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John P Kelly

Publications and source records attributed to John P Kelly.

At least 19 recordsLinked to original sources
PubMed2026

Examining the Relationship Between Physical Neglect, Inflammation and Anterior Cingulate Activation During Facial Emotion Recognition in Patients With Schizophrenia and Healthy Controls: A Functional Magnetic Resonance Imaging Study.

Physical neglect is associated with poorer cognitive functioning in patients with schizophrenia, including deficits in facial emotion recognition. Recent research by our group showed the relationship between physical neglect and facial emotion recognition is mediated by inflammation. While this mediation effect was observed at the level of behaviour, examining the relationship between physical neglect, inflammation and neural activation during facial emotion recognition would help confirm brain regions impacted and support behavioural findings, but these relationships are unclear. Two hundred twelve participants (52 patients with schizophrenia and 160 healthy controls) underwent functional magnetic resonance imaging while performing an established facial emotion recognition task and a subset completed the Childhood Trauma Questionnaire and provided blood samples outside of the scanner. Inflammation was measured using a latent variable that combined basal plasma levels of interleukin-6, tumour necrosis factor-alpha and C-reactive protein. The relationships between physical neglect, inflammation and neural activation were examined using multiple regression. Neither physical neglect nor inflammation predicted altered neural response during facial emotion recognition at p&#x2009;<&#x2009;0.05, family-wise error corrected for multiple comparisons within an anterior cingulate region of interest, across the whole brain, in the whole sample or separately in patients or controls. Future research should examine relationships between physical neglect, inflammation and brain activation in larger samples, which may have sensitivity to detect smaller effects, and use tasks that require active recognition of emotions, in addition to passive viewing of faces, which might be associated with additional neural responses.

Humans↗
PubMed2006

Chronic fluoxetine treatment attenuates stressor-induced changes in temperature, heart rate, and neuronal activation in the olfactory bulbectomized rat.

The olfactory bulbectomized (OB) rat is a well-characterized animal model that exhibits a number of behavioral and neurochemical changes that have relevance to clinical depression. Hyperactivity in the open field is the most widely used parameter assessed in this model and is reversed following chronic, but not acute, antidepressant treatment. This study investigated OB-induced alterations in heart rate, body temperature, and neuronal activation following open-field exposure and the impact of chronic treatment with fluoxetine on these parameters. Upon placement in the open field, OB rats exhibited a characteristic hyperactivity response. Heart rate and body temperature were increased in sham-operated rats following open-field exposure, a predictable response to stress, which was significantly reduced in OB rats. Moreover bulbectomy reduced open field-induced cFOS expression in the basal nucleus of the stria terminalis while concurrently increasing expression in the hippocampus, amygdala, paraventricular nucleus of the thalamus, and dorsal raphe nucleus. Chronic fluoxetine treatment (10 mg/kg subcutaneous once daily for 5 weeks) attenuated all of these OB-associated changes. In conclusion, OB rats exhibit alterations in behavior, body temperature, heart rate, and neuronal activation in response to open-field exposure, which are reversed following chronic fluoxetine administration. These results identify stress-sensitive regions within the brain which are altered following bulbectomy and which may underlie the abnormal behavioral and physiological changes observed in this rodent model of depression.

Animals↗
PubMed2006

In vivo modulation of LPS-induced alterations in brain and peripheral cytokines and HPA axis activity by cannabinoids.

This study investigated cannabinoid receptor-mediated regulation of brain and peripheral cytokines in vivo. The cannabinoid receptor agonist, HU210 attenuated lipopolysaccharide (LPS)-induced increases in IL-1beta and TNFalpha in rat brain and IL-1beta, TNFalpha, IL-6 and IFNgamma in plasma. The CB(1) receptor antagonist, SR141716A, attenuated the immunosupressive effects of HU210 on IL-1beta, but not TNFalpha. SR141716A or the CB(2) receptor antagonist, SR144528, alone attenuated LPS-induced cytokine increases. LPS and/or cannabinoids also reduced circulating lymphocyte numbers and increased corticosterone levels. These data provide evidence for modulation of pro-inflammatory cytokines in vivo by cannabinoid receptors and inform the development of cannabinoids for neuroinflammatory disorders.

Animals↗
PubMed2006

Immunomodulatory effects of caffeine: friend or foe?

Caffeine is a member of the methylxanthine family of drugs, and is the most widely consumed behaviourally active substance in the western world. This article is focused on the impact of caffeine on immune function. In this regard, a number of in vitro and in vivo studies have demonstrated that caffeine modulates both innate and adaptive immune responses. For instance studies indicate that caffeine and its major metabolite paraxanthine suppress neutrophil and monocyte chemotaxis, and also suppress production of the pro-inflammatory cytokine tumour necrosis factor (TNF)-alpha from human blood. Caffeine has also been reported to suppress human lymphocyte function as indicated by reduced T-cell proliferation and impaired production of Th1 (interleukin [IL]-2 and interferon [IFN]-gamma), Th2 (IL-4, IL-5) and Th3 (IL-10) cytokines. Studies also indicate that caffeine suppresses antibody production. The evidence suggests that at least some of the immunomodulatory actions of caffeine are mediated via inhibition of cyclic adenosine monophosphate (cAMP)-phosphodiesterase (PDE), and consequential increase in intracellular cAMP concentrations. Overall, these studies indicate that caffeine, like other members of the methylxanthine family, is largely anti-inflammatory in nature, and based on the pharmacokinetics of caffeine, we suggest that many of its immunomodulatory effects occur at concentrations that are relevant to normal human consumption. Finally, the potential of caffeine-induced immunomodulation to significantly impact upon health and well-being are discussed.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2006

Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade.

In this study, antidepressants with selectivity for the noradrenaline transporter (reboxetine and desipramine), or the serotonin transporter (fluoxetine and clomipramine) were examined in terms of their ability to promote an anti-inflammatory cytokine phenotype in human blood. In addition, we examined the ability of trimipramine; a tricyclic antidepressant that is devoid of monoamine reuptake inhibitory properties on cytokine production. Lipopolysaccharide (LPS) was used to stimulate monocyte-derived pro-inflammatory (IL-1beta, TNF-alpha, IL-12) and anti-inflammatory (IL-10) cytokines, whilst concanavalin A (Con A) was used to stimulate T-cell (Th(1): IFN-gamma and Th(2/3): IL-10) cytokines. All of the antidepressants suppressed IFN-gamma production in the 10-50 microM concentration range, irrespective of their preference for serotonin or noradrenaline transporters. This suppression of IFN-gamma production was paralleled by reduced T-cell proliferation, therefore we suggest that the ability of antidepressants to suppress IFN-gamma production may be related to their anti-proliferative properties. The fact that trimipramine also suppressed IFN-gamma production and T-cell proliferation indicates that these immunomodulatory actions of antidepressants are most likely unrelated to inhibition of monoamine reuptake. Interestingly, exposure to a lower concentration (1 microM) of the antidepressants tended to increase T-cell-derived IL-10 production, with significant effects elicited by the noradrenaline reuptake inhibitors reboxetine and desipramine. In contrast to the robust actions of antidepressants on T-cell derived cytokine production, they failed to induce any consistent change in LPS-induced monocyte cytokine production. Overall, our results indicate that IFN-gamma producing T-cells (Th(1) cells) are the major target for the immunomodulatory actions of antidepressants, and provide evidence questioning the relationship between the monoaminergic reuptake properties of antidepressants and their immunomodulatory effects. The potential clinical significance of the anti-inflammatory actions of antidepressants is discussed.

Adult↗
PubMed2006

Topographical retinal function in oculocutaneous albinism.

PURPOSE: Macular hypoplasia is the major ocular finding in albinism because it underlies reduced acuity and congenital nystagmus. Anatomic studies have shown a lack of foveal differentiation. However, functional anatomy of the macula in albinism is not known. DESIGN: Observational case reports. METHODS: We measured the topology of the retinal response in two patients with oculocutaneous albinism by using simultaneous fundus monitoring and multifocal electroretinographs (ERGs). Stimuli consisted of a 103-hexagon array centered on the macula. Recording conditions eliminated nystagmus artifact. RESULTS: ERG amplitudes were reduced only in the central 5 to 10 degrees compared with adult norms. When the response was scaled by stimulation area, multifocal ERG amplitudes were constant across all retinal eccentricities. CONCLUSIONS: The results suggest a homogeneous density of cone photoreceptors across the central retina in albinism, consistent with anatomic studies showing arrest of postnatal macular development. Further normative data are needed to fully quantify macular development in young children.

Albinism, Oculocutaneous↗
PubMed2006

Comparison of pattern visual-evoked potentials to perimetry in the detection of visual loss in children with optic pathway gliomas.

PURPOSE: We sought to compare visual evoked potentials (VEPs) with standard visual field testing in children with visual pathway gliomas. METHODS: Fifteen of 40 children with visual pathway gliomas verified on magnetic resonance imaging scan who cooperated with Goldmann visual field (GVF) and 3-channel VEPs were studied. GVFs were obtained in 25 eyes with adequate vision. VEP amplitudes, latencies, and signal-to-noise ratios (SNRs) were compared with control subjects. Four of the patients (5 eyes) also had Humphrey visual field testing. RESULTS: Twenty-two of 25 eyes had a field defect, 15 eyes showed a relative or absolute hemianopia, 7 eyes showed a central or generalized depression, and 3 eyes were normal. In hemianopic eyes, 87% showed a depression (GVF) or reduced sensitivity (Humphrey field) in the opposite hemifield. VEP amplitudes and SNRs, normally largest at the midline electrode, were significantly reduced in all eyes with visual field loss. By comparison, lateral electrodes showed significantly lower amplitudes and SNRs in patients and controls. Interhemispheric VEP asymmetry (>2:1 ratio) was seen in 67% of patients with hemianopia and 53% of controls. CONCLUSIONS: Reduction of amplitude and SNR at the midline VEP electrode was a sensitive indicator of visual field loss. Interhemispheric VEP asymmetry was not reliable in detection of a hemianopic field defect. VEPs can be a reliable and objective alternative for the detection of visual loss due to optic pathway glioma in children who are intolerant to visual field testing. We recommend the test protocol include pattern-onset and check reversal stimuli of at least one high and one low spatial frequency.

Adolescent↗
PubMed2004

Acute stress suppresses pro-inflammatory cytokines TNF-alpha and IL-1 beta independent of a catecholamine-driven increase in IL-10 production.

Interleukin (IL)-10 is an anti-inflammatory cytokine that can down-regulate various aspects of the immune response. In this study we demonstrate that exposure to a psychophysiological stressor (swim stress) increases IL-10 production in female rats in response to an in vivo challenge with bacterial lipopolysaccharide (LPS). This increase in LPS-induced IL-10 was associated with suppression of the pro-inflammatory cytokines IL-1beta and TNF-alpha, indicating that overall, swim stress promotes an immunosuppressive cytokine phenotype. Despite the well-documented ability of IL-10 to suppress pro-inflammatory cytokine production, neutralisation of IL-10 failed to block the stress-induced suppression of IL-1beta and TNF-alpha. These data indicate that the suppressive effect of swim stress on these pro-inflammatory cytokines occurs independently of increased IL-10 production. To determine if swim stress-induced immunosuppression was mediated by increased sympathetic nervous system activity, and subsequent beta-adrenoceptor activation, we assessed the ability of the beta-adrenoceptor antagonist nadolol to block stressor-induced changes in cytokine production. Whilst pre-treatment with nadolol completely blocked the stress-induced increase in IL-10, it failed to alter the suppression of TNF-alpha or IL-1beta. Similarly, pre-treatment with the glucocorticoid receptor antagonist mifepristone also failed to attenuate the suppressive effect of swim stress on IL-1beta and TNF-alpha production. These data indicate that neither increased glucocorticoid secretion, nor catecholamine-induced beta-adrenoceptor activation, mediates the suppressive effect of swim stress on pro-inflammatory cytokine production. Taken together, these data demonstrate a role for beta-adrenoceptor activation in the ability of acute swim stress to increase LPS-induced IL-10 production, and also highlight a mechanistic dissociation between the ability of swim stress to increase IL-10 and suppress pro-inflammatory cytokine production.

Adrenergic beta-Antagonists↗
PubMed2004

Methylenedioxymethamphetamine suppresses production of the proinflammatory cytokine tumor necrosis factor-alpha independent of a beta-adrenoceptor-mediated increase in interleukin-10.

Recent data suggest that 3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") has marked immunosuppressive properties. In this study, we investigate the effect of MDMA on production of the anti-inflammatory cytokine interleukin (IL)-10 in response to an in vivo challenge with bacterial lipopolysaccharide (LPS). Our data demonstrate that both acute and repeated administration of MDMA increases production of LPS-induced IL-10 in vivo, and this increase correlates inversely with the ability of MDMA to suppress the proinflammatory cytokine tumor necrosis factor (TNF)-alpha. Despite this correlation, immunoneutralization of IL-10 does not reverse the suppressive effect of MDMA on LPS-induced TNF-alpha production, indicating that suppression of this proinflammatory cytokine is not mediated by IL-10. In vitro exposure to MDMA does not mimic the immunosuppressive cytokine phenotype induced in vivo, suggesting that these immunosuppressive effects are not mediated by a direct action on monocytes per se. As MDMA activates that hypothalamic pituitary adrenal axis and sympathetic nervous system, we examined the role of glucocorticoids and catecholamines in its immunosuppressive actions. However, the immunosuppressive cytokine phenotype induced by MDMA was not altered by adrenalectomy, sympathetic denervation, or ganglionic blockade, indicating that neither glucocorticoids nor adrenal/sympathetic-derived catecholamines mediate these immunosuppressive effects of MDMA. Interestingly, beta-adrenoceptor blockade completely inhibited the increase in IL-10 induced by MDMA without altering the suppression of TNF-alpha. Taken together, these data demonstrate a role for beta-adrenoceptor activation in the ability of MDMA to increase LPS-induced IL-10 and highlight a mechanistic dissociation between the ability of MDMA to increase IL-10 and suppress production of the proinflammatory cytokine TNF-alpha.

Adrenalectomy↗
PubMed2004

Nitric oxide synthase inhibitors augment the effects of serotonin re-uptake inhibitors in the forced swimming test.

The problem of antidepressant-resistant depression has necessitated finding ways of augmenting the actions of currently existing antidepressants. The present studies investigate the possibility of synergistic interactions between nitric oxide (NO) synthase inhibitors and antidepressants in the mouse forced swim test (FST), a pre-clinical test of antidepressant activity. Treatment with a behaviourally subactive dose of the NO synthase inhibitor NG-nitro-L-arginine (L-NA) (3 mg/kg) augmented the behavioural effect of the tricyclic antidepressant imipramine. In a similar fashion L-NA (3 mg/kg) augmented the effect of the selective serotonin re-uptake inhibitor (SSRI) fluoxetine but not the noradrenaline re-uptake inhibitor, reboxetine in the FST. The interaction observed between L-NA and fluoxetine generalised to other selective serotonin re-uptake inhibitors, namely, sertraline and citalopram in the FST. Treatment with a subactive dose of the neuronally selective NO synthase inhibitor, 7-nitroindazole (30 and 50 mg/kg), augmented the behavioural effects of imipramine and fluoxetine, respectively. Thus inhibition of NO synthase enhances the activity of antidepressants that work via a serotonergic mechanism in the FST. The results of the present investigation support a view that antidepressant effects, or enhancement of such effects in the FST, may be elicited via NO synthase inhibition. Furthermore, these data raise the possibility that inhibition of NO synthase could be used as a strategy to enhance the clinical efficacy of serotonergic antidepressants.

Analysis of Variance↗
PubMed2004

Caffeine suppresses TNF-alpha production via activation of the cyclic AMP/protein kinase A pathway.

This study investigated the effect of in vitro exposure to caffeine, and its major metabolite paraxanthine, at concentrations relevant to typical caffeine consumption in humans, on lipopolysaccharide (LPS)-stimulated cytokine production in human whole blood. In addition, a role for the cyclic AMP/protein kinase A (PKA) pathway in the immunomodulatory effect of caffeine was investigated. Diluted whole blood (taken following >/=15 h abstinence from caffeine-containing food and beverages) was preincubated with caffeine or paraxanthine (10-100 microM) and stimulated with LPS (1 proportional, variant g/ml) for 24 h. The proinflammatory cytokines tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-12, and the antiinflammatory cytokine IL-10 were measured in cell-free supernatants. Whilst caffeine and paraxanthine had little or no effect on IL-10, IL-1beta, or IL-12 production, TNF-alpha production was suppressed in all individuals studied. The effect was statistically significant at 100 microM and consistent across seven experiments performed. Although not statistically significant, a similar effect was observed with paraxanthine. Caffeine (100 microM) also increased intracellular cyclic AMP concentrations in LPS-stimulated monocytes isolated from whole blood. Moreover, the effect of caffeine on TNF-alpha production was abolished by pretreatment with the protein kinase A inhibitor Rp-8-Br-cAMPS (10(-4) and 10(-5)M). To conclude, this study demonstrates that concentrations of caffeine that are relevant to human consumption consistently suppress production of the proinflammatory cytokine TNF-alpha in human blood and that this effect is mediated by the cyclic AMP/protein kinase A pathway.

Adult↗
PubMed2004

Spatial-frequency-dependent changes in cortical activation before and after patching in amblyopic children.

PURPOSE: To examine the cortical response under transient stimulus conditions in amblyopic children before and after eye patching. To determine whether improvement in acuity is associated with spatial-frequency-dependent changes in specific peaks of the cortical response. METHODS: Visual evoked potentials (VEPs) to check reversal (163-18 arc min) and onset of sine wave gratings (0.5-4 cyc/deg) were measured in 24 amblyopic children (<7 years of age) before eye patching. VEPs were repeated in nine subjects with 20/40 or better acuity after patching. Age, severity of amblyopia, and VEP amplitudes of positive peak (P)100, P1, and negative peak (N)2 were analyzed by multivariate statistics. RESULTS: Before patching, the amblyopic eye showed decreasing amplitude with increasing spatial frequencies (P < 0.05) when compared with the nonamblyopic eye. Reduced amplitudes occurred at frequencies well below acuity. Latencies were mildly prolonged. After patching, amplitudes increased in the amblyopic eye across all spatial frequencies (ANCOVA; P < 0.0001 for each peak). However, a spatial-frequency-dependent increase in amplitude was significant only for a late negative peak (N2). The patched eye showed no significant changes. CONCLUSIONS: Recovery of acuity after eye patching is associated with an overall increase in cortical activation across a wide range of spatial frequencies below the acuity threshold. A spatial-frequency-dependent increase in a late negative peak suggests that the cortical generator of this peak demonstrates plasticity of acuity recovery.

Amblyopia↗
PubMed2003

Imaging a child's fundus without dilation using a handheld confocal scanning laser ophthalmoscope.

Images of the fundus were acquired in children without pupil dilation using a prototype handheld confocal scanning laser ophthalmoscope (SLO). A 780-nm laser beam imaged a 20 degrees x 20 degrees area of the fundus while a 645-nm beam scanned a fixation target. Scorable images of the optic nerve, macula, and vessels were obtained in 67 (72%) of 93 eyes from pediatric patients with nystagmus, amblyopia, media opacities, or optic nerve or macular abnormalities. Images were obtained in all eyes of pediatric and adult controls. Unsuccessful imaging was associated with media opacities, high refractive error, and poor cooperation. Disadvantages of the SLO were the inability to detect optic nerve pallor or consistently image the periphery. Advantages of the SLO were seen in children with nystagmus, photophobia, eccentric fixation, cone dystrophy, and mild papilledema.

Adolescent↗
PubMed2003

ERGs, cone-isolating VEPs and analytical techniques in children with cone dysfunction syndromes.

Photoreceptor and post-receptoral function in children with congenital and acquired cone disorders was measured by full-field electroretinogram (ERG) and transient visual evoked potentials (VEPs). Subjects were five rod monochromats (RM), five with cone dystrophy (CD), and 30 controls. Patients were diagnosed by clinical findings, ERGs, and standard color vision tests. VEP stimuli were check reversals and color grating onsets that stimulated each photoreceptor type (L-, M-, or S-cones) or post-receptoral pathways (L-M, white/black). VEP signal-to-noise ratios (S/N) were calculated by Fourier analysis of VEP epochs. All RM patients showed extinguished cone ERGs. A near normal S-cone VEP was recorded from a blue-cone rod monochromat without any signal from the L- or M-cone stimuli. Two other RM patients were classified as incomplete RM based on a low-level VEP signal from either L- or M-cone stimuli. CD patients had mildly to severely reduced ERGs and VEPs were abnormal to all cone-isolating stimuli. The VEP S/N ratio was not significantly correlated with the amount of rod contrast in the color stimuli. Color VEPs provide an objective assessment of macular cone function in children with cone dysfunction syndromes that is more sensitive to residual central cone function than standard full-field ERGs. VEP techniques may be useful in the early detection of cone loss in children, especially in children who do not tolerate ERG testing.

Adolescent↗
PubMed2003

Methylenendioxyamphetamine produces serotonin nerve terminal loss and diminished behavioural and neurochemical responses to the antidepressant fluoxetine.

The effect of prior exposure to methylenedioxyamphetamine (MDA) on behavioural and neurochemical responses to fluoxetine were assessed in a rat model of antidepressant action. MDA (7.5 mg/kg, i.p.) was administered to rats twice daily for 4 consecutive days, and 4 weeks later the behavioural effect of fluoxetine (5 or 20 mg/kg; i.p. x 3) was examined in the modified rat forced-swimming test. In addition, the ability of fluoxetine to reduce serotonin (5-HT) metabolism was measured as an index of its efficacy in inhibiting 5-HT reuptake in vivo. In vehicle-treated rats, fluoxetine (5 and 20 mg/kg) produced a characteristic increase in swimming behaviour in the forced-swimming test. In contrast, fluoxetine-induced swimming was markedly attenuated in MDA-treated rats. MDA pretreatment resulted in 5-HT nerve terminal degeneration, indicated by reduced 5-HT and 5-HIAA concentrations in the frontal cortex, amygdala and hippocampus, and reduced [3H]paroxetine binding in the frontal cortex. In vehicle-treated rats, fluoxetine (5 and 20 mg/kg) decreased 5-HT metabolism (5-HIAA : 5-HT ratio) in the frontal cortex, amygdala and hippocampus. MDA pretreatment attenuated the ability of fluoxetine to reduce 5-HT metabolism in all brain regions examined. These findings are the first to demonstrate that prior exposure to the methylenedioxy-substituted amphetamine MDA results in diminished responsiveness to the antidepressant fluoxetine.

3,4-Methylenedioxyamphetamine↗
PubMed2003

A toxicokinetic study of nickel-induced immunosuppression in rats.

The aim of the present study was to investigate dose- and time-dependent effects of NiCl2 on T-lymphocyte and macrophage-derived cytokine production in rats. Moreover we have determined the concentrations of nickel in the plasma that are required to elicit alterations in T-lymphocyte and macrophage function. NiCl2 suppressed T-lymphocyte proliferation and Th1 (IFN-gamma) and Th2 (IL-10) cytokine production in a dose- and time-dependent fashion. In addition, NiCl2 inhibited production of the pro-inflammatory cytokine TNF-alpha and increased production of the anti-inflammatory cytokine IL-10 from lipopolysaccharide (LPS) stimulated cultures. We have determined that the minimal plasma concentrations of nickel required to provoke immunosuppression are in the range 209-585 ng/mL. In the time-course study NiCl2 (3.3 mg/kg) provoked immunological changes that were maximal 1 h following administration, and some of these changes persisted for up to 24 h post administration. Overall these data clearly demonstrate that NiCl2 suppresses T-cell function and promotes an immunosuppressive macrophage phenotype in rats. This study also indicates that measuring T-cell proliferation is as sensitive a marker of NiCl2-induced immunotoxicity as measuring T-cell or macrophage cytokine production. Co-measurement of circulating nickel concentrations and immune parameters yields valuable information with regard to the potency of nickel to alter immune function in vivo. These data also suggest that quite a large quantity of nickel needs to reach the systemic circulation before any adverse effects on immune function are observed.

Animals↗
PubMed2002

Fenfluramine-induced immunosuppression: an in vivo analysis.

We examined the immunomodulatory potential of acute fenfluramine administration, by measuring production of the pro-inflammatory cytokines interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha in response to an in vivo challenge with bacterial lipopolysaccharide in rats. Fenfluramine (2.5-10 mg/kg) suppressed tumor necrosis factor-alpha production, but only fenfluramine (5 and 10 mg/kg) suppressed interleukin-1beta production. Fenfluramine (10 mg/kg)-induced suppression of interleukin-1beta and tumor necrosis factor-alpha production persisted for 6 and 24 h, respectively. Using in vitro analyses, we demonstrated that the immunosuppressive effect of fenfluramine was not due to a direct effect on immune cells. As fenfluramine activates the hypothalamic pituitary adrenal axis, we examined the ability of the glucocorticoid receptor antagonist mifepristone to block fenfluramine-induced immunosuppression. However, mifepristone (10 mg/kg) failed to attenuate the suppressive effect of fenfluramine on interleukin-1beta and tumor necrosis factor-alpha production, indicating that glucocorticoids do not mediate fenfluramine-induced immunosuppression. We also assessed the effect of fenfluramine on production of the anti-inflammatory cytokine interleukin-10, as interleukin-10 can suppresses pro-inflammatory cytokine production. Fenfluramine (10 mg/kg) increased interleukin-10 production following an in vivo lipopolysaccharide challenge. However, the ability of fenfluramine to suppress tumor necrosis factor-alpha production cannot be accounted for by increased interleukin-10 production, as pretreatment with the beta-adrenoceptor antagonist nadolol completely blocked the increase in interleukin-10 without altering the suppression of tumor necrosis factor-alpha induced by fenfluramine. Taken together, these data demonstrate that fenfluramine promotes an immunosuppressive cytokine phenotype in vivo. The suppression of pro-inflammatory cytokines is not due to a direct effect the drug on immune cells, and also occurs independently of glucocorticoid receptor activation. In addition, whilst fenfluramine increases production of the anti-inflammatory cytokine interleukin-10, this cannot account for the suppression of the pro-inflammatory cytokine tumor necrosis factor-alpha induced by fenfluramine.

Adrenergic beta-Antagonists↗