Ginsenoside Rd attenuates mouse experimental autoimmune neuritis by modulating monocyte subsets conversion.

Guillain-Barré Syndrome (GBS), characterized by peripheral nerve demyelination and axonal damage, is initiated and aggravated through various of immunopathogenesis. Ginsenoside Rd, main active components extracted from ginseng saponins, is known to exhibit immune-regulate functions in many immune-mediated diseases. However, the evidence of preventive effect of Ginsenoside Rd on GBS is lacking. Experimental autoimmune neuritis (EAN) mice, classic model of GBS, were established and treated with GSRd or vehicle. Clinical score and nerve tissue histomorphology were evaluated. Monocytes in peripheral blood and tissue were detected by flow cytometry analysis and immunofluorescence staining. For the in vitro study, GSRd and vehicle were added in the culture medium to assess their regulatory function on monocytes phenotype. In vivo data showed a protective role of GSRd on alleviating symptoms and tissue damage on Day 20 and 25. Administration of GSRd increased non-classical Ly6Clo monocytes in both peripheral blood and injured nerve tissue, and also switched tissue macrophages phenotype into resolution-phase. In vitro study indicated similar role of GSRd on monocytes differentiation status. Transcription factors like Nr4a1 were elevated after GSRd treatment. These findings revealed the protective role of GSRd against EAN, and potential preventive function on GBS patients.

Parthenolide inhibits the initiation of experimental autoimmune neuritis.

A growing body of evidence suggests the anti-inflammatory and antitumor effects of parthenolide (PAR). Here we show that PAR treatment inhibits the initiation of experimental autoimmune neuritis (EAN), suppresses the production of TNF-α, IFN-γ, IL-1ß and IL-17, and decreases Th1 and Th17 cells at early time point. However, such anti-inflammatory effect vanishes later and PAR impedes the recovery of EAN in late phase, which is accompanied with inhibited apoptosis of inflammatory cells. Our results indicate that PAR plays dual roles in EAN and it is not proper to be applied in autoimmune diseases of nervous system.

4-Aminopyridine ameliorates experimental autoimmune neuritis in Lewis rats.

We investigated the effect of 4-aminopyridine (4-AP) on experimental autoimmune neuritis (EAN) using a 4-AP-treated group in which 4-AP was administered in the diet, and a control group (n=10 per group). Electrophysiological and pathological assessment was performed in the sciatic nerve. The EAN clinical scores were significantly lower in the 4-AP-treated group than in the control group (p<0.05). The motor conductance velocity two weeks post-immunization was significantly higher in the 4-AP-treated group (p<0.05). Finally, 4-AP did not lead to pathological changes. Thus, 4-AP might be a potential therapeutic agent in demyelinating neuropathy.

Intravenous immunoglobulin preparation attenuates neurological signs in rat experimental autoimmune neuritis with the suppression of macrophage inflammatory protein -1α expression.

To clarify the mechanism of action of an intravenous immunoglobulin (IVIG) preparation in chronic inflammatory demyelinating polyneuropathy, the effects of IVIG were investigated using an experimental autoimmune neuropathy model in the rat. IVIG significantly suppressed the progression of neurologic signs and sciatic nerve conduction velocity with the inhibition of inflammatory cell infiltration, mainly of macrophages, to the peripheral nerves. A significant suppressive effect on the expression of macrophage inflammatory protein 1-α (MIP-1α) was simultaneously observed in the nerves. These results suggest that IVIG is effective for inflammatory demyelinating polyneuropathy by inhibiting the chemotactic factor of macrophages.

Atorvastatin ameliorates experimental autoimmune neuritis by decreased Th1/Th17 cytokines and up-regulated T regulatory cells.

Statins have anti-inflammatory and immune-regulating properties. To investigate the effects of atorvastatin on experimental autoimmune neuritis (EAN), an animal model of Guillain-Barré syndrome (GBS), atorvastatin was administered to Lewis rats immunized with bovine peripheral myelin in complete Freund's adjuvant. We found that atorvastatin ameliorated the clinical symptoms of EAN, decreased the numbers of inflammatory cells as well as IFN-γ(+) and IL-17(+) cells in sciatic nerves, decreased the CD80 expression and increased the number of CD25(+)Foxp3(+) cells in mononuclear cells (MNC), and decreased the levels of IFN-γ in MNC culture supernatants. These data provide strong evidence that atorvastatin can act as an inhibitor in EAN by inhibiting the immune response of Th1 and Th17, decreasing the expression of co-stimulatory molecule, and up-regulating the number of T regulatory cells. These data demonstrated that statins could be used as a therapeutic strategy in human GBS in future.

MS-275, an histone deacetylase inhibitor, reduces the inflammatory reaction in rat experimental autoimmune neuritis.

Experimental autoimmune neuritis (EAN) is a T cell-mediated autoimmune inflammatory demyelinating disease of the peripheral nervous system and serves as the animal model of human inflammatory demyelinating polyradiculoneuropathies. MS-275, a potent histone deacetylase inhibitor currently undergoing clinical investigations for various malignancies, has been reported to demonstrate promising anti-inflammatory activities. In our present study, MS-275 administration (3.5 mg/kg i.p.) to EAN rats once daily from the appearance of first neurological signs greatly reduced the severity and duration of EAN and attenuated local accumulation of macrophages, T cells and B cells, and demyelination of sciatic nerves. Further, significant reduction of mRNA levels of pro-inflammatory interleukin-1beta, interferon-gamma, interleukine-17, inducible nitric oxide synthase and matrix metalloproteinase-9 was observed in sciatic nerves of MS-275 treated EAN rats. In lymph nodes, MS-275 depressed pro-inflammatory cytokines as well, but increased expression of anti-inflammatory cytokine interleukine-10 and of foxhead box protein3 (Foxp3), a unique transcription factor of regulatory T cells. In addition, MS-275 treatment increased proportion of infiltrated Foxp3(+) cells and anti-inflammatory M2 macrophages in sciatic nerves of EAN rats. In summary, our data demonstrated that MS-275 could effectively suppress inflammation in EAN, through suppressing inflammatory T cells, macrophages and cytokines, and inducing anti-inflammatory immune cells and molecules, suggesting MS-275 as a potent candidate for treatment of autoimmune neuropathies.

Administration of dehydroepiandrosterone ameliorates experimental autoimmune neuritis in Lewis rats.

Dehydroepiandrosterone (DHEA) is an abundant adrenal steroid in serum of humans, and has been reported to have anti-inflammatory, anti-proliferative, and certain immune-regulating properties. Experimental autoimmune neuritis (EAN) is a Th1 cell-mediated animal model of Guillain-Barré syndrome (GBS) in humans. In the present study, DHEA was administered subcutaneously to Lewis rats immunized with bovine peripheral myelin (BPM) in Freund's complete adjuvant. Rats treated with DHEA displayed significant delay in onset, decreased inflammatory cell infiltration in the PNS. Benefit was associated with significant decreases in numbers of IFN-gamma and TNF-alpha expressing cells in the PNS, BPM-stimulated T cell proliferation and IFN-gamma, TNF-alpha-secretion in the spleen cells. Only 2 mg DHEA-treated EAN rats decreased peak clinical score. No significant difference of supernatant IL-10 was found among the treatment and control groups. These results suggest that DHEA can ameliorate the severity of EAN by suppressing the proliferation of autoreactive T cell and expression of pro-inflammatory cytokines.

[Effect of dehydroepiandrosterone on cellular immune response in experimental autoimmune neuritis in Lewis rats].

AIM: To explore the effect of dehydroepiandrosterone (DHEA) on cellular immune response in experimental autoimmune neuritis (EAN). METHODS: 21 female Lewis rats were randomly divided into DHEA 0.5 mg treatment groups, 2 mg treatment groups and control group ( n=7). Treatment groups were subcutaneously injected every day with DHEA and the control group with the same level of DHEA dissolvent from day 5 post immunization (p.i) with bovine peripheral myelin (BPM) in Freund's complete adjuvant (CFA). The effects were assessed in terms of of the number of IFN-gamma, TNF-alpha positive cells in sciatic nerve sections, T-cell proliferation and inflammatory cytokines (IFN-gamma, TNF-alpha and IL-10) synthesis by draining lymph node and spleen cells at the height of clinical EAN. RESULTS: Rats treated with DHEA at different doses displayed significant decreases in numbers of IFN-gamma, TNF-alpha expressing cells in the PNS (P<0.05), BPM-stimulated T cell proliferation (P<0.05), IFN-gamma, TNF-alpha secretion in draining lymph node and spleen (P<0.05) compared to control group. No significant difference of supernatant IL-10 was found among the different groups (P<0.05). CONCLUSION: Administration with exogenous DHEA inhabits cellular immune response by suppressing the proliferation of autoreactive T-cell and production of pro-inflammatory cytokines in Lewis rats with EAN.

The effect of cyclooxygenase-2 inhibitor on experimental allergic neuritis.

We studied the effect of the cyclooxygenase (COX)-2 inhibitor nimesulide on experimental allergic neuritis (EAN). In rats fed with nimesulide starting on day 1 post inoculation, the clinical EAN score was significantly lower and the maximal clinical score was reduced compared with the control group. Even if given after the onset of clinical signs, the clinical score was reduced and improvement was faster than the control group. Nimesulide inhibited decreases in weight in the experimental group. The histopathological observations of the sciatic nerve showed a decreased incidence of degenerated nerve fibers in the experimental group. Although the exact mechanism of its efficacy is not clear, a COX-2 inhibitor may have potential as an additional therapeutic agent in human inflammatory neuropathies.

[Effects of T4 monomer of Tripterygium wilfordii and artificial musk on experimental allergic neuritis].

UNLABELLED: Both T4 monomer of Tripterygium wilfordii and artificial musk had effects in regulating immune system and anti-inflammation. The effect of using artificial musk was the earlier the stronger. According to pharmacological features of the two drugs and pathogenesis of experimental allergic neuritis (EAN), 5 experimental groups were established, i.e., artificial musk prevented and treated groups, dexamethasone and T4 monomer treated groups, and control group. RESULTS: T4 monomer could reduce the clinical score of model rabbits of EAN and significantly ameliorated inflammatory cell infiltration and demyelination. It was similar to dexamethasone. Although artificial musk had mild preventing and treating effects on the clinical and pathological changes of EAN, but was not statistically significant in comparing with control group. Our clinical or pathological data suggested that T4 monomer and dexamethasone were effective in the treatment of EAN, and that of artificial musk in preventing and treating EAN as indefinite.

Treatment of experimental allergic neuritis with nedocromil sodium.

Peripheral nervous system mast cells degranulate early in the development of experimental allergic neuritis (EAN). This degranulation is associated with the release of vasoactive amines, chemoattractants and myelinolytic proteases which could provide a focus for inflammatory demyelination. To further assess the importance of mast cell degranulation in the development of EAN, we have treated Lewis rats inoculated with peripheral nervous system myelin and complete Freund's adjuvant, with nedocromil sodium, an anti-inflammatory drug with mast cell stabilizing properties. Treatment with nedocromil sodium (100-150 mg/kg), 3 times daily, starting on day 7 post-inoculation, significantly decreases the incidence and the severity of the disease. Histological examination of sciatic nerves confirms the absence of subclinical disease in successfully treated animals. The possible mode of action of the drug is discussed.