Tofacitinib enhances remyelination and improves myelin integrity in cuprizone-induced mice.

AIM: Demyelination and subsequent remyelination are well-known mechanisms in multiple sclerosis (MS) pathology. Current research mainly focused on preventing demyelination or regulating the peripheral immune system to protect further damage to the central nervous system. However, information about another essential mechanism, remyelination, and its balance of the immune response within the central nervous system's boundaries is still limited. MATERIALS AND METHODS: In this study, we tried to demonstrate the effect of the recently introduced Janus kinase (JAK)-signal transducer and activator of transcription (STAT) inhibitor, tofacitinib, on remyelination.Demyelination was induced by 6-week cuprizone administration, followed by 2-week tofacitinib (10, 30, and 100 mg/kg) treatment. RESULTS: At the functional level, tofacitinib improved cuprizone-induced decline in motor coordination and muscle strength, which were assessed by rotarod and hanging wire tests. Tofacitinib also showed anti-inflammatory effect by alleviating the cuprizone-induced increase in the central levels of interferon-γ (IFN-γ), interleukin (IL)-6, IL-1ß, and tumor necrosis alpha (TNF-α). Furthermore, tofacitinib also suppressed the cuprizone-induced increase in matrix metalloproteinases (MMP)-9 and MMP-2 levels. Additionally, cuprizone-induced loss of myelin integrity and myelin basic protein expression was inhibited by tofacitinib. At the molecular level, we also assessed phosphorylation of STAT-3 and STAT-5, and our data indicates tofacitinib suppressed cuprizone-induced phosphorylation in those proteins. CONCLUSION: Our study highlights JAK/STAT inhibition provides beneficial effects on remyelination via inhibition of inflammatory cascade.

SAHA attenuates rotenone-induced toxicity in primary microglia and HT-22 cells.

Rotenone is an industrial and environmental toxicant that has been strongly associated with neurodegeneration. It is clear that rotenone induces inflammatory and oxidative stress; however, information on the role of histone acetylation in neurotoxicity is limited. Epigenetic alterations, neuroinflammation, and oxidative stress play a role in the progression of neurodegeneration and can be caused by exposure to environmental chemicals, such as rotenone. Histone modifications, such as methylation and acetylation, play an important role in mediating epigenetic changes. Therefore, we here investigated the effects of histone acetylation on rotenone-induced inflammation and oxidative stress in both primary mouse microglia and hippocampal HT-22 cells using the pan-histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA). Our results showed that SAHA suppressed the inflammatory response by decreasing nuclear factor kappa B and inducible nitric oxide synthase expression. Additionally, SAHA inhibited the rotenone-induced elevation of interleukin 6 and tumor necrosis factor α levels in both cell lines. Furthermore, SAHA improved the rotenone-induced antioxidant status by mitigating the decrease in cellular glutathione levels. Additionally, SAHA prevented the rotenone-induced increase in the HDAC activity in microglial and hippocampal HT-22 cells. Together, our results showed that SAHA reduced rotenone-induced inflammatory and oxidative stress, suggesting a role for histone deacetylation in environmental-related neurotoxicity.

Effects of agomelatine in rotenone-induced Parkinson's disease in rats.

The effects of melatonin and melatonin analogs in experimental Parkinson's disease (PD) models remain controversial. Agomelatine, a novel analog of melatonin, is both agonists for melatonin-1 and melatonin-2 receptors and antagonist of 5-HT2C receptors. While agomelatine has been commonly used as an anti-depressant and sleep drug, information about effects of agomelatine in PD are still lacking. Male Sprague-Dawley rats (220-260 g) were injected with rotenone (0.5 µg, n = 16) or vehicle (1 µl DMSO, n = 8) into the left substantia nigra (SN) and ventral tegmental area under stereotaxic surgery. After ten days, the rats were assessed for the confirmation of PD by the rotational test following apomorphine injection (2 mg/kg, i.p.). The confirmed rats were divided into two groups which received daily p.o. agomelatine (40 mg/kg, n = 8) or saline (2 ml/rat, n = 8) for consecutively 18 days. Twenty-four hours after the last drug administration, the rotational test was repeated and motor coordination was assesed just before the decapitation. Brain tissues were taken for biochemical, molecular and histopathological evaluations. Agomelatine treated animals showed augmented apomorphine-induced rotation response and impaired motor coordination compared to the rotenone group. Furthermore, agomelatine treatment significantly induced apoptosis with an increase in caspase-3 expression independent from PARP-1 activation. Agomelatine treatment caused increased protein oxidation levels, in addition to a decrease in neuron number in the striatum. Although we investigated the effects of the agomelatine in the manner of ameliorating the rotenone toxicity in animals, agomelatine exacerbates rotenone-induced toxicity which mimics Parkinson's disease pathology.

Effects of Nonsteroidal Anti-Inflammatory Drugs at the Molecular Level.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for their anti-inflammatory, analgesic, and antipyretic effects. NSAIDs generally work by blocking the production of prostaglandins (PGs) through the inhibition of two cyclooxygenase enzymes. PGs are key factors in many cellular processes, such as gastrointestinal cytoprotection, hemostasis and thrombosis, inflammation, renal hemodynamics, turnover of cartilage, and angiogenesis. Interest has grown in the various effects of NSAIDs during the last decade. Epidemiological studies have revealed the reduced risk of several cancer types and neurodegenerative diseases by prolonged use of NSAIDs. Recent advances in the understanding of the cellular and molecular mechanisms of NSAIDs will accelerate the processes of discovery and clinical implementation. This review summarizes the molecular mechanisms of NSAIDs on the body systems.

Possible role of sildenafil in inhibiting rat vas deferens contractions by influencing the purinergic system.

AIM: To evaluate the effect of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-selective type 5 phosphodiesterase, on isolated rat vas deferens and its connections with the purinergic system. METHODS: Epididymal and prostatic portions of isolated vas deferens were placed in organ baths containing Krebs' solution. Contractions were induced by noradrenaline (NA), adenosine triphosphate (ATP), alpha,beta-methylene ATP and electrical field stimulation (EFS). The effect of sildenafil on the contractions was compared with suramin and Evans blue (EB). RESULTS: NA, ATP, alpha,beta-methylene ATP and EFS caused contractions in both portions of vas deferens. NA-induced contractions were unaffected by sildenafil and suramin but potentiated by EB. ATP-induced contractions were non-competitively inhibited in both portions by sildenafil and suramin but potentiated by EB. alpha,beta-methylene ATP-induced contractions were unaffected by sildenafil but were inhibited in both portions by suramin and EB. EFS-induced contractions were inhibited by sildenafil and suramin while potentiated by EB. CONCLUSION: Sildenafil inhibited the contractions in both portions of vas deferens, as did suramin. We have suggested that purinergic system has a role in this antagonism and it seems to be mediated by an ATP-dependent mechanism instead of a receptor interaction.

Anxiolytic-like profile of propofol, a general anesthetic, in the plus-maze test in mice.

The present study was performed to investigate the effect of propofol on anxiety using the elevated plus-maze test. Groups of mice received propofol (20, 40, 60 mg/kg) or diazepam (2 mg/kg), caffeine (30 mg/kg), L-arginine (100 mg/kg), m-chlorophenylpiperazine (m-CPP, 2.5 mg/kg) and then were placed in an elevated plus-maze that was composed of two opposite closed arms and two opposite open arms. Propofol (20, 40, 60 mg/kg) and diazepam (2 mg/kg) significantly increased the percentage of time spent in the open arms compared to control. Caffeine (30 mg/kg) and m-CPP (2.5 mg/kg) decreased the percentage of time spent in the open arms and these effects were antagonized when propofol (40 mg/kg) was administered before the test. L-arginine (100 mg/kg) has also produced anxiogenic effect and this effect was not prevented by propofol. All drugs used in this study did not significantly change locomotor activity. These results suggest that propofol has anxiolytic effect in plus-maze test.