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Despite of many years of research, the evidence for interactions between the peripheral nervous system and the immune system remains incomplete. Our recent studies have shown that the proinflammatory cytokines interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF) play a critical role in the pathogenesis of the immune response within the peripheral endings of trigeminal ganglion neurons. The goal of the current project was to determine whether peripheral inflammation leads to changes in BDNF expression in trigeminal ganglia. In order to examine the effects of peripheral inflammation on the regulation of BDNF content in trigeminal ganglion neurons in vivo, a model of CFA-evoked inflammation in the TMJ of C57BL mice was employed. BDNF levels in trigeminal ganglia ipsilateral to the CFA-induced inflammation were compared with BDNF levels in the control ganglia from the contralateral (intact) side, on day 3 and 7 after induction of inflammation. A standard sandwich ELISA methodology was used to compare levels of BDNF in the trigeminal ganglion that supplies the tissue that has been affected by the inflammatory process with BDNF levels in the contralateral ganglion. These in vivo data further support the notion that BDNF is a likely key player of trigeminal inflammatory pain.
It is well established that the majority of headache and other trigeminal nerve-associated disorders have higher prevalence in females than in males. However, the pathogenesis of many chronic trigeminal pain conditions, such as trigeminal neuralgia, migraine and temporo-mandibular disorders, is still not known. One of the proposed mechanisms involve calcitonin gene-related peptide (CGRP), which is considered the most important neuropeptide in the trigeminal system. In various animal models of trigeminal nerve-associated disorders concentration of CGRP has been shown to be increased in trigeminal ganglia (TG). Moreover, intraganglionic release of CGRP has been shown to modulate neuronal transmission of pain signals. In most of these models, pathological changes in the trigeminal system are accompanied by inflammation within peripheral endings of TG neurons. The aim of the present study was to investigate the relation between gender and neurochemical changes in trigeminal ganglia evoked by peripheral inflammation, induced by Complete Freund Adjuvant (CFA) administration. Our studies show significant increase in CGRP expression in female mice, comparing to male mice. Furthermore, we demonstrate, that activation of trigeminal nociceptors by peripheral inflammation causes significant increase in expression of IL-ip, IL-6, TNF and BDNF in male mice, comparing to female mice. This phenomenon may be involved in clinically observed gender-dependent differences in the frequency of both migraine and other trigeminal nerve- related facial pain disorders.
BACKGROUND AND AIMS: Our previous studies showed that inflammatory reaction in the area of trigeminal ganglion (TG) nociceptive endings affects neurochemical properties of TG, causing increase in concentration of both brain-derived neurotrophic factor (BDNF) and calcitonin gene-related peptide (CGRP). In the present study we have employed CFA-induced TG inflammation model to begun investigating the underlying molecular mechanisms of the inflammation-induced changes in trigeminal neurons properties. METHODS: A model of orofacial inflammation was obtained by local injection of CFA to the mice whisker pad. Pain reaction was assessed every day by von-Frey filaments. 7 and 14 days after CFA injection mice were euthanized. Both TG were removed for ELISA and quantitative PCR analysis of differences in concentration and expression of BDNF, CGRP and selected proinflammatory cytokines, both in male and female mice. After perfusion with 4% paraformaldehyde, TG were removed from the sculls, crioprotected and cut on the 20 μm sections. Tissue was immunostained using primary antibodies against BDNF and TRPV1 and then with secondary antibodies conjugated with Alexa Fluor. RESULTS: Expression of proinflammatory cytokines, BDNF and CGRP was different in male and female mice. Our results indicate that response of TG to peripheral inflammatory reaction is genderdependent, what may explain differences in frequency and severity of trigeminal nerve-associated disorders observed between women and men. CONCLUSIONS: TG neurons in female mice showed increased expression of CGRPa, this neuropeptide may act as the main mediator of trigeminal signaling during migraine. This project has been supported by the Polish National Science Center, based on the Decision No. DEC-2012/05/B/NZ4/02385. Research subject implemented with CePT infrastructure financed by the European Union – the European Regional Development Fund within the Operational Programme “Innovative economy” for 2007-2013”
Many data suggest involvement of inflammation in neurodegeneration. However, the exact mechanisms of this cooperation are poorly understood. We have previously shown that induction of inflammatory reaction, both before and after injury of the striatum, affects regeneration of dopaminergic neurons. In the present research we studied the role of inflammatory reaction in non-injured striatum. We used myelin oligodendrocyte glycoprotein (MOG) 35-55 in complete Freund’s adjuvant (CFA) to elicit experimental autoimmune encephalomyelitis (EAE) mice model. As determined by HPLC, striatal dopamine (DA) and serotonin levels in mice treated with either MOG 35-55 in CFA or CFA alone were significantly higher compared to vehicle-treated controls on 13th day after induction. The ratio of homovanilic acid/dopamine (HVA/DA) and 3, 4 dihydroxyphenylacetic acid/dopamine (DOPAC/DA) were significantly lower in the MOG and CFA groups on 13th day, indicating decreased DA metabolism. Noradrenaline (NA) concentration did not differ between groups. Moreover, the striatal mRNA IL-1ß and TNF-? levels were elevated during induction phase of EAE in both groups, as determined by RT-PCR. Our data indicate regulatory connection between dopaminergic and immune systems.
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