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1.
Nat Commun ; 11(1): 3688, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32703948

RESUMO

Zeta inhibitory peptide (ZIP), a PKMζ inhibitor, is widely used to interfere with the maintenance of acquired memories. ZIP is able to erase memory even in the absence of PKMζ, via an unknown mechanism. We found that ZIP induces redistribution of the AMPARGluA1 in HEK293 cells and primary cortical neurons, and decreases AMPAR-mediated currents in the nucleus accumbens (NAc). These effects were mimicked by free arginine or by a modified ZIP in which all but the arginine residues were replaced by alanine. Redistribution was blocked by a peptidase-resistant version of ZIP and by treatment with the nitric oxide (NO)-synthase inhibitor L-NAME. ZIP increased GluA1-S831 phosphorylation and ZIP-induced redistribution was blocked by nitrosyl-mutant GluA1-C875S or serine-mutant GluA1-S831A. Introducing the cleavable arginine-alanine peptide into the NAc attenuated expression of cocaine-conditioned reward. Together, these results suggest that ZIP may act as an arginine donor, facilitating NO-dependent downregulation of AMPARs, thereby attenuating learning and memory.


Assuntos
Peptídeos Penetradores de Células/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Lipopeptídeos/farmacologia , Memória de Longo Prazo/efeitos dos fármacos , Óxido Nítrico/metabolismo , Receptores de AMPA/metabolismo , Animais , Cocaína/administração & dosagem , Regulação para Baixo , Endocitose/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Células HEK293 , Humanos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos , Modelos Animais , NG-Nitroarginina Metil Éster/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Óxido Nítrico/antagonistas & inibidores , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Fosforilação , Cultura Primária de Células , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Ratos , Receptores de AMPA/genética , Recompensa , Técnicas Estereotáxicas
2.
Life Sci ; 256: 118018, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32598935

RESUMO

Aim While stress causes brain dysfunction, crocin (as an active component of saffron) and exercise (as part of a healthy lifestyle) improve stress-induced memory impairment. The present study investigated the protective effects of crocin administration, exercise, and crocin-accompanied exercise on neuronal excitability and long-term potentiation (LTP) at the CA1 of hippocampus as well as serum corticosterone and glucose levels in rats subjected to chronic unpredictable stress (CUS). MAIN METHODS: Forty-eight male Wistar rats were randomly allocated to six groups: Control, Sham, CUS, CUS-Crocin30, CUS-Exercise, and CUS-Crocin30-Exercise. The chronic unpredictable stress and treadmill running at 20-21 m/min were applied 2 h/day and 1 h/day, respectively, for 21 days. Crocin (30 mg/kg) was daily intraperitoneally injected to the rats. Electrophysiological variables were recorded from the CA1 of hippocampus. While corticosterone and glucose levels were also measured. KEY FINDINGS: CUS and CUS-Exercise significantly attenuated excitability and LTP. Compared to the CUS and CUS-Exercise treatments, CUS-Crocin30 and CUS-Crocin30-Exercise led to significant increases in slope and amplitude of field excitatory postsynaptic potential. The changes in serum corticosterone and glucose levels nearly matched the electrophysiological data. SIGNIFICANCE: CUS was found to be a highly destructive stress as it failed to allow exercises to edify the CUS-induced memory deficit. This is while crocin (as a herbal drug) was found more effective than exercise (as a daily routine) in remedying the CUS-induced memory deficit. Also, although the treatment with crocin-accompanied exercise did help recovery from the CUS-induced memory deficit, the interaction of crocin administration and exercise had no synergic effects; the protective effect observed was due to crocin administration rather than the exercise.


Assuntos
Carotenoides/farmacologia , Transtornos da Memória/terapia , Condicionamento Físico Animal/fisiologia , Estresse Psicológico/terapia , Animais , Glicemia/metabolismo , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Corticosterona/sangue , Modelos Animais de Doenças , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Transtornos da Memória/etiologia , Distribuição Aleatória , Ratos , Ratos Wistar , Estresse Psicológico/complicações
3.
Environ Toxicol ; 35(9): 961-970, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32255272

RESUMO

Benzo[a]pyrene (B[a]P) is recognized as a neurotoxic pollutant to mammals, which could impair learning and memory function. Although there is some evidence to suggest that N-methyl-d-aspartate receptor (NMDAR), a glutamate receptor and ion channel protein in nerve cells, is involved into the B[a]P induced neurotoxicity, the exact molecular mechanisms remain to be elucidated, particularly the effects of B[a]P on the NMDAR downstream signaling transduction pathways. In the present study, we examined the neurotoxicity of sub-chronic administrated B[a]P on male Sprague-Dawley rats. Our data suggested that B[a]P exposure caused significant deficits in learning and memory function and the impairment of hippocampal LTP in rats. Further mechanistic studies indicate that B[a]P-induced learning and memory deficits are associated with the inhibition of NMDAR NR1 subunit transcription and protein phosphorylation. More importantly, the inactivation of CaMK II/PKC/PKA-ERK-CREB signaling pathways in hippocampus was detected at both the 2.5 and 6.25 mg/kg B[a]P-treated groups, indicating that multiple targets in NMDAR and downstream signaling pathways are involved in the B[a]P-induced neurotoxicity.


Assuntos
Benzo(a)pireno/toxicidade , Região CA1 Hipocampal/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Proteína Quinase C/metabolismo , Receptores de Glutamato/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Região CA1 Hipocampal/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fosforilação , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
4.
Neurobiol Aging ; 91: 66-75, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32224066

RESUMO

Cognitive impairments and circadian rhythm disorders are the main clinical manifestations of Alzheimer's disease (AD). Orexin has been reported as abnormally elevated in the cerebrospinal fluid of AD patients, accompanied with cognitive impairments. Our recent research revealed that suvorexant, a dual orexin receptor antagonist, could improve behavioral circadian rhythm disorders in 9-month-old APP/PS1 mice. Here we further observed whether suvorexant could ameliorate the cognitive decline in APP/PS1 mice by using behavioral tests, and investigated the possible mechanisms by in vivo electrophysiological recording, western blot, and immunochemistry. The results showed that suvorexant treatment effectively ameliorated the cognitive impairments, alleviated in vivo hippocampal long-term potentiation suppression, restored the circadian phosphorylated CREB expression in the hippocampus, and reduced amyloid-ß protein deposition in the hippocampus and cortex in APP/PS1 mice. These results indicate that the neuroprotective effects of suvorexant against AD are involved in the reduction of amyloid-ß plaques, improvement of synaptic plasticity, and circadian expression of phosphorylated CREB, suggesting that suvorexant could be beneficial to the prevention and treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Azepinas/farmacologia , Azepinas/uso terapêutico , Transtornos Cronobiológicos/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Neuroprostanos , Antagonistas dos Receptores de Orexina , Triazóis/farmacologia , Triazóis/uso terapêutico , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/complicações , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Transtornos Cronobiológicos/etiologia , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/etiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Potenciação de Longa Duração/efeitos dos fármacos , Camundongos Transgênicos , Plasticidade Neuronal/efeitos dos fármacos , Orexinas/líquido cefalorraquidiano
5.
J Pharmacol Exp Ther ; 373(2): 311-324, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32094294

RESUMO

Treatments for cognitive deficits associated with central nervous system (CNS) disorders such as Alzheimer disease and schizophrenia remain significant unmet medical needs that incur substantial pressure on the health care system. The α7 nicotinic acetylcholine receptor (nAChR) has garnered substantial attention as a target for cognitive deficits based on receptor localization, robust preclinical effects, genetics implicating its involvement in cognitive disorders, and encouraging, albeit mixed, clinical data with α7 nAChR orthosteric agonists. Importantly, previous orthosteric agonists at this receptor suffered from off-target activity, receptor desensitization, and an inverted U-shaped dose-effect curve in preclinical assays that limit their clinical utility. To overcome the challenges with orthosteric agonists, we have identified a novel selective α7 positive allosteric modulator (PAM), BNC375. This compound is selective over related receptors and potentiates acetylcholine-evoked α7 currents with only marginal effect on the receptor desensitization kinetics. In addition, BNC375 enhances long-term potentiation of electrically evoked synaptic responses in rat hippocampal slices and in vivo. Systemic administration of BNC375 reverses scopolamine-induced cognitive deficits in rat novel object recognition and rhesus monkey object retrieval detour (ORD) task over a wide range of exposures, showing no evidence of an inverted U-shaped dose-effect curve. The compound also improves performance in the ORD task in aged African green monkeys. Moreover, ex vivo 13C-NMR analysis indicates that BNC375 treatment can enhance neurotransmitter release in rat medial prefrontal cortex. These findings suggest that α7 nAChR PAMs have multiple advantages over orthosteric α7 nAChR agonists for the treatment of cognitive dysfunction associated with CNS diseases. SIGNIFICANCE STATEMENT: BNC375 is a novel and selective α7 nicotinic acetylcholine receptor (nAChR) positive allosteric modulator (PAM) that potentiates acetylcholine-evoked α7 currents in in vitro assays with little to no effect on the desensitization kinetics. In vivo, BNC375 demonstrated robust procognitive effects in multiple preclinical models across a wide exposure range. These results suggest that α7 nAChR PAMs have therapeutic potential in central nervous system diseases with cognitive impairments.


Assuntos
Receptor Nicotínico de Acetilcolina alfa7/efeitos dos fármacos , Regulação Alostérica , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cognição/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Macaca mulatta , Masculino , Neurotransmissores/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Escopolamina/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/agonistas
6.
Brain Behav Immun ; 87: 645-659, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32097763

RESUMO

Glioblastoma is a kind of malignant tumour and originates from the central nervous system. In the last century, some researchers and clinician have noticed that the psychosocial and neurocognitive functioning of patients with malignant gliomas can be impaired. Many clinical studies have demonstrated that part of patients, adults or children, diagnosed with glioblastoma will suffer from cognitive deficiency during their clinical course, especially in long-term survivors. Many nanoparticles (NPs) can inhibit the biological functions of tumours by modulating tumour-associated inflammation, which provokes angiogenesis and tumour growth. As one of the best antiviral nanoparticles (AVNPs), AVNP2 is the 2nd generation of AVNP2 that have been conjugated to graphite-graphene for improving physiochemical performance and reducing toxicity. AVNP2 inactivates viruses, such as the H1N1 and H5N1influenza viruses and even the SARS coronavirus, while it inhibits bacteria, such as MRSA and E. coli. As antimicrobials, nanoparticles are considered to be one of the vectors for the administration of therapeutic compounds. Yet, little is known about their potential functionalities and toxicities to the neurotoxic effects of cancer. Herein, we explored the functionality of AVNP2 on inhibiting C6 in glioma-bearing rats. The novel object-recognition test and open-field test showed that AVNP2 significantly improved the neuro-behaviour affected by C6 glioma. AVNP2 also alleviated the decline of long-term potentiation (LTP) and the decreased density of dendritic spines in the CA1 region induced by C6. Western blot assay and immunofluorescence staining showed that the expressions of synaptic-related proteins (PSD-95 and SYP) were increased, and these findings were in accordance with the results mentioned above. It revealed that the sizes of tumours in C6 glioma-bearing rats were smaller after treatment with AVNP2. The decreased expression of inflammatory factors (IL-1ß, IL-6 and TNF-α) by Western blotting assay and ELISA, angiogenesis protein (VEGF) by Western blotting assay and other related proteins (BDNF, NF-ĸB, iNOS and COX-2) by Western blotting assay in peri-tumour tissue indicated that AVNP2 could control tumour-associated inflammation, thus efficiently ameliorating the local inflammatory condition and, to some extent, inhibiting angiogenesis in C6-bearing rats. In conclusion, our results suggested that AVNP2 could have an effect on the peri-tumor environment, obviously restraining the growth progress of gliomas, and eventually improving cognitive levels in C6-bearing rats.


Assuntos
Antivirais/uso terapêutico , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/psicologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/prevenção & controle , Encefalite/etiologia , Encefalite/prevenção & controle , Glioma/complicações , Glioma/psicologia , Nanopartículas/uso terapêutico , Animais , Comportamento Animal , Peso Corporal/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/patologia , Disfunção Cognitiva/psicologia , Citocinas/biossíntese , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/patologia , Humanos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Transplante de Neoplasias , Ratos , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/genética
7.
Chemosphere ; 244: 125445, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31835052

RESUMO

Aluminium is an environmental neurotoxin that comes extensively in contact with human being. The molecular mechanism of aluminium toxicity remains unclear. A number of studies have indicated that exposure to aluminium can impair learning and memory function. The purpose of this study was to investigate the mechanism of long-term potentiation(LTP) injury and the related signalling pathway activated by aluminium exposure. The results showed that aluminium treatment produced dose-dependent inhibition of LTP and reduced the activity of Histone H3K9 demethylation (H3K9me2) demethylase and the expression of the PHD (plant homeodomain) finger protein 8 (PHF8). Interestingly, there was no statistically significant difference in the expression of the PHF8 gene, suggesting that aluminium exposure only affects the translation process. Decrease in brain-derived neurotrophic factor (BDNF) expression may be related to the effect of aluminium. With correlation analysis between the hippocampal standardised field excitatory postsynaptic potential (fEPSP) amplitude and the expression of various proteins in the aluminium-exposed rat, the hippocampal standardised fEPSP amplitude was positively correlated with the expression of hippocampal PHF8 and BDNF proteins, and negatively correlated with the expression of hippocampal H3K9me2 protein. The correlation between H3K9me2 and BDNF was also considered negative. The results suggest that changes in synaptic plasticity might be related to changes in these proteins, which were induced by aluminium exposure. In conclusion, chronic aluminium exposure may inhibit PHF8 and prevent it from functioning as a demethylase. This may block H3K9me2 demethylation, decrease BDNF protein expression, and lead to LTP impairment.


Assuntos
Alumínio/toxicidade , Substâncias Perigosas/toxicidade , Plasticidade Neuronal/efeitos dos fármacos , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Hipocampo/metabolismo , Histona Desmetilases , Humanos , Aprendizagem/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Memória/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Fatores de Transcrição/metabolismo
8.
Life Sci ; 242: 117210, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31874166

RESUMO

OBJECTIVES: Exposure of healthy subjects to ambient airborne dusty particulate matter (PM) causes brain dysfunction. This study aimed to investigate the effect of sub-chronic inhalation of ambient PM in a designed special chamber to create factual dust storm (DS) conditions on spatial cognition, hippocampal long-term potentiation (LTP), inflammatory cytokines, and oxidative stress in the brain tissue. METHODS: Adult male Wistar rats (250-300 g) were randomly divided into four groups: Sham (clean air, the concentration of dusty PM was <150 µg/m3), DS1 (200-500 µg/m3), DS2 (500-2000 µg/m3) and DS3 (2000-8000 µg/m3). Experimental rats were exposed to clean air or different sizes and concentrations of dust PM storm for four consecutive weeks (exposure was during 1-4, 8-11, 15-16 and 20-23 days, 30 min, twice daily) in a real-ambient dust exposure chamber. Subsequently, cognitive performance, hippocampal LTP, blood-brain barrier (BBB) permeability and brain edema of the animals evaluated. As well as, inflammatory cytokines and oxidative stress indexes in the brain tissue measured using ELISA assays. RESULTS: Exposing to dust PM impaired spatial memory (p < 0.001), hippocampal LTP (p < 0.001). These disturbances were in line with the severe damage to respiratory system followed by disruption of BBB integrity (p < 0.001), increased brain edema (p < 0.001), inflammatory cytokines (p < 0.001) excretion and oxidative stress (p < 0.001) in brain tissue. CONCLUSIONS: Our study showed that exposure to ambient dust PM increased brain edema and BBB permeability, induced memory impairment and hippocampal LTP deficiency by increasing the inflammatory responses and oxidative stress in the brain of the rats.


Assuntos
Edema Encefálico/induzido quimicamente , Encéfalo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Material Particulado/efeitos adversos , Memória Espacial/efeitos dos fármacos , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Exposição por Inalação/efeitos adversos , Masculino , Tamanho da Partícula , Ratos , Ratos Wistar
9.
Sci Rep ; 9(1): 19616, 2019 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-31873156

RESUMO

Aging is associated with functional alterations of synapses thought to contribute to age-dependent memory impairment (AMI). While therapeutic avenues to protect from AMI are largely elusive, supplementation of spermidine, a polyamine normally declining with age, has been shown to restore defective proteostasis and to protect from AMI in Drosophila. Here we demonstrate that dietary spermidine protects from age-related synaptic alterations at hippocampal mossy fiber (MF)-CA3 synapses and prevents the aging-induced loss of neuronal mitochondria. Dietary spermidine rescued age-dependent decreases in synaptic vesicle density and largely restored defective presynaptic MF-CA3 long-term potentiation (LTP) at MF-CA3 synapses (MF-CA3) in aged animals. In contrast, spermidine failed to protect CA3-CA1 hippocampal synapses characterized by postsynaptic LTP from age-related changes in function and morphology. Our data demonstrate that dietary spermidine attenuates age-associated deterioration of MF-CA3 synaptic transmission and plasticity. These findings provide a physiological and molecular basis for the future therapeutic usage of spermidine.


Assuntos
Envelhecimento/metabolismo , Região CA3 Hipocampal/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Fibras Musgosas Hipocampais/metabolismo , Espermidina/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Vesículas Sinápticas/metabolismo , Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Animais , Região CA3 Hipocampal/patologia , Camundongos , Fibras Musgosas Hipocampais/patologia , Vesículas Sinápticas/patologia
10.
Sci Rep ; 9(1): 20138, 2019 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-31882891

RESUMO

The prevalence of cognitive decline is increasing as the ageing population is considerably growing. Restricting this age-associated process has become a challenging public health issue. The age-related increase in oxidative stress plays a major role in cognitive decline, because of its harmful effect on functional plasticity of the brain, such as long-term potentiation (LTP). Here, we show that citrulline (Cit) has powerful antioxidant properties that can limit ex vivo oxidative stress-induced LTP impairment in the hippocampus. We also illustrate that a three-month Cit supplementation has a protective effect on LTP in aged rats in vivo. The identification of a Cit oxidation byproduct in vitro suggests that the antioxidant properties of Cit could result from its own oxidation. Cit supplementation may be a promising preventive nutritional approach to limit age-related cognitive decline.


Assuntos
Envelhecimento , Citrulina/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Envelhecimento/metabolismo , Animais , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/farmacologia , Camundongos , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos
11.
Life Sci ; 238: 116969, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31628912

RESUMO

AIMS: Glutamatergic dysfunction is posed as a main stage in neurodegenerative disorders such as Alzheimer's disease (AD). Glutamate-mediated excitotoxicity contributes to cognitive dysfunction and cell death in AD. Ceftriaxone (CFT), a well-known upregulator of GLT-1, selectively induces the expression of glutamate transporter-1 (GLT-1) in different brain regions and therefore can be posed as a potential candidate for elimination of glutamate-induced excitotoxicity which is an early prominent event in AD brains. This study was designed to investigate the electrophysiological and behavioral effects of the ß-lactam antibiotic ceftriaxone in okadaic acid (OKA)-induced model of AD. MATERIALS AND METHODS: Male Wistar rats divided into four control, ceftriaxone (CFT), OKA, and OKA plus ceftriaxone (OKA + CFT) groups. OKA was injected intracerebroventricularly (i.c.v., 200 ng/5 µl) into lateral ventricles and after two weeks the evoked field potential recorded from hippocampal perforant path-DG synapses in order to evaluate the effect of ceftriaxone treatment (200 mg/kg/day, i.p.) on long-term potentiation (LTP) and paired-pulse responses. KEY FINDINGS: Results of this study revealed that ceftriaxone treatment significantly ameliorates the OKA-induced attenuation of field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude following high-frequency stimulation and paired-pulse paradigm indicating its beneficial effects on both short-term and long-term plasticity in these neurons. Ceftriaxone also has an improving effect on OKA-induced impairment in short- and long-term memories evaluated by alternation behavior and passive avoidance tasks in rats. SIGNIFICANCE: Therefore, this study suggests that GLT-1 might be a promising therapeutic target for treatment of neurodegenerative disorders such as AD in the future.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Ceftriaxona/farmacologia , Giro Denteado/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/patologia , Animais , Antibacterianos/farmacologia , Carcinógenos/toxicidade , Giro Denteado/patologia , Hipocampo/patologia , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/patologia , Ácido Okadáico/toxicidade , Ratos , Ratos Wistar , Sinapses/efeitos dos fármacos
12.
PLoS One ; 14(10): e0223509, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31600350

RESUMO

Many in vivo studies suggest that inhalational anesthetics can accelerate or prevent the progression of neuropathology and cognitive impairments in Alzheimer Disease (AD), but the synaptic mechanisms mediating these ambiguous effects are unclear. Here, we show that repeated exposures of neonatal and old triple transgenic AD (3xTg) and non-transgenic (NonTg) mice to isoflurane (Iso) distinctly increased neurodegeneration as measured by S100ß levels, intracellular Aß, Tau oligomerization, and apoptotic markers. Spatial cognition measured by reference and working memory testing in the Morris Water Maze (MWM) were altered in young NonTg and 3xTg. Field recordings in the cornu ammonis 1 (CA1) hippocampus showed that neonatal control 3xTg mice exhibited hypo-excitable synaptic transmission, reduced paired-pulse facilitation (PPF), and normal long-term potentiation (LTP) compared to NonTg controls. By contrast, the old control 3xTg mice exhibited hyper-excitable synaptic transmission, enhanced PPF, and unstable LTP compared to NonTg controls. Repeated Iso exposures reduced synaptic transmission and PPF in neonatal NonTg and old 3xTg mice. LTP was normalized in old 3xTg mice, but reduced in neonates. By contrast, LTP was reduced in old but not neonatal NonTg mice. Our results indicate that Iso-mediated neuropathologic and cognitive defects in AD mice are associated with synaptic pathologies in an age-dependent manner. Based on these findings, the extent of this association with age and, possibly, treatment paradigms warrant further study.


Assuntos
Envelhecimento/patologia , Doença de Alzheimer/complicações , Disfunção Cognitiva/patologia , Hipocampo/patologia , Isoflurano/efeitos adversos , Sinapses/patologia , Doença de Alzheimer/fisiopatologia , Amiloide/metabolismo , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Disfunção Cognitiva/complicações , Disfunção Cognitiva/fisiopatologia , Hipocampo/fisiopatologia , Potenciação de Longa Duração/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Plasticidade Neuronal/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Proteínas tau/metabolismo
13.
J Pharmacol Exp Ther ; 371(3): 633-641, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31578258

RESUMO

N-methyl-d-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) is an established cellular model underlying learning and memory, and involves intracellular signaling mediated by the second messenger cyclic guanosine monophosphate (cGMP). As phosphodiesterase (PDE)9A selectively hydrolyses cGMP in areas of the brain related to cognition, PDE9A inhibitors may improve cognitive function by enhancing NMDA receptor-dependent LTP. This study aimed to pharmacologically characterize BI 409306, a novel PDE9A inhibitor, using in vitro assays and in vivo determination of cGMP levels in the brain. Further, the effects of BI 409306 on synaptic plasticity evaluated by LTP in ex vivo hippocampal slices and on cognitive performance in rodents were also investigated. In vitro assays demonstrated that BI 409306 is a potent and selective inhibitor of human and rat PDE9A with mean concentrations at half-maximal inhibition (IC50) of 65 and 168 nM. BI 409306 increased cGMP levels in rat prefrontal cortex and cerebrospinal fluid and attenuated a reduction in mouse striatum cGMP induced by the NMDA-receptor antagonist MK-801. In ex vivo rat brain slices, BI 409306 enhanced LTP induced by both weak and strong tetanic stimulation. Treatment of mice with BI 409306 reversed MK-801-induced working memory deficits in a T-maze spontaneous-alternation task and improved long-term memory in an object recognition task. These findings suggest that BI 409306 is a potent and selective inhibitor of PDE9A. BI 409306 shows target engagement by increasing cGMP levels in brain, facilitates synaptic plasticity as demonstrated by enhancement of hippocampal LTP, and improves episodic and working memory function in rodents. SIGNIFICANCE STATEMENT: This preclinical study demonstrates that BI 409306 is a potent and selective PDE9A inhibitor in rodents. Treatment with BI 409306 increased brain cGMP levels, promoted long-term potentiation, and improved episodic and working memory performance in rodents. These findings support a role for PDE9A in synaptic plasticity and cognition. The potential benefits of BI 409306 are currently being investigated in clinical trials.


Assuntos
Química Encefálica/efeitos dos fármacos , GMP Cíclico/análise , Memória/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Pirazóis/farmacocinética , Pirimidinas/farmacocinética , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Animais , GMP Cíclico/líquido cefalorraquidiano , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pirazóis/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Wistar
14.
Neurol Res ; 41(11): 1024-1033, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31578943

RESUMO

Objective: Diabetes-associated cognitive deficits is characterized by long-term potentiation (LTP) decline in the hippocampus. DL-3-n-butylphthalide (NBP) is a novel agent exerting protective effect against ischemic brain. However, the effects of NBP on diabetes-associated cognitive deficits and underlying mechanisms are not fully clear. This study was designed to evaluate the effects of NBP on the cognitive deficits through activating CaMKII-mediated LTP process and protecting neuron structure of hippocampus in diabetic db/db mice. Methods: Male db/db mice were randomly divided into db/db group (n = 8) and db/db+NBP group (n = 8, 120mg/Kg NBP by gavage). Male db/m mice (n = 8) were included as control group. All animals were treated for 6 weeks. Morris Water Maze test was carried out to evaluate cognitive function. Electrophysiological recordings were performed to test LTP level. HE-staining and electron microscopy of hippocampus were used to observe structure change of neurons and synapse. RT-PCR and Western blot were used to assess the expression of CaMKII, NR2B, and GluR1. Results: Type 2 diabetes mellitus caused LTP decline, and significantly decreased NR2B, CaMKII, and GluR1 expression. Histological analysis showed that disorganized pyramidal cells, as well as degraded neuron and synapse ultrastructure in db/db mice. NBP treatment restored LTP and its associated proteins in db/db mice. The structure changes of hippocampal cells were partly reversed by NBP intervention. Conclusion: These results suggest that NBP ameliorates cognitive deficits induced by type 2 diabetes mellitus through improving CaMKII-mediated LTP and cell ultrastructure in the hippocampus. NBP is a potential therapeutic agent for diabetes-associated cognitive deficits. Abbreviations: NBP: DL-3-n-butylphthalide; LTP: long-term potentiation; CaMKII: calcium/calmodulin-dependent protein kinase II; NR2B: N-methyl-D-aspartic acid receptor subtype 2B; GluR1: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subtype 1.


Assuntos
Benzofuranos/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Animais , Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Modelos Animais de Doenças , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/metabolismo
15.
PLoS One ; 14(10): e0223180, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31581202

RESUMO

Cognitive impairments are a common consequence of traumatic brain injury (TBI). The hippocampus is a subcortical structure that plays a key role in the formation of declarative memories and is highly vulnerable to TBI. The α7 nicotinic acetylcholine receptor (nAChR) is highly expressed in the hippocampus and reduced expression and function of this receptor are linked with cognitive impairments in Alzheimer's disease and schizophrenia. Positive allosteric modulation of α7 nAChRs with AVL-3288 enhances receptor currents and improves cognitive functioning in naïve animals and healthy human subjects. Therefore, we hypothesized that targeting the α7 nAChR with the positive allosteric modulator AVL-3288 would enhance cognitive functioning in the chronic recovery period of TBI. To test this hypothesis, adult male Sprague Dawley rats received moderate parasagittal fluid-percussion brain injury or sham surgery. At 3 months after recovery, animals were treated with vehicle or AVL-3288 at 30 min prior to cue and contextual fear conditioning and the water maze task. Treatment of TBI animals with AVL-3288 rescued learning and memory deficits in water maze retention and working memory. AVL-3288 treatment also improved cue and contextual fear memory when tested at 24 hr and 1 month after training, when TBI animals were treated acutely just during fear conditioning at 3 months post-TBI. Hippocampal atrophy but not cortical atrophy was reduced with AVL-3288 treatment in the chronic recovery phase of TBI. AVL-3288 application to acute hippocampal slices from animals at 3 months after TBI rescued basal synaptic transmission deficits and long-term potentiation (LTP) in area CA1. Our results demonstrate that AVL-3288 improves hippocampal synaptic plasticity, and learning and memory performance after TBI in the chronic recovery period. Enhancing cholinergic transmission through positive allosteric modulation of the α7 nAChR may be a novel therapeutic to improve cognition after TBI.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Regulação Alostérica/efeitos dos fármacos , Anilidas/sangue , Anilidas/farmacocinética , Anilidas/farmacologia , Anilidas/uso terapêutico , Animais , Atrofia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Doença Crônica , Transtornos Cognitivos/fisiopatologia , Condicionamento Clássico , Medo , Isoxazóis/sangue , Isoxazóis/farmacocinética , Isoxazóis/farmacologia , Isoxazóis/uso terapêutico , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto , Memória de Curto Prazo , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos
16.
Bull Exp Biol Med ; 167(4): 467-469, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31493257

RESUMO

Second messengers cAMP and cGMP play an important role in synaptic plasticity and memory consolidation. The inhibitors of phosphodiesterases, enzymes hydrolyzing these cyclic nucleotides, are actively studied as potential drugs for the treatment of various cognitive disorders and depression. We studied the effects of a new inhibitor of phosphodiesterase 7 AGF2.20 on the formation of long-term potentiation in hippocampal slices. Administration of AGF2.20 (10 nM) in 90 min after weak tetanization prevented a decrease in the amplitude of excitatory post-synaptic potentials and stabilized long-term potentiation. These data attest to the involvement of phosphodiesterase 7 in the development of synaptic plasticity in the hippocampus. The inhibitor AGF2.20 is considered for the further analysis as a promising substance for the treatment of cognitive impairments.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/antagonistas & inibidores , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/metabolismo , Inibidores Enzimáticos/farmacologia , Hipocampo/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Animais , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos
17.
Psychopharmacology (Berl) ; 236(12): 3687-3693, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31392357

RESUMO

BACKGROUND: NYX-2925 is a novel N-methyl-D-aspartate receptor (NMDAR) modulator that has been shown to facilitate both NMDAR-dependent long-term potentiation (LTP) in vitro and learning and memory in vivo. OBJECTIVE: The present studies examine the effects of NYX-2925 on NMDAR-dependent auditory LTP (aLTP) in vivo. METHODS: NMDAR-dependent aLTP and NMDAR-dependent auditory mismatch negativity (MMN) was measured, as well as changes in resting-state qEEG power. RESULTS: NYX-2925 (1, 10 mg/kg PO) increased aLTP 1 h after auditory tetanus measured by the post- minus pre-tetanus difference waveform 140-180 ms post tone onset. NYX-2925 (0.1, 1 mg/kg PO) facilitated MMN measured by the difference waveform (i.e., deviant minus standard tones). NYX-2925 (0.1, 1, 10 mg/kg PO) also enhanced resting-state alpha qEEG power. Conversely, the NMDAR glutamate site antagonist CPP (10 mg/kg IP) reduces alpha power and MMN and produces an opposite effect as NYX-2925 on aLTP. CONCLUSIONS: Together, these data suggest that the activation of the NMDAR by NYX-2925 enhances synaptic plasticity in vivo, which may both reduce symptoms of neurological disorders and serve as a biomarker for drug effects. This is the first demonstration of a long-lasting (1-h post-tetanus) effect of NMDAR modulation on synaptic plasticity processes in vivo using a noninvasive technique in freely behaving animals.


Assuntos
Eletroencefalografia/métodos , Plasticidade Neuronal/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/fisiologia , Compostos de Espiro/farmacologia , Pesquisa Médica Translacional/métodos , Animais , Eletroencefalografia/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/agonistas
18.
Neurobiol Learn Mem ; 163: 107039, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31278985

RESUMO

Activity dependent setting of synaptic tags is critical for the establishment and maintenance of long-term plasticity and its associative properties such as synaptic tagging and capture (STC), a widely studied cellular model of associative memory. Although the known mechanisms of STC such as setting of synaptic tags or distribution of plasticity related proteins (PRPs) are the processes mainly happening within the neuronal compartments, the role of non-neuronal components is still elusive. Here, we report that microglia has a specific role in setting the synaptic tags and thus promotes long-term plasticity and STC. Treatment of hippocampal slices with clodronate, a specific inhibitor of microglia, resulted in an activated morphology of microglia but not of the hippocampal pyramidal neurons, oligodendrocytes or astrocytes. Activation of microglia before or 60 min after the induction of long-term plasticity prevented its maintenance and thus the expression of STC. Interestingly, activation of microglia 2 h after the induction of long-term plasticity neither prevented its maintenance nor its associative interaction with activated nearby synaptic populations. Given the half-life of synaptic tags is until about 60-90 min, activation of microglia beyond this time point while the maintenance phase is still unperturbed, suggests a lack of microglial interference in the synthesis or trigger of plasticity related products. Thus, our study provides the first evidence that microglia play a critical role in the setting of synaptic tags during the early phase of activity dependent plasticity.


Assuntos
Região CA1 Hipocampal/fisiologia , Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Microglia/fisiologia , Sinapses/fisiologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/fisiologia , Região CA1 Hipocampal/efeitos dos fármacos , Ácido Clodrônico/farmacologia , Imunofluorescência , Hipocampo/efeitos dos fármacos , Interleucina-1beta/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/fisiologia , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Sinapses/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
19.
Neuroscience ; 414: 154-167, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31310731

RESUMO

Accumulating evidence suggests that glutamatergic signaling and synaptic plasticity underlie one of a number of ways psychiatric disorders appear. The present study reveals a possible mechanism by which this occurs, through highlighting the importance of LMTK3, in the brain. Behavioral analysis of Lmtk3-KO mice revealed a number of abnormalities that have been linked to psychiatric disease such as hyper-sociability, PPI deficits and cognitive dysfunction. Treatment with clozapine suppressed these behavioral changes in Lmtk3-KO mice. As synaptic dysfunction is implicated in human psychiatric disease, we analyzed the LTP of Lmtk3-KO mice and found that induction is severely impaired. Further investigation revealed abnormalities in GluA1 trafficking after AMPA stimulation in Lmtk3-KO neurons, along with a reduction in GluA1 expression in the post-synaptic density. Therefore, we hypothesize that LMTK3 is an important factor involved in the trafficking of GluA1 during LTP, and that disruption of this pathway contributes to the appearance of behavior associated with human psychiatric disease in mice.


Assuntos
Comportamento Animal/fisiologia , Proteínas de Membrana/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de AMPA/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Clozapina/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Inibição Pré-Pulso/efeitos dos fármacos , Inibição Pré-Pulso/genética , Transporte Proteico/genética , Proteínas Serina-Treonina Quinases/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/genética , Comportamento Social , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologia
20.
Neurobiol Aging ; 81: 88-101, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31255922

RESUMO

Neurodegenerative disorders such as Alzheimer's disease (AD) are characterized by the irreversible neuronal loss and memory impairment, and current treatments are merely symptomatic. Erythropoietin (EPO) has been shown to possess neurotrophic, neuroprotective, anti-inflammatory, and memory-enhancing effects, which could be therapeutically beneficial in the different aspects of AD. However, the hematopoietic effect of EPO has hampered its potential as a neuroprotective and procognitive agent. In this study, we characterized a novel small peptide, NL100, derived from a conserved C-helix region of EPO. NL100 was shown to bind to the EPO receptor, induce neuritogenesis, and protect hippocampal neurons from oxidative- and Aß25-35-induced neurodegeneration in vitro. Importantly, long-term NL100 treatment did not induce hematopoiesis, overcoming this challenge associated with EPO. Memory-enhancing effects were demonstrated after NL100 treatment in social recognition test for short-term memory, in both healthy rats and rats challenged centrally with Aß25-35 peptide, and in the Morris water maze test for spatial memory. Moreover, NL100 was shown to reverse Aß25-35-induced hippocampal degeneration and gliosis as well as pilocarpine-induced suppression of long-term potentiation in rats. In conclusion, NL100 is a novel EPO-derived nonhematopoietic peptide with neuroprotective and memory-enhancing effects and could therefore be a potential candidate for the development of new treatments for neurodegenerative disorders and dementia.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Demência/tratamento farmacológico , Demência/etiologia , Eritropoetina , Potenciação de Longa Duração/efeitos dos fármacos , Memória/efeitos dos fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/etiologia , Fármacos Neuroprotetores , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Animais , Eritropoetina/química , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Camundongos Endogâmicos BALB C , Crescimento Neuronal/efeitos dos fármacos , Ratos Sprague-Dawley , Ratos Wistar
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