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1.
Chemosphere ; 263: 128008, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32841879

RESUMO

The anthranilic diamide, chlorantraniliprole is a systemic insecticide affecting ryanodine receptors. This insecticide is used to control caterpillars in soybean crops because it has low toxicity to non-target organisms. The objective was to identify side-effects of chlorantraniliprole on midgut histopathology, respiration and behavior of the velvetbean caterpillar Anticarsia gemmatalis in laboratoty. Chlorantraniliprole has LC50 = 0.61 (0.58-0.64) mg mL-1 for A. gemmatalis fourth instar caterpillars after 96 h. The insecticide causes severe histopathological effects in the midgut with epithelial disorganization, microvilli degeneration, cytoplasm vacuolization, cell fragmentation, and peritrophic matrix disorganization. The respiratory rate and the walking speed decrease, whereas the resting period increase for caterpillars exposed to this insecticide. Chlorantraniliprole is toxic to A. gemmatalis at median lethal concentrations causing severe histological and ultrastructural changes with degeneration of the midgut epithelium, reduction of respiratory rates and inducing an arresting behavioral response of this insect.


Assuntos
Inseticidas/toxicidade , Lepidópteros/fisiologia , ortoaminobenzoatos/toxicidade , Animais , Sistema Digestório , Larva , Locomoção/efeitos dos fármacos , Microvilosidades , Mariposas , Respiração/efeitos dos fármacos , Soja
2.
Nat Commun ; 11(1): 6157, 2020 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-33268792

RESUMO

Norepinephrine adjusts sensory processing in cortical networks and gates plasticity enabling adaptive behavior. The actions of norepinephrine are profoundly altered by recreational drugs like ethanol, but the consequences of these changes on distinct targets such as astrocytes, which exhibit norepinephrine-dependent Ca2+ elevations during vigilance, are not well understood. Using in vivo two-photon imaging, we show that locomotion-induced Ca2+ elevations in mouse astroglia are profoundly inhibited by ethanol, an effect that can be reversed by enhancing norepinephrine release. Vigilance-dependent astroglial activation is abolished by deletion of α1A-adrenergic receptor from astroglia, indicating that norepinephrine acts directly on these ubiquitous glial cells. Ethanol reduces vigilance-dependent Ca2+ transients in noradrenergic terminals, but has little effect on astroglial responsiveness to norepinephrine, suggesting that ethanol suppresses their activation by inhibiting norepinephrine release. Since abolition of astroglia Ca2+ activation does not affect motor coordination, global suppression of astroglial networks may contribute to the cognitive effects of alcohol intoxication.


Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Cálcio/metabolismo , Etanol/farmacologia , Norepinefrina/farmacologia , Vigília/efeitos dos fármacos , Intoxicação Alcoólica/genética , Intoxicação Alcoólica/metabolismo , Intoxicação Alcoólica/fisiopatologia , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Cerebelo/citologia , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Transportador 1 de Aminoácido Excitatório/deficiência , Transportador 1 de Aminoácido Excitatório/genética , Feminino , Regulação da Expressão Gênica , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Knockout , Microscopia de Fluorescência por Excitação Multifotônica , Neurogênese/efeitos dos fármacos , Neurogênese/genética , Norepinefrina/antagonistas & inibidores , Receptores Adrenérgicos alfa 1/deficiência , Receptores Adrenérgicos alfa 1/genética , Vigília/fisiologia , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismo
3.
Chem Biol Interact ; 331: 109278, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33038329

RESUMO

Only in the last decade the long-term consequences of sepsis started to be studied and even less attention has been given to the treatment of psychological symptoms of sepsis survivors. It is estimated that 60% of sepsis survivors have psychological disturbances, including depression, anxiety, and cognitive impairment. Although the causative factors remain largely poorly understood, blood-brain barrier (BBB) disturbances, neuroinflammation, and oxidative stress have been investigated. Therefore, we sought to explore if the immunomodulatory and antioxidant selenocompound 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole (CMI) would be able to ameliorate long-term behavioral and biochemical alterations in sepsis survivors male Swiss mice. CMI treatment (1 mg/kg, given orally for seven consecutive days) attenuated depression- and anxiogenic-like behaviors and cognitive impairment present one month after the induction of sepsis (lipopolysaccharide, 5 mg/kg intraperitoneally). Meantime, CMI treatment modulated the number of neutrophils and levels of reactive species in neutrophils, lymphocytes, and monocytes. In addition, peripheral markers of liver and kidneys dysfunction (AST, ALT, urea, and creatinine) were reduced after CMI treatment in post-septic mice. Notably, CMI treatment to non-septic mice did not alter AST, ALT, urea, and creatinine levels, indicating the absence of acute hepatotoxicity and nephrotoxicity following CMI treatment. Noteworthy, CMI ameliorated BBB dysfunction induced by sepsis, modulating the expression of inflammation-associated genes (NFκB, IL-1ß, TNF-α, IDO, COX-2, iNOS, and BDNF) and markers of oxidative stress (reactive species, nitric oxide, and lipid peroxidation levels) in the prefrontal cortices and hippocampi of mice. In conclusion, we unraveled crucial molecular pathways that are impaired in post-septic mice and we present CMI as a promising therapeutic candidate aimed to manage the long-lasting behavioral alterations of sepsis survivors to improve their quality of life.


Assuntos
Comportamento Animal , Indóis/química , Estresse Oxidativo , Sepse/patologia , Animais , Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Comportamento Animal/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Depressão/tratamento farmacológico , Depressão/etiologia , Depressão/patologia , Modelos Animais de Doenças , Indóis/farmacologia , Indóis/uso terapêutico , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Lipopolissacarídeos/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Neutrófilos/citologia , Neutrófilos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Sepse/complicações
4.
PLoS One ; 15(10): e0236606, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33031370

RESUMO

In this study, we investigated locomotor activity and responses to repeated light and dark stimuli to assess cannabinoid-induced abnormal behavior in zebrafish larvae (Danio rerio), as an alternative to standard rodent models. To induce the desired responses, we used cannabidiol and WIN55,212-2, two major cannabinoid components. A repeated light and dark test was used to assess how drug exposure influences locomotory responses. Larvae were examined after moderate cannabidiol and WIN55,212-2 exposure and at 24 h after transfer to untreated water. We found that cannabidiol did not produce a dose-dependent inhibitory effect on locomotor activity, with both 0.5 and 10 µg/mL concentrations reducing movement velocity and the total distance moved. However, 10 µg/mL cannabidiol was observed to attenuate the responses of larvae exposed to darkness. No differences were detected between the control and cannabidiol-treated groups after 24 h in fresh water. Fish treated with WIN55,212-2 at 0.5 and 1 µg/mL showed virtually no activity, even in darkness, whereas a concentration of 10 µg/mL induced mortality. A 24-h period in fresh water had the effect of reversing most of the drug-induced immobilization, even in the WIN55,212-2-treated groups. Larvae were also evaluated for their responses to cannabidiol subsequent to an initial exposure to WIN55,212-2, and it was accordingly found that treatment with cannabidiol could attenuate WIN55,212-2-induced abnormal immobilization, whereas equivalent doses of cannabidiol and WIN55,212-2 produced a mixed response. In conclusion, the behavioral effects of the two cannabinoids cannabidiol and WIN55,212-2 appear to be ratio dependent. Furthermore, the repeated light and dark test could serve as a suitable method for assaying drug-induced behavior.


Assuntos
Comportamento Animal/efeitos dos fármacos , Canabinoides/toxicidade , Locomoção/efeitos dos fármacos , Peixe-Zebra/crescimento & desenvolvimento , Animais
5.
J Med Chem ; 63(21): 12682-12692, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33063995

RESUMO

Venom peptides are promising drug leads, but their therapeutic use is often limited by stability and bioavailability issues. In this study, we designed cyclic analogues of α-conotoxin CIA, a potent muscle nicotinic acetylcholine receptor (nAChR) blocker with a significantly lower affinity at the neuronal α3ß2 subtype. Remarkably, all analogues retained the low nanomolar activity of native CIA toward muscle-type nAChRs but showed greatly improved resistance to degradation in human serum and, surprisingly, displayed up to 52-fold higher potency for the α3ß2 neuronal nAChR subtype (IC50 1.3 nM). Comparison of nuclear magnetic resonance-derived structures revealed some differences that might explain the gain of potency at α3ß2 nAChRs. All peptides were highly paralytic when injected into adult zebrafish and bath-applied to zebrafish larvae, suggesting barrier-crossing capabilities and efficient uptake. Finally, these cyclic CIA analogues were shown to be unique pharmacological tools to investigate the contribution of the presynaptic α3ß2 nAChR subtype to the train-of-four fade.


Assuntos
Ligantes , Músculos/metabolismo , Neurônios/metabolismo , Antagonistas Nicotínicos/química , Peptídeos/química , Receptores Nicotínicos/metabolismo , Peçonhas/metabolismo , Sequência de Aminoácidos , Animais , Conotoxinas/química , Ciclização , Larva/efeitos dos fármacos , Larva/fisiologia , Locomoção/efeitos dos fármacos , Camundongos , Contração Muscular/efeitos dos fármacos , Antagonistas Nicotínicos/metabolismo , Antagonistas Nicotínicos/farmacologia , Peptídeos/metabolismo , Peptídeos/farmacologia , Ligação Proteica , Estrutura Terciária de Proteína , Receptores Nicotínicos/química , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/fisiologia
6.
J Neuroimmunol ; 349: 577401, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33002724

RESUMO

Immune activation contributes to the pathophysiology of psychiatric disorders. Administration of a single dose of lipopolysaccharides (LPS) has been shown to induce depressive- and anxiety-like behaviors in rodents through activation of the kynurenine pathway, increasing levels of the N-methyl-d-aspartate (NMDA) receptor agonist quinolinic acid. Conversely, repeated administration of LPS produces increased levels of the NMDA receptor antagonist kynurenic acid. Here we show that repeated LPS administration increases sensitivity to D-amphetamine and produces cognitive deficits and anxiety-like behavior. Together, our behavioral data suggests that repeated LPS administration may be useful to study the contribution of inflammation to psychiatric disorders such as schizophrenia.


Assuntos
Anfetamina/toxicidade , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/toxicidade , Locomoção/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Animais , Estimulantes do Sistema Nervoso Central/toxicidade , Esquema de Medicação , Sinergismo Farmacológico , Locomoção/fisiologia , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/fisiopatologia , Transtornos da Memória/psicologia , Camundongos , Camundongos Endogâmicos C57BL
7.
PLoS One ; 15(9): e0238637, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32903270

RESUMO

Neonicotinoids, a class of insecticides structurally similar to nicotine that target biting and sucking insects, are the most widely used insecticides today, in part due to their supposed low toxicity in other organisms. However, a growing body of research has found that even low doses of neonicotinoids can induce unexpected negative effects on the physiology and survival of a wide range of non-target organisms. Importantly, no work has been done on the commercial formulations of pesticides that include imidacloprid as the active ingredient, but that also contain many other components. The present study examines the sublethal effects of "Tree and Shrub"™ ("T+S"), a commercial insecticide containing the neonicotinoid imidacloprid as its active ingredient, on Caenorhabditis elegans. We discovered that "T+S" significantly stunted the overall growth in wildtype nematodes, an effect that was exacerbated by concurrent exposure to heat stress. "T+S" also negatively impacted fecundity as measured by increased germline apoptosis, a decrease in egg-laying, and fewer viable offspring. Lastly, exposure to "T+S" resulted in degenerative changes in nicotinic cholinergic neurons in wildtype nematodes. As a whole, these findings demonstrate widespread toxic effects of neonicotinoids to critical functions in nematodes.


Assuntos
Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/fisiologia , Inseticidas/toxicidade , Locomoção/efeitos dos fármacos , Neonicotinoides/toxicidade , Animais , Apoptose/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/metabolismo , Aberrações Cromossômicas , Fertilidade/efeitos dos fármacos , Células Germinativas/citologia , Células Germinativas/efeitos dos fármacos , Resposta ao Choque Térmico , Degeneração Neural/patologia , Oviposição/efeitos dos fármacos , Reprodução/efeitos dos fármacos
8.
J Pharmacol Exp Ther ; 375(2): 276-285, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32862143

RESUMO

Histamine H3 receptor antagonists/inverse agonists are known to enhance the activity of histaminergic neurons in the brain, thereby promoting arousal and cognition. Here, we report the in vitro and in vivo pharmacological profiles for a newly synthesized histamine H3 receptor antagonist/inverse agonist: [1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazol-4-yl](morpholin-4-yl)methanone monohydrochloride (enerisant hydrochloride). In vitro assays showed that enerisant was a competitive antagonist/inverse agonist with a high affinity and selectivity for human and rat histamine H3 receptors. Enerisant showed antagonist activity in vivo, as assessed using R-α-methylhistamine (a histamine H3 receptor agonist)-induced dipsogenia, and occupied the histamine H3 receptor in the frontal cortex in a dose-dependent manner. Enerisant also enhanced the extracellular levels of histamine in the posterior hypothalamus and the levels of dopamine and acetylcholine in the medial prefrontal cortex of rats. Enerisant exerted a procognitive effect or reversed scopolamine-induced cognitive impairment in a social recognition test and a novel object recognition test in rats at doses at which less than 50% of the histamine H3 receptor were occupied (0.03-0.3 mg/kg, p.o.). In contrast, higher doses (3-10 mg/kg, p.o.) at which nearly all the histamine H3 receptors were occupied were needed to exert wake-promoting effects in rats. These results indicate that enerisant is a potent and selective histamine H3 receptor antagonist/inverse agonist with the potential to promote arousal and procognition in rats. Moreover, the results also suggest that the histamine H3 receptor occupancy required to exert a pharmacological effect may vary depending on the domain that is being tested. SIGNIFICANCE STATEMENT: Enerisant is a novel histamine H3 receptor antagonist/inverse agonist that exerts wake-promoting and procognitive effects in addition to increasing the release of neurotransmitters related to these pharmacological effects in rodents. Moreover, an in vivo receptor binding study revealed that the in vivo occupancy of the histamine H3 receptor required to exert the pharmacological effects of enerisant varied, and such variations in required occupancy should be taken into account when performing dose selection in clinical studies.


Assuntos
Cognição/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/farmacologia , Receptores Histamínicos H3/metabolismo , Vigília/efeitos dos fármacos , Animais , Eletroencefalografia , Antagonistas dos Receptores Histamínicos/farmacocinética , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Neurotransmissores/metabolismo , Ratos
9.
Phytomedicine ; 78: 153307, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32846405

RESUMO

BACKGROUND: Current therapies for neuropathic pain are generally symptomatic and possess several side effects, limiting their prolonged usage. HYPOTHESIS/PURPOSE: Thus, it is urgent to develop novel and safe candidates for the management of this chronical condition. For this purpose, we investigated the analgesic effect of a standardized extract from Zingiber officinale Roscoe rhizomes (ZOE) obtained by CO2 supercritical extraction, in a mice model of peripheral neuropathy. We also explored the mechanism of action of ZOE and its main constituents using an in vitro model of neuroinflammation. METHODS: Peripheral mono-neuropathy was induced in mice, by spared nerve injury (SNI). The analgesic effect of ZOE after oral administration was assessed by measuring mechanical and thermal allodynia in SNI mice. The mechanism of action of ZOE and its main constituents were investigated using spinal cords samples and in an in vitro model of neuroinflammation by ELISA, western blotting and immunofluorescence techniques. RESULTS: Oral administration of ZOE 200 mg kg-1 ameliorated mechanical and thermal allodynia in SNI mice, with a rapid and a long-lasting effect. ZOE did not alter locomotor activity. In BV2 cells and spinal cord samples, ZOE, 6-gingerol and 6-shogaol reduced pERK levels, whereas ZOE and terpene fraction reduced HDAC1 protein levels, inhibited NF-κB signalling activation and decreased IL-1ß, TNF-α and IL-6 release. ZOE and each tested constituent had a positive effect on inflammation-impaired SH-SY5Y cell viability. CONCLUSIONS: The oral administration of ZOE attenuated SNI-induced neuropathic pain symptoms by reducing spinal neuroinflammation, suggesting ZOE as a novel and interesting candidate for the management of neuropathic pain.


Assuntos
Analgésicos não Entorpecentes/farmacologia , Gengibre/química , Neuralgia/tratamento farmacológico , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Administração Oral , Analgésicos não Entorpecentes/administração & dosagem , Analgésicos não Entorpecentes/química , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Histona Desacetilase 1/metabolismo , Hiperalgesia/tratamento farmacológico , Inflamação/tratamento farmacológico , Locomoção/efeitos dos fármacos , Masculino , Camundongos Endogâmicos , Neuralgia/metabolismo , Extratos Vegetais/administração & dosagem , Rizoma/química , Medula Espinal/efeitos dos fármacos
10.
Ecotoxicol Environ Saf ; 206: 111170, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32861007

RESUMO

The widespread use of the herbicides Atrazine (ATR) has been raised attention due to its ubiquitous occurrence in the environment. As an endocrine disruptor, ATR causes reproductive, immune, nervous system toxicity in biota. In this study, we aimed to investigate metabolic profile characteristics and potential metabolic biomarker that reflects specific damage in toxic effect after ATR exposure. Hence, a metabolomics study was performed to determine the significantly affected metabolites and the reproduction and locomotion of C. elegans were investigated. Mediation analysis was used to evaluate the mediating effect of metabolites on association between ATR exposure and toxic effect. ATR (≥0.04 mg/L) caused the significant dose dependent reduction of brood size and locomotion behavior, however, the body length and width were significantly decreased only in 40 mg/L group. These results suggesting that brood size, head thrashes and body bends are more sensitive indictor to assessment ATR toxicity in C. elegans. Meanwhile, metabolomics analysis revealed that ATR exposure can induce metabolic profiles significant alterations in C. elegans. We found that 9 metabolites significantly increased and 18 metabolites significantly decreased, such as phosphatidylcholine, GMP, CDP-choline, neopterin etc. Those alteration of metabolites were mainly involved in the pathways: glycerophospholipid metabolism, glycolysis/gluconeogenesis, folate biosynthesis, glycine, serine and threoninemetabolism, pyrimidine and purine metabolism. Overall, these changes are signs of possible oxidative stress and ATP synthesis disruption modification. Mediation analysis showed a significant indirect effect of ATR exposure on brood size, via 7,8-dihydroneopterin 2',3'-cyclic-p, and phosphatidylcholine might mediate association between ATR exposure and body bends, suggesting that 7,8-dihydroneopterin 2',3'-cyclic-p and phosphatidylcholine might be potentially specificity marker for brood size and body bend respectively. This preliminary analysis investigates metabolic characteristics in C. elegans after ATR exposure, helping to understand the pathways involved in the response to ATR exposure and provide potential biomarkers for the safety evaluation of ATR.


Assuntos
Atrazina/toxicidade , Caenorhabditis elegans/fisiologia , Herbicidas/toxicidade , Animais , Biomarcadores/metabolismo , Caenorhabditis elegans/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/metabolismo , Cromatografia Líquida de Alta Pressão , Glicina/metabolismo , Locomoção/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Metabolômica/métodos , Estresse Oxidativo/efeitos dos fármacos , Reprodução/efeitos dos fármacos
11.
Nat Commun ; 11(1): 3996, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778725

RESUMO

Psychomotor stimulants increase dopamine levels in the striatum and promote locomotion; however, their effects on striatal pathway function in vivo remain unclear. One model that has been proposed to account for these motor effects suggests that stimulants drive hyperactivity via activation and inhibition of direct and indirect pathway striatal neurons, respectively. Although this hypothesis is consistent with the cellular actions of dopamine receptors and received support from optogenetic and chemogenetic studies, it has been rarely tested with in vivo recordings. Here, we test this model and observe that cocaine increases the activity of both pathways in the striatum of awake mice. These changes are linked to a dopamine-dependent cocaine-induced strengthening of upstream orbitofrontal cortex (OFC) inputs to the dorsomedial striatum (DMS) in vivo. Finally, depressing OFC-DMS pathway with a high frequency stimulation protocol in awake mice over-powers the cocaine-induced potentiation of OFC-DMS pathway and attenuates the expression of locomotor sensitization, directly linking OFC-DMS potentiation to cocaine-induced hyperactivity.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Cocaína/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Hipercinese/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Animais , Comportamento Animal , Modelos Animais de Doenças , Dopamina , Feminino , Hipercinese/induzido quimicamente , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Optogenética
12.
Nat Commun ; 11(1): 3848, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737286

RESUMO

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by the degeneration of upper and lower motor neurons (MNs). We find a significant reduction of the retromer complex subunit VPS35 in iPSCs-derived MNs from ALS patients, in MNs from ALS post mortem explants and in MNs from SOD1G93A mice. Being the retromer involved in trafficking of hydrolases, a pathological hallmark in ALS, we design, synthesize and characterize an array of retromer stabilizers based on bis-guanylhydrazones connected by a 1,3-phenyl ring linker. We select compound 2a as a potent and bioavailable interactor of VPS35-VPS29. Indeed, while increasing retromer stability in ALS mice, compound 2a attenuates locomotion impairment and increases MNs survival. Moreover, compound 2a increases VPS35 in iPSCs-derived MNs and shows brain bioavailability. Our results clearly suggest the retromer as a valuable druggable target in ALS.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Hidrazonas/farmacologia , Neurônios Motores/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas de Transporte Vesicular/genética , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Diferenciação Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Hidrazonas/síntese química , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/síntese química , Ligação Proteica/efeitos dos fármacos , Multimerização Proteica , Relação Estrutura-Atividade , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Proteínas de Transporte Vesicular/metabolismo
13.
Biochem Pharmacol ; 180: 114158, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32702371

RESUMO

Inhibitors of Type 4 cAMP-phosphodiesterases (PDE4s) exert a number of promising therapeutic benefits, including potent anti-inflammatory, memory- and cognition-enhancing, metabolic, and antineoplastic effects. We report here that treatment with a number of distinct PDE4 inhibitors, including Rolipram, Piclamilast, Roflumilast and RS25344, but not treatment with the PDE3-selective inhibitor Cilostamide, induces a rapid (10-30 min), substantial (-5 °C) and long-lasting (up to 5 h) decrease in core body temperature of C57BL/6 mice; thus, identifying a critical role of PDE4 also in the regulation of body temperature. As little as 0.04 mg/kg of the archetypal PDE4 inhibitor Rolipram induces hypothermia. As similar or higher doses of Rolipram were used in a majority of published animal studies, most of the reported findings are likely paralleled by, or potentially impacted by hypothermia induced by these drugs. We further show that PDE4 inhibition affects central body temperature regulation and acts by lowering the cold-defense balance point of behavioral (including posture and locomotion) and autonomous (including cutaneous tail vasodilation) cold-defense mechanisms. In line with the idea of an effect on central body temperature regulation, hypothermia is induced by moderate doses of various brain-penetrant PDE4 inhibitors, but not by similar doses of YM976, a PDE4 inhibitor that does not efficiently cross the blood-brain barrier. Finally, to begin delineating the mechanism of drug-induced hypothermia, we show that blockade of D2/3-type dopaminergic, but not ß-adrenergic, H1-histaminergic or opiate receptors, can alleviate PDE4 inhibitor-induced hypothermia. We thus propose that increased D2/3-type dopaminergic signaling, triggered by PDE4 inhibitor-induced and cAMP-mediated dopamine release in the thermoregulatory centers of the hypothalamus, is a significant contributor to PDE4 inhibitor-induced hypothermia.


Assuntos
Regulação da Temperatura Corporal/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Hipotermia/induzido quimicamente , Hipotermia/metabolismo , Locomoção/fisiologia , Inibidores da Fosfodiesterase 4/toxicidade , Animais , Benzamidas/farmacologia , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Regulação da Temperatura Corporal/fisiologia , Relação Dose-Resposta a Droga , Feminino , Hipotermia/fisiopatologia , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibidores da Fosfodiesterase 4/farmacologia , Piridinas/farmacologia
14.
J Neurosci ; 40(34): 6649-6659, 2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32669353

RESUMO

In vivo functional and structural brain imaging of synucleinopathies in humans have provided a rich new understanding of the affected networks across the cortex and subcortex. Despite this progress, the temporal relationship between α-synuclein (α-syn) pathology and the functional and structural changes occurring in the brain is not well understood. Here, we examine the temporal relationship between locomotor ability, brain microstructure, functional brain activity, and α-syn pathology by longitudinally conducting rotarod, diffusion magnetic resonance imaging (MRI), resting-state functional MRI (fMRI), and sensory-evoked fMRI on 20 mice injected with α-syn fibrils and 20 PBS-injected mice at three timepoints (10 males and 10 females per group). Intramuscular injection of α-syn fibrils in the hindlimb of M83+/- mice leads to progressive α-syn pathology along the spinal cord, brainstem, and midbrain by 16 weeks post-injection. Our results suggest that peripheral injection of α-syn has acute systemic effects on the central nervous system such that structural and resting-state functional activity changes occur in the brain by four weeks post-injection, well before α-syn pathology reaches the brain. At 12 weeks post-injection, a separate and distinct pattern of structural and sensory-evoked functional brain activity changes was observed that are co-localized with previously reported regions of α-syn pathology and immune activation. Microstructural changes in the pons at 12 weeks post-injection were found to predict survival time and preceded measurable locomotor deficits. This study provides preliminary evidence for diffusion and fMRI markers linked to the progression of synuclein pathology and has translational importance for understanding synucleinopathies in humans.SIGNIFICANCE STATEMENT α-Synuclein (α-syn) pathology plays a critical role in neurodegenerative diseases such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. The longitudinal effects of α-syn pathology on locomotion, brain microstructure, and functional brain activity are not well understood. Using high field imaging, we show preliminary evidence that peripheral injection of α-syn fibrils induces unique patterns of functional and structural changes that occur at different temporal stages of α-syn pathology progression. Our results challenge existing assumptions that α-syn pathology must precede changes in brain structure and function. Additionally, we show preliminary evidence that diffusion and functional magnetic resonance imaging (fMRI) are capable of resolving such changes and thus should be explored further as markers of disease progression.


Assuntos
Encéfalo/fisiologia , Encéfalo/fisiopatologia , Potenciais Somatossensoriais Evocados , Locomoção/fisiologia , Sinucleinopatias/patologia , Sinucleinopatias/fisiopatologia , alfa-Sinucleína/administração & dosagem , Animais , Comportamento Animal , Encéfalo/efeitos dos fármacos , Mapeamento Encefálico , Imagem de Difusão por Ressonância Magnética , Feminino , Temperatura Alta , Humanos , Locomoção/efeitos dos fármacos , Masculino , Camundongos Transgênicos , Estimulação Física
15.
Nature ; 583(7816): 421-424, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32641825

RESUMO

The suprachiasmatic nucleus (SCN) serves as the body's master circadian clock that adaptively coordinates changes in physiology and behaviour in anticipation of changing requirements throughout the 24-h day-night cycle1-4. For example, the SCN opposes overnight adipsia by driving water intake before sleep5,6, and by driving the secretion of anti-diuretic hormone7,8 and lowering body temperature9,10 to reduce water loss during sleep11. These responses can also be driven by central osmo-sodium sensors to oppose an unscheduled rise in osmolality during the active phase12-16. However, it is unknown whether osmo-sodium sensors require clock-output networks to drive homeostatic responses. Here we show that a systemic salt injection (hypertonic saline) given at Zeitgeber time 19-a time at which SCNVP (vasopressin) neurons are inactive-excited SCNVP neurons and decreased non-shivering thermogenesis (NST) and body temperature. The effects of hypertonic saline on NST and body temperature were prevented by chemogenetic inhibition of SCNVP neurons and mimicked by optogenetic stimulation of SCNVP neurons in vivo. Combined anatomical and electrophysiological experiments revealed that osmo-sodium-sensing organum vasculosum lamina terminalis (OVLT) neurons expressing glutamic acid decarboxylase (OVLTGAD) relay this information to SCNVP neurons via an excitatory effect of γ-aminobutyric acid (GABA). Optogenetic activation of OVLTGAD neuron axon terminals excited SCNVP neurons in vitro and mimicked the effects of hypertonic saline on NST and body temperature in vivo. Furthermore, chemogenetic inhibition of OVLTGAD neurons blunted the effects of systemic hypertonic saline on NST and body temperature. Finally, we show that hypertonic saline significantly phase-advanced the circadian locomotor activity onset of mice. This effect was mimicked by optogenetic activation of the OVLTGAD→ SCNVP pathway and was prevented by chemogenetic inhibition of OVLTGAD neurons. Collectively, our findings provide demonstration that clock time can be regulated by non-photic physiologically relevant cues, and that such cues can drive unscheduled homeostatic responses via clock-output networks.


Assuntos
Relógios Circadianos/fisiologia , Vias Neurais , Neurônios/metabolismo , Sódio/metabolismo , Núcleo Supraquiasmático/fisiologia , Ácido gama-Aminobutírico/metabolismo , Animais , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Relógios Circadianos/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/fisiologia , Ingestão de Líquidos/efeitos dos fármacos , Glutamato Descarboxilase/metabolismo , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Vias Neurais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Optogenética , Organum Vasculosum/citologia , Organum Vasculosum/efeitos dos fármacos , Organum Vasculosum/enzimologia , Organum Vasculosum/fisiologia , Concentração Osmolar , Solução Salina Hipertônica/administração & dosagem , Solução Salina Hipertônica/metabolismo , Solução Salina Hipertônica/farmacologia , Sódio/administração & dosagem , Sódio/farmacologia , Núcleo Supraquiasmático/citologia , Núcleo Supraquiasmático/efeitos dos fármacos , Vasopressinas/metabolismo
16.
Sci Rep ; 10(1): 11206, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641780

RESUMO

Glutamate (Glu), the key excitatory neurotransmitter in the central nervous system, is considered essential for brain functioning and has a vital role in learning and memory formation. Earlier it was considered as a harmful agent but later found to be useful for many body functions. However, studies regarding the effects of free L-Glu administration on CNS function are limited. Therefore, current experiment is aimed to monitor the neurobiological effects of free L-Glu in male rats. L-Glu was orally administered to rats for 5-weeks and changes in behavioral performance were monitored. Thereafter, brain and hippocampus were collected for oxidative and neurochemical analysis. Results showed that chronic supplementation of free L-Glu enhanced locomotor performance and cognitive function of animals which may be attributed to the improved antioxidant status and cholinergic, monoaminergic and glutamatergic neurotransmission in brain and hippocampus. Current results showed that chronic supplementation of L-Glu affects the animal behaviour and brain functioning via improving the neurochemical and redox system of brain. Free L-Glu could be a useful therapeutic agent to combat neurological disturbances however this requires further targeted studies.


Assuntos
Química Encefálica/efeitos dos fármacos , Ácido Glutâmico/administração & dosagem , Hipocampo/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Memória/efeitos dos fármacos , Administração Oral , Animais , Comportamento Animal , Química Encefálica/fisiologia , Suplementos Nutricionais , Ácido Glutâmico/análise , Ácido Glutâmico/metabolismo , Hipocampo/química , Hipocampo/fisiologia , Locomoção/fisiologia , Masculino , Memória/fisiologia , Modelos Animais , Oxirredução/efeitos dos fármacos , Ratos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/análise , Ácido gama-Aminobutírico/metabolismo
17.
Eur J Med Chem ; 200: 112405, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32492595

RESUMO

A series of 4-phenyl-6H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-7-carboxylate esters were synthesized and tested as central benzodiazepine receptor (CBR) ligands by the ability to displace [3H]flumazenil from rat cortical membranes. All the compounds showed high affinity with IC50 values ranging from 5.19 to 16.22 nM. In particular, compounds 12b (IC50 = 8.66 nM) and 12d (IC50 = 5.19 nM) appeared as the most effective ligands being their affinity values significantly lower than that of diazepam (IC50 = 18.52 nM). Compounds 12a-f were examined in vivo for their pharmacological effects in mice and five potential benzodiazepine (BDZ) actions were thus taken into consideration: anxiolytic, anticonvulsant, anti-amnesic, hypnotic, and locomotor activities. All the new synthesized compounds were able to induce a significant antianxiety effect and, among them, compound 12f protected pentylenetetrazole (PTZ)-induced convulsions in a dose-dependent manner reaching a 40% effect at 30 mg/kg. In addition, all the compounds were able to significantly prevent the memory impairment evoked by scopolamine, while none of them was able to interfere with pentobarbital-evoked sleep and influence motor coordination. Moreover, title compounds did not affect locomotor and exploratory activity at the same time and doses at which the anti-anxiety effect was observed. Finally, molecular docking simulations were carried out in order to assess the binding mode for compounds 12a-f. The obtained results demonstrated that these compounds bind the BDZ binding site in a similar fashion to flumazenil.


Assuntos
Ansiolíticos/síntese química , Benzodiazepinas/química , Desenho de Fármacos , Animais , Ansiolíticos/farmacologia , Anticonvulsivantes , Benzodiazepinas/metabolismo , Sítios de Ligação , Locomoção/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/prevenção & controle , Camundongos , Simulação de Acoplamento Molecular , Ratos , Receptores de GABA-A/metabolismo
18.
J Pharmacol Exp Ther ; 374(2): 252-263, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32493725

RESUMO

Deposition of hyperphosphorylated and aggregated tau protein in the central nervous system is characteristic of Alzheimer disease and other tauopathies. Tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification, and O-GlcNAcylation of tau has been shown to influence tau phosphorylation and aggregation. Inhibition of O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc moieties, is a novel strategy to attenuate the formation of pathologic tau. Here we described the in vitro and in vivo pharmacological properties of a novel and selective OGA inhibitor, MK-8719. In vitro, this compound is a potent inhibitor of the human OGA enzyme with comparable activity against the corresponding enzymes from mouse, rat, and dog. In vivo, oral administration of MK-8719 elevates brain and peripheral blood mononuclear cell O-GlcNAc levels in a dose-dependent manner. In addition, positron emission tomography imaging studies demonstrate robust target engagement of MK-8719 in the brains of rats and rTg4510 mice. In the rTg4510 mouse model of human tauopathy, MK-8719 significantly increases brain O-GlcNAc levels and reduces pathologic tau. The reduction in tau pathology in rTg4510 mice is accompanied by attenuation of brain atrophy, including reduction of forebrain volume loss as revealed by volumetric magnetic resonance imaging analysis. These findings suggest that OGA inhibition may reduce tau pathology in tauopathies. However, since hundreds of O-GlcNAcylated proteins may be influenced by OGA inhibition, it will be critical to understand the physiologic and toxicological consequences of chronic O-GlcNAc elevation in vivo. SIGNIFICANCE STATEMENT: MK-8719 is a novel, selective, and potent O-linked N-acetylglucosamine (O-GlcNAc)-ase (OGA) inhibitor that inhibits OGA enzyme activity across multiple species with comparable in vitro potency. In vivo, MK-8719 elevates brain O-GlcNAc levels, reduces pathological tau, and ameliorates brain atrophy in the rTg4510 mouse model of tauopathy. These findings indicate that OGA inhibition may be a promising therapeutic strategy for the treatment of Alzheimer disease and other tauopathies.


Assuntos
Inibidores Enzimáticos/farmacologia , Tauopatias/tratamento farmacológico , Tauopatias/metabolismo , beta-N-Acetil-Hexosaminidases/antagonistas & inibidores , Proteínas tau/metabolismo , Animais , Atrofia/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Inibidores Enzimáticos/uso terapêutico , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Células PC12 , Ratos , Tauopatias/patologia , Tauopatias/fisiopatologia
19.
J Neuroimmunol ; 345: 577270, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32480241

RESUMO

The purpose of current study was to evaluate the effect of curcumin (CUR) loaded lipid-core nanocapsules (CUR-LNC) treatment on neuroinflammatory and behavioral alterations in a model of sickness behavior induced by lipopolysaccharide (LPS) in rats. Rats were treated with CUR-LNC and CUR daily for 14 days. After the last treatments, sickness behavior was induced with LPS. Sickness behavior LPS-induced was confirmed by behavioral tests, an increase in levels of proinflammatory cytokines, decrease in levels of IL-10, overexpression of IDO-1 and IDO-2. In conclusion, CUR-LNC treatment attenuated the neuroinflammatory and behavioral changes caused in sickness behavior model.


Assuntos
Curcumina/administração & dosagem , Comportamento de Doença/fisiologia , Mediadores da Inflamação/imunologia , Lipopolissacarídeos/toxicidade , Locomoção/fisiologia , Nanocápsulas/administração & dosagem , Animais , Portadores de Fármacos/administração & dosagem , Comportamento de Doença/efeitos dos fármacos , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Lipídeos , Locomoção/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar
20.
Psychopharmacology (Berl) ; 237(9): 2809-2822, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32556369

RESUMO

RATIONALE: The behavioral effects of the nicotine metabolites nornicotine and cotinine have not been investigated extensively. OBJECTIVES: To evaluate the effects of nicotine, cotinine, and nornicotine, given alone or in combination, on locomotor activity and emission of ultrasonic vocalizations in male adult rats. METHODS: Rats were first given home cage nicotine injections to make them tolerant to the drug's locomotor depressant effects. On subsequent days, locomotor activity (LMA) and ultrasonic vocalizations were recorded in an open field, for 60 min after challenge injection, using repeated measures designs. In single-drug experiments, subjects were tested with nicotine 0.05-0.4 mg/kg, cotinine 0.03-3 mg/kg, or nornicotine 0.1-10 mg/kg. In drug-combination experiments, saline or nicotine 0.2 mg/kg challenge was preceded by cotinine (0, 0.3, 3 mg/kg) or nornicotine (0, 0.1, 0.3, 1, 3 mg/kg) injection. RESULTS: High doses of nornicotine increased LMA and blunted the locomotor stimulant effect of nicotine. Less consistently, nicotine and high doses of nornicotine decreased the 50-kHz call rate, with no clear evidence of a nornicotine × nicotine interaction. Cotinine, given alone or before nicotine injection, altered neither LMA nor the call rate. No drug altered the relative prevalence of flat vs. trill 50-kHz call subtypes, except that the highest dose of nornicotine promoted flat calls over trills. No drug evoked 22-kHz calls. CONCLUSION: Nornicotine can exert an acute anti-nicotine effect in vivo, as previously reported in vitro. The finding that nicotine did not detectably alter the 50-kHz call profile appears consistent with this drug's mild subjective effects in human subjects.


Assuntos
Cotinina/administração & dosagem , Locomoção/efeitos dos fármacos , Nicotina/análogos & derivados , Nicotina/administração & dosagem , Ondas Ultrassônicas , Vocalização Animal/efeitos dos fármacos , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Locomoção/fisiologia , Masculino , Ratos , Ratos Long-Evans , Vocalização Animal/fisiologia
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