Both constitutive and inducible interleukin-1 (IL-1) gene expressions have been described in the ... more Both constitutive and inducible interleukin-1 (IL-1) gene expressions have been described in the central nervous system, the former being associated with immunoreactive IL-1 neurons in human and rat hypothalami. While most studies have focused on the role of IL-1 as a mediator of pathological events in the brain, the cytokine of neuronal origin might also be involved in the regulation
The aim of this study was to investigate the mechanisms through which bacterial lipopolysaccharid... more The aim of this study was to investigate the mechanisms through which bacterial lipopolysaccharide (LPS) stimulates prostaglandin (PG) production in rat hypothalamic astroglial cells in vitro. The latter were treated with LPS alone or LPS plus antagonists of the interleukin-1 (IL-1) and nitric oxide (NO) pathways, and the subsequent changes in cyclooxygenase (COX) activity were monitored by measuring a COX end-product, prostaglandin E2 (PGE2), released into the incubation medium. LPS produced a concentration-dependent increase in PGE2 release from astroglia after 24 h incubation; experiments with selective antagonists showed that the increase in PGE2 release induced by LPS may be, at least in part, mediated by IL-1 and NO.
Background Migraine is a complex, chronic, painful, neurovascular disorder characterized by episo... more Background Migraine is a complex, chronic, painful, neurovascular disorder characterized by episodic activation of the trigeminal system. Increased levels of calcitonin gene-related peptide (CGRP) are found at different levels during migraine attacks. Interestingly, CGRP is also released within the trigeminal ganglia suggesting possible local effects on satellite cells, a specialized type of glia that ensheaths trigeminal neurons. CGRP was shown to enhance satellite-cell production of interleukin 1β (IL-1β), while trigeminal neurons express an activity-dependent production of nitric oxide (NO). Thus, in the present study we tested the hypothesis that IL-1β and NO induce trigeminal satellite cell activation, and that once activated these cells can influence neuronal responses. Results Primary cultures of rat trigeminal satellite cells isolated from neuronal cultures were characterized in vitro. Cyclooxygenase (COX) expression and activity were taken as a marker of glial pro-inflammatory activation. Most of the experiments were carried out to characterize satellite cell responses to the two different pro-inflammatory stimuli. Subsequently, medium harvested from activated satellite cells was used to test possible modulatory effects of glial factors on trigeminal neuronal activity. IL-1β and the NO donor diethylenetriamine/nitric oxide (DETA/NO) elevated PGE2 release by satellite cells. The stimulatory effect of IL-1β was mediated mainly by upregulation of the inducible form of COX enzyme (COX2), while NO increased the constitutive COX activity. Regardless of the activator used, it is relevant that short exposures of trigeminal satellite cells to both activators induced modifications within the cells which led to significant PGE2 production after removal of the pro-inflammatory stimuli. This effect allowed us to harvest medium from activated satellite cells (so-called 'conditioned medium') that did not contain any stimulus, and thus test the effects of glial factors on neuronal activation. Conditioned medium from satellite cells activated by either IL-1β or NO augmented the evoked release of CGRP by trigeminal neurons. Conclusion These findings indicate that satellite cells contribute to migraine-related neurochemical events and are induced to do so by autocrine/paracrine stimuli (such as IL-1β and NO). The responsiveness of IL-1β to CGRP creates the potential for a positive feedback loop and, thus, a plurality of targets for therapeutic intervention in migraine.
Rationale Originally described as a pivotal mediator of acute neuroendocrine responses to stress,... more Rationale Originally described as a pivotal mediator of acute neuroendocrine responses to stress, corticotropin-releasing hormone (CRH) is currently envisioned as a peptide neurotransmitter involved in the pathogenesis of anxiety and depressive disorders; it has been postulated that antidepressant drugs are clinically effective insofar as they are able to reduce central CRH production and release. Objectives and methods In this study we used a well validated in vitro model, i.e. acute rat hypothalamic explants, to investigate the effects of the antidepressant mirtazapine on the production and release of CRH from the hypothalamus in short-term experiments. CRH release was assessed through the measurement of CRH immunoreactivity in the incubation medium. Results We found that mirtazapine reduces in a concentration-dependent manner both basal and K+-stimulated CRH release in 30-min and 60-min experiments. Mirtazapine had no effect on CRH mRNA expression in 1-h and 3-h experiments; the intra-hypothalamic levels of peptide were not reduced, and even tended to increase, with respect to controls. Conclusion Mirtazapine reduces CRH release from CRH-containing neurons in the rat hypothalamus through a mechanism independent from the modulation of CRH gene expression and peptide production.
Both constitutive and inducible interleukin-1 (IL-1) gene expressions have been described in the ... more Both constitutive and inducible interleukin-1 (IL-1) gene expressions have been described in the central nervous system, the former being associated with immunoreactive IL-1 neurons in human and rat hypothalami. While most studies have focused on the role of IL-1 as a mediator of pathological events in the brain, the cytokine of neuronal origin might also be involved in the regulation
The aim of this study was to investigate the mechanisms through which bacterial lipopolysaccharid... more The aim of this study was to investigate the mechanisms through which bacterial lipopolysaccharide (LPS) stimulates prostaglandin (PG) production in rat hypothalamic astroglial cells in vitro. The latter were treated with LPS alone or LPS plus antagonists of the interleukin-1 (IL-1) and nitric oxide (NO) pathways, and the subsequent changes in cyclooxygenase (COX) activity were monitored by measuring a COX end-product, prostaglandin E2 (PGE2), released into the incubation medium. LPS produced a concentration-dependent increase in PGE2 release from astroglia after 24 h incubation; experiments with selective antagonists showed that the increase in PGE2 release induced by LPS may be, at least in part, mediated by IL-1 and NO.
Background Migraine is a complex, chronic, painful, neurovascular disorder characterized by episo... more Background Migraine is a complex, chronic, painful, neurovascular disorder characterized by episodic activation of the trigeminal system. Increased levels of calcitonin gene-related peptide (CGRP) are found at different levels during migraine attacks. Interestingly, CGRP is also released within the trigeminal ganglia suggesting possible local effects on satellite cells, a specialized type of glia that ensheaths trigeminal neurons. CGRP was shown to enhance satellite-cell production of interleukin 1β (IL-1β), while trigeminal neurons express an activity-dependent production of nitric oxide (NO). Thus, in the present study we tested the hypothesis that IL-1β and NO induce trigeminal satellite cell activation, and that once activated these cells can influence neuronal responses. Results Primary cultures of rat trigeminal satellite cells isolated from neuronal cultures were characterized in vitro. Cyclooxygenase (COX) expression and activity were taken as a marker of glial pro-inflammatory activation. Most of the experiments were carried out to characterize satellite cell responses to the two different pro-inflammatory stimuli. Subsequently, medium harvested from activated satellite cells was used to test possible modulatory effects of glial factors on trigeminal neuronal activity. IL-1β and the NO donor diethylenetriamine/nitric oxide (DETA/NO) elevated PGE2 release by satellite cells. The stimulatory effect of IL-1β was mediated mainly by upregulation of the inducible form of COX enzyme (COX2), while NO increased the constitutive COX activity. Regardless of the activator used, it is relevant that short exposures of trigeminal satellite cells to both activators induced modifications within the cells which led to significant PGE2 production after removal of the pro-inflammatory stimuli. This effect allowed us to harvest medium from activated satellite cells (so-called 'conditioned medium') that did not contain any stimulus, and thus test the effects of glial factors on neuronal activation. Conditioned medium from satellite cells activated by either IL-1β or NO augmented the evoked release of CGRP by trigeminal neurons. Conclusion These findings indicate that satellite cells contribute to migraine-related neurochemical events and are induced to do so by autocrine/paracrine stimuli (such as IL-1β and NO). The responsiveness of IL-1β to CGRP creates the potential for a positive feedback loop and, thus, a plurality of targets for therapeutic intervention in migraine.
Rationale Originally described as a pivotal mediator of acute neuroendocrine responses to stress,... more Rationale Originally described as a pivotal mediator of acute neuroendocrine responses to stress, corticotropin-releasing hormone (CRH) is currently envisioned as a peptide neurotransmitter involved in the pathogenesis of anxiety and depressive disorders; it has been postulated that antidepressant drugs are clinically effective insofar as they are able to reduce central CRH production and release. Objectives and methods In this study we used a well validated in vitro model, i.e. acute rat hypothalamic explants, to investigate the effects of the antidepressant mirtazapine on the production and release of CRH from the hypothalamus in short-term experiments. CRH release was assessed through the measurement of CRH immunoreactivity in the incubation medium. Results We found that mirtazapine reduces in a concentration-dependent manner both basal and K+-stimulated CRH release in 30-min and 60-min experiments. Mirtazapine had no effect on CRH mRNA expression in 1-h and 3-h experiments; the intra-hypothalamic levels of peptide were not reduced, and even tended to increase, with respect to controls. Conclusion Mirtazapine reduces CRH release from CRH-containing neurons in the rat hypothalamus through a mechanism independent from the modulation of CRH gene expression and peptide production.
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