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  • Sage Publications (CrossRef)  (9)
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  • 1
    Language: English
    In: Multiple Sclerosis Journal, October 2011, Vol.17(10), pp.1155-1161
    Description: The delayed conditioned eyeblink reflex, in which an individual learns to close the eyelid in response to a conditioned stimulus (e.g. a tone) relies entirely on the functional integrity of a cerebellar motor circuitry that involves the contingent activation of Purkinje cells by parallel and climbing fibres. Molecular changes that disrupt the function of this circuitry, in particular a loss of type-1 metabotropic glutamate receptors (mGlu1 receptors), occur in Purkinje cells of patients with multiple sclerosis and in mice with experimental autoimmune encephalomyelitis as a result of neuroinflammation. mGlu1 receptors are required for cerebellar motor learning associated with the conditioned eyeblink reflex. We propose that the delayed paradigm of the eyeblink conditioning might be particularly valuable for the detection of subtle abnormalities of cerebellar motor learning that are clinically silent and are not associated with demyelinating lesions or axonal damage. In addition, the test might have predictive value following a clinically isolated syndrome, and might be helpful for the evaluation of the efficacy of drug treatment in multiple sclerosis.
    Keywords: Cerebellum ; Eyeblink Conditioning ; Mglu1 Receptors ; Motor Learning ; Multiple Sclerosis ; Purkinje Cells ; Medicine
    ISSN: 1352-4585
    E-ISSN: 1477-0970
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  • 2
    Language: English
    In: Molecular Pain, March 2017, Vol.13
    Description: Background L-acetylcarnitine, a drug marketed for the treatment of chronic pain, causes analgesia by epigenetically up-regulating type-2 metabotropic glutamate (mGlu2) receptors in the spinal cord. Because the epigenetic mechanisms are typically long-lasting, we hypothesized that analgesia could outlast the duration of L-acetylcarnitine treatment in models of inflammatory and neuropathic pain. Results A seven-day treatment with L-acetylcarnitine (100 mg/kg, once a day, i.p.) produced an antiallodynic effect in the complete Freund adjuvant mouse model of chronic inflammatory pain. L-Acetylcarnitine-induced analgesia persisted for at least 14 days after drug withdrawal. In contrast, the analgesic effect of pregabalin, amitryptiline, ceftriaxone, and N-acetylcysteine disappeared seven days after drug withdrawal. L-acetylcarnitine treatment enhanced mGlu2/3 receptor protein levels in the dorsal region of the spinal cord. This effect also persisted for two weeks after drug withdrawal and was associated with increased levels of acetylated histone H3 bound to the Grm2 gene promoter in the dorsal root ganglia. A long-lasting analgesic effect of L-acetylcarnitine was also observed in mice subjected to chronic constriction injury of the sciatic nerve. In these animals, a 14-day treatment with pregabalin, amitryptiline, tramadol, or L-acetylcarnitine produced a significant antiallodynic effect, with pregabalin displaying the greatest efficacy. In mice treated with pregabalin, tramadol or L-acetylcarnitine the analgesic effect was still visible 15 days after the end of drug treatment. However, only in mice treated with L-acetylcarnitine analgesia persisted 37 days after drug withdrawal. This effect was associated with an increase in mGlu2/3 receptor protein levels in the dorsal horns of the spinal cord. Conclusions Our findings suggest that L-acetylcarnitine has the unique property to cause a long-lasting analgesic effect that might reduce relapses in patients suffering from chronic pain.
    Keywords: Pain ; L-Acetylcarnitine ; Metabotropic Glutamate Receptors ; Long-Lasting Analgesia ; Medicine ; Anatomy & Physiology
    E-ISSN: 1744-8069
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  • 3
    Language: English
    In: Molecular Pain, October 2018, Vol.14
    Description: Vortioxetine is a multimodal antidepressant that potently antagonizes 5-HT3 serotonin receptors, inhibits the high-affinity serotonin transporter, activates 5-HT1A and 5-HT1B receptors, and antagonizes 5-HT1D and 5-HT7 receptors. 5-HT3 receptors largely mediate the hyperalgesic activity of serotonin that occurs in response to nerve injury. Activation of 5-HT3 receptors contributes to explain why selective serotonin reuptake inhibitors, such as fluoxetine, are not indicated in the treatment of neuropathic pain. Here, we studied the analgesic action of vortioxetine in the chronic constriction injury model of neuropathic pain in mice. Vortioxetine was injected once a day for 27 days at doses (10 mg/kg, intraperitoneally) that determine 〉90% 5-HT3 receptor occupancy in the central nervous system. The action of vortioxetine was compared to the action of equal doses of the serotonin-noradrenaline reuptake inhibitor, venlafaxine (one of the gold standard drugs in the treatment of neuropathic pain), and fluoxetine. Vortioxetine caused a robust analgesia in chronic constriction injury mice, and its effect was identical to that produced by venlafaxine. In contrast, fluoxetine was inactive in chronic constriction injury mice. Vortioxetine enhanced mechanical pain thresholds in chronic constriction injury mice without changing motor activity, as assessed by the open-field and horizontal bar tests. None of the three antidepressants caused analgesia in the complete Freund’s adjuvant model of chronic inflammatory pain. These findings raise the attractive possibility that vortioxetine can be effective in the treatment of neuropathic pain, particularly in patients with comorbid depression and cognitive dysfunction.
    Keywords: Vortioxetine ; Neuropathic Pain ; Inflammatory Pain ; Fluoxetine ; Venlafaxine ; Medicine ; Anatomy & Physiology
    E-ISSN: 1744-8069
    Source: SAGE Clinical Medicine (Sage Publications)
    Source: SAGE Health Sciences (Sage Publications)
    Source: Sage Journals (Sage Publications)
    Source: SAGE STM (Sage Publications)
    Source: SAGE Neurology (Sage Publications)
    Source: SAGE Open Access Journals (Sage Publications)
    Source: SAGE Communication and Media Studies (Sage Publications)
    Source: SAGE Journals (Sage Publications)
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  • 4
    Language: English
    In: International journal of immunopathology and pharmacology, 2019, Vol.33, pp.2058738419838383
    Description: Neuropathic pain is characterized by abnormal hypersensitivity to stimuli (hyperalgesia) and nociceptive responses to non-noxious stimuli (allodynia). The conditions and the pathophysiological states that determine the onset of neuropathic pain are heterogeneous, such as metabolic disorders, neuropathy caused by viral infections, and autoimmune diseases affecting the central nervous system (CNS). Neuropathic pain in the general population is estimated to have a prevalence ranging between 3% and 17%. Most of the available treatments for neuropathic pain have moderate efficacy and present side effects that limit their use; therefore, other therapeutic approaches are needed for patients. In this article, the current standard of care treatment, the emerging pharmacological approaches from the completed phase III clinical trials, and the preclinical studies on novel promising therapeutic options will be reviewed.
    Keywords: Animal Models ; Neuropathic Pain ; Phase III Clinical Trials ; Therapy
    E-ISSN: 2058-7384
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 5
    Language: English
    In: Multiple Sclerosis, April 2001, Vol.7(2), pp.101-104
    Description: We have evaluated the effect of the immunosuppressant sodium fusidate (fusidin) on the course of acute monophasic experimental encephalomyelitis (EAE) in male Lewis rats. Prophylactic treatment with fusidin, 80 or 120 mg/kg bd wt., markedly ameliorated the course of the disease in rats immunized with myelin basic proteins in complete Freund's adjuvant, entailing delayed onset of symptoms, lower clinical scores and more rapid recovery than PBS-treated control rats. The fusidin-treated, immunized rats exhibited milder mononuclear cell infiltration of brains and spinal cords than control animals. These data provide further evidence for the anti-inflammatory effect of fusidin and suggest that this drug may be valuable for the treatment of human multiple sclerosis.
    Keywords: Experimental Allergic Encephalomyelitis ; Immunotherapy ; Multiple Sclerosis ; Sodium Fusidate ; Medicine
    ISSN: 1352-4585
    E-ISSN: 1477-0970
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  • 6
    Language: English
    In: Experimental Biology and Medicine, May 2004, Vol.229(5), pp.425-436
    Description: This laboratory has reported that multiple low doses of streptozotocin (MLD-STZ) similarly upregulate the T helper (Th)1-type proinflammatory cytokines tumor necrosis factor (TNF)-α and interferon (IFN)-γ in islets of both the diabetes-susceptible male and the diabetes-resistant female C57BL/6 mice and that MLD-STZ downregulates the anti-inflammatory Th2-type cytokines interleukin (IL)-4 and IL-10, as well as the anti-inflammatory Th3-type cytokine-transforming growth factor (TGF)β1 in islets of male, but not female, mice. Thus, diabetes is associated with a relative preponderance of local proinflammatory cytokines. Here, we investigated the effects of MLD-STZ on the anti-inflammatory cytokine IL-11 and the transcription factors nuclear factor (NF)-κB and activator protein (AP)-1, which are involved in gene activation of proinflammatory cytokines, and on the cytosolic kinase (IKK-α) of NF-κB inhibitor (IκB). Furthermore, the effect of recombinant human (rh)IL-11 on MLD-STZ diabetes, insulitis, cytokines, IKK-α, NF-κB, and AP-1 was analyzed in islets. Interleukin-11 prevented diabetes without affecting insulitis; attenuated TNF-α and IFN-γ response; and stimulated IL-4 production and inhibited activation of IKK-α, NF-κB, and AP-1. The results demonstrated the potential of rhIL-11 in preventing MLD-STZ diabetes through enhancement of anti-inflammatory responses in islets. In this process, the transcription factors NF-κB and AP-1 might play a key role.
    Keywords: Mld-Stz Diabetes ; Cytokines ; Nf-Κb ; AP-1 ; Ikk-Α ; Medicine ; Biology ; Anatomy & Physiology
    ISSN: 1535-3702
    E-ISSN: 1535-3699
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  • 7
    Language: English
    In: Multiple Sclerosis, December 1999, Vol.5(6), pp.377-377
    Keywords: Medicine
    ISSN: 1352-4585
    E-ISSN: 1477-0970
    Source: Sage Journals (Sage Publications)
    Source: SAGE Clinical Medicine (Sage Publications)
    Source: SAGE Health Sciences (Sage Publications)
    Source: SAGE STM (Sage Publications)
    Source: SAGE Palliative Medicine and Chronic Care (Sage Publications)
    Source: SAGE Pharmacology and Biomedical (Sage Publications)
    Source: SAGE Neurology (Sage Publications)
    Source: SAGE Mental Health (Sage Publications)
    Source: SAGE Communication and Media Studies (Sage Publications)
    Source: SAGE Journals (Sage Publications)
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  • 8
    Language: English
    In: Journal of Autoimmunity, September 1999, Vol.13(2), pp.187-195
    Description: AIMS: NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione (2-(4-methylsulphonyl-2-nitrobenzoyl)-1,3-cyclohexanedione) are inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD). NTBC has been successfully used as a treatment for hereditary tyrosinaemia type 1 (HT-1), while mesotrione has been developed as an herbicide. The pharmacokinetics of the two compounds were investigated in healthy male volunteers following single oral administration. The aim of the NTBC study was to assess the bioequivalence of two different formulations and to determine the extent of the induced tyrosinaemia. The mesotrione study was performed to determine the magnitude and duration of the effect on tyrosine catabolism. Additionally, the urinary excretion of unchanged mesotrione was measured to assess the importance of this route of clearance and to help develop a strategy for monitoring occupational exposure.METHODS: A total of 28 volunteers participated in two separate studies with the compounds. In the first study, the relative bioavailability of NTBC from liquid and capsule formulations was compared and the effect on plasma tyrosine concentrations measured. In the second study the pharmacokinetics of mesotrione were determined at three doses. Plasma tyrosine concentrations were monitored and the urinary excretion of mesotrione and tyrosine metabolites was measured.RESULTS: Both compounds were well tolerated at the dose levels studied. Peak plasma concentrations of NTBC were rapidly attained following a single oral dose of 1 mg x kg(-1) body weight of either formulation and the half-life in plasma was approximately 54 h. There were no statistical differences in mean (+/- s.d.) AUC(0,infinity) (capsule 602 +/- 154 vs solution 602 +/- 146 microg x ml(-1) h) or t1/2 (capsule 55 +/- 13 vs solution 54 +/- 8 h) and these parameters supported the bioequivalence of the two formulations. Mesotrione was also rapidly absorbed, with a significant proportion of the dose eliminated unchanged in urine. The plasma half-life was approximately 1 h and was independent of dose and AUC(0,infinity) and Cmax increased linearly with dose. Following administration of 1 mg NTBC x kg(-1) in either formulation, the concentrations of tyrosine in plasma increased to approximately 1100 nmol x ml(-1). Concentrations were still approximately 8 times those of background at 14 days after dosing, but had returned to background levels within 2 months of the second dose. Administration of mesotrione resulted in an increase in tyrosine concentrations which reached a maximum of approximately 300 nmol x ml(-1) following a dose of 4 mg x kg(-1) body weight. Concentrations returned to those of background within 2 days of dosing. Urinary excretion of tyrosine metabolites was increased during the 24 h immediately following a dose of 4 mg mesotrione x kg(-1), but returned to background levels during the following 24 h period.CONCLUSIONS: NTBC and mesotrione are both inhibitors of HPPD, although the magnitude and duration of their effect on tyrosine concentrations are very different. When normalized for dose, the extent of the induced tyrosinaemia after administration of NTBC and over the duration of these studies, was approximately 400 fold greater than that following administration of mesotrione. The persistent and significant effect on HPPD following administration of NTBC make it suitable for the treatment of patients with hereditary tyrosinaemia type 1 (HT-1), whilst the minimal and transient effects of mesotrione minimize the likelihood of a clinical effect in the event of systemic exposure occurring during occupational use.
    Keywords: Autoimmunity, Experimental Allergic Neuritis, Guillain-Barrè Syndrome, Sodium Fusidate ; Medicine ; Biology
    ISSN: 0896-8411
    ISSN: 03065251
    E-ISSN: 1095-9157
    E-ISSN: 13652125
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  • 9
    Language: English
    In: Cephalalgia, August 1983, Vol.3(1_suppl), pp.31-34
    Description: Endogenous hyperprolactinaemia induced by anterior pituitary transplantation under the kidney capsule has been found to reduce the behavioural responsiveness to electrical footshock and to increase morphine-induced analgesia. The apparent analgesic effect of prolactin has been related to the stimulation of nigro-striatal dopaminergic transmission, as suggested by the increase in striatal dopamine turnover observed in hyperprolactinaemic rats. It seems likely that central opiate system is involved in the behavioural effects of prolactin. Thus, naloxone prevents the effects of hyperprolactinaemia on footshock responsiveness and heroin self-administration is decreased in hyperprolactinaemic rats. Il a été remarqué que l'hyperprolactinémie causée per la greffe de l'hypophyse antérieure sous la capsule rénale réduit la réponse comportamentale au footshock électrique et augmente l'analgésie produite par la morphine. L'effet analgésique apparent de la prolactine a été mis en relation avec le stimulus de la transmission dopaminergique nigro-striée, comme il est suggéré par l'augmentation du turnover de la dopamine striée chez les rats hyperprolac-tinémiques. Il est probable que le système central opioide joue un rôle dans les effets comportamentaux de la prolactine. Le naloxone est donc à même de prévenir les effets de l'hyperprolactinémie sur la réponse au footshock et de réduire l'autoadministration de l'héroine chez les rats hyperprolactinémiques. L'iperprolattinemia indotta da trapianto di ipofisi anteriore sotto la capsula renale è nota ridurre la risposta comportamentale al footshock elettrico e l'analgesia indotta da morfina. Questo apparente effetto analgesico della prolattina è stato messo in rapporto con la stimolazione della trasmissione dopaminergica nigro-striatale, come suggerito dall'incremento del turnover di dopamina striatale osservato in ratti iperprolattinemici. Sembra quindi verosimile che il sistema oppioide centrale sia coinvolto negli effetti comportamentali della prolattina. Il naloxone peraltro è in grado di prevenire gli effetti della iperprolattinemia sulla risposta al footshock come di ridurre l'autosomministrazione di eroina nei ratti iperprolattinemici.
    Keywords: Analgesia ; Dopamine ; Opiate System ; Prolactin ; Medicine
    ISSN: 0333-1024
    E-ISSN: 1468-2982
    Source: Sage Journals (Sage Publications)
    Source: SAGE Clinical Medicine (Sage Publications)
    Source: SAGE STM (Sage Publications)
    Source: SAGE Health Sciences (Sage Publications)
    Source: SAGE Mental Health (Sage Publications)
    Source: SAGE Pharmacology and Biomedical (Sage Publications)
    Source: SAGE Neurology (Sage Publications)
    Source: SAGE Journals (Sage Publications)
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