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Search Results: 1 - 10 of 551 matches for " Ferdinando Nicoletti "
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MGluR5 Mediates the Interaction between Late-LTP, Network Activity, and Learning
Arthur Bikbaev, Sergey Neyman, Richard Teke Ngomba, Jeffrey Conn, Ferdinando Nicoletti, Denise Manahan-Vaughan
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002155
Abstract: Hippocampal synaptic plasticity and learning are strongly regulated by metabotropic glutamate receptors (mGluRs) and particularly by mGluR5. Here, we investigated the mechanisms underlying mGluR5-modulation of these phenomena. Prolonged pharmacological blockade of mGluR5 with MPEP produced a profound impairment of spatial memory. Effects were associated with 1) a reduction of mGluR1a-expression in the dentate gyrus; 2) impaired dentate gyrus LTP; 3) enhanced CA1-LTP and 4) suppressed theta (5–10 Hz) and gamma (30–100 Hz) oscillations in the dentate gyrus. Allosteric potentiation of mGluR1 after mGluR5 blockade significantly ameliorated dentate gyrus LTP, as well as suppression of gamma oscillatory activity. CA3-lesioning prevented MPEP effects on CA1-LTP, suggesting that plasticity levels in CA1 are driven by mGluR5-dependent synaptic and network activity in the dentate gyrus. These data support the hypothesis that prolonged mGluR5-inactivation causes altered hippocampal LTP levels and network activity, which is mediated in part by impaired mGluR1-expression in the dentate gyrus. The consequence is impairment of long-term learning.
mGlu2 metabotropic glutamate receptors restrain inflammatory pain and mediate the analgesic activity of dual mGlu2/mGlu3 receptor agonists
Magda Zammataro, Santina Chiechio, Michael C Montana, Anna Traficante, Agata Copani, Ferdinando Nicoletti, Robert W Gereau
Molecular Pain , 2011, DOI: 10.1186/1744-8069-7-6
Abstract: In this study we used mGlu2 or mGlu3 knock-out mice to dissect the specific role for these two receptors in the endogenous control of inflammatory pain and their specific contribution to the analgesic activity of mixed mGlu2/3 receptor agonists.Our results showed that mGlu2-/- mice display a significantly greater pain response compared to their wild type littermates. Interestingly the increased pain sensitivity in mGlu2-/- mice occurred only in the second phase of the formalin test. No differences were observed in the first phase. In contrast, mGlu3-/- mice did not significantly differ from their wild type littermates in either phase of the formalin test.When systemically injected, a single administration of the mGlu2/3 agonist, LY379268 (3 mg/kg, ip), showed a significant reduction of both phases in wild-type mice and in mGlu3-/- but not in mGlu2-/- mice. However tolerance to the analgesic effect of LY379268 (3 mg/kg, ip) in mGlu3-/- mice developed following 5 consecutive days of injection.Taken together, these results demonstrate that: (i) mGlu2 receptors play a predominant role over mGlu3 receptors in the control of inflammatory pain in mice; (ii) the analgesic activity of mixed mGlu2/3 agonists is entirely mediated by the activation of the mGlu2 subtype and (iii) the development of tolerance to the analgesic effect of mGlu2/3 agonists develops despite the lack of mGlu3 receptors.Metabotropic glutamate (mGlu) receptors are considered promising targets in the treatment of chronic pain. All mGlu receptor subtypes (mGlu1-8), except mGlu6, are widely distributed along the pain neuraxis, and modulate cellular mechanisms of nociceptive sensitization that underlie the development of chronic pain [1-3]. We and others have focused on the role of group-II mGlu receptors (mGlu2 and mGlu3), which are coupled to Gi proteins and depress pain transmission at synapses between primary afferent fibers and second order sensory neurons in the dorsal horn of the spinal cord [4,5]. mG
Transcriptional regulation of metabotropic glutamate receptor 2/3 expression by the NF-κB pathway in primary dorsal root ganglia neurons: a possible mechanism for the analgesic effect of L-acetylcarnitine
Santina Chiechio, Agata Copani, Laura De Petris, Maria Elena P Morales, Ferdinando Nicoletti, Robert W Gereau
Molecular Pain , 2006, DOI: 10.1186/1744-8069-2-20
Abstract: Activation of group II metabotropic glutamate receptors (mGlu2 and mGlu3) induces antinociception in several pain models in rodents [1-5]. Consistent with these studies, we have shown that L-acetylcarnitine (LAC), a drug clinically effective in the treatment of neuropathic pain of various origins [6-9], up-regulates the expression of mGlu2 in the dorsal root ganglia (DRG) and in the dorsal horn (DH) of the spinal cord [10,11]. This has challenged the previous view that LAC increases pain thresholds and relieves neuropathic pain by enhancing brain acetylcholine synthesis [12] or by increasing the trophism of peripheral nerves [13,14]. Consistent with the "mGlu2 hypothesis of LAC-induced analgesia," the mGlu2/3 receptor antagonist, LY341495, prevents LAC-induced analgesia in rodents [10]. Interestingly, LAC selectively enhances the expression of mGlu2 receptors and has no effect on the expression of mGlu3 receptors [10,15], although these two receptor subtypes are highly homologous and share similar functions in the CNS [16]. This suggests that the expression of mGlu2 and mGlu3 is differentially regulated and that unraveling the nature of this difference may lead to the identification of new targets for the treatment of neuropathic pain.Analysis of the 5'-region upstream of the coding sequence of the human GRM2 gene (encoding mGlu2) [GenBank: AB045011], using the Transcription Factor Binding Sites Database TRANSFACT and TFSEARCH, revealed the presence of many potential regulatory elements for transcription factors of the NF-κB family, including p50 and p65/Rel-A, and for the coactivator p300. In contrast, only one binding site for the NF-κB family protein, c-Rel, and no binding sites for p65/RelA and p300 have been described in the putative promoter region of the human GRM3 gene encoding mGlu3 [17]. Hence, we focused on the NF-κB pathway in the search for mechanisms that account for the selective effect of LAC on mGlu2 expression.NF-κB consists of transcription factor
17 -Ethynyl-androst-5-ene-3 ,7 ,17 -triol (HE3286) Is Neuroprotective and Reduces Motor Impairment and Neuroinflammation in a Murine MPTP Model of Parkinson’s Disease
Ferdinando Nicoletti,Ingrid Philippens,Paolo Fagone,Clarence N. Ahlem,Christopher L. Reading,James M. Frincke,Dominick L. Auci
Parkinson's Disease , 2012, DOI: 10.1155/2012/969418
Abstract: 17α-Ethynyl-androst-5-ene-3β,7β,17β-triol (HE3286) is a synthetic androstenetriol in Phase II clinical development for the treatment of inflammatory diseases. HE3286 was evaluated for blood-brain barrier (BBB) permeability in mice, and efficacy in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of Parkinson’s disease (PD). We found that HE3286 freely penetrated the BBB. HE3286 treatment significantly improved motor function compared to vehicle in the rotarod test (mean 58.2?sec versus 90.9?sec, ), and reduced inflammatory mediator gene expression in the brain (inducible nitric oxide synthase, 20%, ; tumor necrosis factor α, 40%, , and interleukin-1β, 33%, ) measured by reverse-transcriptase polymerase chain reaction. Brain tissue histopathology and immunohistochemistry showed that HE3286 treatment increased the numbers of tyrosine hydroxylase-positive cells by 17% compared to vehicle ( ), and decreased the numbers of damaged neurons by 38% relative to vehicle ( ). L-3,4-dihydroxyphenylalanine (L-DOPA) efficacy was not enhanced by concurrent administration of HE3286. HE3286 administration prior to MPTP did not enhance efficacy. Our data suggest a potential role for HE3286 in PD treatment, and provides incentive for further investigation. 1. Introduction PD is a neurodegenerative disorder characterized by a progressive degeneration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) and decreased levels of dopamine in the putamen of the dorsolateral striatum. The loss of dopamine in the striatum manifests clinically as motor disabilities that include bradykinesia, resting tremor, and muscular rigidity. Diagnosis is based on motor symptoms, which become evident only after the loss of more than 50% of the SNpc DAergic neurons and 60–80% of striatal dopamine [1]. Prolonged treatment of PD with L-DOPA usually results in a dyskinesia that can be more disabling than the disease itself; therefore, there is a great need for alternative therapeutic modalities. The acute MPTP mouse model of nigrostriatal degeneration recapitulates the DAergic neuron loss seen in PD and currently represents the most commonly used toxin-induced mouse model of PD [2]. MPTP’s mechanism of toxicity is complex, and exerted through its toxic metabolite, methyl-4-phenylpyridinium (MPP+) ion, which is taken up selectively by DAergic neurons through the dopamine transporter. Inside the cell, MPP+ is a mitochondrial toxin, which induces neuronal death through several mechanisms that include oxidative stress [3], excitotoxicity [4], and
Comparative Oral Absorption of Different Citicoline and Homotaurine Formulations: A Single-Dose, Two-Period Crossover Trial in the Dog  [PDF]
Andrea Marchegiani, Ferdinando Nicoletti, Maria Rosaria Romano, Decio Capobianco, Ciro Costagliola, Carlotta Marini, Giuseppe Lubrano Lavadera, Roberto Ciccocioppo, Andrea Spaterna
Journal of Biomedical Science and Engineering (JBiSE) , 2019, DOI: 10.4236/jbise.2019.127028
Abstract: Background: Citicoline and homotaurine are compounds with a potent neuroprotective activity and they have been administered for many years in the treatment of numerous neurodegenerative and ophthalmological diseases, including glaucoma. Initially available only as liquid form, through parenteral route, nowadays citicoline can be administered also as tablet but no data on bioavailability of these different forms are available. In the present study, pharmacokinetics of citicoline in tablet versus vials, each at the therapeutic dose of 500 mg, in addition to 50 mg of homotaurine was investigated. Materials and methods: Ten mixed breed dogs received a single dose of 50 mg oral homotaurine and 500 mg citicoline in tablet and vials with the same dose were administered after a seven days wash-out period. Parameters assessed for citicoline metabolites (cytidine, uridine and choline) were AUC0t, Cmax and Tmax. Results: Citicoline bioavailability appeared to be slightly higher for the tablet compared to the vial formulation. Cytidine is equivalent in absorption dynamics both for tablet and liquid form; uridine for tablet reaches its maximum and is reabsorbed more quickly while choline for the liquid form reaches the maximum first and is reabsorbed more quickly. Conclusions: Citicoline in tablet and liquid formulation have pharmacokinetic properties leading to a very similar bioavailability.
5-Androstenediol Ameliorates Pleurisy, Septic Shock, and Experimental Autoimmune Encephalomyelitis in Mice
Ferdinando Nicoletti,Dominick L. Auci,Katia Mangano,Jaime Flores-Riveros,Sonia Villegas,James M. Frincke,Christopher L. Reading,Halina Offner
Autoimmune Diseases , 2010, DOI: 10.4061/2010/757432
Abstract: Androstenediol (androst-5-ene-3 ,17 -diol; 5-AED), a natural adrenal steroid, has been shown to suppress experimental autoimmune encephalomyelitis (EAE) in female SJL/J mice. We here report that 5-AED limits inflammation and proinflammatory cytokines including TNF in murine models of carrageenan-induced pleurisy and lippopolysaccaride- (LPS) induced septic shock. 5-AED binds to and transactivates sex steroid receptors with the same general rank order of potency (ERβ > ERα ? AR). 5-AED provides benefit in EAE in a dose-dependent fashion, even when treatment is delayed until onset of disease. The minimally effective dose may be as low as 4?mg/kg in mice. However, benefit was not observed when 5-AED was given in soluble formulation, leading to a short half-life and rapid clearance. These observations suggest that treatment with 5-AED limits the production of pro-inflammatory cytokines in these animal models and, ultimately, when formulated and administered properly, may be beneficial for patients with multiple sclerosis and other Th1-driven autoimmune diseases. 1. Introduction Nonglucocorticoid steroids are subjects of intense scientific investigation as perturbations are associated with various diseases including the pathogenesis of autoimmunity [1]. The “gender gap” [2] with respect to incidence and severity of autoimmune disease has been the focus of efforts to uncover new therapies. For example, estrogens [3] and androgens [4, 5] are protective in several autoimmune disease models, including experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Recent work has dissociated the anti-inflammatory effect from the neuroprotective effect of estrogen treatment in EAE and has shown that its neuroprotective effects do not necessarily depend on anti-inflammatory properties [6]. Specifically, an estrogen receptor (ER) agonist reduced central nervous system inflammation, whereas an ER agonist treatment did not, but instead, was neuroprotective. Preliminary clinical results were encouraging. In a pilot trial, oral estriol treatment of relapsing remitting multiple sclerosis patients caused significant decreases in enhancing lesions on brain magnetic resonance imaging [7]. However, sex steroid therapy involves serious risks. For example, estrogen treatment involves increased risk for breast cancer in women [8]. Because such estrogen-related toxicities are mediated almost exclusively through ER , ER ligand treatment has been suggested as a potentially safer neuroprotective strategy in multiple sclerosis and other
Lack or Inhibition of Dopaminergic Stimulation Induces a Development Increase of Striatal Tyrosine Hydroxylase-Positive Interneurons
Carla Letizia Busceti, Domenico Bucci, Gemma Molinaro, Paola Di Pietro, Luca Zangrandi, Roberto Gradini, Rosario Moratalla, Giuseppe Battaglia, Valeria Bruno, Ferdinando Nicoletti, Francesco Fornai
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044025
Abstract: 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.
HE3286, an oral synthetic steroid, treats lung inflammation in mice without immune suppression
Douglas Conrad, Angela Wang, Raymond Pieters, Ferdinando Nicoletti, Katia Mangano, Anna M van Heeckeren, Steven K White, James M Frincke, Christopher L Reading, Dwight Stickney, Dominick L Auci
Journal of Inflammation , 2010, DOI: 10.1186/1476-9255-7-52
Abstract: In mice, oral treatment with HE3286 (40 mg/kg) significantly (p < 0.05) decreased neutrophil counts and exudate volumes (~50%) in carrageenan-induced pleurisy, and myeloperoxidase in lipopolysaccharide-induced lung injury. HE3286 (40 mg/kg) was not found to be profoundly immune suppressive in any of the classical animal models of immune function, including those used to evaluate antigen specific immune responses in vivo (ovalbumin immunization). When mice treated for two weeks with HE3286 were challenged with K. pneumoniae, nearly identical survival kinetics were observed in vehicle-treated, HE3286-treated and untreated groups.HE3286 represents a novel, first-in-class anti-inflammatory agent that may translate certain benefits of β-AET observed in rodents into treatments for chronic inflammatory pulmonary disease.Chronic obstructive pulmonary disease (COPD), a term most often used to describe chronic bronchitis and emphysema [1,2] is an inflammatory disease of the lungs marked by a loss of elastic recoil, an increased resistance to airflow and decreased expiratory flow rate leading to dyspnea [3]. Chronic bronchitis, emphysema and cystic fibrosis (CF), all forms of COPD, share many features including a progressive airway remodeling driven by chronic inflammation [4-7]. COPD is a major cause of morbidity and mortality in industrialized countries and novel treatments are urgently needed because many patients respond poorly to conventional therapies [8-10]. Even in responders, narrow therapeutic windows and a myriad of unwanted side effects, including immune suppression are treatment limiting [9-12]. We have suggested that suitable agents may be found within the adrenal metabolome [13].Dehydroepiandrosterone (DHEA) is an abundant adrenal steroid and a precursor in the biosynthesis of androgens, estrogens and other anti-inflammatory immune regulating steroids [14,15]. From studies reporting aberrant metabolism of adrenal steroids in CF patients [16,17] we surmised that
Hyperalgesic activity of kisspeptin in mice
Simona Spampinato, Angela Trabucco, Antonella Biasiotta, Francesca Biagioni, Giorgio Cruccu, Agata Copani, William H Colledge, Maria Sortino, Ferdinando Nicoletti, Santina Chiechio
Molecular Pain , 2011, DOI: 10.1186/1744-8069-7-90
Abstract: Immunofluorescent staining in the mouse skin showed the presence of GPR54 receptors in PGP9.5-positive sensory fibers. Intraplantar injection of kisspeptin (1 or 3 nmol/5 μl) induced a small nocifensive response in naive mice, and lowered thermal pain threshold in the hot plate test. Both intraplantar and intrathecal (0.5 or 1 nmol/3 μl) injection of kisspeptin caused hyperalgesia in the first and second phases of the formalin test, whereas the GPR54 antagonist, p234 (0.1 or 1 nmol), caused a robust analgesia. Intraplantar injection of kisspeptin combined with formalin enhanced TRPV1 phosphorylation at Ser800 at the injection site, and increased ERK1/2 phosphorylation in the ipsilateral dorsal horn as compared to naive mice and mice treated with formalin alone.These data demonstrate for the first time that kisspeptin regulates pain sensitivity in rodents and suggest that peripheral GPR54 receptors could be targeted by novel drugs in the treatment of inflammatory pain.Kisspeptin is a 54-amino acid peptide originally discovered for its activity as metastasis-suppressor [1]. It is encoded by the Kiss1 gene as a 145-amino acid precursor protein and cleaved to a 54-amino acid protein as well as into shorter products (kisspeptin-10,-13,-14) known to play a critical role in the neuroendocrine regulation of reproduction [2-5].In the brain, kisspeptin is localized not only in areas involved in gonadotropin secretion, but also in other regions such as the amygdala, hippocampus, and the periacqueductal gray [6,7].Its action is mediated by a 7-TM receptor named GPR54, also known as KISS1R, which is coupled to polyphosphoinositide hydrolysis via a Gq/11 GTP binding protein [2,8].Loss-of-function mutations of GPR54 cause a non-Kallman variant of hypogonadotropic/hypogonadism in humans (i.e. hypogonadotropic/hypogonadism without anosmia) [2,9]. Interestingly, the expression of kisspeptin and GPR54 is not restricted to the hypothalamus. Relatively high levels of kisspeptin and GPR5
HPTLC fingerprint: a modern approach for the analytical determination of botanicals
Nicoletti, Marcello;
Revista Brasileira de Farmacognosia , 2011, DOI: 10.1590/S0102-695X2011005000131
Abstract: availability of rapid and reliable methods for detection of quality in plant raw materials and botanicals is urgently needed. the recent hptlc instrumentation allows to obtain fingerprints useful to ascertain identity and composition. the results of direct application of hptlc devices in selected cases, using the fingerprint approach, are here reported, considered and compared with other methods. hptlc is proposed as an useful tool for analytical validation of the novel forms of natural products.
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