monomethyl-fumarate and Disease-Models--Animal

Research has connected Parkinson's disease (PD) with impaired intestinal barrier. The activation of G-protein-coupled receptor 109A (GPR109A) protects the intestinal barrier by inhibiting the NF-κB signaling pathway. Sodium butyrate (NaB), which is a GPR109A ligand, may have anti-PD effects. The current study's objective is to demonstrate that NaB or monomethyl fumarate (MMF, an agonist of the GPR109A) can treat PD mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) via repairing the intestinal barrier. Male C57BL/6J mice were divided into four groups randomly: control, MPTP + vehicle, MPTP + NaB, and MPTP + MMF. Modeling mice received MPTP (20 mg/kg/day, i.p.) for a week, while control mice received sterile PBS. Then, four groups each received two weeks of sterile PBS (10 mL/kg/day, i.g.), sterile PBS (10 mL/kg/day, i.g.), NaB (600 mg/kg/day, i.g.), or MMF (100 mg/kg/day, i.g.). We assessed the expression of tight junction (TJ) proteins (occludin and claudin-1), GPR109A, and p65 in the colon, performed microscopic examination via HE staining, quantified markers of intestinal permeability and proinflammatory cytokines in serum, and evaluated motor symptoms and pathological changes in the substantia nigra (SN) or striatum. According to our results, MPTP-induced defected motor function, decreased dopamine and 5-hydroxytryptamine levels in the striatum, decreased tyrosine hydroxylase-positive neurons and increased activated microglia in the SN, and systemic inflammation were ameliorated by NaB or MMF treatment. Additionally, the ruined intestinal barrier was also rebuilt and NF-κB was suppressed after the treatment, with higher levels of TJ proteins, GPR109A, and decreased intestinal permeability. These results show that NaB or MMF can remedy motor symptoms and pathological alterations in PD mice by restoring the intestinal barrier with activated GPR109A. We demonstrate the potential for repairing the compromised intestinal barrier and activating GPR109A as promising treatments for PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Butyric Acid; Claudin-1; Cytokines; Disease Models, Animal; Dopamine; Fumarates; Ligands; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; NF-kappa B; Occludin; Parkinson Disease; Receptors, G-Protein-Coupled; Serotonin; Tyrosine 3-Monooxygenase

Macrophage activation syndrome (MAS) is characterized by increased serum levels of ferritin and heme oxygenase 1 (HO-1), and yet no known function is ascribed to these molecules in MAS. Because HO-1 is antiinflammatory, we hypothesized that pharmacologic activation of HO-1 could ameliorate MAS disease activity. Dimethyl fumarate (DMF), a treatment approved by the US Food and Drug Administration for multiple sclerosis, activates HO-1. Monomethyl fumarate (MMF) is the active metabolite of DMF. We therefore evaluated whether MMF could elicit HO-1-dependent therapeutic improvements in a murine model of MAS.. We induced MAS by repeated activation of Toll-like receptor 9 (TLR-9) in wild-type and myeloid-specific HO-1-deficient mice. MMF was administered twice daily to test its efficacy. We assessed organ weights, serum cytokine levels, histologic features of the spleen and liver tissue, and complete blood cell counts to evaluate disease activity. Statistical testing was performed using Student's t-test or by 2-way analysis of variance as appropriate.. The presence of HO-1 was required for the majority of TLR-9-induced interleukin-10 (IL-10). IL-10 production in TLR-9-induced MAS was found to correlate with the myeloid-HO-1 gene dose in myeloid cells (P < 0.001). MMF treatment increased the levels of HO-1 in splenic macrophages by ~2-fold (P < 0.01), increased serum levels of IL-10 in an HO-1-dependent manner in mice with TLR-9-induced MAS (P < 0.005), and improved multiple disease parameters in both an HO-1-dependent and HO-1-independent manner.. TLR-9-induced production of IL-10 is regulated by HO-1 activity both in vitro and in vivo. Therapeutic enhancement of the HO-1/IL-10 axis in a murine model was able to significantly ameliorate MAS disease activity. These results suggest that HO-1 may be viable as a MAS therapeutic target, and treatment with DMF and MMF should be considered in future investigations of MAS therapy.

Topics: Animals; Cytokines; Disease Models, Animal; Fumarates; Heme Oxygenase-1; Interleukin-10; Liver; Macrophage Activation Syndrome; Macrophages; Membrane Proteins; Mice; Mice, Knockout; Oligodeoxyribonucleotides; Organ Size; Spleen; Toll-Like Receptor 9

Monomethyl fumarate (MF) exerts anti-inflammatory and antioxidant capacities. Whether microRNA-139 and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) are involved in the pharmacological activity of MF remain unclear. We aim to elucidate the potential function of MF in intracerebral hemorrhage (ICH), and its possible mechanism.. Twenty-four Sprague Dawley (SD) rats were randomly assigned into sham group, ICH group and MF group, with 8 rats in each group. Rats in ICH and MF group were subjected to ICH procedures. Rat brain tissues were harvested at 48 h after ICH procedures. Evans blue extravasation was performed to evaluate ICH-induced rat brain damage. Content of cerebral edema and neurological deficit were examined to reflect the neuronal pathological lesions. Reactive oxygen species (ROS) content in rat brain was examined by immunofluorescence. Activities of oxidative stress indexes in rat brain homogenate were detected using relative commercial kits. MicroRNA-139 expression in rat brain was quantified by quantitative Real-time polymerase chain reaction (qRT-PCR). Finally, protein levels of Nrf2, HO-1, NQO1 and nuclear factor-kappa B (NF-κB) in rat brain tissues were examined by Western blot.. Compared with rats in sham group, neurological deficit scores of rats in ICH group were lower. Disruption of blood-brain barrier and brain tissue edema of rats were pronounced in ICH group. However, MF pretreatment markedly alleviated the above mentioned cerebral lesions. In addition, MF pretreatment increased activities of SOD, GSH and CAT, but decreased MDA and ROS contents in rat brain homogenate relative to those in ICH group (p<0.05). Western blot analysis found that expression levels of Nrf2, HO-1 and NQO-1 were markedly upregulated after MF pretreatment, while the expression level of NF-κB was downregulated. At the cellular level, we altered microRNA-139 expression in SH-SY5Y cells by transfection of microRNA-139 mimics or inhibitor. Overexpression of microRNA-139 remarkably increased Nrf2 expression and decreased NF-κB expression. Treatment of high-dose MF upregulated Nrf2, downregulated NF-κB and decreased ROS content in SH-SY5Y cells.. MF protects ICH in rats by inhibiting oxidative stress and inflammatory response through activating microRNA-139/Nrf2 axis.

Topics: Animals; Anti-Inflammatory Agents; Brain; Cell Line, Tumor; Cerebral Hemorrhage; Disease Models, Animal; Fumarates; Humans; MicroRNAs; Neurons; NF-E2-Related Factor 2; Oxidative Stress; Rats; Signal Transduction