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  • Gradini, Roberto  (29)
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  • 1
    Language: English
    In: Current Opinion in Pharmacology, 2015, Vol.20, p.89(6)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.coph.2014.12.002 Byline: Ferdinando Nicoletti, Valeria Bruno, Richard Teke Ngomba, Roberto Gradini, Giuseppe Battaglia Abstract: * There is still hope for a clinical use of mGlu ligands. * Targeted disorders may still include schizophrenia and Parkinson's disease. * Other disorders, such as SCA1 and absence epilepsy might be treated with mGlu drugs. Author Affiliation: (1) Department of Physiology and Pharmacology, University Sapienza, Piazzale Aldo Moro, 5, 00185 Roma, Italy (2) I.R.C.C.S Neuromed, Localita Camerelle, 86077 Pozzilli, Italy (3) Department of Experimental Medicine, University 'Sapienza', Viale Regina Elena, 324, 00161 Roma, Italy
    Keywords: Glutamate
    ISSN: 1471-4892
    Source: Cengage Learning, Inc.
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  • 2
    In: PLoS ONE, 2012, Vol.7(9)
    Description: We examined the role of endogenous dopamine (DA) in regulating the number of intrinsic tyrosine hydroxylase-positive (TH + ) striatal neurons using mice at postnatal day (PND) 4 to 8, a period that corresponds to the developmental peak in the number of these neurons. We adopted the strategy of depleting endogenous DA by a 2-day treatment with α-methyl- p -tyrosine (αMpT, 150 mg/kg, i.p.). This treatment markedly increased the number of striatal TH + neurons, assessed by stereological counting, and the increase was highly correlated to the extent of DA loss. Interestingly, TH + neurons were found closer to the clusters of DA fibers after DA depletion, indicating that the concentration gradient of extracellular DA critically regulates the distribution of striatal TH + neurons. A single i.p. injection of the D1 receptor antagonist, SCH23390 (0.1 mg/kg), the D2/D3 receptor antagonist, raclopride (0.1 mg/kg), or the D4 receptor antagonist, L-745,870 (5 mg/kg) in mice at PND4 also increased the number of TH + neurons after 4 days. Treatment with the D1-like receptor agonist SKF38393 (10 mg/kg) or with the D2-like receptor agonist, quinpirole (1 mg/kg) did not change the number of TH + neurons. At least the effects of SCH23390 were prevented by a combined treatment with SKF38393. Immunohistochemical analysis indicated that striatal TH + neurons expressed D2 and D4 receptors, but not D1 receptors. Moreover, treatment with the α4β2 receptor antagonist dihydro-β-erythroidine (DHβE) (3.2 mg/kg) also increased the number of TH + neurons. The evidence that DHβE mimicked the action of SCH23390 in increasing the number of TH + neurons supports the hypothesis that activation of D1 receptors controls the number of striatal TH + neurons by enhancing the release of acetylcholine. These data demonstrate for the first time that endogenous DA negatively regulates the number of striatal TH + neurons by direct and indirect mechanisms mediated by multiple DA receptor subtypes.
    Keywords: Research Article ; Biology
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: 2012, Vol.7(9), p.e44025
    Description: We examined the role of endogenous dopamine (DA) in regulating the number of intrinsic tyrosine hydroxylase-positive (TH + ) striatal neurons using mice at postnatal day (PND) 4 to 8, a period that corresponds to the developmental peak in the number of these neurons. We adopted the strategy of depleting endogenous DA by a 2-day treatment with α-methyl- p -tyrosine (αMpT, 150 mg/kg, i.p.). This treatment markedly increased the number of striatal TH + neurons, assessed by stereological counting, and the increase was highly correlated to the extent of DA loss. Interestingly, TH + neurons were found closer to the clusters of DA fibers after DA depletion, indicating that the concentration gradient of extracellular DA critically regulates the distribution of striatal TH + neurons. A single i.p. injection of the D1 receptor antagonist, SCH23390 (0.1 mg/kg), the D2/D3 receptor antagonist, raclopride (0.1 mg/kg), or the D4 receptor antagonist, L-745,870 (5 mg/kg) in mice at PND4 also increased the number of TH + neurons after 4 days. Treatment with the D1-like receptor agonist SKF38393 (10 mg/kg) or with the D2-like receptor agonist, quinpirole (1 mg/kg) did not change the number of TH + neurons. At least the effects of SCH23390 were prevented by a combined treatment with SKF38393. Immunohistochemical analysis indicated that striatal TH + neurons expressed D2 and D4 receptors, but not D1 receptors. Moreover, treatment with the α4β2 receptor antagonist dihydro-β-erythroidine (DHβE) (3.2 mg/kg) also increased the number of TH + neurons. The evidence that DHβE mimicked the action of SCH23390 in increasing the number of TH + neurons supports the hypothesis that activation of D1 receptors controls the number of striatal TH + neurons by enhancing the release of acetylcholine. These data demonstrate for the first time that endogenous DA negatively regulates the number of striatal TH + neurons by direct and indirect mechanisms mediated by multiple DA receptor subtypes.
    Keywords: Research Article ; Biology ; Neuroscience ; Developmental Biology
    E-ISSN: 1932-6203
    Source: PLoS
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  • 4
    Language: English
    In: PLoS ONE, 01 January 2011, Vol.6(1), p.e16447
    Description: The identification of mechanisms that mediate stress-induced hippocampal damage may shed new light into the pathophysiology of depressive disorders and provide new targets for therapeutic intervention. We focused on the secreted glycoprotein...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 5
    Language: English
    In: Psychoneuroendocrinology, October 2012, Vol.37(10), pp.1646-1658
    Description: Epidemiological studies suggest that emotional liability in infancy could be a predictor of anxiety-related disorders in the adulthood. Rats exposed to prenatal restraint stress (“PRS rats”) represent a valuable model for the study of the interplay between environmental triggers and neurodevelopment in the pathogenesis of anxious/depressive like behaviours. Repeated episodes of restraint stress were delivered to female Sprague-Dawley rats during pregnancy and male offspring were studied. Ultrasonic vocalization (USV) was assessed in pups under different behavioural paradigms. After weaning, anxiety was measured by conventional tests. Expression of GABA receptor subunits and metabotropic glutamate (mGlu) receptors was assessed by immunoblotting. Plasma leptin levels were measured using a LINCOplex bead assay kit. The offspring of stressed dams emitted more USVs in response to isolation from their mothers and showed a later suppression of USV production when exposed to an unfamiliar male odour, indicating a pronounced anxiety-like profile. Anxiety like behaviour in PRS pups persisted one day after weaning. PRS pups did not show the plasma peak in leptin levels that is otherwise seen at PND14. In addition, PRS pups showed a reduced expression of the γ2 subunit of GABA receptors in the amygdala at PND14 and PND22, an increased expression of mGlu5 receptors in the amygdala at PND22, a reduced expression of mGlu5 receptors in the hippocampus at PND14 and PND22, and a reduced expression of mGlu2/3 receptors in the hippocampus at PND22. These data offer a clear-cut demonstration that the early programming triggered by PRS could be already translated into anxiety-like behaviour during early postnatal life.
    Keywords: Prenatal Restraint Stress ; Infancy ; Anxiety-Like Behaviour ; Anxiety-Related Receptors ; Leptin ; Medicine ; Anatomy & Physiology
    ISSN: 0306-4530
    E-ISSN: 1873-3360
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  • 6
    Language: English
    In: Current Opinion in Pharmacology, February 2015, Vol.20, pp.89-94
    Description: The question in the title: ‘what's new?’ has two facets. First, are ‘clinical’ expectations met with success? Second, is the number of CNS disorders targeted by mGlu drugs still increasing? The answer to the first question is ‘no’, because development program with promising drugs in the treatment of schizophrenia, Parkinson's disease, and Fragile X syndrome have been discontinued. Nonetheless, we continue to be optimistic because there is still the concrete hope that some of these drugs are beneficial in targeted subpopulations of patients. The answer to the second question is ‘yes’, because mGlu ligands are promising targets for ‘new’ disorders such as type-1 spinocerebellar ataxia and absence epilepsy. In addition, the increasing availability of pharmacological tools may push mGlu7 and mGlu8 receptors into the clinical scenario. After almost 30 years from their discovery, mGlu receptors are still alive.
    Keywords: Pharmacy, Therapeutics, & Pharmacology
    ISSN: 1471-4892
    E-ISSN: 1471-4973
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  • 7
    Language: English
    In: Neuropharmacology, August 2015, Vol.95, pp.50-58
    Description: Neuroadaptive changes involving the indirect pathway of the basal ganglia motor circuit occur in the early phases of parkinsonism. The precise identification of these changes may shed new light into the pathophysiology of parkinsonism and better define the time window of pharmacological intervention. We examined some of these changes in mice challenged with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), or with the dopamine receptor blocker, haloperidol. These two models clearly diverge from Parkinson's disease (PD); however, they allow an accurate time-dependent analysis of neuroadaptive changes occurring in the striatum. Acute haloperidol injection caused a significant increase in the transcripts of mGlu4 receptors, CB1 receptors and preproenkephalin-A at 2 and 24 h, and a reduction in the transcripts of mGlu5 and A receptors at 2 h. At least changes in the expression of mGlu4 receptors might be interpreted as compensatory because haloperidol-induced catalepsy was enhanced in mGlu4 mice. Mice injected with 30 mg/kg of MPTP also showed an increase in the transcripts of mGlu4 receptors, CB1 receptors, and preproenkephalin-A at 3 d, and a reduction of the transcript of A receptors at 1 d in the striatum. Genetic deletion of mGlu4 receptors altered the functional response to MPTP, assessed by counting c-Fos neurons in the external globus pallidus and ventromedial thalamic nucleus. These findings offer the first evidence that changes in the expression of mGlu4 and mGlu5 receptors occur in acute models of parkinsonisms, and lay the groundwork for the study of these changes in models that better recapitulate the temporal profile of nigrostriatal dysfunction associated with PD.
    Keywords: Metabotropic Glutamate Receptors ; Haloperidol ; Mptp ; Parkinsonism ; Indirect Pathway ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0028-3908
    E-ISSN: 1873-7064
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  • 8
    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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  • 9
    Language: English
    In: Molecular brain, 19 November 2013, Vol.6, pp.48
    Description: Spinocerebellar ataxia type 1 (SCA1) is a genetic disorder characterized by severe ataxia associated with progressive loss of cerebellar Purkinje cells. The mGlu1 metabotropic glutamate receptor plays a key role in mechanisms of activity-dependent synaptic plasticity in the cerebellum, and its dysfunction is linked to the pathophysiology of motor symptoms associated with SCA1. We used SCA1 heterozygous transgenic mice (Q154/Q2) as a model for testing the hypothesis that drugs that enhance mGlu1 receptor function may be good candidates for the medical treatment of SCA1. Symptomatic 30-week old SCA1 mice showed reduced mGlu1 receptor mRNA and protein levels in the cerebellum. Interestingly, these mice also showed an intense expression of mGlu5 receptors in cerebellar Purkinje cells, which normally lack these receptors. Systemic treatment of SCA1 mice with the mGlu1 receptor positive allosteric modulator (PAM), Ro0711401 (10 mg/kg, s.c.), caused a prolonged improvement of motor performance on the rotarod and the paw-print tests. A single injection of Ro0711401 improved motor symptoms for several days, and no tolerance developed to the drug. In contrast, the mGlu5 receptor PAM, VU0360172 (10 mg/kg, s.c.), caused only a short-lasting improvement of motor symptoms, whereas the mGlu1 receptor antagonist, JNJ16259685 (2.5 mg/kg, i.p.), further impaired motor performance in SCA1 mice. The prolonged symptomatic benefit caused by Ro0711401 outlasted the time of drug clearance from the cerebellum, and was associated with neuroadaptive changes in the cerebellum, such as a striking reduction of the ectopically expressed mGlu5 receptors in Purkinje cells, increases in levels of total and Ser880-phosphorylated GluA2 subunit of AMPA receptors, and changes in the length of spines in the distal dendrites of Purkinje cells. These data demonstrate that pharmacological enhancement of mGlu1 receptors causes a robust and sustained motor improvement in SCA1 mice, and lay the groundwork for the development of mGlu1 receptor PAMs as novel "cerebellum-specific", effective, and safe symptomatic drugs for the treatment of SCA1 in humans.
    Keywords: Amides -- Pharmacology ; Receptors, Metabotropic Glutamate -- Metabolism ; Spinocerebellar Ataxias -- Metabolism
    E-ISSN: 1756-6606
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  • 10
    Language: English
    In: Current Neuropharmacology, 2017, Vol.15(6), p.918-925
    Description: Background: Spike-wave discharges, underlying absence seizures, are generated within a cortico-thalamo-cortical network that involves the somatosensory cortex, the reticular thalamic nucleus, and the ventrobasal thalamic nuclei. Activation of T-type voltage-sensitive calcium channels (VSCCs) contributes to the pathological oscillatory activity of this network, and some of the first-line drugs used in the treatment of absence epilepsy inhibit T-type calcium channels. The ?2? subunit is a component of high voltage-activated VSCCs (i.e., L-, N-, P/Q-, and R channels) and studies carried out in heterologous expression systems suggest that it may also associate with T channels. The ?2? subunit is also targeted by thrombospondins, which regulate synaptogenesis in the central nervous system. 〈P〉〈/P〉 Objective: To discuss the potential role for the thrombospondin/?2? axis in the pathophysiology of absence epilepsy. 〈P〉〈/P〉 Methods: We searched PubMed articles for the terms “absence epilepsy”, “T-type voltage-sensitive calcium channels”, “?2? subunit”, “ducky mice”, “pregabalin”, “gabapentin”, “thrombospondins”, and included papers focusing this Review's scope. 〈P〉〈/P〉 Results: We moved from the evidence that mice lacking the ?2?-2 subunit show absence seizures and ? 2? ligands (gabapentin and pregabalin) are detrimental in the treatment of absence epilepsy. This suggests that ?2? may be protective against absence epilepsy via a mechanism that does not involve T channels. We discuss the interaction between thrombospondins and ?2? and its potential relevance in the regulation of excitatory synaptic formation in the cortico-thalamo-cortical network. 〈P〉〈/P〉 Conclusion: We speculate on the possibility that the thrombospondin/?2 ? axis is critical for the correct functioning of the cortico-thalamo-cortical network, and that abnormalities in this axis may play a role in the pathophysiology of absence epilepsy.
    Keywords: ?2? Subunit T-Type Voltage-Sensitive Ca≪Sup≫2+≪/Sup≫ Channels Non-T-Type Voltage-Sensitive Ca≪Sup≫2+≪/Sup≫ Channels Ducky Mice Pregabalin Gabapentin Absence Epilepsy Thrombospondins.
    ISSN: 1570-159X
    E-ISSN: 1875-6190
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