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1.
Int J Mol Sci ; 23(24)2022 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-36555191

RESUMO

Impaired activation of the N-methyl-D-aspartate subtype of glutamate receptors (NMDAR) by D-serine is linked to cognitive aging. Whether this deregulation may be used to initiate pharmacological strategies has yet to be considered. To this end, we performed electrophysiological extracellular recordings at CA3/CA1 synapses in hippocampal slices from young and aged mice. We show that 0.1 nM of the soluble N-terminal recombinant fragment of the secreted amyloid-protein precursor-α (sAPPα) added in the bath significantly increased NMDAR activation in aged but not adult mice without impacting basal synaptic transmission. In addition, sAPPα rescued the age-related deficit of theta-burst-induced long-term potentiation. Significant NMDAR improvement occurred in adult mice when sAPPα was raised to 1 nM, and this effect was drastically reduced in transgenic mice deprived of D-serine through genetic deletion of the synthesizing enzyme serine racemase. Altogether, these results emphasize the interest to consider sAPPα treatment targeting D-serine-dependent NMDAR deregulation to alleviate cognitive aging.


Assuntos
Envelhecimento Saudável , Serina , Camundongos , Animais , Serina/farmacologia , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Precursor de Proteína beta-Amiloide/genética , Hipocampo/metabolismo , Sinapses/metabolismo , Camundongos Transgênicos
2.
Br J Clin Pharmacol ; 2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35939367

RESUMO

AIMS: Due to their central mechanism of action, antiseizure medications (ASMs) could lead to adverse effects likely to impair driving skills. Their extended use to neuropsychiatric disorders makes it a class of drugs to monitor for their road traffic accidental (RTA) potential. We aimed to assess the reporting association between ASMs and RTAs using the World Health Organization pharmacovigilance database (VigiBase). METHODS: We performed a disproportionality analysis to compute adjusted reporting odds ratios to evaluate the strength of reporting association between ASMs and RTAs. A univariate analysis using the reporting odds-ratio was used to assess drug-drug interactions between ASMs and RTAs. RESULTS: There were 1 341 509 reports associated with at least 1 ASM in VigiBase of whom 2.91‰ were RTAs reports. Eight ASMs were associated with higher reporting of RTAs compared to others (ranging from 1.35 [95% confidence interval 1.11-1.64] for lamotrigine to 4.36 [95% confidence interval 3.56-5.32] for cannabis). Eight significant drug-drug interactions were found between ASMs and the onset of RTA, mainly involving CYP450 induction. CONCLUSION: A significant safety signal between RTAs and some ASMs was identified. Association of several ASMs might further increase the occurrence of RTA. ASMs prescription in patients with identified risk factors of RTA should be considered with caution. Study number: ClinicalTrials.gov, NCT04480996.

3.
Int J Mol Sci ; 22(21)2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34769511

RESUMO

The hippocampus has long been considered as a key structure for memory processes. Multilevel alterations of hippocampal function have been identified as a common denominator of memory impairments in a number of psychiatric and neurodegenerative diseases. For many years, the glutamatergic and cholinergic systems have been the main targets of therapeutic treatments against these symptoms. However, the high rate of drug development failures has left memory impairments on the sideline of current therapeutic strategies. This underscores the urgent need to focus on new therapeutic targets for memory disorders, such as type 4 serotonin receptors (5-HT4Rs). Ever since the discovery of their expression in the hippocampus, 5-HT4Rs have gained growing interest for potential use in the treatment of learning and memory impairments. To date, much of the researched information gathered by scientists from both animal models and humans converge on pro-mnesic and anti-amnesic properties of 5-HT4Rs activation, although the mechanisms at work require more work to be fully understood. This review addresses a fundamental, yet poorly understood set of evidence of the potential of 5-HT4Rs to re-establish or limit hippocampal alterations related to neurological diseases. Most importantly, the potential of 5-HT4Rs is translated by refining hypotheses regarding the benefits of their activation in memory disorders at the hippocampal level.


Assuntos
Hipocampo/efeitos dos fármacos , Aprendizagem/fisiologia , Transtornos da Memória/tratamento farmacológico , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Receptores 5-HT4 de Serotonina/química , Antagonistas da Serotonina/farmacologia , Animais , Hipocampo/metabolismo , Humanos , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Receptores 5-HT4 de Serotonina/metabolismo
4.
Nutrients ; 13(7)2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34371954

RESUMO

Anxiety appears among the most frequent psychiatric disorders. During recent years, a growing incidence of anxiety disorders can be attributed, at least in part, to the modification of our eating habits. To treat anxiety disorders, clinicians use benzodiazepines, which unfortunately display many side effects. Herein, the anxiolytic-like properties of two natural products (αS1-casein hydrolysate and Gabolysat®) were investigated in rats and compared to the efficacy of benzodiazepine (diazepam). Thus, the conditioned defensive burying test was performed after a unique oral dose of 15 mg/kg, at two time-points (60 min and then 30 min post oral gavage) to show potential fast-onset of anxiolytic effect. Both natural products proved to be as efficient as diazepam to reduce the time rats spent burying the probe (anxiety level). Additionally, when investigated as early as 30 min post oral gavage, Gabolysat® also revealed a fast-anxiolytic activity. To date, identification of bioactive peptide, as well as how they interact with the gut-brain axis to sustain such anxiolytic effect, still remains poorly understood. Regardless, this observational investigation argues for the consideration of natural compounds in care pathway.


Assuntos
Ansiolíticos/administração & dosagem , Ansiedade/psicologia , Comportamento Animal/efeitos dos fármacos , Caseínas/administração & dosagem , Hidrolisados de Proteína/administração & dosagem , Animais , Condicionamento Psicológico , Diazepam/administração & dosagem , Proteínas de Peixes/administração & dosagem , Masculino , Ratos
5.
Behav Brain Res ; 413: 113473, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34280461

RESUMO

Schizophrenia is a major psychiatric disease still lacking efficient treatment, particularly for cognitive deficits. To go further in research of new treatments that would encompass all the symptoms associated with this pathology, preclinical animal models need to be improved. To date, the aetiology of schizophrenia is unknown, but there is increasing evidence to highlight its multifactorial nature. We built a new neurodevelopmental mouse model gathering a triple factor combination (3-M): a genetic factor (partial deletion of MAP6 gene), an early stress (maternal separation) and a late pharmacological factor (MK801 administration, 0.05 mg/kg, i.p., daily for 5 days). The effects of each factor and of their combination were investigated on several behaviours including cognitive functions. While each individual factor induced slight deficits in one or another behavioural test, 3-M conditioning induces a wider phenotype with hyperlocomotion and cognitive deficits (working memory and social recognition). This study confirms the hypothesis that genetic, environmental and pharmacological factors, even if not deleterious by themselves, could act synergistically to induce a deleterious behavioural phenotype. It moreover encourages the use of such combined models to improve translational research on neurodevelopmental disorders.


Assuntos
Comportamento Animal , Disfunção Cognitiva , Maleato de Dizocilpina/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Privação Materna , Proteínas Associadas aos Microtúbulos/deficiência , Transtornos do Neurodesenvolvimento , Estresse Psicológico , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/genética , Modelos Animais de Doenças , Interação Gene-Ambiente , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Transtornos do Neurodesenvolvimento/induzido quimicamente , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/genética , Estresse Psicológico/complicações
6.
Psychopharmacology (Berl) ; 238(10): 2883-2893, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34173033

RESUMO

RATIONALE: Tramadol is widely used for pain relief especially in seniors. However, long-term use of tramadol has serious adverse effects, including cognitive impairment. Besides its memory effects, already demonstrated in animals, a recent clinical report suggests that tramadol could also affect executive function in seniors. Several studies have hypothesized that the anti-muscarinic properties of tramadol could be responsible for the deleterious effects of tramadol on cognition. OBJECTIVES: We aimed at investigating the effects of chronic administration of tramadol on cognitive flexibility in adult male mice, as assessed by a visual discrimination reversal task using a touchscreen device. The effects of tramadol were further compared to those of scopolamine, a reference muscarinic antagonist. RESULTS: We found that, during the early phase of the reversal task, when cognitive flexibility is most in demand, both tramadol-treated mice (20 mg/kg, s.c., twice a day) and scopolamine-treated mice (0.5 mg/kg, s.c., twice a day) needed more correction trials and showed a higher perseveration index than saline-treated mice. Therefore, tramadol affects cognitive flexibility, and its anticholinergic properties could be at least partly involved in these deficits. CONCLUSIONS: In view of these deleterious cognitive effects of tramadol, physicians should be cautious when prescribing this analgesic, especially in seniors who are more vulnerable to adverse drug events and in which alternative prescription should be preferred whenever possible.


Assuntos
Tramadol , Animais , Cognição , Discriminação Psicológica , Masculino , Camundongos , Escopolamina/farmacologia , Tramadol/farmacologia , Percepção Visual
7.
Proc Natl Acad Sci U S A ; 118(23)2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34083436

RESUMO

Prefrontal control of cognitive functions critically depends upon glutamatergic transmission and N-methyl D-aspartate (NMDA) receptors, the activity of which is regulated by dopamine. Yet whether the NMDA receptor coagonist d-serine is implicated in the dopamine-glutamate dialogue in the prefrontal cortex (PFC) and other brain areas remains unexplored. Here, using electrophysiological recordings, we show that d-serine is required for the fine-tuning of glutamatergic neurotransmission, neuronal excitability, and synaptic plasticity in the PFC through the actions of dopamine at D1 and D3 receptors. Using in vivo microdialysis, we show that D1 and D3 receptors exert a respective facilitatory and inhibitory influence on extracellular levels and activity of d-serine in the PFC, with actions expressed primarily via the cAMP/protein kinase A (PKA) signaling cascade. Further, using functional magnetic resonance imaging (fMRI) and behavioral assessment, we show that d-serine is required for the potentiation of cognition by D3R blockade as revealed in a test of novel object recognition memory. Collectively, these results unveil a key role for d-serine in the dopaminergic neuromodulation of glutamatergic transmission and PFC activity, findings with clear relevance to the pathogenesis and treatment of diverse brain disorders involving alterations in dopamine-glutamate cross-talk.


Assuntos
Dopamina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Serina/metabolismo , Animais , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Camundongos Knockout , Racemases e Epimerases/deficiência , Racemases e Epimerases/genética , Receptores Dopaminérgicos/metabolismo , Esquizofrenia , Transmissão Sináptica/efeitos dos fármacos
8.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807989

RESUMO

For a better translation from treatment designs of schizophrenia to clinical efficiency, there is a crucial need to refine preclinical animal models. In order to consider the multifactorial nature of the disorder, a new mouse model associating three factors (genetic susceptibility-partial deletion of the MAP6 gene, early-life stress-maternal separation, and pharmacological treatment-chronic Δ-9-tetrahydrocannabinol during adolescence) has recently been described. While this model depicts a schizophrenia-like phenotype, the neurobiological correlates remain unknown. Synaptic transmission and functional plasticity of the CA1 hippocampal region of male and female 3-hit mice were therefore investigated using electrophysiological recordings on the hippocampus slice. While basal excitatory transmission remained unaffected, NMDA receptor (NMDAr)-mediated long-term potentiation (LTP) triggered by theta-burst (TBS) but not by high-frequency (HFS) stimulation was impaired in 3-hit mice. Isolated NMDAr activation was not affected or even increased in female 3-hit mice, revealing a sexual dimorphism. Considering that the regulation of LTP is more prone to inhibitory tone if triggered by TBS than by HFS, the weaker potentiation in 3-hit mice suggests a deficiency of intrinsic GABA regulatory mechanisms. Indeed, NMDAr activation was increased by GABAA receptor blockade in wild-type but not in 3-hit mice. This electrophysiological study highlights dysregulations of functional properties and plasticity in hippocampal networks of 3-hit mice, one of the mechanisms suspected to contribute to the pathophysiology of schizophrenia. It also shows differences between males and females, supporting the sexual dimorphism observed in the disorder. Combined with the previously reported study, the present data reinforce the face validity of the 3-hit model that will help to consider new therapeutic strategies for psychosis.


Assuntos
Região CA1 Hipocampal/fisiopatologia , Potenciação de Longa Duração , Esquizofrenia/fisiopatologia , Transmissão Sináptica , Ritmo Teta , Animais , Região CA1 Hipocampal/patologia , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Mutantes , Esquizofrenia/genética , Esquizofrenia/patologia
9.
Cereb Cortex ; 31(1): 694-701, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32935845

RESUMO

The type 4 serotonin receptor (5-HT4R) is highly involved in cognitive processes such as learning and memory. Behavioral studies have shown a beneficial effect of its activation and conversely reported memory impairments by its blockade. However, how modulation of 5HT4R enables modifications of hippocampal synaptic plasticity remains elusive. To shed light on the mechanisms at work, we investigated the effects of the 5-HT4R agonist RS67333 on long-term potentiation (LTP) within the hippocampal CA1 area. Although high-frequency stimulation-induced LTP remained unaffected by RS67333, the magnitude of LTP induced by theta-burst stimulation was significantly decreased. This effect was blocked by the selective 5-HT4R antagonist RS39604. Further, 5-HT4R-induced decrease in LTP magnitude was fully abolished in the presence of bicuculline, a GABAAR antagonist; hence, demonstrating involvement of GABA neurotransmission. In addition, we showed that the application of a GABABR antagonist, CGP55845, mimicked the effect of 5-HT4R activation, whereas concurrent application of CGP55845 and RS67333 did not elicit an additive inhibition effect on LTP. To conclude, through investigation of theta burst induced functional plasticity, we demonstrated an interplay between 5-HT4R activation and GABAergic neurotransmission within the hippocampal CA1 area.


Assuntos
Região CA1 Hipocampal/fisiologia , Potenciação de Longa Duração/fisiologia , Plasticidade Neuronal/fisiologia , Receptores 5-HT4 de Serotonina/metabolismo , Animais , Estimulação Elétrica/métodos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipocampo/fisiologia , Masculino , Camundongos
10.
Cereb Cortex ; 31(1): 620-634, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32959057

RESUMO

Cognitive decline appears across aging. While some studies report beneficial effects of musical listening and practice on cognitive aging, the underlying neurobiological mechanisms remain unknown. This study aims to determine whether chronic (6 h/day, 3 times/week) and long-lasting (4-8 months) music exposure, initiated at middle age in rats (15 months old), can influence behavioral parameters sensitive to age effects and reduce age-related spatial memory decline in rats. Spontaneous locomotor, circadian rhythmic activity, and anxiety-like behavior as well as spatial working and reference memory were assessed in 14-month-old rats and then after 4 and 8 months of music exposure (19 and 23 months old, respectively). Spatial learning and reference memory data were followed up by considering cognitive status of animals prior to music exposure (14 months old) given by K-means clustering of individual Z-score. Hippocampal cell proliferation and brain-derived neurotrophic factor (BDNF) level in the hippocampus and frontal cortex were measured. Results show that music exposure differentially rescues age-related deficits in spatial navigation tasks according to its duration without affecting spontaneous locomotor, circadian rhythmic activity, and anxiety-like behavior. Hippocampal cell proliferation as well as hippocampal and frontal cortex BDNF levels was not affected by music across aging. Cognitive improvement by music in aging rats may require distinct neurobiological mechanisms than hippocampal cell proliferation and BDNF.


Assuntos
Envelhecimento/fisiologia , Transtornos Cognitivos/prevenção & controle , Disfunção Cognitiva/prevenção & controle , Música , Tempo , Animais , Ansiedade/psicologia , Cognição/fisiologia , Transtornos Cognitivos/fisiopatologia , Hipocampo/fisiologia , Hipocampo/fisiopatologia , Masculino , Neurogênese/fisiologia , Ratos Wistar , Aprendizagem Espacial/fisiologia
11.
Schizophr Res ; 228: 519-528, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33298334

RESUMO

Whether the etiology of schizophrenia remains unknown, its multifactorial aspect is conversely now well admitted. However, most preclinical models of the disease still rely on a mono-factorial construction and do not allow discover unequivocal treatments, particularly for negative and cognitive symptoms. The main interaction factors that have been implicated in schizophrenia are a genetic predisposition and unfavorable environmental factors. Here we propose a new animal model combining a genetic predisposition (1st hit: partial deletion of MAP-6 (microtubule-associated protein)) with an early postnatal stress (2nd hit: 24 h maternal separation at post-natal day 9), and a late cannabinoid exposure during adolescence (3rd hit: tetrahydrocannabinol THC from post-natal day 32 to 52; 8 mg/kg/day). The 2-hit mice displayed spatial memory deficits, decreased cortical thickness and fractional anisotropy of callosal fibers. The 3-hit mice were more severely affected as attested by supplementary deficits such a decrease in spontaneous activity, sociability-related behavior, working memory performances, an increase in anxiety-like behavior, a decrease in hippocampus volume together with impaired integrity of corpus callosum fibers (less axons, less myelin). Taken together, these results show that the new 3-hit model displays several landmarks mimicking negative and cognitive symptoms of schizophrenia, conferring a high relevance for research of new treatments. Moreover, this 3-hit model possesses a strong construct validity, which fits with gene x environment interactions hypothesis of schizophrenia. The 2-hit model, which associates maternal separation with THC exposure in wild-type mice gives a less severe phenotype, and could be useful for research on other forms of psychiatric diseases.


Assuntos
Esquizofrenia , Animais , Modelos Animais de Doenças , Interação Gene-Ambiente , Hipocampo , Privação Materna , Camundongos , Esquizofrenia/genética
12.
Eur J Med Chem ; 210: 113059, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33310288

RESUMO

Beside acetylcholinesterase, butyrylcholinesterase could be considered as a putative target of interest for the symptomatic treatment of Alzheimer's disease (AD). As a result of complexity of AD, no molecule has been approved since 2002. Idalopirdine, a 5-HT6 receptors antagonist, did not show its effectiveness in clinical trial despite its evaluation as adjunct to cholinesterase inhibitors. Pleiotropic molecules, known as multitarget directed ligands (MTDLs) are currently developed to tackle the multifactorial origin of AD. In this context, we have developed a pleiotropic carbamate 7, that behaves as a covalent inhibitor of BuChE (IC50 = 0.97 µM). The latter will deliver after hydrolysis, compound 6, a potent 5-HT6 receptors antagonist (Ki = 11.4 nM) related to idalopirdine. In silico and in vitro evaluation proving our concept were performed completed with first in vivo results that demonstrate great promise in restoring working memory.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Pró-Fármacos/farmacologia , Receptores de Serotonina/metabolismo , Doença de Alzheimer/metabolismo , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Humanos , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade
13.
Int J Mol Sci ; 21(24)2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33322577

RESUMO

d-serine is the major co-agonist of N-methyl-D-aspartate receptors (NMDAR) at CA3/CA1 hippocampal synapses, the activation of which drives long-term potentiation (LTP). The use of mice with targeted deletion of the serine racemase (SR) enzyme has been an important tool to uncover the physiological and pathological roles of D-serine. To date, some uncertainties remain regarding the direction of LTP changes in SR-knockout (SR-KO) mice, possibly reflecting differences in inhibitory GABAergic tone in the experimental paradigms used in the different studies. On the one hand, our extracellular recordings in hippocampal slices show that neither isolated NMDAR synaptic potentials nor LTP were altered in SR-KO mice. This was associated with a compensatory increase in hippocampal levels of glycine, another physiologic NMDAR co-agonist. SR-KO mice displayed no deficits in spatial learning, reference memory and cognitive flexibility. On the other hand, SR-KO mice showed a weaker LTP and a lower increase in NMDAR potentials compared to controls when GABAA receptors were pharmacologically blocked. Our results indicate that depletion of endogenous D-serine caused a reduced inhibitory activity in CA1 hippocampal networks, altering the excitatory/inhibitory balance, which contributes to preserve functional plasticity at synapses and to maintain related cognitive abilities.


Assuntos
Região CA1 Hipocampal/metabolismo , Racemases e Epimerases/metabolismo , Aminoácidos/metabolismo , Animais , Eletrofisiologia , Hipocampo/metabolismo , Potenciação de Longa Duração/fisiologia , Masculino , Memória/fisiologia , Camundongos , Teste do Labirinto Aquático de Morris , Plasticidade Neuronal/fisiologia , Racemases e Epimerases/genética , Receptores de N-Metil-D-Aspartato/metabolismo
14.
Pharmacol Biochem Behav ; 194: 172933, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32371059

RESUMO

Lurasidone is an atypical antipsychotic that has been shown to be effective in reversing schizophrenia-related cognitive impairment. The development of new preclinical models of schizophrenia is a key for improving treatments of cognitive symptoms. This study investigated the effects of chronic lurasidone treatment in C57BL/6 male mice via intraperitoneal injection (1 mg/kg daily at 5 p.m. for 5 weeks). A large battery of behavioural tests was performed (between 9 a.m. and 5 p.m.), which is currently used to assess face validity in animal models of psychiatric diseases. Overall, lurasidone did not interfere with behavioural performances, which characterises very good tolerance to such a high dose. Moreover, pharmacokinetic parameters after i.p. and oral administration were measured. Mean transit time (MTT) values were 1.91 h (1 mg/kg acute i.p.) and 1.74 h (8.3 mg/kg acute oral), respectively, and relative bioavailability comparing these two routes of administration was of 19.8%. This last result gives important data to adapt oral chronic administration of lurasidone with a more ethical perspective in comparison with chronic i.p. injections. This study brings tools to improve pharmacological validity of preclinical models of psychiatric diseases, and to adapt dosage of antipsychotics according to the route used.


Assuntos
Antipsicóticos/farmacocinética , Comportamento Animal/efeitos dos fármacos , Cloridrato de Lurasidona/farmacocinética , Administração Oral , Animais , Antipsicóticos/administração & dosagem , Ansiedade/metabolismo , Disponibilidade Biológica , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Humanos , Injeções Intraperitoneais , Cloridrato de Lurasidona/administração & dosagem , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Reflexo de Sobressalto/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo
15.
Sci Rep ; 10(1): 6030, 2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-32242040

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

16.
Br J Pharmacol ; 177(9): 1988-2005, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31881553

RESUMO

BACKGROUND AND PURPOSE: We recently identified donecopride as a pleiotropic compound able to inhibit AChE and to activate 5-HT4 receptors. Here, we have assessed the potential therapeutic effects of donecopride in treating Alzheimer's disease (AD). EXPERIMENTAL APPROACH: We used two in vivo animal models of AD, transgenic 5XFAD mice and mice exposed to soluble amyloid-ß peptides and, in vitro, primary cultures of rat hippocampal neurons. Pro-cognitive and anti-amnesic effects were evaluated with novel object recognition, Y-maze, and Morris water maze tests. Amyloid load in mouse brain was measured ex vivo and effects of soluble amyloid-ß peptides on neuronal survival and neurite formation determined in vitro. KEY RESULTS: In vivo, chronic (3 months) administration of donecopride displayed potent anti-amnesic properties in the two mouse models of AD, preserving learning capacities, including working and long-term spatial memories. These behavioural effects were accompanied by decreased amyloid aggregation in the brain of 5XFAD mice and, in cultures of rat hippocampal neurons, reduced tau hyperphosphorylation. In vitro, donecopride increased survival in neuronal cultures exposed to soluble amyloid-ß peptides, improved the neurite network and provided neurotrophic benefits, expressed as the formation of new synapses. CONCLUSIONS AND IMPLICATIONS: Donecopride acts like a Swiss army knife, exhibiting a range of sustainable symptomatic therapeutic effects and potential disease-modifying effects in models of AD. Clinical trials with this promising drug candidate will soon be undertaken to confirm its therapeutic potential in humans.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Compostos de Anilina , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Aprendizagem em Labirinto , Camundongos , Camundongos Transgênicos , Piperidinas , Ratos
17.
Sci Rep ; 9(1): 18432, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31804545

RESUMO

Hypothalamic orexin neurons are involved in various physiological functions, including thermoregulation. The orexinergic system has been considered as a potent mediator of the exercise response. The present study describes how the antagonization of the orexinergic system by a dual orexin receptor antagonist (DORA) modifies the thermoregulatory process during exercise. Core Body Temperature (CBT) and Spontaneous Locomotor Activity (SLA) of 12 male Wistar rats were recorded after either oral administration of DORA (30 mg/kg or 60 mg/kg) or placebo solution, both at rest and in exercise conditions with treadmill running. DORA ingestion decreased SLA for 8 hours (p < 0.001) and CBT for 4 hours (p < 0.01). CBT (°C) response was independent of SLA. The CBT level decreased from the beginning to the end of exercise when orexin receptors were antagonized, with a dose-dependent response (39.09 ± 0.36 and 38.88 ± 0.28 for 30 and 60 mg/kg; p < 0.001) compared to placebo (39.29 ± 0.31; p < 0.001). CBT increased during exercise was also blunted after DORA administration, but without dose effects of DORA. In conclusion, our results favor the role of orexin in the thermoregulation under stress related to exercise conditions.


Assuntos
Regulação da Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Animais , Temperatura Corporal/fisiologia , Regulação da Temperatura Corporal/fisiologia , Hipotálamo/citologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Modelos Animais , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Condicionamento Físico Animal , Ratos
18.
Molecules ; 24(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370232

RESUMO

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease which is still poorly understood. The drugs currently used against AD, mainly acetylcholinesterase inhibitors (AChEI), are considered clinically insufficient and are responsible for deleterious side effects. AChE is, however, currently receiving renewed interest through the discovery of a chaperone role played in the pathogenesis of AD. But AChE could also serve as an activating protein for pleiotropic prodrugs. Indeed, inhibiting central AChE with brain-penetrating designed carbamates which are able to covalently bind to the enzyme and to concomitantly liberate active metabolites in the brain could constitute a clinically more efficient approach which, additionally, is less likely to cause peripheral side effects. We aim in this article to pave the road of this new avenue with an in vitro and in vivo study of pleiotropic prodrugs targeting both the 5-HT4 receptor and AChE, in order to display a neuroprotective activity associated with a sustained restoration of the cholinergic neurotransmission and without the usual peripheral side effects associated with classic AChEI. This plural activity could bring to AD patients effective, relatively safe, symptomatic and disease-modifying therapeutic benefits.


Assuntos
Acetilcolinesterase/genética , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Pró-Fármacos/farmacologia , Acetilcolinesterase/química , Doença de Alzheimer/enzimologia , Doença de Alzheimer/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Carbamatos/química , Inibidores da Colinesterase/química , Humanos , Ligantes , Pró-Fármacos/química , Receptores 5-HT4 de Serotonina/genética
19.
Front Aging Neurosci ; 11: 148, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31316368

RESUMO

This work describes the conception, synthesis, in vitro and in vivo biological evaluation of novel Multi-Target Directed Ligands (MTDL) able to both activate 5-HT4 receptors, block 5-HT6 receptors and inhibit acetylcholinesterase activity (AChE), in order to exert a synergistic anti-amnesic effect, potentially useful in the treatment of Alzheimer's disease (AD). Indeed, both activation of 5-HT4 and blockage of 5-HT6 receptors led to an enhanced acetylcholine release, suggesting it could lead to efficiently restoring the cholinergic neurotransmission deficit observed in AD. Furthermore, 5-HT4 receptor agonists are able to promote the non-amyloidogenic cleavage of the amyloid precursor protein (APP) and to favor the production of the neurotrophic protein sAPPα. Finally, we identified a pleiotropic compound, [1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-(3-methylbenzyl)piperidin-4-yl)propan-1-one fumaric acid salt (10)], which displayed in vivo an anti-amnesic effect in a model of scopolamine-induced deficit of working memory at a dose of 0.3 mg/kg.

20.
J Neurochem ; 147(4): 514-525, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30187927

RESUMO

Activation of the N-methyl-D-aspartate subtype of glutamate receptor (NMDA-R) represents a key functional process for memory formation. A decreased synthesis of the NMDA-R co-agonist d-serine was recently proposed to contribute to alterations of hippocampus-dependent memory mechanisms with ageing. Nevertheless, other pathways could also be involved and thus considered to be targets of interest to prevent cognitive ageing. Herein, we demonstrate that the Asc-1 subtype of neutral amino acid (nAA) transporters that regulates d-serine and glycine release from neurons could be viewed as one of these targets. At CA3/CA1 hippocampal synapses, Asc-1 activation did not modify basal glutamate neurotransmission either in adult or aged rats. In contrast, Asc-1 activation significantly increased NMDA-R-dependent long-term potentiation (LTP) in both groups of animals and fully rescued the age-related LTP deficits. This rescue in aged animals was observed only when Asc-1 activation was selectively managed by d-Isoleucine (d-Ile), but not when less specifically driven by a mixture of nAA. Similarly, while any activation of Asc-1 improved the isolated NMDA-R-induced synaptic potentials in adult rats, only d-Ile was efficient in aged animals. Taken together, these results strengthen the interest in specifically targeting Asc-1 transporters to better cure age-associated memory decline. OPEN PRACTICES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.


Assuntos
Sistema ASC de Transporte de Aminoácidos/metabolismo , Região CA1 Hipocampal/crescimento & desenvolvimento , Região CA3 Hipocampal/crescimento & desenvolvimento , Plasticidade Neuronal/fisiologia , Envelhecimento/fisiologia , Animais , Região CA1 Hipocampal/fisiologia , Região CA3 Hipocampal/fisiologia , Fenômenos Eletrofisiológicos , Glicina/metabolismo , Potenciação de Longa Duração , Masculino , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Serina/metabolismo , Transmissão Sináptica/fisiologia
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