high electron mobility transistor with high power-added efficiency (PDBS-HEMT) is proposed in this paper. Through the modelling and simulation of ISE-TCAD and ADS software, the influence of the P-type doped region on the performance parameters is studied, and the power-added efficiency (PAE) obtained and effectively improved is further verified. The drain saturation current and the threshold voltage of PDBS-HEMT has no major change compared with the traditional structure; the peak transconductance decreases slightly, but the breakdown voltage is significantly enhanced. Furthermore, the gate-source capacitance and gate-drain capacitance are reduced by 14.6% and 14.3%, respectively. By simulating the RF output characteristics of the device, the maximum oscillation frequency of the proposed structure is increased from 57 GHz to 63 GHz, and the saturated output power density is 10.9 W/mm, 9.3 W/mm and 6.4 W/mm at the frequency of 600 MHz, 1200 MHz and 2400 MHz, respectively. The highest PAE of 88.4% was obtained at 1200 MHz. The results show that the PDBS structure has an excellent power and efficiency output capability. Through the design of the P-type doped region, the DC and RF parameters and efficiency of the device are balanced, demonstrating the great potential of PDBS structure in high energy efficiency applications.

Cognitive impairment in the Tg6590 transgenic rat model of Alzheimer's disease.

Recently, interest in the rat as an animal model of Alzheimer's disease (AD) has been growing. We have previously described the Tg6590 transgenic rat line expressing the amyloid precursor protein containing the Swedish AD mutation (K670M/N671L) that shows early stages of Abeta deposition, predominantly in cerebrovascular blood vessels, after 15 months of age. Here we show that by the age of 9 months, that is long before the appearance of Abeta deposits, the Tg6590 rats exhibit deficits in the Morris water maze spatial navigation task and altered spontaneous behaviour in the open-field test. The levels of soluble Abeta were elevated both in the hippocampus and cortex of transgenic animals. Magnetic resonance imaging showed no major changes in the brains of transgenic animals, although they tended to have enlarged lateral ventricles when compared to control animals. The Tg6590 transgenic rat line should prove a suitable model of early AD for advanced studies including serial cerebrospinal fluid sampling, electrophysiology, neuroimaging or complex behavioural testing.

Improved MRD 4H-SiC MESFET with High Power Added Efficiency.

An improved multi-recessed double-recessed p-buffer layer 4H-SiC metal semiconductor field effect transistor (IMRD 4H-SiC MESFET) with high power added efficiency is proposed and studied by co-simulation of advanced design system (ADS) and technology computer aided design (TCAD) Sentaurus software in this paper. Based on multi-recessed double-recessed p-buffer layer 4H-SiC metal semiconductor field effect transistor (MRD 4H-SiC MESFET), the recessed area of MRD MESFET on both sides of the gate is optimized, the direct current (DC), radio frequency (RF) parameters and efficiency of the device is balanced, and the IMRD MESFET with a best power-added efficiency (PAE) is finally obtained. The results show that the PAE of the IMRD MESFET is 68.33%, which is 28.66% higher than the MRD MESFET, and DC and RF performance have not dropped significantly. Compared with the MRD MESFET, the IMRD MESFET has a broader prospect in the field of microwave radio frequency.

Novel High-Energy-Efficiency AlGaN/GaN HEMT with High Gate and Multi-Recessed Buffer.

A novel AlGaN/GaN high-electron-mobility transistor (HEMT) with a high gate and a multi-recessed buffer (HGMRB) for high-energy-efficiency applications is proposed, and the mechanism of the device is investigated using technology computer aided design (TCAD) Sentaurus and advanced design system (ADS) simulations. The gate of the new structure is 5 nm higher than the barrier layer, and the buffer layer has two recessed regions in the buffer layer. The TCAD simulation results show that the maximum drain saturation current and transconductance of the HGMRB HEMT decreases slightly, but the breakdown voltage increases by 16.7%, while the gate-to-source capacitance decreases by 17%. The new structure has a better gain than the conventional HEMT. In radio frequency (RF) simulation, the results show that the HGMRB HEMT has 90.8%, 89.3%, and 84.4% power-added efficiency (PAE) at 600 MHz, 1.2 GHz, and 2.4 GHz, respectively, which ensures a large output power density. Overall, the results show that the HGMRB HEMT is a better prospect for high energy efficiency than the conventional HEMT.

Improved DRUS 4H-SiC MESFET with High Power Added Efficiency.

A 4H-SiC metal semiconductor field effect transistor (MESFET) with layered doping and undoped space regions (LDUS-MESFET) is proposed and simulated by ADS and ISE-TCAD software in this paper. The structure (LDUS-MESFET) introduced layered doping under the lower gate of the channel, while optimizing the thickness of the undoped region. Compared with the double-recessed 4H-SiC MESFET with partly undoped space region (DRUS-MESFET), the power added efficiency of the LDUS-MESFET is increased by 85.8%, and the saturation current is increased by 27.4%. Although the breakdown voltage of the device has decreased, the decrease is within an acceptable range. Meanwhile, the LDUS-MESFET has a smaller gate-source capacitance and a large transconductance. Therefore, the LDUS-MESFET can better balance DC and AC characteristics and improve power added efficiency (PAE).

An Improved 4H-SiC MESFET with a Partially Low Doped Channel.

An improved 4H-SiC metal semiconductor field effect transistor (MESFET) based on the double-recessed MESFET (DR-MESFET) for high power added efficiency (PAE) is designed and simulated in this paper and its mechanism is explored by co-simulation of ADS and ISE-TCAD software. This structure has a partially low doped channel (PLDC) under the gate, which increases the PAE of the device by decreasing the absolute value of the threshold voltage (Vt), gate-source capacitance (Cgs) and saturation current (Id). The simulated results show that with the increase of H, the PAE of the device increases and then decreases when the value of NPLDC is low enough. The doping concentration and thickness of the PLDC are respectively optimized to be NPLDC = 1 × 1015 cm-3 and H = 0.15 µm to obtain the best PAE. The maximum PAE obtained from the PLDC-MESFET is 43.67%, while the PAE of the DR-MESFET is 23.43%; the optimized PAE is increased by 86.38%.

Extinction-induced "despair" in aged and adult rats: links to neurotrophins in frontal cortex and hippocampus.

In the search for animal models of human geriatric depression, we found that operant extinction of escape from water results in the expression of immobility in different age groups, indicative of behavioral "despair", which was also associated with the resistance-to-extinction (RTE) expressed by these animals. With respect to the neurotrophin hypothesis of depression, nerve-growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) protein levels in frontal cortex (FC) and hippocampus (HP) were examined and related to behavioral immobility and RTE in the water maze in aged and adult Wistar rats. Age-related increases in levels of NGF were found in HP and of NT-3 in FC. Indices of immobility showed relationships in the aged with NGF and, in adults, with BDNF, pointing to a dissociation of neurotrophic involvement in extinction trial-induced "despair" in aged and adult rats. The present results support the hypothesis, that extinction-induced immobility in the water maze reflects a state akin to behavioral despair and point to age-related differences of neurotrophic involvement in depressive-like symptoms. The concept of extinction-induced behavioral "despair" in the aged subsumes several aspects of human geriatric depression, such as co-morbidity of learning impairment and anxiety, and, thus could represent a useful paradigm to examine the neuronal mechanisms underlying depression, especially in aged rodents.

Gender differences in susceptibility to kainic acid-induced neurodegeneration in aged C57BL/6 mice.

Some epidemiological studies concerning gender differences in Alzheimer's disease (AD) support the higher prevalence and incidence of AD in women, while most studies using animal models of aging have included only male subjects. It is still uncommon for aged males and females to be compared in the same study. In the present study, we investigated how age and gender influence the excitotoxic neurodegeneration by treating C57BL/6 mice (aged females and males as well as adult females and males) with kainic acid (KA) intranasally. Clinical signs, behavioural changes, pathological changes and astrocyte proliferation were tested; and the levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were measured after KA treatment. The results showed that aged female mice were more sensitive to KA-induced excitotoxicity as demonstrated by severer seizure activity, increased locomotion and rearing in open-field test, prominent hippocampal neuronal damage, enhanced astrocyte proliferation compared with aged males, adult females and adult male mice. In addition, higher BDNF level in hippocampus of aged female mice was observed. These results denote the disparity of aging and gender in KA-induced hippocampal neurodegeneration and aged female mice are more sensitive to the excitotoxicity.

An Improved UU-MESFET with High Power Added Efficiency.

An improved ultrahigh upper gate 4H-SiC metal semiconductor field effect transistor (IUU-MESFET) is proposed in this paper. The structure is obtained by modifying the ultrahigh upper gate height h of the ultrahigh upper gate 4H-SiC metal semiconductor field effect transistor (UU-MESFET) structure, and the h is 0.1 µm and 0.2 µm for the IUU-MESFET and UU-MESFET, respectively. Compared with the UU-MESFET, the IUU-MESFET structure has a greater threshold voltage and trans-conductance, and smaller breakdown voltage and saturation drain current, and when the ultrahigh upper gate height h is 0.1 µm, the relationship between these parameters is balanced, so as to solve the contradictory relationship that these parameters cannot be improved simultaneously. Therefore, the power added efficiency (PAE) of the IUU-MESFET structure is increased from 60.16% to 70.99% compared with the UU-MESFET, and advanced by 18%.

Neurotrophin levels and behaviour in BALB/c mice: impact of intermittent exposure to individual housing and wheel running.

This study assessed the effects of intermittent individual housing on behaviour and brain neurotrophins, and whether physical exercise could influence alternate individual-housing-induced effects. Five-week-old BALB/c mice were either housed in enhanced social (E) or standard social (S) housing conditions for 2 weeks. Thereafter they were divided into six groups and for 6 weeks remained in the following experimental conditions: Control groups remained in their respective housing conditions (E-control, S-control); enhanced individual (E-individual) and standard individual (S-individual) groups were exposed every other day to individual cages without running-wheels; enhanced running-wheel (E-wheel) and standard running-wheel (S-wheel) groups were put on alternate days in individual running-wheel cages. Animals were assessed for activity in an automated individual cage system (LABORAS) and brain neurotrophins analysed. Intermittent individual housing increased behavioural activity and reduced nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) levels in frontal cortex; while it increased BDNF level in the amygdala and BDNF protein and mRNA in hippocampus. Besides normalizing motor activity and regulating BDNF and NGF levels in hippocampus, amygdala and cerebellum, physical exercise did not attenuate reduction of cortical NGF and BDNF induced by intermittent individual housing. This study demonstrates that alternate individual housing has significant impact on behaviour and brain neurotrophin levels in mice, which can be partially altered by voluntary physical exercise. Our results also suggest that some changes in neurotrophin levels induced by intermittent individual housing are not similar to those caused by continuous individual housing.

Influence of differential housing on emotional behaviour and neurotrophin levels in mice.

Environmental enrichment condition (EC) induces profound behavioural, neurochemical and neuroanatomical changes. Increasing evidence has shown that the hippocampus, which is implicated in a range of cognitive functions, including learning and memory, is one of the most susceptible brain areas to the effects of enriched rearing. Recent work also suggests that the hippocampus is functionally segregated; lesion studies have shown that the dorsal hippocampus is important for spatial learning, whereas the ventral part is critical in emotional behaviour in rats. We investigated the effects of differential housing environments on anxiety-related behaviour and neurotrophin levels in dorsal and ventral hippocampus, and other brain regions. Ninety-six male and female C57BL/6 mice were reared in EC or standard housing condition (SC) for 4 months after weaning. Thereafter sixty-four animals were tested in the elevated plus-maze, open-field, novel-objects exploration and food neophobia. Thirty-two animals remained as untested. Subsequently, brain nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were analysed in selected brain regions of the tested and non-tested animals. Differential housing influenced anxiety-related behaviour in the plus-maze and brain neurotrophins. Baseline levels of BDNF and NGF protein were differently distributed in dorsal and ventral parts of hippocampus in both male and female mice, with levels in the dorsal hippocampal being consistently higher than those in ventral hippocampus. Exposure to behavioural testing induced complex changes on neurotrophin levels in selected brain regions. This study demonstrates for the first time the differential distribution of normal levels of neurotrophin protein in dorsal and ventral hippocampus in mice, and these levels can be affected by environmental enrichment and have an impact on emotional behaviour.

CXCL1 Triggers Caspase-3 Dependent Tau Cleavage in Long-Term Neuronal Cultures and in the Hippocampus of Aged Mice: Implications in Alzheimer's Disease.

Truncation of tau protein is considered an early event in Alzheimer's disease (AD) and is believed to play a major pathogenic role in sporadic AD. However, causative factors that trigger tau truncation in AD remain poorly understood. In the present study, we demonstrate that CXCL1 (C-X-C motif ligand 1), a specific ligand for the chemokine receptor CXCR2, induced cleavage of tau at ASP421 in a caspase-3-dependent manner in long-term but not short-term cultured neurons. The cleaved tau formed varicosities or bead-like structures along the neurites, an abnormal distribution of tau induced by CXCL1 that has not been observed previously. CXCL1-induced activation of GSK3ß and the subsequent phosphorylation of tau preceded and were required for caspase-3 activation and tau cleavage. Moreover, intrahippocampal microinjection of lentiviral CXCL1 induced tau cleavage in hippocampal neurons in aged (15-18 months of age) but not adult mice (5-10 months of age). Our data highlight a new role of CXCR2 in tau cleavage and suggest that targeting CXCR2 may offer therapeutic benefits to patients with AD and potentially other tauopathies.

Neutralizing antibodies to IL-18 ameliorate experimental autoimmune neuritis by counter-regulation of autoreactive Th1 responses to peripheral myelin antigen.

Experimental autoimmune neuritis (EAN) is a demyelinating disease of the peripheral nervous system (PNS). This acute inflammatory disease is mediated by CD4+ T cells and bears significant similarities to the Guillain-Barré syndrome of humans. In the present study, we investigated the function of IL-18 in T cell-mediated autoimmunity of EAN in mice induced by P0 peptide 180-199 and Freund's complete adjuvant. Our data indicate that in 2 different therapeutic regimens, anti-IL-18 monoclonal antibody (mAb) effectively ameliorates the clinical and pathological signs of EAN. The suppression is associated with reduced inflammatory cell infiltration into the PNS and an insufficiency of autoreactive Th1 cells, as reflected by a reduced mononuclear cell proliferation and IFN-gamma-secretion in the spleen. Increased numbers of IL-4 expressing cells and decreased numbers of IFN-gamma and TNF-alpha expressing cells were found in the PNS. Our results suggest that shifting the Th1/Th2 balance towards Th2 cells may be one mechanism underlying EAN suppression by anti-IL-18 mAb. In addition, anti-IL-18 mAb treatment reduced anti-P0 peptide 180-199 autoantibody responses, which may also contribute to EAN suppression. We conclude that endogenous IL-18 plays a critical role in the pathogenesis of autoimmune demyelinating disease of the PNS and that IL-18 antagonists may provide a new therapy for these diseases.

Increased susceptibility to experimental autoimmune neuritis after upregulation of the autoreactive T cell response to peripheral myelin antigen in apolipoprotein E-deficient mice.

Experimental autoimmune neuritis (EAN), an acute demyelinating inflammatory disease of the peripheral nervous system (PNS), is a good model for the human counterpart, Guillain-Barré syndrome. Apolipoprotein E (ApoE), a 34 kDa glycosylated protein with multiple biological properties, has been linked both with the innate immune response of mice and with neurological disease. The present study investigated the previously unexplored role of ApoE in autoimmune-mediated demyelination. ApoE-deficient (apoE -/-) mice exhibited a greater susceptibility to EAN induced by the PNS myelin P0 protein peptide 180-199, as compared to wild type (apoE +/+) mice. The augmented susceptibility seen in apoE -/- mice was associated with increased inflammatory cell infiltrates in the PNS during the effector phase. Although the 2 groups of mice exhibited no quantitative or proportional differences in splenic lymphocyte populations, the apoE -/- mice showed enhanced antigen-specific proliferation of T cells of spleen, which is related to modified macrophage function, upregulation of Th1 and downregulation of Th2-autoreactive responses to P0 peptide. These effects were shown as increased numbers of IFN-gamma expressing cells in the spleen and of IFN-gamma, IL-12 and TNF-alpha expressing cells in the PNS, as well as a decreased IL-10 production by splenic cells in apoE -/- mice. In addition, apoE -/- mice had enhanced antigen-specific antibody responses, which might have contributed to their aggravated EAN. These data provide strong evidence that apoE acts as an inhibitor of this inflammatory and demyelinating disease by upregulating IL-10, as well as by inhibiting Th1 responses and antigen-specific antibody formation. These data may aid the development of new and more effective therapeutic strategies for inflammatory and demyelinating diseases such as Guillain-Barré syndrome.

Reduced susceptibility to kainic acid-induced excitoxicity in T-cell deficient CD4/CD8(-/-) and middle-aged C57BL/6 mice.

Kainic acid (KA)-induced hippocampal injury is a good model for studying human neurodegenerative diseases. To investigate the roles of immune cells and age related changes in neurodegeneration, we used this model to assess reactions in young and middle-aged wild-type and CD4/CD8(-/-) mice by intranasal administration of KA. We found that CD4/CD8-deficiency resulted in a significant reduction of the severity of clinical signs and pathological changes in KA-treated young, but not in KA-treated middle-aged mice. Middle-aged wild-type mice had a similar reaction to KA insult as young and middle-aged CD4/CD8(-/-) mice. CD4/CD8(-/-) mice exhibited decreased locomotor and rearing activities as they approached to middle-aged state, which was not seen in wild-type mice. In addition, CD4/CD8-deficiency and increased age prevented KA-induced increase of both locomotor and rearing activities. The results suggest that a decline of immunological function is associated with aging, and both of them may contribute to the relative resistance to KA-induced neurotoxicity.