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1.
Molecules ; 26(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34361547

RESUMO

Essential oils of aromatic plants represent an alternative to classical pest control with synthetic chemicals. They are especially promising for the alternative control of stored product pest insects. Here, we tested behavioral and electrophysiological responses of the stored product pest Tribolium confusum, to the essential oil of a Brazilian indigenous plant, Varronia globosa, collected in the Caatinga ecosystem. We analyzed the essential oil by GC-MS, tested the effects of the entire oil and its major components on the behavior of individual beetles in a four-way olfactometer, and investigated responses to these stimuli in electroantennogram recordings (EAG). We could identify 25 constituents in the essential oil of V. globosa, with anethole, caryophyllene and spathulenole as main components. The oil and its main component anethole had repellent effects already at low doses, whereas caryophyllene had only a repellent effect at a high dose. In addition, the essential oil abolished the attractive effect of the T. confusum aggregation pheromone. EAG recordings revealed dose-dependent responses to the individual components and increasing responses to the blend and even more to the entire oil. Our study reveals the potential of anethole and the essential oil of V. globosa in the management of stored product pests.


Assuntos
Antenas de Artrópodes/fisiologia , Comportamento Animal/efeitos dos fármacos , Repelentes de Insetos , Magnoliopsida/química , Óleos Voláteis , Tribolium/fisiologia , Animais , Repelentes de Insetos/química , Repelentes de Insetos/farmacologia , Óleos Voláteis/química , Óleos Voláteis/farmacologia
2.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445602

RESUMO

Cannabis is the most-used recreational drug worldwide, with a high prevalence of use among adolescents. In animal models, long-term adverse effects were reported following chronic adolescent exposure to the main psychotomimetic component of the plant, delta-9-tetrahydrocannabinol (THC). However, these studies investigated the effects of pure THC, without taking into account other cannabinoids present in the cannabis plant. Interestingly, cannabidiol (CBD) content seems to mitigate some of the side effects of THC, at least in adult animals. Thus, in female rats, we evaluated the long-term consequences of a co-administration of THC and CBD at a 3:1 ratio, chosen based on the analysis of recently confiscated illegal cannabis samples in Europe. CBD content is able to mitigate some of the long-term behavioral alterations induced by adolescent THC exposure as well as long-term changes in CB1 receptor and microglia activation in the prefrontal cortex (PFC). We also investigated, for the first time, possible long-term effects of chronic administration of a THC/CBD combination reminiscent of "light cannabis" (CBD:THC in a 33:1 ratio; total THC 0.3%). Repeated administration of this CBD:THC combination has long-term adverse effects on cognition and leads to anhedonia. Concomitantly, it boosts Glutamic Acid Decarboxylase-67 (GAD67) levels in the PFC, suggesting a possible lasting effect on GABAergic neurotransmission.


Assuntos
Comportamento Animal/efeitos dos fármacos , Canabidiol/administração & dosagem , Cognição/efeitos dos fármacos , Dronabinol/administração & dosagem , Alucinógenos/administração & dosagem , Córtex Pré-Frontal/efeitos dos fármacos , Animais , Feminino , Memória/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica
3.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445611

RESUMO

Trace Amine-Associated Receptor 1 (TAAR1) is a potential target for the treatment of depression and other CNS disorders. However, the precise functional roles of TAAR1 to the actions of clinically used antidepressants remains unclear. Herein, we addressed these issues employing the TAAR1 agonist, o-phenyl-iodotyramine (o-PIT), together with TAAR1-knockout (KO) mice. Irrespective of genotype, systemic administration of o-PIT led to a similar increase in mouse brain concentrations. Consistent with the observation of a high density of TAAR1 in the medial preoptic area, o-PIT-induced hypothermia was significantly reduced in TAAR1-KO mice. Furthermore, the inhibition of a prepulse inhibition response by o-PIT, as well as its induction of striatal tyrosine hydroxylase phosphorylation and elevation of extracellular DA in prefrontal cortex, were all reduced in TAAR1-KO compared to wildtype mice. O-PIT was active in both forced-swim and marble-burying tests, and its effects were significantly blunted in TAAR1-KO mice. Conversely, the actions on behaviour and prefrontal cortex dialysis of a broad suite of clinically used antidepressants were unaffected in TAAR1-KO mice. In conclusion, o-PIT is a useful tool for exploring the hypothermic and other functional antidepressant roles of TAAR1. By contrast, clinically used antidepressants do not require TAAR1 for expression of their antidepressant properties.


Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Monoaminas Biogênicas/farmacologia , Receptores Acoplados a Proteínas G/fisiologia , Tiramina/análogos & derivados , Tiramina/farmacologia , Inibidores da Captação Adrenérgica/farmacologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
4.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445623

RESUMO

Human breast milk lipids have major beneficial effects: they promote infant early brain development, growth and health. To identify the relationship between human breast milk lipids and infant neurodevelopment, multivariate analyses that combined lipidomics and psychological Bayley-III scales evaluation were utilized. We identified that 9,12-octadecadiynoic acid has a significantly positive correlation with infant adaptive behavioral development, which is a crucial neurodevelopment to manage risk from environmental stress. To further clarify the biological function of 9,12-octadecadiynoic acid in regulating neurodevelopment, Caenorhabditis elegans (C. elegans) was used as a model to investigate the effect of 9,12-octadecadiynoic acid on neurobehavioral development. Supplementation with 9,12-octadecadiynoic acid from the L1 to L4 stage in larvae affected locomotive behaviors and foraging ability that were not socially interactive, implying that 9,12-octadecadiynoic acid is involved in regulating the serotonergic neuronal ability. We found that supplementary 0.1 µM 9,12-octadecadiynoic acid accelerated the locomotive ability and foraging ability via increasing the expression of serotonin transporter mod-1. Antioxidant defense genes, sod-1, sod-3 and cyp-35A2 are involved in 9,12-octadecadiynoic acid-induced motor neuronal activity. Nevertheless, supplementary 9,12-octadecadiynoic acid at concentrations above 1 µM significantly attenuated locomotive behaviors, foraging ability, serotonin synthesis, serotonin-related gene expressions and stress-related gene expression, resulting in the decreased longevity of worms in the experiment. In conclusion, our study demonstrates the biological function of 9,12-octadecadiynoic acid in governing adaptive behavioral development.


Assuntos
Comportamento Animal/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Larva/efeitos dos fármacos , Ácido Linoleico/farmacologia , Sistema Nervoso/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Larva/crescimento & desenvolvimento , Sistema Nervoso/crescimento & desenvolvimento
5.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445626

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the Substantia Nigra pars compacta, leading to classical PD motor symptoms. Current therapies are purely symptomatic and do not modify disease progression. Cannabidiol (CBD), one of the main phytocannabinoids identified in Cannabis Sativa, which exhibits a large spectrum of therapeutic properties, including anti-inflammatory and antioxidant effects, suggesting its potential as disease-modifying agent for PD. The aim of this study was to evaluate the effects of chronic treatment with CBD (10 mg/kg, i.p.) on PD-associated neurodegenerative and neuroinflammatory processes, and motor deficits in the 6-hydroxydopamine model. Moreover, we investigated the potential mechanisms by which CBD exerted its effects in this model. CBD-treated animals showed a reduction of nigrostriatal degeneration accompanied by a damping of the neuroinflammatory response and an improvement of motor performance. In particular, CBD exhibits a preferential action on astrocytes and activates the astrocytic transient receptor potential vanilloid 1 (TRPV1), thus, enhancing the endogenous neuroprotective response of ciliary neurotrophic factor (CNTF). These results overall support the potential therapeutic utility of CBD in PD, as both neuroprotective and symptomatic agent.


Assuntos
Comportamento Animal/efeitos dos fármacos , Canabidiol/farmacologia , Fator Neurotrófico Ciliar/metabolismo , Modelos Animais de Doenças , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Canais de Cátion TRPV/metabolismo , Animais , Anticonvulsivantes/farmacologia , Fator Neurotrófico Ciliar/genética , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Masculino , Doença de Parkinson/etiologia , Doença de Parkinson/patologia , Ratos , Ratos Sprague-Dawley , Canais de Cátion TRPV/genética
6.
Nutrients ; 13(7)2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34371954

RESUMO

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


Assuntos
Ansiolíticos/administração & dosagem , Ansiedade/psicologia , Comportamento Animal/efeitos dos fármacos , Caseínas/administração & dosagem , Hidrolisados de Proteína/administração & dosagem , Animais , Condicionamento Psicológico , Diazepam/administração & dosagem , Proteínas de Peixes/administração & dosagem , Masculino , Ratos
7.
Nutrients ; 13(8)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34444918

RESUMO

Mild cognitive impairment (MCI) designates the boundary area between cognitive function in natural aging and dementia, and this is viewed as a therapeutic window to prevent the occurrence of dementia. The current study investigated the neurocognitive effects of oral creatine (Cr) supplementation in young female Wistar rats that received intracerebroventricular injections of lipopolysaccharide (LPS) to mimic MCI. Neuromolecular changes within the dentate gyrus were analyzed following behavioral testing. We also investigated both neurocognitive and neuromolecular changes following Cr supplementation in the absence of LPS in young female Wistar rats to further investigate mechanisms. Interestingly, based on trial 2 of Barnes maze test, Cr supplementation ameliorated spatial learning and memory deficit induced by LPS, shown by decreased latency time and errors to reach the escape box (p < 0.0001, n = 12). Cr supplementation also attenuated recognition memory deficit induced by LPS, shown by increased amount of time taken to explore the new object (p = 0.002, n = 12) during novel object recognition testing. Within the dentate gyrus, Cr supplementation in LPS injected rats upregulated mTORC1 signaling (p = 0.026 for mTOR phosphorylation, p = 0.002 for p70S6K phosphorylation, n = 8) as well as the synapsin (p = 0.008) and PSD-95 synaptic proteins (p = 0.015), in comparisons to LPS injected rats. However, Cr supplementation failed to further enhance spatial memory and recognition memory in the absence of LPS. In conclusion, Cr ameliorates LPS-induced cognitive impairment in a rodent MCI model. Mechanistically, these phenotypic effects may, in part, be mitigated via an upregulation of mTORC1 signaling, and an enhancement in synaptogenesis in the dentate gyrus. While preliminary, these findings may inform future research investigating neurocognitive effects of Cr for MCI patients.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Creatina/administração & dosagem , Giro Denteado/metabolismo , Suplementos Nutricionais , Transtornos da Memória/tratamento farmacológico , Fenômenos Fisiológicos da Nutrição Animal/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Disfunção Cognitiva/induzido quimicamente , Modelos Animais de Doenças , Feminino , Lipopolissacarídeos , Aprendizagem em Labirinto , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Transtornos da Memória/induzido quimicamente , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
8.
Biomolecules ; 11(7)2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34356631

RESUMO

Chronic sensitization to serotonin 1A and 7 receptors agonist 8-OH-DPAT induces compulsive checking and perseverative behavior. As such, it has been used to model obsessive-compulsive disorder (OCD)-like behavior in mice and rats. In this study, we tested spatial learning in the 8-OH-DPAT model of OCD and the effect of co-administration of memantine and riluzole-glutamate-modulating agents that have been shown to be effective in several clinical trials. Rats were tested in the active place avoidance task in the Carousel maze, where they learned to avoid the visually imperceptible shock sector. All rats were subcutaneously injected with 8-OH-DPAT (0.25 mg/kg) or saline (control group) during habituation. During acquisition, they were pretreated with riluzole (1 mg/kg), memantine (1 mg/kg), or saline solution 30 min before each session and injected with 8-OH-DPAT ("OH" groups) or saline ("saline" groups) right before the experiment. We found that repeated application of 8-OH-DPAT during both habituation and acquisition significantly increased locomotion, but it impaired the ability to avoid the shock sector. However, the application of 8-OH-DPAT in habituation had no impact on the learning process if discontinued in acquisition. Similarly, memantine and riluzole did not affect the measured parameters in the "saline" groups, but in the "OH" groups, they significantly increased locomotion. In addition, riluzole increased the number of entrances and decreased the maximum time avoided of the shock sector. We conclude that monotherapy with glutamate-modulating agents does not reduce but exacerbates cognitive symptoms in the animal model of OCD.


Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Memantina/farmacologia , Transtorno Obsessivo-Compulsivo , Riluzol/farmacologia , Aprendizagem Espacial/efeitos dos fármacos , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Modelos Animais de Doenças , Masculino , Memória/efeitos dos fármacos , Transtorno Obsessivo-Compulsivo/induzido quimicamente , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/fisiopatologia , Ratos , Ratos Long-Evans
9.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360852

RESUMO

Fluoxetine is an antidepressant commonly prescribed not only to adults but also to children for the treatment of depression, obsessive-compulsive disorder, and neurodevelopmental disorders. The adverse effects of the long-term treatment reported in some patients, especially in younger individuals, call for a detailed investigation of molecular alterations induced by fluoxetine treatment. Two-year fluoxetine administration to juvenile macaques revealed effects on impulsivity, sleep, social interaction, and peripheral metabolites. Here, we built upon this work by assessing residual effects of fluoxetine administration on the expression of genes and abundance of lipids and polar metabolites in the prelimbic cortex of 10 treated and 11 control macaques representing two monoamine oxidase A (MAOA) genotypes. Analysis of 8871 mRNA transcripts, 3608 lipids, and 1829 polar metabolites revealed substantial alterations of the brain lipid content, including significant abundance changes of 106 lipid features, accompanied by subtle changes in gene expression. Lipid alterations in the drug-treated animals were most evident for polyunsaturated fatty acids (PUFAs). A decrease in PUFAs levels was observed in all quantified lipid classes excluding sphingolipids, which do not usually contain PUFAs, suggesting systemic changes in fatty acid metabolism. Furthermore, the residual effect of the drug on lipid abundances was more pronounced in macaques carrying the MAOA-L genotype, mirroring reported behavioral effects of the treatment. We speculate that a decrease in PUFAs may be associated with adverse effects in depressive patients and could potentially account for the variation in individual response to fluoxetine in young people.


Assuntos
Antidepressivos/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Fluoxetina/efeitos adversos , Metabolismo dos Lipídeos/efeitos dos fármacos , Transtornos Mentais/tratamento farmacológico , Animais , Ácidos Graxos Insaturados/metabolismo , Macaca mulatta , Masculino
10.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445476

RESUMO

4,4'-Dimethylaminorex (4,4'-DMAR) is a new synthetic stimulant, and only a little information has been made available so far regarding its pharmaco-toxicological effects. The aim of this study was to investigate the effects of the systemic administration of both the single (±)cis (0.1-60 mg/kg) and (±)trans (30 and 60 mg/kg) stereoisomers and their co-administration (e.g., (±)cis at 1, 10 or 60 mg/kg + (±)trans at 30 mg/kg) in mice. Moreover, we investigated the effect of 4,4'-DMAR on the expression of markers of oxidative/nitrosative stress (8-OHdG, iNOS, NT and NOX2), apoptosis (Smac/DIABLO and NF-κB), and heat shock proteins (HSP27, HSP70, HSP90) in the cerebral cortex. Our study demonstrated that the (±)cis stereoisomer dose-dependently induced psychomotor agitation, sweating, salivation, hyperthermia, stimulated aggression, convulsions and death. Conversely, the (±)trans stereoisomer was ineffective whilst the stereoisomers' co-administration resulted in a worsening of the toxic (±)cis stereoisomer effects. This trend of responses was confirmed by immunohistochemical analysis on the cortex. Finally, we investigated the potentially toxic effects of stereoisomer co-administration by studying urinary excretion. The excretion study showed that the (±)trans stereoisomer reduced the metabolism of the (±)cis form and increased its amount in the urine, possibly reflecting its increased plasma levels and, therefore, the worsening of its toxicity.


Assuntos
Comportamento Animal/efeitos dos fármacos , Oxazóis/toxicidade , Transtornos Psicofisiológicos/metabolismo , Transtornos Psicofisiológicos/patologia , Psicotrópicos/toxicidade , Animais , Masculino , Camundongos , Camundongos Endogâmicos ICR , Oxazóis/classificação , Oxazóis/urina , Transtornos Psicofisiológicos/induzido quimicamente , Psicotrópicos/classificação , Psicotrópicos/urina , Estereoisomerismo
11.
Molecules ; 26(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34443414

RESUMO

Natural antioxidants, especially those of plant origins, have shown a plethora of biological activities with substantial economic value, as they can be extracted from agro-wastes and/or under exploited plant species. The perennial hydrophyte, Potamogeton perfoliatus, has been used traditionally to treat several health disorders; however, little is known about its biological and its medicinal effects. Here, we used an integrated in vitro and in vivo framework to examine the potential effect of P. perfoliatus on oxidative stress, nociception, inflammatory models, and brewer's yeast-induced pyrexia in mice. Our results suggested a consistent in vitro inhibition of three enzymes, namely 5-lipoxygenase, cyclooxygenases 1 and 2 (COX-1 and COX-2), as well as a potent antioxidant effect. These results were confirmed in vivo where the studied extract attenuated carrageenan-induced paw edema, carrageenan-induced leukocyte migration into the peritoneal cavity by 25, 44 and 64% at 200, 400 and 600 mg/kg, p.o., respectively. Moreover, the extract decreased acetic acid-induced vascular permeability by 45% at 600 mg/kg, p.o., and chemical hyperalgesia in mice by 86% by 400 mg/kg, p.o., in acetic acid-induced writhing assay. The extract (400 mg/kg) showed a longer response latency at the 3 h time point (2.5 fold of the control) similar to the nalbuphine, the standard opioid analgesic. Additionally, pronounced antipyretic effects were observed at 600 mg/kg, comparable to paracetamol. Using LC-MS/MS, we identified 15 secondary metabolites that most likely contributed to the obtained biological activities. Altogether, our findings indicate that P. perfoliatus has anti-inflammatory, antioxidant, analgesic and antipyretic effects, thus supporting its traditional use and promoting its valorization as a potential candidate in treating oxidative stress-associated diseases.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Antipiréticos/farmacologia , Extratos Vegetais/farmacologia , Potamogetonaceae/química , Ácido Acético , Animais , Antioxidantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Carragenina , Movimento Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Avaliação Pré-Clínica de Medicamentos , Edema/patologia , Febre/patologia , Glucosídeos Iridoides/farmacologia , Leucócitos/efeitos dos fármacos , Masculino , Camundongos , Cavidade Peritoneal/patologia , Fenilpropionatos/farmacologia , Compostos Fitoquímicos/análise , Ratos , Saccharomyces cerevisiae
12.
Molecules ; 26(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34443380

RESUMO

The popular tobacco and e-cigarette chemical flavorant (-)-menthol acts as a nonselective, noncompetitive antagonist of nicotinic acetylcholine receptors (nAChRs), and contributes to multiple physiological effects that exacerbates nicotine addiction-related behavior. Menthol is classically known as a TRPM8 agonist; therefore, some have postulated that TRPM8 antagonists may be potential candidates for novel nicotine cessation pharmacotherapies. Here, we examine a novel class of TRPM8 antagonists for their ability to alter nicotine reward-related behavior in a mouse model of conditioned place preference. We found that these novel ligands enhanced nicotine reward-related behavior in a mouse model of conditioned place preference. To gain an understanding of the potential mechanism, we examined these ligands on mouse α4ß2 nAChRs transiently transfected into neuroblastoma-2a cells. Using calcium flux assays, we determined that these ligands act as positive modulators (PMs) on α4ß2 nAChRs. Due to α4ß2 nAChRs' important role in nicotine dependence, as well as various neurological disorders including Parkinson's disease, the identification of these ligands as α4ß2 nAChR PMs is an important finding, and they may serve as novel molecular tools for future nAChR-related investigations.


Assuntos
Comportamento Animal/efeitos dos fármacos , Nicotina/farmacologia , Receptores Nicotínicos/metabolismo , Recompensa , Animais , Cálcio/metabolismo , Feminino , Masculino , Camundongos Endogâmicos C57BL , Fatores de Tempo
13.
Molecules ; 26(16)2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34443679

RESUMO

Alcohol consumption is associated with gut dysbiosis, increased intestinal permeability, endotoxemia, and a cascade that leads to persistent systemic inflammation, alcoholic liver disease, and other ailments. Craving for alcohol and its consequences depends, among other things, on the endocannabinoid system. We have analyzed the relative role of central vs. peripheral cannabinoid CB1 receptors (CB1R) using a "two-bottle" as well as a "drinking in the dark" paradigm in mice. The globally acting CB1R antagonist rimonabant and the non-brain penetrant CB1R antagonist JD5037 inhibited voluntary alcohol intake upon systemic but not upon intracerebroventricular administration in doses that elicited anxiogenic-like behavior and blocked CB1R-induced hypothermia and catalepsy. The peripherally restricted hybrid CB1R antagonist/iNOS inhibitor S-MRI-1867 was also effective in reducing alcohol consumption after oral gavage, while its R enantiomer (CB1R inactive/iNOS inhibitor) was not. The two MRI-1867 enantiomers were equally effective in inhibiting an alcohol-induced increase in portal blood endotoxin concentration that was caused by increased gut permeability. We conclude that (i) activation of peripheral CB1R plays a dominant role in promoting alcohol intake and (ii) the iNOS inhibitory function of MRI-1867 helps in mitigating the alcohol-induced increase in endotoxemia.


Assuntos
Consumo de Bebidas Alcoólicas/patologia , Antagonistas de Receptores de Canabinoides/farmacologia , Endotoxemia/patologia , Etanol/efeitos adversos , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Receptor CB1 de Canabinoide/antagonistas & inibidores , Consumo de Bebidas Alcoólicas/sangue , Animais , Ansiedade/sangue , Ansiedade/complicações , Comportamento Animal/efeitos dos fármacos , Catalepsia/induzido quimicamente , Catalepsia/complicações , Cicloexanóis/administração & dosagem , Teste de Labirinto em Cruz Elevado , Endotoxemia/sangue , Endotoxemia/complicações , Endotoxinas/sangue , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Hipotermia Induzida , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/metabolismo , Pirazóis/administração & dosagem , Receptor CB1 de Canabinoide/metabolismo , Rimonabanto/administração & dosagem , Rimonabanto/farmacologia , Estereoisomerismo , Sulfonamidas/administração & dosagem
14.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361071

RESUMO

3,4-Methylenedioxypyrovalerone (MDPV) is a new psychoactive substance (NPS) and the most widespread and life-threatening synthetic cathinone of the "bath salts". Preclinical research has proven the cocaine-like psychostimulant effects of MDPV and its potential for abuse. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid that has emerged as a new potential treatment for drug addiction. Here, we tested the effects of CBD (20 mg/kg) on MDPV (2 mg/kg)-induced conditioned place preference and MDPV (0.05 and 0.075 mg/kg/infusion) self-administration paradigms. In addition, we assessed the effects of the co-administration of CBD and MDPV (3 and 4 mg/kg) on anxiety-like behaviour using the elevated plus maze (EPM). CBD mitigated the MDPV-induced conditioned place preference. On the contrary, CBD administration throughout the MDPV (0.075 mg/kg/infusion) self-administration increased drug-seeking and taking behaviours, but only in the high-responders group of mice. Furthermore, CBD exerted anxiolytic-like effects, exclusively in MDPV-treated mice. Taken together, our results indicate that CBD modulation of MDPV-induced motivational responses in mice varies depending on the requirements of the learning task, resulting in a complex response. Therefore, further research attempting to decipher the behavioural and molecular interactions between CBD and MDPV is needed.


Assuntos
Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Benzodioxóis/toxicidade , Canabidiol/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Pirrolidinas/toxicidade , Inibidores da Captação Adrenérgica/toxicidade , Animais , Anticonvulsivantes/farmacologia , Ansiedade/induzido quimicamente , Ansiedade/patologia , Condicionamento Clássico/efeitos dos fármacos , Masculino , Camundongos
15.
Nutrients ; 13(7)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34371921

RESUMO

The study of different natural products can provide a wealth of bioactive compounds, and more interestingly, their combination can exert a new strategy for several neurodegenerative diseases with major public health importance, such as Alzheimer's disease (AD). Here, we investigated the synergistic neuroprotective effects of a mixed extract composed of docosahexaenoic acid, Ginkgo biloba, D-pinitol, and ursolic acid in several transgenic Caenorhabditis elegans (C. elegans) and a senescence-accelerated prone mice 8 (SAMP8) model. First, we found a significantly higher survival percentage in the C. elegans group treated with the natural product mixture compared to the single extract-treated groups. Likewise, we found a significantly increased lifespan in group of C. elegans treated with the natural product mixture compared to the other groups, suggesting synergistic effects. Remarkably, we determined a significant reduction in Aß plaque accumulation in the group of C. elegans treated with the natural product mixture compared to the other groups, confirming synergy. Finally, we demonstrated better cognitive performance in the group treated with the natural product mixture in both AD models (neuronal Aß C. elegans strain CL2355 and the SAMP8 mice model), confirming the molecular results and unraveling the synergist effects of this combination. Therefore, our results proved the potential of this new natural product mixture for AD therapeutic strategies.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Produtos Biológicos/farmacologia , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Animais , Animais Geneticamente Modificados , Encéfalo/metabolismo , Encéfalo/patologia , Caenorhabditis elegans/genética , Modelos Animais de Doenças , Longevidade , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Placa Amiloide
16.
J Stroke Cerebrovasc Dis ; 30(9): 105987, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34273708

RESUMO

OBJECTIVES: The 10-O-(N N-dimethylaminoethyl)-ginkgolide B methane-sulfonate (XQ-1H) is an effective novel drug for the treatment of ischemic cerebrovascular disease derived from Ginkgolide B, a traditional Chinese medicine, has been widely used in the treatment of cardiovascular and cerebrovascular diseases. However, whether XQ-1H exerts neuroprotective effect via regulating neuronal apoptosis and the underlying mechanism remain to be elucidated. MATERIALS AND METHODS: This study was aimed to investigate the neuroprotective effect of XQ-1H in rats subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) and the oxygen glucose deprivation/reoxygenation (OGD/R) induced neuronal apoptosis on pheochromocytoma (PC-12) cells. RESULTS: The results showed that administration of XQ-1H at different dosage (7.8, 15.6, 31.2 mg/kg) reduced the brain infarct and edema, attenuated the neuro-behavioral dysfunction, and improved cell morphology in brain tissue after MCAO/R in rats. Moreover, incubation with XQ-1H (1 µM, 3 µM, 10 µM, 50 µM, 100 µM) could increase the cell viability, and showed no toxic effect to PC-12 cells. XQ-1H at following 1 µM, 10 µM, 100 µM decreased the lactate dehydrogenase (LDH) activity and suppressed the cell apoptosis in PC-12 cells exposed to OGD/R. In addition, XQ-1H treatment could significantly inhibit caspase-3 activation both in vivo and in vitro, reciprocally modulate the expression of apoptosis related proteins, bcl-2, and bax via activating PI3K/Akt signaling pathway. For mechanism verification, LY294002, the inhibitor of PI3K/Akt pathway was introduced the expressions of bcl-2 and phosphorylated Akt were down-regulated, the expression of bax was up-regulated, indicating that XQ-1H could alleviate the cell apoptosis through activating the PI3K/Akt pathway. CONCLUSIONS: Our findings demonstrated that XQ-1H treatment could provide a neuroprotective effect against ischemic stroke induced by cerebral ischemia/reperfusion injury in vivo and in vitro through regulating neuronal survival and inhibiting apoptosis. The findings of the study confirmed that XQ-1H could be develop as a potential drug for treatment of cerebral ischemic stroke.


Assuntos
Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Ginkgolídeos/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Lactonas/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Edema Encefálico/prevenção & controle , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Atividade Motora/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Células PC12 , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais
17.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209274

RESUMO

Fetal alcohol spectrum disorders (FASDs) are one of the most common consequences of ethanol exposure during pregnancy. In adulthood, these disorders can be manifested by learning and memory deficits and depressive-like behavior. Ethanol-induced oxidative stress may be one of the factors that induces FASD development. The mammalian target of the Rapamycin (mTOR) signaling pathway that acts via two distinct multiprotein complexes, mTORC1 and mTORC2, can affect oxidative stress. We investigated whether mTOR-dependent or mTOR-independent mechanisms are engaged in this phenomenon. Thus, Rapamycin-a selective inhibitor of mTORC1, Torin-2-a non-selective mTORC1/mTORC2 inhibitor, and FK-506-a drug that impacts oxidative stress in an mTOR-independent manner were used. Behavioral tests were performed in adult (PND60-65) rats using a passive avoidance (PA) task (aversive learning and memory) and forced swimming test (FST) (depressive-like behaviors). In addition, the biochemical parameters of oxidative stress, such as lipid peroxidation (LPO), as well as apurinic/apyrimidinic (AP)-sites were determined in the hippocampus and prefrontal cortex in adult (PND65) rats. The rat FASD model was induced by intragastric ethanol (5 g/kg/day) administration at postnatal day (PND)4-9 (an equivalent to the third trimester of human pregnancy). All substances (3 mg/kg) were given 30 min before ethanol. Our results show that neonatal ethanol exposure leads to deficits in context-dependent fear learning and depressive-like behavior in adult rats that were associated with increased oxidative stress parameters in the hippocampus and prefrontal cortex. Because these effects were completely reversed by Rapamycin, an mTORC1 inhibitor, this outcome suggests its usefulness as a preventive therapy in disorders connected with prenatal ethanol exposure.


Assuntos
Comportamento Animal/efeitos dos fármacos , Depressão , Transtornos do Espectro Alcoólico Fetal , Deficiências da Aprendizagem , Estresse Oxidativo/efeitos dos fármacos , Sirolimo/farmacologia , Animais , Depressão/metabolismo , Depressão/fisiopatologia , Depressão/prevenção & controle , Transtornos do Espectro Alcoólico Fetal/metabolismo , Transtornos do Espectro Alcoólico Fetal/fisiopatologia , Transtornos do Espectro Alcoólico Fetal/prevenção & controle , Deficiências da Aprendizagem/metabolismo , Deficiências da Aprendizagem/fisiopatologia , Deficiências da Aprendizagem/prevenção & controle , Ratos , Ratos Wistar
18.
J Chem Ecol ; 47(7): 614-627, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34224074

RESUMO

The polyphagous invasive brown marmorated stink bug, Halyomorpha halys, reportedly discriminates among phenological stages of host plants. To determine whether olfaction is involved in host plant stage discrimination, we selected (dwarf) sunflower, Helianthus annuus, as a model host plant species. When adult females of a still-air laboratory experiment were offered a choice of four potted sunflowers at distinct phenological stages (vegetative, pre-bloom, bloom, seeding), most females settled onto blooming plants but oviposited evenly on plants of all four stages. In moving-air two-choice olfactometer experiments, we then tested each plant stage versus filtered air and versus one another, for attraction of H. halys females. Blooming sunflowers performed best overall, but no one plant stage was most attractive in all experiments. Capturing and analyzing (by GC-MS) the headspace odorants of each plant stage revealed a marked increase of odorant abundance (e.g., monoterpenes) as plants transitioned from pre-bloom to bloom. Analyzing the headspace odorant blend of blooming sunflower by gas chromatographic-electroantennographic detection (GC-EAD) revealed 13 odorants that consistently elicited responses from female H. halys antennae. An 11-component synthetic blend of these odorants attracted H. halys females in laboratory olfactometer experiments. Furthermore, in field settings, the synthetic blend enhanced the attractiveness of synthetic H. halys pheromone as a trap lure, particularly in spring (April to mid-June). A simpler yet fully effective sunflower semiochemical blend could be developed and coupled with synthetic H. halys aggregation pheromones to improve monitoring efforts or could improve the efficacy of modified attract-and-kill control tactics for H. halys.


Assuntos
Comportamento Animal/efeitos dos fármacos , Helianthus/química , Heterópteros/fisiologia , Feromônios/farmacologia , Animais , Feminino , Flores/química , Flores/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Helianthus/metabolismo , Oviposição/efeitos dos fármacos , Feromônios/análise , Feromônios/química , Estações do Ano
19.
Molecules ; 26(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299631

RESUMO

Efficient repetitive clinical use of morphine is limited by its numerous side effects, whereas analgesic tolerance necessitates subsequent increases in morphine dose to achieve adequate levels of analgesia. While many studies focused on analgesic tolerance, the effect of morphine dosing on non-analgesic effects has been overlooked. This study aimed to characterize morphine-induced behavior and the development and progression of morphine-induced behavioral tolerance. Adult male Sprague-Dawley rats were repetitively treated with subcutaneous morphine for 14 days in two dose groups (A: 5 mg/kg/day (b.i.d.) → 10 mg/kg/day; B: 10 mg/kg/day (b.i.d.) → 20 mg/kg/day). Motor behavior was assessed daily (distance traveled, speed, moving time, rearing, rotation) in an open-field arena, before and 30 min post-injections. Antinociception was measured using tail-flick and hot-plate assays. All measured parameters were highly suppressed in both dosing groups on the first treatment day, followed by a gradual manifestation of behavioral tolerance as the treatment progressed. Animals in the high-dose group showed increased locomotor activity after 10 days of morphine treatment. This excitatory phase converted to an inhibition of behavior when a higher morphine dose was introduced. We suggest that the excitatory locomotor effects of repetitive high-dose morphine exposure represent a signature of its behavioral and antinociceptive tolerance.


Assuntos
Analgésicos Opioides/farmacologia , Comportamento Animal/efeitos dos fármacos , Morfina/farmacologia , Atividade Motora/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Masculino , Dor/tratamento farmacológico , Dor/fisiopatologia , Ratos , Ratos Sprague-Dawley
20.
Molecules ; 26(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299447

RESUMO

Tobacco (Nicotiana tabacum Linn.) is a famous traditional herb used in folk medicine. The essential oils of tobacco have been demonstrated in modern studies to possess antioxidant, anti-inflammatory, and neuroprotective properties, while its anxiolytic effect has not been reported. The purpose of this study was to evaluate the anxiolytic effect of Yunnan tobacco essential oil (YTO) and Zimbabwe tobacco essential oil (ZTO) on mice. The constituents of YTO and ZTO were analyzed by GC/MS. The anxiolytic effect of YTO and ZTO (0.1%, 1%, and 10%, v/v) on male ICR mice was evaluated in the light-dark box test (LDB) and the elevated plus maze test (EPM) test via inhalation and transdermal administration. After the behavioral tests, salivary corticosterone levels in mice were measured. The behavioral analysis showed that the administration of both YTO and ZTO elevated the time that the mice spent in the light chamber in the LDB test compared to the untreated control. In the EPM test, YTO and ZTO increased the time spent in open arms and the number of entries into the open arms. In addition, both YTO and ZTO significantly decreased salivary corticosterone levels in mice (p ≤ 0.001). In summary, our results demonstrated that inhalation and transdermal administration of both YTO and ZTO showed anxiolytic effect on male ICR mice.


Assuntos
Óleos Voláteis/farmacologia , Extratos Vegetais/farmacologia , Tabaco/metabolismo , Animais , Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , China , Feminino , Masculino , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Óleos Voláteis/administração & dosagem , Extratos Vegetais/administração & dosagem
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