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Giuseppe Battaglia

Publications and source records attributed to Giuseppe Battaglia.

At least 19 recordsLinked to original sources
PubMed2006

Pharmacological activation of mGlu2/3 metabotropic glutamate receptors protects retinal neurons against anoxic damage in the goldfish Carassius auratus.

We examined the expression of mGlu2/3 metabotropic glutamate receptors in the retina of the goldfish Carassius auratus. mGlu2/3 receptors were expressed in all retinal layers internal to the photoreceptor layer, particularly in the outer and inner nuclear layers. Although the goldfish brain is able to tolerate prolonged periods of anoxia, we examined whether anoxia could induce retinal damage. Three hours of anoxia induced in the retina the development of apoptotic cell death, as assessed 48 h later by TUNEL staining. TUNEL-positive cells were particularly found in the inner and outer nuclear layers, and were also present in the ganglion cell layer. Pharmacological activation of mGlu2/3 receptors by systemic injection of LY379268 (0.5 mg/kg, i.p., 15 min before the onset of anoxia) substantially protected retinas against anoxia-induced cell death. In contrast, systemic injection of the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p., 15 min before the onset of anoxia), significantly amplified cell death. Finally, as mGlu2/3 receptors are implicated in the control of extracellular glutamate concentrations, we examined the stimulation of glutamate release in isolated goldfish retinas. Depolarizing medium containing 30 mM KCl led to a significant increase in glutamate release, which was substantially reduced by LY379268. We conclude that activation of mGlu2/3 receptors may provide a major defensive mechanism against ischemic/anoxic retinal damage.

Amino Acids↗
PubMed2006

Transglutaminase 2 ablation leads to defective function of mitochondrial respiratory complex I affecting neuronal vulnerability in experimental models of extrapyramidal disorders.

Transglutaminase 2 (TG2) represents the most ubiquitous isoform belonging to the TG family, and has been implicated in the pathophysiology of basal ganglia disorders, such as Parkinson's disease and Huntington's disease. We show that ablation of TG2 in knockout mice causes a reduced activity of mitochondrial complex I associated with an increased activity of complex II in the whole forebrain and striatum. Interestingly, TG2-/- mice were protected against nigrostriatal damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which is converted in vivo into the mitochondrial complex I inhibitor, 1-methyl-4-phenyl-pyridinium ion. In contrast, TG2-/- mice were more vulnerable to nigrostriatal damage induced by methamphetamine or by the complex II inhibitor, 3-nitropropionic acid. Proteomic analysis showed that proteins involved in the mitochondrial respiratory chain, such as prohibitin and the beta-chain of ATP synthase, are substrates for TG2. These data suggest that TG2 is involved in the regulation of the respiratory chain both in physiology and pathology, contributing to set the threshold for neuronal damage in extrapyramidal disorders.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2006

Pharmacological activation of mGlu4 metabotropic glutamate receptors inhibits the growth of medulloblastomas.

Moving from the evidence that activation of type 4 metabotropic glutamate (mGlu4) receptors inhibits proliferation and promotes differentiation of cerebellar granule cell neuroprogenitors, we examined the expression and function of mGlu4 receptors in medulloblastoma cells. mGlu4 receptors were expressed in 46 of 60 human medulloblastoma samples. Expression varied in relation to the histotype (nodular desmoplastic>classic>>large-cell anaplastic) and was inversely related to tumor severity, spreading, and recurrence. mGlu4 receptors were also found in D283med, D341med, and DAOY medulloblastoma cell lines, where receptor activation with the selective enhancer PHCCC inhibited adenylyl cyclase and the phosphatidylinositol-3-kinase pathway without affecting the mitogen-activated protein kinase, Sonic Hedgehog, and Wnt pathways. Interestingly, mGlu4 receptor activation reduced DNA synthesis and cell proliferation in all three cell lines. This effect was abrogated by the phosphatidylinositol-3-kinase inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one]. In in vivo experiments, repeated subcutaneous injections of N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC) reduced the growth of D283med and DAOY cell xenografts in nude mice. More remarkably, subcutaneous or intracranial injections of PHCCC during the first week of life prevented the development of medulloblastomas in mice lacking one Patched-1 allele and x-irradiated 1 d after birth. These data suggest that mGlu4 receptor enhancers are promising drugs for the treatment of medulloblastomas.

Animals↗
PubMed2006

Pharmacological activation of mGlu4 metabotropic glutamate receptors reduces nigrostriatal degeneration in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

We examined whether selective activation of mGlu4 metabotropic glutamate receptors attenuates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal damage in mice. C57BL mice were treated with a single dose of MPTP (30 mg/kg, i.p.) preceded, 30 min earlier, by a systemic injection of the mGlu4 receptor enhancer N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC). PHCCC was injected either subcutaneously in cremophor EL or intraperitoneally in saline containing 50% DMSO. PHCCC treatment (3 or 10 mg/kg) significantly reduced MPTP toxicity, as assessed by measurements of the striatal levels of dopamine and its metabolites and by tyrosine hydroxylase, dopamine transporter, and glial fibrillary acidic protein immunostaining in the corpus striatum and substantia nigra. In another set of experiments, a higher cumulative dose of MPTP (80 mg/kg divided into four injections with 2 h of interval) was injected to mGlu4-/- mice and their Sv129/CD1 wild-type controls. A higher dose was used in these experiments because Sv129/CD1 mice are less sensitive to MPTP toxicity. Systemic administration of PHCCC was protective in wild-type mice but failed to affect nigrostriatal damage in mGlu4-/- mice. Finally, unilateral infusion of PHCCC in the external globus pallidus protected the ipsilateral nigrostriatal pathway against MPTP toxicity. These data support the view that mGlu4 receptors are potential targets for the experimental treatment of parkinsonism.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2006

Pathways of polymeric vesicle formation.

Polymeric vesicle formation is dictated by the mutual diffusion of water into the bulk block copolymer and vice versa. The hydration of three poly(ethylene oxide)-co-poly(butylene oxide) copolymers with different molecular weights has been monitored both macroscopically (confocal laser scanning microscopy) and microscopically (small-angle X-ray scattering). Both methods have revealed that the amphiphilic block copolymers swell in water following two qualitatively different growth regimes. Initially, water and copolymer diffuse into each other following a subdiffusional growth as the result of a molecular-level arrangement of the amphiphilic membranes that comprise the swollen copolymer. After a critical time, which is exponential in polymer molecular weight, the amphiphilic membranes reach their equilibrium morphology and as a consequence the growth starts to follow Fickian diffusion. The complex hydration kinetics dictate the phases formed at the interface between the amphiphilic copolymer and water. Upon hydration of simple amphiphiles, the amphiphilic film swells and the concentration gradient at the interface with water gradually drops to zero. This strongly affects the complex driving forces that control vesicle formation. Indeed, to form vesicles, an energy barrier has to be overcome, and therefore a constant concentration gradient is required. We show, by enhancing the hydration kinetics via an ac field, how the interface concentration gradient is kept constant and the magnitude of this gradient dictates the final size of the vesicles.

Journal Article↗
PubMed2006

Polymeric vesicle permeability: a facile chemical assay.

We present a simple method to characterize vesicles and determine, at the same time, the membrane permeability to specific molecules. The method is based on encapsulating highly hydrophilic 3,3',3' '-phosphinidynetris-benzenesulfonic acid (PH) into vesicles and subsequently monitoring its reaction with 5,5'-dithiobis-2-nitrobenzoic acid (DTNB). We tested the method by measuring the membrane permeability of vesicles formed from a series of poly(ethylene oxide)-co-polybutylene oxide (EB) copolymers and egg yolk phosphatidylcholine. We found that the experimental data are in good agreement with calculations based on Fick's first law. We therefore quantified the DTNB permeability across vesicle membranes, finding that polymeric EB membranes have a more selective permeability toward polar molecules compared to phospholipids membranes.

Dithionitrobenzoic Acid↗
PubMed2006

Insulin secretion is controlled by mGlu5 metabotropic glutamate receptors.

Recent evidence suggests that metabotropic glutamate (mGlu) receptors are involved in the regulation of hormone secretion in the endocrine pancreas. We report here that endogenous activation of mGlu5 receptors is required for an optimal insulin response to glucose both in clonal beta-cells and in mice. In clonal beta-cells, mGlu5 receptors were expressed at the cell surface and were also found in purified insulin-containing granules. These cells did not respond to a battery of mGlu5 receptor agonists that act extracellularly, but instead responded to a cell-permeant analog of glutamate with an increase in [Ca2+]i and insulin secretion. Both effects were largely attenuated by the mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP). MPEP and its structural analog, (E)-2-methyl-6-styryl-pyridine (SIB-1893), reduced the increase in [Ca2+]i and insulin secretion induced by glucose in clonal beta-cells, whereas a mGlu1 receptor antagonist was inactive. mGlu5 knockout mice showed a defective insulin response at all times after a glucose pulse (1.5 g/kg, i.p.), whereas wild-type mice treated with MPEP (10 mg/kg, i.p.) showed a selective impairment in the late phase of insulin secretion in response to glucose challenge. Mice injected with MPEP or lacking mGlu5 receptors also showed a blunted glucagon response to an insulin challenge. We conclude that insulin secretion is under the control of mGlu5 receptors both in clonal beta-cells and in vivo. Drugs that modulate the function of mGlu5 receptors might affect glucose homeostasis by altering the secretion of pancreatic hormones.

Animals↗
PubMed2006

Interaction between ephrins/Eph receptors and excitatory amino acid receptors: possible relevance in the regulation of synaptic plasticity and in the pathophysiology of neuronal degeneration.

There is increasing evidence that Eph receptors and their transmembrane ligands, named ephrins, interact with glutamate receptors in both developing and adult neurons. EphB receptors interact with proteins that regulate the membrane trafficking of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor subunits, and both ephrins and EphB receptors have been found to co-localize with N-methyl-d-aspartate (NMDA) receptors and to positively modulate NMDA receptor function. Moreover, pharmacologic activation of ephrin-Bs amplifies group-I metabotropic glutamate receptor signaling through mechanisms that involve NMDA receptors. The interaction with ionotropic or metabotropic glutamate receptors provides a substrate for the emerging role of ephrins and Eph receptors in the regulation of activity-dependent forms of synaptic plasticity, such as long-term potentiation and long-term depression, which are established electrophysiologic models of associative learning. In addition, these interactions explain the involvement of ephrins/Eph receptors in the regulation of pain threshold and epileptogenesis, as well as their potential implication in processes of neuronal degeneration. This may stimulate the search for new drugs that might modulate excitatory synaptic transmission by interacting with the ephrin/Eph receptor system.

Animals↗
PubMed2006

Dopamine stimulation via infusion in the lateral ventricle.

Continuous dopamine (DA) stimulation is a therapeutic approach that applies to the treatment of motor fluctuations due to pulsatile DA stimulation in Parkinson's disease (PD), to cure the abuse of drugs, such as cocaine or amphetamine (which produce short-lasting peaks of extracellular DA), and as a safe therapeutic approach to avoid hedonistic homeostatic dysregulation (which sometime develops as an abuse pattern in PD patients receiving a pulsatile DA replacement therapy). However, systemic continuous delivery of DA agonists leads to a variety of side effects. In search for an alterative approach, in the present study we evaluated the possibility of delivering intracerebroventricularly (i.c.v.), a DA agonist: lisuride that was already shown to be effective when administered continuously subcutaneously (s.c.). In particular, we were interested in examining whether lisuride infused within the lateral ventricle was still able to stimulate DA receptor by inducing contralateral turning behavior in hemiparkinsonian rats. We found that lisuride, when infused in the lateral ventricle was effective in reducing the threshold for stimulating DA receptors. These results offer a more reliable and safe therapeutic approach to deliver continuous DA selectively in the brain.

Animals↗
PubMed2005

Tic disorders: from pathophysiology to treatment.

Tic disorders are stereotypic behaviours,more frequent than once believed, and therefore likely to be encountered by primary care physicians. Tics usually begin in childhood and are the clinical hallmark of Tourette Syndrome (TS), the most common cause of tics. TS is a relatively common neurobehavioural disorder with a spectrum of manifestations that wax and wane during its natural course. The pathophysiology of tics, at molecular and cellular level, is still unknown,whereas structural and functional neuroimaging studies have shown the involvement of the basal ganglia and related cortico-striato-thalamo-cortical circuits, and the dopaminergic neuronal system. Moreover, TS has a strong genetic background. The management of TS is often complicated by the presence of attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, and other behaviour disorders. The correct diagnosis is a fundamental step for a proper management of these disorders, and a multimodal treatment is usually indicated. This approach includes educational and supportive interventions, as well as pharmacological treatments when tics are at their worst.

Humans↗
PubMed2005

Bilayers and interdigitation in block copolymer vesicles.

Amphiphilic block copolyethers assemble into membranes with thickness between 2.4 and 7.5 nm. The vesicular morphology has been confirmed by small-angle X-ray scattering combined with electron microscopy for diblock copolymers and triblock copolymers of both architectures. The scaling of the membrane thicknesses with the length of the hydrophobic block is in good agreement with the strong segregation theory for block copolymer melts, indicating a mixed and stretched conformation of the hydrophobic chain inside the vesicle membrane. This result is in contrast to previously published results where the hydrophobic membranes were observed to have bilayer geometry and polymer chains that are relatively unperturbed from their ideal Gaussian dimensions.

Biomimetic Materials↗
PubMed2005

Nicergoline, a drug used for age-dependent cognitive impairment, protects cultured neurons against beta-amyloid toxicity.

Nicergoline, a drug used for the treatment of Alzheimer's disease and other types of dementia, was tested for its ability to protect neurons against beta-amyloid toxicity. Pure cultures of rat cortical neurons were challenged with a toxic fragment of beta-amyloid peptide (betaAP(25-35)) and toxicity was assessed after 24 h. Micromolar concentrations of nicergoline or its metabolite, MDL, attenuated betaAP(25-35)-induced neuronal death, whereas MMDL (another metabolite of nicergoline), the alpha1-adrenergic receptor antagonist, prazosin, or the serotonin 5HT-2 receptor antagonist, methysergide, were inactive. Nicergoline increased the basal levels of Bcl-2 and reduced the increase in Bax levels induced by beta-amyloid, indicating that the drug inhibits the execution of an apoptotic program in cortical neurons. In mixed cultures of rat cortical cells containing both neurons and astrocytes, nicergoline and MDL were more efficacious than in pure neuronal cultures in reducing beta-amyloid neurotoxicity. Experiments carried out in pure cultures of astrocytes showed that a component of neuroprotection was mediated by a mechanism of glial-neuronal interaction. The conditioned medium of cultured astrocytes treated with nicergoline or MDL for 72-96 h (collected 24 h after drug withdrawal) was neuroprotective when transferred to pure neuronal cultures challenged with beta-amyloid. In cultured astrocytes, nicergoline increased the intracellular levels of transforming-growth factor-beta and glial-derived neurotrophic factor, two trophic factors that are known to protect neurons against beta-amyloid toxicity. These results raise the possibility that nicergoline reduces neurodegeneration in the Alzheimer's brain.

Alzheimer Disease↗
PubMed2005

Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is required for the development of ischemic neuronal death.

Expression of Dickkopf-1 (Dkk-1), a secreted protein that negatively modulates the Wnt pathway, was induced in the hippocampus of gerbils and rats subjected to transient global cerebral ischemia as well as in cultured cortical neurons challenged with an excitotoxic pulse. In ischemic animals, the temporal and regional pattern of Dkk-1 expression correlated with the profile of neuronal death, as assessed by Nissl staining and Dkk-1 immunostaining in adjacent hippocampal sections. Treatment of ischemic animals with either Dkk-1 antisense oligonucleotides or lithium ions (which rescue the Wnt pathway acting downstream of the Dkk-1 blockade) protected vulnerable hippocampal neurons against ischemic damage. The same treatments protected cultured cortical neurons against NMDA toxicity. We conclude that induction of Dkk-1 with the ensuing inhibition of the canonical Wnt signaling pathway is required for the development of ischemic and excitotoxic neuronal death.

Animals↗
PubMed2005

Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha-synuclein.

In animals, sporadic injections of the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) selectively damage dopaminergic neurons but do not fully reproduce the features of human Parkinson's disease. We have now developed a mouse Parkinson's disease model that is based on continuous MPTP administration with an osmotic minipump and mimics many features of the human disease. Although both sporadic and continuous MPTP administration led to severe striatal dopamine depletion and nigral cell loss, we find that only continuous administration of MPTP produced progressive behavioral changes and triggered formation of nigral inclusions immunoreactive for ubiquitin and alpha-synuclein. Moreover, only continuous MPTP infusions caused long-lasting activation of glucose uptake and inhibition of the ubiquitin-proteasome system. In mice lacking alpha-synuclein, continuous MPTP delivery still induced metabolic activation, but induction of behavioral symptoms and neuronal cell death were almost completely alleviated. Furthermore, the inhibition of the ubiquitinproteasome system and the production of inclusion bodies were reduced. These data suggest that continuous low-level exposure of mice to MPTP causes a Parkinson-like syndrome in an alpha-synuclein-dependent manner.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2005

Endogenous activation of mGlu5 metabotropic glutamate receptors supports self-renewal of cultured mouse embryonic stem cells.

Cultured mouse embryonic stem (ES) cells maintained under undifferentiated conditions (i.e. grown in medium containing 15% FCS and leukemia inhibitory factor--LIF) expressed mGlu5 metabotropic glutamate receptors. Activation of these receptors with quisqualate increased [Ca2+]i but only when cultures were deprived of extracellular glutamate, indicating that the receptor was saturated by the endogenous glutamate. Pharmacological blockade of mGlu5 receptors with 2-methyl-6-(phenylethynyl)pyridine (MPEP) or antisense-induced knock-down of mGlu5 receptors decreased the expression of the two main transcription factors that sustain ES cell self-renewal, i.e. Oct-4 and Nanog, as assessed by real-time PCR and immunoblotting. Exposure of ES cell cultures to MPEP also reduced alkaline phosphatase activity, a marker of undifferentiated ES cells. These data support a critical role for mGlu receptors in early development showing that mGlu5 receptors are expressed by ES cells and their activation sustains ES cell self-renewal in culture.

Alanine Transaminase↗
PubMed2005

The evolution of vesicles from bulk lamellar gels.

The remarkable ability of phospholipids to generate vesicles and lamellar morphologies has been mimicked by amphiphilic block copolymers and both classes of amphiphiles have been extensively studied in bulk and in dilute solution. The most common vesicle preparation method involves diffusion of water into a lamellar gel. The transformation proceeds from a collection of water-poor planar lamellae, to a water-rich interconnected layer-phase and then a collection of closed lamellae (vesicles) that form a close-packed gel. This is demonstrated by scattering and microscopy with the evolution of the gel structure being driven by increasing curvature. Vesicles have been observed to form when the copolymer-water system still has long-range order, with a discrete, clustered-vesicle structure leading to a turbid dispersion. Eventually, at very low concentration, the packed vesicles separate, generating very stable isotropic dispersions that are transparent. This phase sequence, involving a dispersion of close-packed vesicles, accounts for the formation of a narrow size distribution in these systems.

Evolution, Chemical↗
PubMed2005

Metabotropic glutamate receptors in the basal ganglia motor circuit.

In recent years there have been tremendous advances in our understanding of the circuitry of the basal ganglia and our ability to predict the behavioural effects of specific cellular changes in this circuit on voluntary movement. These advances, combined with a new understanding of the rich distribution and diverse physiological roles of metabotropic glutamate receptors in the basal ganglia, indicate that these receptors might have a key role in motor control and raise the exciting possibility that they might provide therapeutic targets for the treatment of Parkinson's disease and related disorders.

Animals↗