Xanthotoxin modulates oxidative stress, inflammation, and MAPK signaling in a rotenone-induced Parkinson's disease model.

AIMS: Parkinson's disease (PD) is characterized by motor disabilities precipitated by α-synuclein aggregation and dopaminergic neurodegeneration. The roles of oxidative stress, neuroinflammation, dysfunction of the mitogen-activated protein kinase (MAPK) pathway, and apoptosis in dopaminergic neurodegeneration have been established. We investigated the potential neuroprotective effect of xanthotoxin, a furanocoumarin extracted from family Apiaceae, in a rotenone-induced PD model in rats since it has not yet been elucidated. MAIN METHODS: For 21 days, rats received 11 rotenone injections (1.5 mg/kg, s.c.) on the corresponding days to induce a PD model and xanthotoxin (15 mg/kg, i.p.) daily. KEY FINDINGS: Xanthotoxin preserved dopaminergic neurons and restored tyrosine hydroxylase positive cells, with suppression of α-synuclein accumulation and restoration of striatal levels of dopamine and its metabolites resulting in amelioration of motor deficits. Furthermore, xanthotoxin impeded rotenone-stimulated neurodegeneration by reducing oxidative stress, which was confirmed by malondialdehyde suppression and glutathione antioxidant enzyme augmentation. It also suppressed neurotoxic inflammatory mediators including tumor necrosis factor-α, interleukin-1ß, and inducible nitric oxide synthase. Additionally, xanthotoxin attenuated the rotenone-mediated activation of MAPK kinases, C-Jun N-terminal kinase, p38 MAPK, and extracellular signal-regulated kinases 1/2, with consequent ablation of apoptotic mediators including Bax, cytochrome c, and caspase-3. SIGNIFICANCE: This study revealed the neuroprotective effect of xanthotoxin in a rotenone-induced PD model in rats, an action that could be attributed to its antioxidant, anti-inflammatory activities as well as to its ability to maintain the function of the MAPK signaling pathway and attenuate apoptosis. Therefore, it could be a valuable therapy for PD.

Protective effect of methylene blue on TNBS-induced colitis in rats mediated through the modulation of inflammatory and apoptotic signalling pathways.

Ulcerative colitis (UC) is a common type of chronic, idiopathic inflammatory bowel disease (IBD) that affects the mucosal lining of the colon. Long-term UC remission has shed light on the necessity of modified therapeutic strategies. In this study, UC was induced in rats by intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS). The anticolitis effect of methylene blue (MB), a well-known dye and antioxidant and a potent mitochondrial enhancer was tested. MB was injected intraperitoneally (i.p.) at a dose of 1 mg/kg, 2 mg/kg or 4 mg/kg, and colosalazine was administered orally (p.o.) at a dose of 500 mg/kg 11 days after the administration of TNBS, which was injected on the 8th day. All treatment group results were compared to the TNBS group results. Macroscopically, limited body weight loss and decrease in the colon weight per unit length ratio were observed in the MB groups. MB improved histological damage and decreased the expression of myeloperoxidase (MPO) and accumulation of CD4+ lymphocytes observed by immunohistochemistry. Downregulation of Bax/Bcl2 protein expression was detected using Western blotting, and increased mRNA expression of nuclear factor erythroid 2-related factor 2 (Nrf2) was measured by qPCR. MB produced biochemical alterations, such as significant decrease in interleukin-6 (IL-6), interleukin-17 (IL-17) and intercellular adhesion molecule-1 (ICAM-1) levels measured by enzyme-linked immunosorbent assay (ELISA). Significant decrease in malondialdehyde (MDA) and inducible nitric oxide synthase (iNOS) levels as well as significant increase in superoxide dismutase (SOD) and mitochondrial cytochrome c oxidase levels were observed with MB, and these effects were similar to those produced by colosalazine. Thus, MB altered disease pathogenesis and could be a promising and challenging therapeutic target for UC treatment.