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  • 1
    Language: English
    In: Endocrinology, December 2012, Vol.153(12), pp.5940-8
    Description: Pretreatment with 10 nm 17β-estradiol (17βE2) or 100 μm of the metabotropic glutamate 1 receptor (mGlu1R) agonist, dihydroxyphenylglycine (DHPG), protected neurons against N-methyl-d-aspartate (NMDA) toxicity. This effect was sensitive to blockade of both estrogen receptors and mGlu1R by their respective antagonists. In contrast, 17βE2 and/or DHPG, added after a low-concentration NMDA pulse (45 μm), produced an opposite effect, i.e. an exacerbation of NMDA toxicity. Again this effect was prevented by both receptor antagonists. In support of an interaction of estrogen receptors and mGlu1R in mediating a neurotoxic response, exacerbation of NMDA toxicity by 17βE2 disappeared when cultures were treated with DHPG prior to NMDA challenge, and conversely, potentiation of NMDA-induced cell death by DHPG was prevented by pretreatment with 17βE2. Addition of calpain III inhibitor (10 μm), 2 h before NMDA, prevented the increased damage induced by the two agonists, an affect that can be secondary to cleavage of mGlu1R by calpain. Accordingly, NMDA stimulation reduced expression of the full-length (140 kDa) mGluR1, an effect partially reversed by calpain inhibitor. Finally, in the presence of NMDA, the ability of 17βE2 to stimulate phosphorylation of AKT and ERK was impaired. Pretreatment with calpain inhibitor prevented the reduction of phosphorylated ERK but had no significant effect on phosphorylated AKT. Accordingly, the inhibition of ERK signaling by U0126 (1 μm) counteracted the effect of calpain inhibition on 17βE2-induced exacerbation of NMDA toxicity. The present data confirm the dual role of estrogens in neurotoxicity/neuroprotection and highlight the role of the timing of exposure to estrogens.
    Keywords: Cell Death -- Drug Effects ; Estradiol -- Metabolism ; N-Methylaspartate -- Pharmacology ; Neurons -- Metabolism ; Receptors, Metabotropic Glutamate -- Metabolism
    ISSN: 00137227
    E-ISSN: 1945-7170
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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: Neuron, 02 October 2013, Vol.80(1), pp.72-79
    Description: A novel experience induces the gene as well as plasticity of CA1 neural networks. To understand how these are linked, we briefly exposed GFP reporter mice of transcription to a novel environment. Excitatory synaptic function of CA1 neurons with recent in vivo induction ( GFP+) was similar to neighboring noninduced neurons. However, in response to group 1 metabotropic glutamate receptor (mGluR) activation, GFP+ neurons preferentially displayed long-term synaptic depression (mGluR-LTD) and robust increases in dendritic Arc protein. mGluR-LTD in GFP+ neurons required rapid protein synthesis and , suggesting that dendritic translation of Arc underlies the priming of mGluR-LTD. In support of this idea, novelty exposure increased messenger RNA in CA1 dendrites and promoted mGluR-induced translation of Arc in hippocampal synaptoneurosomes. Repeated experience suppressed synaptic transmission onto GFP+ neurons and occluded mGluR-LTD ex vivo. mGluR-LTD priming in neurons with similar activation history may contribute to encoding a novel environment. The consequence of experience-induced Arc gene on synaptic function is unknown. Jakkamsetti et al. find that novelty-induced Arc primes CA1 neurons for mGluR-dependent long-term synaptic depression through rapid translation of dendritic Arc mRNA, which may contribute to encoding of a salient experience.
    Keywords: Biology ; Anatomy & Physiology
    ISSN: 0896-6273
    E-ISSN: 1097-4199
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  • 4
    Language: English
    In: Neuroscience and Biobehavioral Reviews, October 2014, Vol.46, pp.228-241
    Description: Activation of group-I metabotropic glutamate receptors, mGlu1 and mGlu5, triggers a variety of signalling pathways in neurons and glial cells, which are differently implicated in synaptic plasticity. The earliest and much of key studies discovered abnormal mGlu5 receptor function in Fragile X syndrome (FXS) mouse models which then motivated more recent work that finds mGlu5 receptor dysfunction in related disorders such as intellectual disability (ID), obsessive-compulsive disorder (OCD) and autism. Therefore, mGlu1/5 receptor dysfunction may represent a common aetiology of these complex diseases. Furthermore, many studies have focused on dysregulation of mGlu5 signalling to synaptic protein synthesis. However, emerging evidence finds abnormal mGlu5 receptor interactions with its scaffolding proteins in FXS which results in mGlu5 receptor dysfunction and phenotypes independent of signalling to protein synthesis. Finally, both an increased and reduced mGlu5 functioning seem to be associated with ID and autism spectrum disorders, with important consequences for potential treatment of these developmental disorders.
    Keywords: Synaptic Plasticity ; Developmental Disorders ; Mental Retardation ; Fragile X ; Fmrp ; TSC ; Pten ; Neuroligin ; Homer ; Shank ; Sapap3 ; Anatomy & Physiology
    ISSN: 0149-7634
    E-ISSN: 1873-7528
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  • 5
    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 Dickkopf-1 (Dkk-1), an inhibitor of the canonical Wnt pathway, involved in neurodegeneration. Mice exposed to mild restraint stress showed increased hippocampal levels of Dkk-1 and reduced expression of β-catenin, an intracellular protein positively regulated by the canonical Wnt signalling pathway. In adrenalectomized mice, Dkk-1 was induced by corticosterone injection, but not by exposure to stress. Corticosterone also induced Dkk-1 in mouse organotypic hippocampal cultures and primary cultures of hippocampal neurons and, at least in the latter model, the action of corticosterone was reversed by the type-2 glucocorticoid receptor antagonist mifepristone. To examine whether induction of Dkk-1 was causally related to stress-induced hippocampal damage, we used doubleridge mice, which are characterized by a defective induction of Dkk-1. As compared to control mice, doubleridge mice showed a paradoxical increase in basal hippocampal Dkk-1 levels, but no Dkk-1 induction in response to stress. In contrast, stress reduced Dkk-1 levels in doubleridge mice. In control mice, chronic stress induced a reduction in hippocampal volume associated with neuronal loss and dendritic atrophy in the CA1 region, and a reduced neurogenesis in the dentate gyrus. Doubleridge mice were resistant to the detrimental effect of chronic stress and, instead, responded to stress with increases in dendritic arborisation and neurogenesis. Thus, the outcome of chronic stress was tightly related to changes in Dkk-1 expression in the hippocampus. These data indicate that induction of Dkk-1 is causally related to stress-induced hippocampal damage and provide the first evidence that Dkk-1 expression is regulated by corticosteroids in the central nervous system. Drugs that rescue the canonical Wnt pathway may attenuate hippocampal damage in major depression and other stress-related disorders.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 6
    In: Annals of Neurology, May 2013, Vol.73(5), pp.667-678
    Description: Objective The concept of inflammation-induced sensitization is emerging in the field of perinatal brain injury, stroke, Alzheimer disease, and multiple sclerosis. However, mechanisms underpinning this process remain unidentified. Methods We combined in vivo systemic lipopolysaccharide-induced or interleukin (IL)-1[beta]-induced sensitization of neonatal and adult rodent cortical neurons to excitotoxic neurodegeneration with in vitro IL-1[beta] sensitization of human and rodent neurons to excitotoxic neurodegeneration. Within these inflammation-induced sensitization models, we assessed metabotropic glutamate receptors (mGluR) signaling and regulation. Results We demonstrate for the first time that group I mGluRs mediate inflammation-induced sensitization to neuronal excitotoxicity in neonatal and adult neurons across species. Inflammation-induced G protein-coupled receptor kinase 2 (GRK2) downregulation and genetic deletion of GRK2 mimicked the sensitizing effect of inflammation on excitotoxic neurodegeneration. Thus, we identify GRK2 as a potential molecular link between inflammation and mGluR-mediated sensitization. Interpretation Collectively, our findings indicate that inflammation-induced sensitization is universal across species and ages and that group I mGluRs and GRK2 represent new avenues for neuroprotection in perinatal and adult neurological disorders. Ann Neurol 2013; 73:667-678
    Keywords: Age ; Glutamic Acid Receptors (Metabotropic) ; Double Prime G Protein-Coupled Receptor Kinase 2 ; Brain Injury ; Neurological Diseases ; Multiple Sclerosis ; Alzheimer'S Disease ; Stroke ; Animal Models ; Neuroprotection ; Inflammation ; Neurodegenerative Diseases ; Cortex ; Beta -Adrenergic-Receptor Kinase ; Neonates ; Excitotoxicity ; Neurology & Neuropathology ; Natural Toxins;
    ISSN: 0364-5134
    E-ISSN: 1531-8249
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  • 7
    Language: English
    In: Cell and Tissue Research, Jan, 2012, Vol.347(1), p.291(11)
    Description: Abstract Alzheimer's disease (AD) is a neurodegenerative disorder that affects about 35 million people worldwide. Current drugs for AD only treat the symptoms and do not interfere with the underlying pathogenic mechanisms of the disease. AD is characterized by the presence of [beta]-amyloid (A[beta]) plaques, neurofibrillary tangles, and neuronal loss. Identification of the molecular determinants underlying Ferdinando Nicoletti and Agata Copani are co-senior authors. A[beta]-induced neurodegeneration is an essential step for the development of disease-modifying drugs. Recently, an impairment of the transforming growth factor-[beta]1 (TGF[beta]1) signaling pathway has been demonstrated to be specific to the AD brain and, particularly, to the early phase of the disease. TGF-[beta]1 is a neurotrophic factor responsible for the initiation and maintenance of neuronal differentiation and synaptic plasticity. The deficiency of TGF-[beta]1 signaling is associated with A[beta] pathology and neurofibrillary tangle formation in AD animal models. Reduced TGF-[beta]1 signaling seems to contribute both to microglial activation and to ectopic cell-cycle re-activation in neurons, two events that contribute to neurodegeneration in the AD brain. The neuroprotective features of TGF-[beta]1 indicate the advantage of rescuing TGF-[beta]1 signaling as a means to slow down the neurodegenerative process in AD. Keywords Alzheimer's disease * [beta]-Amyloid * Transforming growth factor-[beta]1 * Apoptosis * Cell cycle activation. Neuroprotection
    Keywords: Alzheimer's Disease -- Development And Progression ; Bone Morphogenetic Proteins ; Amyloid Beta-protein ; Transforming Growth Factors
    ISSN: 0302-766X
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  • 8
    Language: English
    In: European Journal of Pharmacology, 22 August 2005, Vol.518(2-3), pp.111-115
    Description: We compared the neurotoxic profile of racemic bupivacaine and levobupivacaine in: (i) a mouse model of -methyl- -aspartate (NMDA)-induced seizures and (ii) in an in vitro model of excitotoxic cell death. When used at high doses (36 mg/kg) both bupivacaine and levobupivacaine reduced the latency to NMDA-induced seizures and increased seizure severity. However, levobupivacaine-treated animals underwent less severe seizures as compared with bupivacaine-treated animals. Lower doses of levobupivacaine and bupivacaine had opposite effects on NMDA-induced seizures. At doses of 5 mg/kg, levobupivacaine increased the latency to partial seizures and prevented the occurrence of generalized seizures, whereas bupivacaine decreased the latency to partial seizures and did not influence the development of generalized seizures. In in vitro experiments, we exposed primary cultures of mouse cortical cells, containing both neurons and astrocytes, to 100 μM NMDA for 10 min for the induction of excitotoxic neuronal death. This treatment killed 70–80% of the neuronal population, as assessed 24 h after the excitotoxic pulse. In this particular model, both levobupivacaine and bupivacaine were neuroprotective against NMDA toxicity. However, neuroprotection by levobupivacaine was seen at lower concentrations (with respect to bupivacaine) and was maintained at concentrations of 3 mM, which are much higher than the plasma security threshold for the drug in vivo. In contrast, no protection against NMDA toxicity was detected when 3 mM concentrations of bupivacaine were applied to the cultures. Our data show a better neurotoxic profile of levobupivacaine as compared to racemic bupivacaine, and are indicative of a safer profile of levobupivacaine in clinical practice.
    Keywords: Bupivacaine ; Levobupivacaine ; Neurotoxicity ; Nmda ; Mice Mixed Cultures of Cortical Neurons ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0014-2999
    E-ISSN: 1879-0712
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  • 9
    Language: English
    In: Trends in Neurosciences, 2001, Vol.24(1), pp.25-31
    Description: Cell-cycle-related proteins, such as cyclins or cyclin-dependent kinases, are re-expressed in neurons committed to death in response to a variety of insults, including excitotoxins, hypoxia and ischemia, loss of trophic support, or [Beta]-amyloid peptide. In some of these conditions events that are typical of the mid-G1 phase, such as cyclin-dependent kinase 4/6 activation, are required for the induction of neuronal death. In other cases, the cycle must proceed further and recruit steps that are typical of the G1/S transition for death to occur. Finally, there are conditions in which cell-cycle proteins might be re-expressed, but do not contribute to neuronal death. We hypothesize that cell-cycle signaling becomes a mandatory component of neuronal demise when other mechanisms are not enough for neurons to reach the threshold for death. Under this scheme, the death threshold is set by the extent of DNA damage. Whenever the extent of DNA damage is below this threshold, a cell-cycle signaling becomes crucial for the induction of neuronal death through p53-dependent or -independent pathways.
    Keywords: Cell Cycle ; Neuronal Apoptosis ; Triphic Deprivation ; DNA Damage ; Excitotoxicity ; Beta-Amyloid ; Medicine ; Anatomy & Physiology
    ISSN: 0166-2236
    E-ISSN: 1878-108X
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  • 10
    Language: English
    In: Trends in Pharmacological Sciences, 2010, Vol.31(4), pp.153-160
    Description: Activation of metabotropic glutamate 2 (mGlu2) receptors inhibits pain transmission at the synapses between primary afferent fibers and neurons in the dorsal horn of the spinal cord. In addition, mGlu2 receptors are found in peripheral nociceptors, and in pain-regulatory centers of the brain stem and forebrain. mGlu2 receptor agonists produce analgesia in models of inflammatory and neuropathic pain, but their use is limited by the development of tolerance. A new therapeutic strategy could be based on the transcriptional regulation of mGlu2 receptors via the acetylation-promoted activation of the p65/RelA transcription factor. “Epigenetic” drugs that increase mGlu2 receptor expression, including -acetylcarnitine and inhibitors of histone deacetylases, have a different analgesic profile with no tolerance to the therapeutic effect after repeated dosing.
    Keywords: Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0165-6147
    E-ISSN: 1873-3735
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