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1.
Mol Psychiatry ; 23(4): 812-823, 2018 04.
Article in English | MEDLINE | ID: mdl-29158584

ABSTRACT

Among neurobiological mechanisms underlying antidepressant properties of ketamine, structural remodeling of prefrontal and hippocampal neurons has been proposed as critical. The suggested mechanism involves downstream activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which trigger mammalian target of rapamycin (mTOR)-dependent structural plasticity via brain-derived neurotrophic factor (BDNF) and protein neo-synthesis. We evaluated whether ketamine elicits similar molecular events in dopaminergic (DA) neurons, known to be affected in mood disorders, using a novel, translational strategy that involved mouse mesencephalic and human induced pluripotent stem cells-derived DA neurons. Sixty minutes exposure to ketamine elicited concentration-dependent increases of dendritic arborization and soma size in both mouse and human cultures as measured 72 hours after application. These structural effects were blocked by mTOR complex/signaling inhibitors like rapamycin. Direct evidence of mTOR activation by ketamine was revealed by its induction of p70S6 kinase. All effects of ketamine were abolished by AMPA receptor antagonists and mimicked by the AMPA-positive allosteric modulator CX614. Inhibition of BDNF signaling prevented induction of structural plasticity by ketamine or CX614. Furthermore, the actions of ketamine required functionally intact dopamine D3 receptors (D3R), as its effects were abolished by selective D3R antagonists and absent in D3R knockout preparations. Finally, the ketamine metabolite (2R,6R)-hydroxynorketamine mimicked ketamine effects at sub-micromolar concentrations. These data indicate that ketamine elicits structural plasticity by recruitment of AMPAR, mTOR and BDNF signaling in both mouse mesencephalic and human induced pluripotent stem cells-derived DA neurons. These observations are of likely relevance to the influence of ketamine upon mood and its other functional actions in vivo.


Subject(s)
Dopaminergic Neurons/drug effects , Ketamine/metabolism , Mesencephalon/drug effects , Neuronal Plasticity/drug effects , Animals , Antidepressive Agents/pharmacology , Brain/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Hippocampus/metabolism , Humans , Induced Pluripotent Stem Cells/drug effects , Ketamine/pharmacology , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, AMPA/drug effects , Receptors, AMPA/metabolism , Receptors, Dopamine D3/metabolism , Receptors, Glutamate/drug effects , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism
2.
Naunyn Schmiedebergs Arch Pharmacol ; 389(5): 529-38, 2016 May.
Article in English | MEDLINE | ID: mdl-26905520

ABSTRACT

Preclinical data indicate a direct anti-tumor effect of zoledronic acid (ZA) outside the skeleton, but its molecular mechanism is still not completely clarified. The aim of this study was to investigate the anti-cancer effects of ZA in human breast cancer cell lines, suggesting that they may in part be mediated via the miR-21/PTEN/Akt signaling pathway. The effect of ZA on cell viability was measured by MTT assay, and cell death induction was analyzed using either a double AO/EtBr staining and M30 ELISA assay. A Proteome Profiler Human Apoptosis Array was executed to evaluate the molecular basis of ZA-induced apoptosis. Cell cycle analysis was executed by flow cytometry. The effect of ZA on miR-21 expression was quantified by qRT-PCR, and the amount of PTEN protein and its targets were analyzed by Western blot. ZA inhibited cell growth in a concentration- and time-dependent manner, through the activation of cell death pathways and arrest of cell cycle progression. ZA downregulated the expression of miR-21, resulting in dephosphorilation of Akt and Bad and in a significant increase of p21 and p27 proteins expression. These results were observed also in MDA-MB-231 cells, commonly used as an experimental model of bone metastasis of breast cancer. This study revealed, for the first time, an involvement of the miR-21/PTEN/Akt signaling pathway in the mechanism of ZA anti-cancer actions in breast cancer cells. We would like to underline that this pathway is present both in the hormone responsive BC cell line (MCF-7) as well as in a triple negative cell line (MDA-MB-231). Taken together these results reinforce the use of ZA in clinical practice, suggesting the role of miR-21 as a possible mediator of its therapeutic efficacy.


Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/metabolism , Diphosphonates/pharmacology , Imidazoles/pharmacology , MicroRNAs/metabolism , PTEN Phosphohydrolase/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Female , Humans , Signal Transduction/drug effects , Zoledronic Acid
3.
Neuroscience ; 302: 112-20, 2015 Aug 27.
Article in English | MEDLINE | ID: mdl-25450955

ABSTRACT

Activation of microglia associated with neuroinflammation and loss of phagocytic activity is considered to play a prominent role in the pathogenesis of Alzheimer's disease (AD). CHF5074 (CSP-1103) has been shown to improve cognition and reduce brain inflammation in patients with mild cognitive impairment (MCI). CHF5074 was also found to reverse impairments in recognition memory and improve hippocampal long-term potentiation when administered to plaque-free Tg2576 mice (5-month-old) for 4 weeks. Though, no investigation has focused on the consequence of CHF5074 treatment on microglia polarization yet. In this study we evaluated the effect of CHF5074 administration (375 ppm in the diet) to 5-month-old Tg2576 mice on the expression of pro-inflammatory (M1) genes, Interleukin 1 beta (IL-1ß), Tumor Necrosis Factor alpha (TNFα) and inducible Nitric Oxide Synthase (iNOS), and anti-inflammatory/phagocytic (M2) markers Mannose Receptor type C 1 (MRC1/CD206), Triggering Receptor Expressed on Myeloid cells 2 (TREM2) and Chitinase 3-like 3 (Ym1). No changes of pro-inflammatory gene transcription but a reduced expression of MRC1/CD206, TREM2 and Ym1 were detected in the hippocampus of young Tg2576 mice receiving normal diet, when compared to wild-type littermates. CHF5074 did not affect the pro-inflammatory transcription but significantly increased the expression of MRC1/CD206 and Ym1. CHF5074 effects appeared to be hippocampus-specific, as the M2 transcripts were only slightly modified in the cerebral cortex. In primary cultures of mouse astrocyte-microglia, CHF5074 totally suppressed the expression of TNF-α, IL-1ß and iNOS induced by 10 µM ß-amyloid1-42 (Aß42). Moreover, CHF5074 significantly increased the expression of anti-inflammatory/phagocytic markers MRC1/CD206 and TREM2, reduced by the Aß42 application alone. The effect of CHF5074 was not reproduced by ibuprofen (3 µM or 500 µM) or R-flurbiprofen (3 µM or 100 µM), as both compounds limited the pro-inflammatory gene expression but did not modify the anti-inflammatory/phagocytic transcription. These data show that CHF5074 specifically drives the expression of microglia M2 markers either in young Tg2576 hippocampus or in primary astrocyte-microglia cultures, suggesting its potential therapeutic efficacy as microglial modulator in the early phase of AD.


Subject(s)
Alzheimer Disease/pathology , Amyloid beta-Peptides/pharmacology , Brain/pathology , Cyclopropanes/therapeutic use , Flurbiprofen/analogs & derivatives , Neuroglia/drug effects , Alzheimer Disease/drug therapy , Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/genetics , Animals , Animals, Newborn , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antipsychotic Agents/pharmacology , Antipsychotic Agents/therapeutic use , Case-Control Studies , Cells, Cultured , Cyclopropanes/pharmacology , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Female , Flurbiprofen/pharmacology , Flurbiprofen/therapeutic use , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutation/genetics , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/metabolism , Time Factors
4.
Mol Cell Endocrinol ; 284(1-2): 11-20, 2008 Mar 12.
Article in English | MEDLINE | ID: mdl-18280641

ABSTRACT

A dysregulation of the nerve growth factor (NGF)-mediated control of prostate cell growth is associated with the malignant progression of prostate epithelial cells. Exogenous NGF induced in prostate cancer (PCa) cell lines DU145 and PC3 the expression of p75(NGFR), accompanied by a reduction of the cell malignancy. The aim of this study was to analyze the profile of NGF-regulated genes the PCa cell line DU145 by using the cDNA microarray technique. NGF treatment of DU145 cells decreased the expression of 52 known genes, while the expression of 40 known genes was increased. NGF treatment of the DU145 cell line modified the expression profile of clusters of genes involved in invasion and metastasis, in cell proliferation and apoptosis, inflammation, cell metabolism and transcriptional activity. Interestingly, NGF induced the same pattern of gene modifications in both PCa cell lines. Data presented here may help to identify gene/proteins that dispose to PCa progression and to assess future markers that could allow the development of new clinic diagnostic and therapeutical approaches.


Subject(s)
Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Nerve Growth Factor/metabolism , Prostatic Neoplasms/genetics , Apoptosis/genetics , Cell Differentiation , Cell Line, Tumor , Cell Proliferation , Gene Expression Profiling/methods , Humans , Male , Neoplasm Invasiveness/genetics , Neoplasm Metastasis/genetics , Nerve Tissue Proteins/metabolism , Oligonucleotide Array Sequence Analysis , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Receptors, Nerve Growth Factor/metabolism , Recombinant Proteins/metabolism , Reproducibility of Results , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/genetics , Transcription Factors/genetics
5.
Curr Top Med Chem ; 6(8): 801-8, 2006.
Article in English | MEDLINE | ID: mdl-16719818

ABSTRACT

Dopamine and glutamate have been shown to extensively interact in the striatum, nucleus accumbens, hippocampus and prefrontal cortex, to regulate different physiological functions, including locomotor activity, positive reinforcement, attention and working memory. Although dysfunctions of dopamine transmission have long been identified as critical determinants of neurological and neuropsychiatric disorders, such as Parkinson's disease and schizophrenia, there is now increasing evidence that concurrent alterations of dopamine and glutamate function may play a central role in the pathophysiology of these diseases. Thus, defining the characteristics of dopamine-glutamate interactions may be crucial to identify alternative molecular targets for the development of novel pharmacological tools. At the postsynaptic level, interactions between the dopamine D1 and the glutamate NMDA receptors appear to be particularly relevant. Different mechanisms are involved in this interactions: 1) D1R-dependent, second messenger-mediated phosphorylation of NMDAR subunits; 2) coordinated regulation of receptor trafficking at synaptic sites; 3) formation of an heteromeric D1/NMDA receptor complex. In this paper we review the molecular mechanisms, functional implications and pharmacological significance of D1R/NMDAR interaction via direct protein-protein oligomerization.


Subject(s)
Receptors, Dopamine D1/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Drug Design , Parkinson Disease , Schizophrenia
6.
Acta Neurochir Suppl ; 93: 59-63, 2005.
Article in English | MEDLINE | ID: mdl-15986728

ABSTRACT

NF-kappaB is a nuclear transcription factor involved in the control of fundamental cellular functions including regulation of cell survival. We investigated NF-kappaB activation induced by two opposing modulators of cell viability: IL-1beta and glutamate. We found that IL-1beta activated p50, p65 and c-Rel subunits of NF-kappaB, while glutamate activated only p50 and p65 proteins. Cell stimulation by glutamate, correlated with expression of the pro-apoptotic genes Caspase-3, Caspase-2L and Bax. Conversely, IL-1beta induced the expression of the short anti-apoptotic isoform of Caspase-2. Finally, we analysed the effect of the inhibition of IkappaBalpha degradation on glutamate-induced toxicity by using BAY 11-7082, a selective inhibitor of IkappaBalpha phosphorylation. Our results suggest that BAY 11-7082 preserves neuron viability from the glutamate-mediated injury.


Subject(s)
Apoptosis/physiology , Glutamic Acid/pharmacology , I-kappa B Proteins/metabolism , Interleukin-1/pharmacology , Neurons/metabolism , Animals , Apoptosis/drug effects , Cells, Cultured , Cerebellum/cytology , Cerebellum/drug effects , Cerebellum/metabolism , Enzyme Activation/drug effects , Enzyme Inhibitors , I-kappa B Proteins/antagonists & inhibitors , NF-KappaB Inhibitor alpha , NF-kappa B , Neurons/drug effects , Phosphorylation/drug effects , Rats , Rats, Sprague-Dawley
7.
Cell Death Differ ; 12(7): 761-72, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15818410

ABSTRACT

Opposite effects of nuclear factor-kappaB (NF-kappaB) on neuron survival rely on activation of diverse NF-kappaB factors. While p65 is necessary for glutamate-induced cell death, c-Rel mediates prosurvival effects of interleukin-1beta. However, it is unknown whether activation of c-Rel-dependent pathways reduces neuron vulnerability to amyloid-beta (Abeta), a peptide implicated in Alzheimer's disease pathogenesis. We show that neuroprotection elicited by activation of metabotropic glutamate receptors type 5 (mGlu5) against Abeta toxicity depends on c-Rel activation. Abeta peptide induced NF-kappaB factors p50 and p65. The mGlu5 agonists activated c-Rel, besides p50 and p65, and the expression of manganese superoxide dismutase (MnSOD) and Bcl-X(L). Targeting c-Rel expression by RNA interference suppressed the induction of both antiapoptotic genes. Targeting c-Rel or Bcl-X(L) prevented the prosurvival effect of mGlu5 agonists. Conversely, c-Rel overexpression or TAT-Bcl-X(L) addition rescued neurons from Abeta toxicity. These data demonstrate that mGlu5 receptor activation promotes a c-Rel-dependent antiapoptotic pathway responsible for neuroprotection against Abeta peptide.


Subject(s)
Amyloid beta-Peptides/toxicity , NF-kappa B/metabolism , Neurons/drug effects , Neuroprotective Agents/pharmacology , Proto-Oncogene Proteins c-rel/metabolism , Receptors, Metabotropic Glutamate/agonists , Receptors, Metabotropic Glutamate/metabolism , Animals , Cell Line, Tumor , Cell Survival/drug effects , Cells, Cultured , Cerebral Cortex/cytology , Enzyme Inhibitors/pharmacology , Excitatory Amino Acid Agonists/pharmacology , Gene Deletion , Gene Silencing , Glycine/analogs & derivatives , Glycine/pharmacology , Humans , Mice , Mice, Inbred C57BL , Neurons/cytology , Neurons/metabolism , Neurons/pathology , Neuroprotective Agents/metabolism , Phenylacetates/pharmacology , Proto-Oncogene Proteins c-rel/deficiency , Proto-Oncogene Proteins c-rel/genetics , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Receptors, Metabotropic Glutamate/genetics , Superoxide Dismutase/metabolism
8.
Neurosci Lett ; 377(3): 147-51, 2005 Apr 04.
Article in English | MEDLINE | ID: mdl-15755516

ABSTRACT

NF-kappaB is a nuclear transcription factor involved in the control of fundamental cellular functions including cell survival. Among the many target genes of this factor, both pro- and anti-apoptotic genes have been described. To evaluate the contribution of NF-kappaB activation to excitotoxic insult, we analysed the effect of IkappaBalpha (IkappaBalpha) phosphorylation blockade on glutamate-induced toxicity in adult mouse hippocampal slices. By using immunocytochemical and EMSA techniques, we found that (i) acute exposure of hippocampal slices to NMDA induced nuclear translocation of NF-kappaB, (ii) NMDA-mediated activation of NF-kappaB was prevented by BAY 11-7082, an inhibitor of IkappaBalpha phosphorylation and degradation, and (iii) BAY 11-7082-mediated inhibition of NF-kappaB activation was associated with neuroprotection.


Subject(s)
Hippocampus/drug effects , I-kappa B Proteins/antagonists & inhibitors , N-Methylaspartate/antagonists & inhibitors , N-Methylaspartate/toxicity , Nitriles/pharmacology , Sulfones/pharmacology , Animals , Hippocampus/metabolism , Hippocampus/pathology , I-kappa B Proteins/metabolism , In Vitro Techniques , Mice , NF-KappaB Inhibitor alpha , Phosphorylation/drug effects
9.
Neuroscience ; 114(1): 91-8, 2002.
Article in English | MEDLINE | ID: mdl-12207957

ABSTRACT

Impairments of cortical cholinergic inputs from the nucleus basalis magnocellularis fundamentally alter information processing and attentional function, thereby advancing the severity of psychopathology in major neuropsychiatric disorders. It was previously shown in adult rats that bilateral 192 IgG saporin-induced selective immunolesioning of the cholinergic neurons in the nucleus basalis produces pronounced and long-lasting deficits in sensorimotor gating measured by prepulse inhibition of the startle reflex. This behavioral paradigm is considered a valid model of sensorimotor gating deficits in the psychotic spectrum and efforts to analyze the significance of the cholinergic basal forebrain in this context are of great interest. In the present study the predictive value of the selective cholinergic immunolesioning model was tested by examining the ability of the cholinesterase inhibitor rivastigmine to restore prepulse inhibition in immunolesioned rats. We report here a pronounced restoring effect of acute (0.75 or 1.5 mg/kg s.c.) as well as repeated (0.75 mg/kg s.c. b.i.d., for 10 days) treatment with rivastigmine in this model of disrupted prepulse inhibition. Intra-nucleus basalis magnocellularis infusions of 192 IgG saporin resulted in extensive loss of basal-cortical cholinergic neurons as shown by the marked decrease in basal telencephalic choline acetyltransferase immunopositive neurons and cortical choline acetyltransferase activity. In this condition, rivastigmine was found to significantly increase cortical acetylcholine extracellular levels in lesioned animals measured by in vivo microdialysis. Taken together, our results strengthen the proposal that the nucleus basalis represents a critical station of the startle gating circuitry. In addition, our findings strongly indicate that even after dramatic decrease of cholinergic neurons, inhibition of acetylcholinesterase restores the cholinergic synaptic function to a point approaching normalization of experimentally induced psychopathology.


Subject(s)
Basal Nucleus of Meynert/drug effects , Carbamates/pharmacology , Cerebral Cortex/drug effects , Cholinergic Fibers/drug effects , Cholinesterase Inhibitors/pharmacology , Neural Pathways/drug effects , Phenylcarbamates , Psychotic Disorders/drug therapy , Acetylcholine/metabolism , Acetylcholinesterase/metabolism , Animals , Antibodies, Monoclonal , Basal Nucleus of Meynert/metabolism , Basal Nucleus of Meynert/physiopathology , Cerebral Cortex/metabolism , Cerebral Cortex/physiopathology , Choline O-Acetyltransferase/metabolism , Cholinergic Fibers/metabolism , Disease Models, Animal , Immunohistochemistry , Immunotoxins , Male , N-Glycosyl Hydrolases , Neural Inhibition/drug effects , Neural Inhibition/physiology , Neural Pathways/metabolism , Neural Pathways/physiopathology , Neurons/drug effects , Neurons/metabolism , Psychotic Disorders/metabolism , Psychotic Disorders/physiopathology , Rats , Rats, Sprague-Dawley , Reflex, Startle/drug effects , Reflex, Startle/physiology , Ribosome Inactivating Proteins, Type 1 , Rivastigmine , Saporins , Treatment Outcome
10.
Dement Geriatr Cogn Disord ; 13(3): 183-92, 2002.
Article in English | MEDLINE | ID: mdl-11893841

ABSTRACT

This study was designed to assess the effects of rivastigmine (Exelon) on the cognitive functioning of patients suffering from dementia with Lewy bodies. This was a prospective, multi-centre, randomised, double-blind, placebo-controlled exploratory study conducted at sites in the UK, Spain and Italy. The treatment period was 20 weeks with a 3-week posttreatment follow-up. The primary outcome measures were the Cognitive Drug Research (CDR) computerised assessment system and the Neuropsychiatric Inventory. Testing was conducted prior to dosing and then again at weeks 12, 20 and 23. Analysis of the data from the 92 patients who completed the study identified a significant pattern of benefits of rivastigmine over placebo on the CDR system. These benefits were seen on tests of attention, working memory and episodic secondary memory. Taking attention for example, patients given placebo showed a significant deterioration from predosing scores at 12 and 20 weeks, whereas patients on rivastigmine performed significantly above their predosing levels. These effects were also large in magnitude, the decline under placebo at week 12 being 19%, while the improvement under rivastigmine was 23%. The clinical relevance of this 23% improvement was that it took the patients 33% towards being normal for their age on this assessment of attention. These benefits to cognitive function were accompanied by a significant improvement of the other primary outcome measure, the Neuropsychiatric Inventory. Three weeks after discontinuation of rivastigmine, most parameters of cognitive performance returned to predrug levels.


Subject(s)
Carbamates/administration & dosage , Lewy Body Disease/drug therapy , Neuroprotective Agents/administration & dosage , Phenylcarbamates , Aged , Diagnosis, Computer-Assisted , Double-Blind Method , Female , Follow-Up Studies , Humans , Lewy Body Disease/diagnosis , Male , Neurology , Neuropsychological Tests , Prospective Studies , Rivastigmine , Treatment Outcome
11.
Neuropeptides ; 36(6): 391-5, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12507432

ABSTRACT

A role of nerve growth factor (NGF) in the neuro-endocrine-immune interactions has been recently suggested by the presence of NGF and its receptors in cells of the immune and endocrine systems. The improvement in the comprehension of the role played by NGF in humans is linked to the availability of a sensitive and reliable method to quantify NGF concentrations in body fluids and tissues. As a consequence of different methods used, normal levels of human serum NGF reported in the literature show wide differences. The present results indicate that ELISA appears very sensitive (detection limit 1.4pg/ml) and allows the discrimination of subtle variations of serum NGF concentrations. ELISA performed in serum obtained from men indicated that NGF concentration was 40.8+/-10.8pg/ml, whereas women showed significantly lower levels that were influenced by the menstrual cycle. In particular, the mean value of this neurotrophin during the follicular phase was 8.2+/-1.4pg/ml; the luteal phase, in turn, showed levels up to 14.4+/-2.9pg/ml. The difference of serum NGF concentrations between the follicular and luteal phase in each woman was statistically significant. Differences in NGF concentrations between men and women (in both phases of the menstrual cycles) were also statistically significant. In conclusion, a possible role of sex steroids as modulators of NGF secretion in humans is strongly supported by the present paper. However, mechanisms underlying this phenomenon are still unknown. The evidence indicating physiological sex hormone-related variations in NGF levels would be of interest in view of the possible use of circulating NGF modifications as a laboratory biomarker in different diseases.


Subject(s)
Nerve Growth Factor/blood , Sex Characteristics , Adult , Female , Follicular Phase/blood , Humans , Immunoenzyme Techniques , Luteal Phase/blood , Male
12.
J Neurol ; 247(2): 88-96, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10751109

ABSTRACT

Several neurological conditions have been reported to be associated with peripheral or central deficits of olfactory system. In recent years particular emphasis has been placed on the early and severe olfactory impairment in Parkinson's disease (PD), in which limited neuropathological studies have revealed a marked dopaminergic deficit in the olfactory tubercles. Moreover, indirect evidence suggests that dysfunction of the dopaminergic pathways from mesencephalon to the piriform cortex may play a role in olfactory impairment in PD. A large number of clinical studies have reported that olfactory loss in idiopathic PD is bilateral, present in hemiparkinsonism, unrelated to the stage or clinical subtype of the disease, and independent of antiparkinsonian medication. In addition, major olfactory alterations have been reported in familial PD and dementia with Lewy bodies but not in progressive supranuclear palsy and essential tremor. These findings might stimulate further research targeted to determine the biological substrate of dissimilar olfactory performances in these movement disorders. The present review summarizes standardized procedures for the assessment of olfactory acuity (detection threshold), identification (multiple choice odor naming), discrimination (differentiation between similar/dissimilar odorants), and memory (recognition of a substance previously smelled). Specific suggestions concerning the psychometric and neuropsychological evaluation of PD patients are provided.


Subject(s)
Olfactory Pathways/physiopathology , Parkinson Disease/physiopathology , Humans
13.
Neuropharmacology ; 39(5): 903-10, 2000 Mar 03.
Article in English | MEDLINE | ID: mdl-10699456

ABSTRACT

Research has provided evidence about the role of excitotoxicity in the pathophysiology of sporadic amyotrophic lateral sclerosis and suggests that AMPA/kainate receptor activation contributes greatly in mediating glutamate injury to motor neurons. The recent finding of variable expression of metabotropic glutamate (mGlu) receptor subtypes in adult rat spinal cord has prompted us to investigate their contribution to the excitotoxic process. We report here that stimulation of mGlu receptors efficiently prevents motor neuron degeneration induced by kainate. The application of kainate to lumbar spinal cord slices from adult rats induced a massive degeneration of motor neurons which became shrunken, dark and TUNEL-positive. On the contrary, no significant neurotoxicity was observed after NMDA application. A blockade of ionotropic non-NMDA receptors by CNQX, and mGlu receptor stimulation, efficiently counteracted kainate-mediated cell death. Among the various agonists for mGlu receptors, we tested 3-hydroxyphenylglycine (3HPG), which selectively stimulates group I mGlu receptors. In addition, we tested 2-(carboxycyclopropyl)glycine (L-CCG-I) and 4-carboxy-3-hydroxyphenylglycine (4C3HPG), two selective agonists for group II receptors, as well as L-amino-4-phosphonobutyrate (L-AP4), a preferential agonist for group III. The results suggest that all three groups of mGlu receptors are involved in inhibiting excitotoxic phenomena mediated by kainate on spinal cord motor neurons. This was despite being localized differently and, possibly, activating different neuroprotective pathways.


Subject(s)
Excitatory Amino Acid Agonists/pharmacology , Motor Neurons/drug effects , Nerve Degeneration/prevention & control , Neuroprotective Agents/pharmacology , Receptors, Metabotropic Glutamate/agonists , Spinal Cord/drug effects , 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology , Animals , Benzoates/pharmacology , Cell Survival/drug effects , Choline O-Acetyltransferase/metabolism , Cycloleucine/analogs & derivatives , Cycloleucine/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Glycine/analogs & derivatives , Glycine/pharmacology , In Situ Nick-End Labeling , In Vitro Techniques , Kainic Acid , Male , Motor Neurons/enzymology , Motor Neurons/pathology , N-Methylaspartate/pharmacology , Nerve Degeneration/chemically induced , Rats , Rats, Sprague-Dawley , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Receptors, Metabotropic Glutamate/metabolism , Spinal Cord/enzymology , Spinal Cord/pathology
14.
Neuropharmacology ; 38(10): 1477-84, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10530809

ABSTRACT

The role of group-I metabotropic glutamate receptors (mGlu1 and 5) in neurodegeneration is still controversial. While antagonists of these receptors are consistently neuroprotective, agonists have been found to either amplify or attenuate excitotoxic neuronal death. At least three variables affect responses to agonists: (i) the presence of the NR2C subunit in the NMDA receptor complex; (ii) the existence of an activity-dependent functional switch of group-I mGlu receptors, similar to that described for the regulation of glutamate release; and (iii) the presence of astrocytes expressing mGlu5 receptors. Thus, a number of factors, including the heteromeric composition of NMDA receptors, the exposure time to drugs or to ambient glutamate, and the function of astrocytes clearing extracellular glutamate and producing neurotoxic or neuroprotective factors, must be taken into account when examining the role of group-I mGlu receptors in neurodegeneration/neuroprotection.


Subject(s)
Glutamic Acid/physiology , Neuroprotective Agents , Neurotoxins , Receptors, Metabotropic Glutamate/physiology , Animals , Astrocytes/physiology , Humans , Nerve Degeneration/physiopathology
16.
Proc Natl Acad Sci U S A ; 95(9): 5366-71, 1998 Apr 28.
Article in English | MEDLINE | ID: mdl-9560282

ABSTRACT

Nerve growth factor (NGF) has antiproliferative and differentiating effects on adenomas of neuroendocrine origin. Cell lines derived from small-cell lung carcinoma (SCLC), a very aggressive neuroendocrine tumor, express NGF receptors. The role of NGF in the control of proliferation and progression of this carcinoma, however, has never been investigated. Chronic exposure of NCI-N-592 and GLC8 SCLC cell lines to NGF remarkably inhibited their proliferation rate both in vitro and in vivo, prevented their anchorage-independent clonal growth in soft agar, impaired their invasive capacity in vitro, and abolished their tumorigenic potential in nude mice. The proliferative response of SCLC cell lines to nicotine was also remarkably impaired by in vitro NGF treatment. Furthermore, NGF treatment activates in SCLC cell lines the expression and secretion of NGF. NGF thus reverts SCLC cell lines to a noninvasive, nontumorigenic phenotype that does not respond to nicotine and produces NGF.


Subject(s)
Carcinoma, Small Cell/pathology , Lung Neoplasms/pathology , Nerve Growth Factors/pharmacology , Receptors, Nerve Growth Factor/metabolism , Animals , Cell Division/drug effects , Humans , Mice , Mice, Nude , Neoplasm Invasiveness , Neoplasms, Experimental/pathology , Nicotine/pharmacology , Tumor Cells, Cultured
17.
Neurosci Lett ; 243(1-3): 77-80, 1998 Feb 27.
Article in English | MEDLINE | ID: mdl-9535117

ABSTRACT

Human NT2-N neurons derived from retinoic acid treatment of the NTera 2 cell line were used to determine the consequences of ionotropic glutamate receptor (iGluR) hyperstimulation and possible modulatory role(s) exerted by metabotropic glutamate receptor (mGluR) activation. We found that NT2-N neurons express the NR1 subunit of N-methyl-D-aspartate (NMDA) iGluRs and mRNA encoding the 1a isoform of mGluRs. A 15 min pulse with 100 microM NMDA induced an increase in the levels of tau proteins in NT2-N cells. This effect was prevented by incubating NT2-N neurons in the presence of the mGluR agonist (1 S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD). This phenomenon was related, in terms of doses and time, with the observed 1S,3R-ACPD-mediated protection against NMDA-induced NT2-N cell death. Our findings suggest that iGluRs and mGluRs might participate in the control of human neuron viability by differentially affecting the expression of tau proteins.


Subject(s)
Neurons/metabolism , Receptors, Metabotropic Glutamate/genetics , Receptors, N-Methyl-D-Aspartate/genetics , tau Proteins/metabolism , Cell Death/drug effects , Cell Line , Cycloleucine/analogs & derivatives , Cycloleucine/pharmacology , Excitatory Amino Acid Agonists/pharmacology , Gene Expression/physiology , Humans , N-Methylaspartate/pharmacology , Nerve Degeneration/metabolism , Neurons/chemistry , Neurons/cytology , Neuroprotective Agents/pharmacology , RNA, Messenger/analysis , Receptors, Metabotropic Glutamate/agonists , Receptors, N-Methyl-D-Aspartate/agonists
18.
Neurosci Lett ; 235(3): 149-53, 1997 Oct 17.
Article in English | MEDLINE | ID: mdl-9406891

ABSTRACT

Here we report three experimental paradigms in which tau proteins are differentially localized and expressed in human neuroblastoma cells SH-SY5Y. We found that in undifferentiated cells, tau proteins were predominantly localized in the nucleus. Western blot analysis of nuclear extracts revealed, among the others, a high molecular weight tau isoform and evaluation of tau mRNA levels showed a single tau isoform. After differentiation, tau immunoreactivity was detected only in cytosol and along neuritic processes. The high molecular weight tau isoform disappeared and an additional tau mRNA species was detected. Treatment of differentiated cells with doxorubicin or okadaic acid resulted in an increase of tau immunoreactivity and in a subsequent cell loss. Our results indicate that both subcellular localization and pattern of expression of tau proteins vary depending on the developmental and functional state of the cells, thus suggesting different roles in cell function.


Subject(s)
Neurons/chemistry , tau Proteins/analysis , Antibiotics, Antineoplastic/pharmacology , Cell Death/drug effects , Cell Differentiation/physiology , Doxorubicin/pharmacology , Enzyme Inhibitors/pharmacology , Humans , Immunohistochemistry , Neuroblastoma , Okadaic Acid/pharmacology , Tumor Cells, Cultured
19.
Eur J Neurosci ; 8(7): 1516-21, 1996 Jul.
Article in English | MEDLINE | ID: mdl-8758959

ABSTRACT

Metabotropic glutamate receptors (mGluRs) belong to a relative large receptor family consisting of multiple members with important roles in a number of brain functions. We report here that activation of mGluRs prevents the neurotoxic effect induced by N-methyl-D-aspartate (NMDA) in slices from the rat hippocampus. Neuroprotection was elicited when slices were simultaneously exposed to both the selective mGluR agonist (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (tACPD) and NMDA. Persisting stimulation of mGluRs after the toxic exposure did not improve the survival of pyramidal or granular cells. The neuroprotection elicited by tACPD toxic exposure did not improve the survival of pyramidal or granular cells. The neuroprotection elicited by tACPD was also evoked by its active isomer, (1S, 3R)-ACPD, and was prevented by the selective mGluR antagonist (+)-alpha-methyl-4-carboxyphenyl-glycine (500 microM), confirming that mGluR activation is involved in the mechanism of action of tACPD. The effect of 100 microM tACPD was reproduced by 100 microM quisqualate, an agonist of mGluR2 and mGluR3 subtypes. No neuroprotection was induced by L-2-amino-4-phosphonobutyrate, a selective agonist for mGluR4, mGluR6, mGluR7 and mGluR8, at 500 microM. Since the NMDA-mediated cell death in hippocampal slices is considered relevant to ischaemia-induced brain injury, these results indicate that mGluRs may be important safety devices used by neurons to decrease their sensitivity to excitotoxic stimuli and increase their chance of survival.


Subject(s)
Cycloleucine/analogs & derivatives , Hippocampus/drug effects , N-Methylaspartate/antagonists & inhibitors , Neuroprotective Agents/pharmacology , Receptors, Metabotropic Glutamate/agonists , Animals , Benzoates/pharmacology , Cycloleucine/antagonists & inhibitors , Cycloleucine/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Female , Glycine/analogs & derivatives , Glycine/pharmacology , Hippocampus/metabolism , In Vitro Techniques , Male , Pyrrolidinones/antagonists & inhibitors , Pyrrolidinones/pharmacology , Rats , Rats, Sprague-Dawley
20.
Trends Pharmacol Sci ; 17(4): 155-60, 1996 Apr.
Article in English | MEDLINE | ID: mdl-8984743

ABSTRACT

The concept of heterogeneity of Alzheimer's disease is based on molecular, neuropathological, clinical and neuropsychological features, and also supported by the observation that Alzheimer's patients differ in their response to pharmacological interventions. Recent investigations evaluating the therapeutic potential of cholinesterase inhibitors have disclosed the existence of at least two subsets of patients with dementia, defined as 'responders' and 'nonresponders' to this therapy. In this article, Paolo Liberini and colleagues suggest that the cluster of responders to the cholinesterase inhibitors might include a significant number of subjects with a rather selective dysfunction of the cholinergic system, as in the case of Lewy-body dementia. A neuropathological demonstration of this correlation should open up new therapeutic perspectives.


Subject(s)
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/therapeutic use , Dementia/drug therapy , Lewy Bodies , Alzheimer Disease/pathology , Dementia/pathology , Humans
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