Neurocentre Magendie

Gian-Marco LEGGIO

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9 publication(s) depuis Février 2009:

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10/02/2016 | Pharmacol Res   IF 4.5
The antineoplastic drug flavopiridol reverses memory impairment induced by Amyloid-ss oligomers in mice.
Leggio GM, Catania MV, Puzzo D, Spatuzza M, Pellitteri R, Gulisano W, Torrisi SA, Giurdanella G, Piazza C, Impellizzeri AR, Gozzo L, Navarria A, Bucolo C, Nicoletti F, Palmeri A, Salomone S, Copani A, Caraci F, Drago F

The ectopic re-activation of cell cycle in neurons is an early event in the pathogenesis of Alzheimer's disease (AD), which could lead to synaptic failure and ensuing cognitive deficits before frank neuronal death. Cytostatic drugs that act as cyclin-dependent kinase (CDK) inhibitors have been poorly investigated in animal models of AD. In the present study, we examined the effects of flavopiridol, an inhibitor of CDKs currently used as antineoplastic drug, against cell cycle reactivation and memory loss induced by intracerebroventricular injection of Ass1-42 oligomers in CD1 mice. Cycling neurons, scored as NeuN-positive cells expressing cyclin A, were found both in the frontal cortex and in the hippocampus of Abeta-injected mice, paralleling memory deficits. Starting from three days after Abeta injection, flavopiridol (0.5, 1 and 3mg/kg) was intraperitoneally injected daily, for eleven days. Here we show that a treatment with flavopiridol (0.5 and 1mg/kg) was able to rescue the loss of memory induced by Abeta1-42, and to prevent the occurrence of ectopic cell-cycle events in the mouse frontal cortex and hippocampus. This is the first evidence that a cytostatic drug can prevent cognitive deficits in a non-transgenic animal model of AD.

01/02/2016 | Eur J Pharmacol   IF 2.9
TGF-beta1 prevents rat retinal insult induced by amyloid-beta (1-42) oligomers.
Fisichella V, Giurdanella G, Maria Platania CB, Romano GL, Leggio GM, Salomone S, Drago F, Caraci F, Bucolo C

To set up a retinal degenerative model in rat that mimics pathologic conditions such as age-related macular degeneration (AMD) using amyloid-beta (Abeta) oligomers, and assess the effect of TGF-beta1. Sprague-Dawley male rats were used. Human Abeta1-42 oligomers were intravitreally (ITV) injected (10microM) in the presence or in the absence of recombinant human TGF-beta1 (1 ng/mul ITV injected). After 48h, the animals were sacrificed and the eyes removed and dissected. The apoptotic markers Bax and Bcl-2 were assessed by western blot analysis in retina lysates. Gene-pathway network analysis was carried out in order to identify pathways involved in AMD. Treatment with Abeta oligomers induced a strong increase in Bax protein level (about 4-fold; p<0.01) and a significant reduction in Bcl-2 protein level (about 2-fold; p<0.05). Co-injection of TGF-beta1 triggered a significant reduction of Bax protein induced by Abeta oligomers. Bioinformatic analysis revealed that Bcl-2 and PI3K-Akt are the most connected nodes, for genes and pathways respectively, in the enriched gene-pathway network common to AMD and Alzheimer disease (AD). Overall, these data indicate that ITV injection of Abeta1-42 oligomers in rat induces molecular changes associated with apoptosis in rat retina, highlighting a potential pathogenetic role of Abeta oligomers in AMD. Bioinformatics analysis confirms that apoptosis pathways can take part in AMD. Furthermore, these findings suggest that human recombinant TGF-beta1 can prevent retinal damage elicited by Abeta oligomers.

09/2015 | Eur Neuropsychopharmacol   IF 4.2
Dopamine D3 receptor-dependent changes in alpha6 GABAA subunit expression in striatum modulate anxiety-like behaviour: Responsiveness and tolerance to diazepam.
Leggio GM, Torrisi SA, Castorina A, Platania CB, Impellizzeri AA, Fidilio A, Caraci F, Bucolo C, Drago F, Salomone S

Increasing evidence indicates that central dopamine (DA) neurotransmission is involved in pathophysiology of anxiety, in particular the DA receptor subtype 3 (D3R). We previously reported that D3R null mice (D3R(-/-)) exhibit low baseline anxiety levels and that acutely administrated diazepam is more effective in D3R(-/-) than in wild type (WT) when tested in the elevated plus maze test (EPM). Here we tested the hypothesis that genetic deletion or pharmacological blockade of D3R affect GABAA subunit expression, which in turn modulates anxiety-like behaviour as well as responsiveness and tolerance to diazepam. D3R(-/-) mice exhibited tolerance to diazepam (0.5mg/kg, i.p.), assessed by EPM, as fast as after 3 day-treatment, performing similarly to untreated D3R(-/-) mice; conversely, WT exhibited tolerance to diazepam after a 14-21 day-treatment. Analysis of GABAA alpha6 subunit mRNA expression by qPCR in striatum showed that it was about 15-fold higher in D3R(-/-) than in WT. Diazepam treatment did not modify alpha6 expression in D3R(-/-), but progressively increased alpha6 expression in WT, to the level of untreated D3R(-/-) after 14-21 day-treatment. BDNF mRNA expression in striatum was remarkably (>10-fold) increased after 3 days of diazepam-treatment in both WT and D3R(-/-); such expression level, however, slowly declined below control levels, by 14-21 days. Following a 7 day-treatment with the selective D3R antagonist SB277011A, WT exhibited a fast tolerance to diazepam accompanied by a robust increase in alpha6 subunit expression. In conclusion, genetic deletion or pharmacological blockade of D3R accelerate the development of tolerance to repeated administrations of diazepam and increase alpha6 subunit expression, a GABAA subunit that has been linked to diazepam insensitivity. Modulation of GABAA receptor by DA transmission may be involved in the mechanisms of anxiety and, if occurring in humans, may have therapeutic relevance following repeated use of drugs targeting D3R.

05/11/2013 | Eur J Pharmacol   IF 2.9
Dopamine D(3) receptor as a new pharmacological target for the treatment of depression.
Leggio GM, Salomone S, Bucolo C, Platania C, Micale V, Caraci F, Drago F

A substantial proportion of depressed patients do not respond to current antidepressant drug therapies. So far, antidepressant drugs have been developed based on the 'monoaminergic hypothesis' of depression, which considers a synaptic deficiency in 5-hydroxytryptamine (5-HT; serotonin) or noradrenaline as main cause. More recently, the dopaminergic system has been implicated in the efficacy of some antidepressants, such as desipramine, amineptine, nomifensine. Dysfunction of dopaminergic neurotransmission within the mesolimbic system may contribute to anhedonia, loss of motivation and psychomotor retardation in severe depressive disorders. Dopamine D3 receptor subtype is located both pre- and postsynaptically in brain areas regulating motivation and reward-related behavior and has been implicated in depression-like behaviors. Activity of mesolimbic dopamine neurons in the reward circuit is a key determinant of behavioral susceptibility/resilience to chronic stress, which plays a central role in the pathogenesis of depression. Dopamine D3 receptor expression and function are both down-regulated in stress and depression, and these changes are reversed by antidepressant treatments, suggesting that enhanced dopaminergic neurotransmission mediated by dopamine D3 receptor participates in adaptive changes related to antidepressant activity. Of note, brain derived neurotrophic factor (BDNF) controls the expression of the dopamine D3 receptor in some brain areas and BDNF induction by antidepressant treatments is related to their behavioral activity. A number of experimental drugs in pre-clinical or clinical development, including aripiprazole and cariprazine, may act as antidepressants because of their partial agonist activity at dopamine D3 receptors. These preclinical and clinical data are discussed in the present review.

04/2013 | br j clin pharmacol   IF 3.5
Epigenetic drugs for Alzheimer's disease: hopes and challenges.
Caraci F, Leggio GM, Drago F, Salomone S


2013 | curr top med chem   IF 2.6
Clinical pharmacology of novel anti-Alzheimer disease modifying medications.
Caraci F, Bosco P, Leggio GM, Malaguarnera M, Drago F, Bucolo C, Salomone S

In recent years, efforts have been directed to develop 'disease-modifying' medications to treat Alzheimer's disease (AD), able to halt or slow the pathological process. Because the earlier the treatment starts, the greater is the possibility of efficacy, it is important to set up biomarkers for early diagnosis of functional brain abnormalities, before the clinical manifestation of the overt disease. Up to now, strategies to develop disease-modifying drugs have mainly targeted beta amyloid (Abeta, accumulation, aggregation, clearance) and/or tau protein (phosphorylation and aggregation). Active and passive immunotherapy is the main strategy aimed at increasing Abeta clearance. Unfortunately several candidate diseasemodifying drugs have failed in phase III clinical trials conducted in mild to moderate AD. More recently, in phase III studies, bapineuzumab has been discontinued because it did not prove clinically effective (despite its significant effect on biomarkers), while solaneuzumab has been found effective in slowing AD progression. Several methological problems have been recently pointed out to explain the lack of clinical efficacy of novel disease-modifying drug-treatments; moreover, new insights in pathophysiology of AD give the premise to develop novel drug targeting. Clinical trials recently completed and/or still ongoing are discussed in the present review.

04/2012 | br j clin pharmacol   IF 3.5
New pharmacological strategies for treatment of Alzheimer's disease: focus on disease modifying drugs.
Salomone S, Caraci F, Leggio GM, Fedotova J, Drago F

Current approved drug treatments for Alzheimer disease (AD) include cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the NMDA receptor antagonist memantine. These drugs provide symptomatic relief but poorly affect the progression of the disease. Drug discovery has been directed, in the last 10 years, to develop 'disease modifying drugs' hopefully able to counteract the progression of AD. Because in a chronic, slow progressing pathological process, such as AD, an early start of treatment enhances the chance of success, it is crucial to have biomarkers for early detection of AD-related brain dysfunction, usable before clinical onset. Reliable early biomarkers need therefore to be prospectively tested for predictive accuracy, with specific cut off values validated in clinical practice. Disease modifying drugs developed so far include drugs to reduce beta amyloid (Abeta) production, drugs to prevent Abeta aggregation, drugs to promote Abeta clearance, drugs targeting tau phosphorylation and assembly and other approaches. Unfortunately none of these drugs has demonstrated efficacy in phase 3 studies. The failure of clinical trials with disease modifying drugs raises a number of questions, spanning from methodological flaws to fundamental understanding of AD pathophysiology and biology. Recently, new diagnostic criteria applicable to presymptomatic stages of AD have been published. These new criteria may impact on drug development, such that future trials on disease modifying drugs will include populations susceptible to AD, before clinical onset. Specific problems with completed trials and hopes with ongoing trials are discussed in this review.

Control of the mesoaccumbens dopamine (DA) pathway by central serotonin(2C) receptors (5-HT(2C)Rs) involves different 5-HT(2C)R populations located within multiple brain areas. Here, using in vivo microdialysis in halothane-anesthetized rats, we assessed the role of medial prefrontal cortex (mPFC) 5-HT(2C)Rs in the control of basal and activated accumbal DA outflow, to identify the modalities of their recruitment and the role of 5-HT(2C)R constitutive activity. Intra-mPFC injection of the 5-HT(2C)R inverse agonist SB 206553 (0.5 microg/0.2 microL), without effect by itself, decreased accumbal DA outflow induced by morphine (2.5-10 mg/kg, s.c.), haloperidol (0.01 mg/kg, s.c.) or GBR 12909 (2.5 mg/kg, i.p.). Conversely, intra-mPFC injection of the 5-HT(2C)R antagonist SB 242084 (0.5 microg/0.2 microL), without effect by itself, decreased the effect of 10 mg/kg morphine, the only drug enhancing basal 5-HT outflow in the mPFC. The inhibitory effect of SB 206553 on 2.5 mg/kg morphine-stimulated DA outflow was suppressed by the concomitant intra-mPFC injection of SB 242084. Finally, changes of basal DA outflow induced by the 5-HT(2C)R agonist Ro 60-0175 (3 mg/kg, i.p.) or SB 206553 (5 mg/kg, i.p.) were unaffected by intra-mPFC injection of SB 242084. These results, showing that 5-HT(2C)R antagonist and inverse agonist behave differently in vivo, demonstrate that mPFC 5-HT(2C)Rs facilitate activated accumbal DA outflow and that 5-HT(2C)R constitutive activity participates in this interaction.

02/2009 | Neuropharmacology   IF 5
Serotonin2C receptors in the medial prefrontal cortex facilitate cocaine-induced dopamine release in the rat nucleus accumbens.
Leggio GM, Cathala A, Moison D, Cunningham KA, Piazza PV, Spampinato U

A functional balance between excitatory and inhibitory control over dopamine (DA)-dependent behavioral and neurochemical effects of cocaine is afforded by the serotonin(2C) receptor (5-HT(2C)R) located within the ventral tegmental area and the nucleus accumbens (NAc). The 5-HT(2C)R located in the medial prefrontal cortex (mPFC) has also been shown to inhibit cocaine-induced behaviors perhaps through inhibition of DA function in the NAc. Using in vivo microdialysis in halothane-anesthetized rats, we tested this hypothesis by assessing the influence of mPFC 5-HT(2C)Rs on cocaine-induced DA outflow in the NAc shell. Intra-mPFC injection of the 5-HT(2C)R agonist Ro 60-0175 at 5 microg/0.2 microl, but not 1 microg/0.2 microl, potentiated the increase in accumbal DA outflow induced by the intraperitoneal administration of 10 mg/kg of cocaine. Conversely, cocaine-induced accumbal DA outflow was significantly reduced by the intra-mPFC injection of the selective 5-HT(2C)R antagonist SB 242084 (0.5 microg/0.2 microl) or SB 243213 (0.5 and 1 microg/0.2 microl). These results show that mPFC 5-HT(2C)Rs exert a positive control over cocaine-induced accumbal DA outflow. Observations further support the idea that the overall action of central 5-HT(2C)Rs on accumbal DA output is dependent on the functional balance among different 5-HT(2C)R populations located within the mesocorticoaccumbens system, and that 5-HT(2C)Rs can modulate DA-dependent behaviors independently of changes of accumbal DA release itself.