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1.
Behav Brain Res ; 466: 115001, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38642861

RESUMO

INTRODUCTION: Anorexia Nervosa (AN) is a psycho-socio-biological disease characterized by severe weight loss as result of dieting and hyperactivity. Effective treatments are scarce, despite its significant prevalence and mortality. AN patients show lower basal insulin levels and increased metabolic clearance, leading to weight loss, cognitive deficits, and hormonal imbalances. Low-dose polymer insulin could potentially reverse these effects by restoring brain function, reducing fear of weight gain, encouraging food intake, and restoring fat depots. This study evaluates an insulin delivery system designed for sustained release and AN treatment. METHODS: AN-like model was established through dietary restriction (DR). On days 1-25, mice were on DR, and on days 26-31 they were on ad libitum regimen. An insulin-loaded delivery system was administered subcutaneously (1% w/w insulin). The impact of insulin treatment on gene expression in the hippocampus (cognition, regulation of stress, neurogenesis) and hypothalamus (eating behavior, mood) was assessed. Behavioral assays were conducted to evaluate motor activity and cognitive function. RESULTS: The delivery system demonstrated sustained insulin release, maintaining therapeutic plasma levels. Diet restriction mice treated with the insulin delivery system showed body weight restoration. Gene expression analysis revealed enhanced expression of CB1 and CB2 genes associated with improved eating behavior and cognition, while POMC expression was reduced. Insulin-polymer treatment restored cognitive function and decreased hyperactivity in the AN-like model. CONCLUSION: The PSA-RA-based insulin delivery system effectively restores metabolic balance, body weight, and cognitive function in the AN model. Its ability to steadily release insulin makes it a promising candidate for AN treatment."


Assuntos
Anorexia Nervosa , Peso Corporal , Modelos Animais de Doenças , Insulina , Animais , Insulina/administração & dosagem , Insulina/farmacologia , Camundongos , Anorexia Nervosa/tratamento farmacológico , Anorexia Nervosa/metabolismo , Peso Corporal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Feminino , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Camundongos Endogâmicos C57BL
2.
Chem Biodivers ; 20(8): e202300212, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37461813

RESUMO

Introduction - The obesity pandemic is multifactorial. Nutritional, pharmacologic and surgical interventions are limited in reach and efficacy, raising need for new therapeutics. Aims - Characterization of anorexigenic and cognitive effect and central mechanism of action of novel N-acylethanolamide derivatives. Methods - Sabra mice divided to similar experimental groups, injected IP with: oleyl-L-leucinolamide (1 A), linoleyl-L-leucinolamide (4 A), linoleyl-L-valinolamide (5 A), oleyl-oxycarbonyl-L-valinolamide (1 B), oleyl-oxycarbonyl-D-valinolamide (2 B), oleylamine-carbonyl-L-valinolamide (3 B), oleylamine-carbonyl-D-valinolamide (4 B), and oleyl-L-hydroxyvalineamide (5 B). Control group with vehicle. Body weight and food consumption followed for 39 days. Motor activity and cognitive function by open field test and eight-arm maze. Mice sacrificed and mechanism of action investigated by qPCR. The genes analyzed involved in energy balance and regulation of appetite. Catecholamines and serotonin evaluated. Results - Compounds 1 A, 5 A, 1 B-4 B, caused significant weight loss of 4.2-5.6 % and 5 A, 1 B-4 B, improved cognitive function following 8 i. p. injections of 1 mg/kg during 39 days, by different mechanisms. 5 A, 3 B and 4 B decreased food consumption, whereas 1 A, 5 A and 2 B increased motor activity. 1 A, 4 A, 1 B and 3 B elevated SIRT-1, associated with survival. POMC upregulated by 1 B and 2 B, CART by 1 B, 2 B and 1 A. NPY and CAMKK2 downregulated by 5 A. 4 B enhanced 5-HT levels. 4 A, 5 A, 1 B, 4 B, 5 B decreased FAAH, showing long lasting effect. Conclusions - These new compounds might be developed for the treatment of obesity and for improved cognitive function.


Assuntos
Obesidade , Serotonina , Camundongos , Animais , Peso Corporal , Obesidade/tratamento farmacológico
3.
Physiol Behav ; 249: 113738, 2022 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-35182554

RESUMO

INTRODUCTION: Anorexia nervosa is a psycho-socio-biological disease, characterized by self-starvation and distorted perception of body weight. Patients often over-exercise. Insulin is an anabolic hormone that increases food intake and restores body fat and is present in low levels in anorexia nervosa patients: thus may have therapeutic potential in treating anorexia nervosa. AIMS: to explore whether low levels insulin administration may result in recovery of cerebral function and restoration of metabolic disorder providing a treatment option for anorexia nervosa. METHODS: Female Sabra mice maintained on DR of 2.0 hours per day for 32 days, in cages with or without wheel attached to an electronic counter (activity wheel). They were then permitted to eat ad libitum for additional 15 days. On the second week, mice were injected ip with 0.5U/kg long acting Insulin(Lantus) or saline and cognitive function was evaluated. Insulin administered three times a week during days 8-32. Mice euthanized on day 48 and cerebral levels of monoamines, 2-AG and expression of genes associated with metabolic status were evaluated. RESULTS: Activity wheel mice decreased body weight, 2-AG, dopamine levels and 5-HT1A and increased Camkk2 and SIRT1 gene expression compared to mice without it. Insulin increased body weight, decreased revolutions, enhanced NPY and normalized Camkk2, SIRT-1, BDNF, elevated 2-AG and improved cognition in the wheel group. CONCLUSION: low dose insulin administration to animal model of anorexia associated with exercise, led to alterations and normalization in brain metabolic status and improved cognition. Insulin should be further explored as potential novel treatment for anorexia nervosa.


Assuntos
Anorexia Nervosa , Animais , Anorexia , Anorexia Nervosa/complicações , Anorexia Nervosa/tratamento farmacológico , Peso Corporal , Encéfalo/metabolismo , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Feminino , Humanos , Insulina , Camundongos
4.
Bioorg Chem ; 115: 105224, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34392174

RESUMO

Autistic Spectrum Disorders (ASD) are neurodevelopmental disorders characterized by impaired social interaction & communication as well as restricted and repetitive behavior. The currently reported incidence of ASD is 1-2%, and it increases dramatically to 10-20% in families predisposed to ASD. To date, there is no effective way to treat or prevent ASD, and only symptomatic treatment with limited efficacy is available. Oxytocin (Oxt) enhances affiliative behavior and improves social cognition. Social deficits characteristic of autism may be related to dysfunctional Oxt neurotransmission. Thus, administration of Oxt may relieve ASD, however it has a short plasma half-life and poor Blood Brain Barrier (BBB) permeability. CD38, a multifunctional ecto-enzyme expressed in brain and immune cells, was found to be critical for social behavior via regulation of Oxt secretion. All-trans retinoic acid (ATRA) is a potent inducer of CD38 and improves social behavior, but it is toxic and teratogenic. We have shown that beta-carotene has a similar therapeutic effect. The present study aimed to investigate the activity of novel beta-carotene derivatives in rescuing low sociability found in BTBR mice, providing an in vivo "proof of principle" that beta-carotene derivatives are potential agents to prevent/ameliorate the reappearance of ASD in high-risk populations for ASD. Beta-carotene and its synthetic analogs were administered orally to newborn BTBR mice with ASD associated like behavior. After 2 months, they were tested (at dosages of 0.1 and 1.0 mg/kg) by cognitive (T-maze spontaneous alteration and neurological score) and behavioral tests (reciprocal social interaction, repetitive grooming / bedding behavior), previously shown as indicators for autistic behavior. The following biochemical and molecular biology parameters were also examined: serum Oxt; gene expression in hippocampus and hypothalamus of CD 38, Oxt, Oxt receptor, BDNF, and retinoic acid receptor. The new compounds were significantly more effective than control. The most effective compounds, both in the behavioral tests and in their biochemical effects, were (3R,3'R)-astaxanthin bis(N-Cbz-l-alanine ester) (3B(and (3S,3'S)-astaxanthin bis(N,N-dimethylglycine ester (5). They did not exert any neurological symptoms. Thus, beta-carotene derivatives may have the potential to prevent and/or ameliorate autistic symptoms when administered orally after birth to newborns of families predisposed to autism.


Assuntos
Transtorno Autístico/tratamento farmacológico , beta Caroteno/uso terapêutico , Administração Oral , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Relação Estrutura-Atividade , beta Caroteno/administração & dosagem , beta Caroteno/química
5.
Behav Brain Res ; 364: 469-479, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-28963040

RESUMO

Autism-affected individuals are characterized by lower plasma oxytocin and its ectoenzyme regulator CD38. Oxytocin, a hypothalamic hormone secreted upon the release of CD38, plays a role in social behavior and bonding. All-trans retinoic acid is a potent inducer of CD38 and can be used as a novel therapeutic strategy in autism. We investigated the role of beta-carotene in rescuing autistic-like behavior in BALB/c and BTBR mice. Beta-carotene derivatives are preferred as they are neither toxic nor teratogenic. Beta-carotene at 0.1-5.0 mg/kg was administered orally to BALB/c and BTBR newborn mice on days 1-7. They were tested at age 2-3 months for five behavioral tests for "autism"; in addition, brain CD38, oxytocin, oxytocin receptor, Brain Derived Neurotrophic Factor (BDNF) and retinoic acid receptor gene expression, serum oxytocin levels, and neurological score were evaluated. Beta-carotene administered at birth significantly increased T-maze alternations and led to longer time spent with an unfamiliar mouse in the "three-chamber test" and less time spent in the empty chamber. Furthermore, enhanced activity in the open field test; increased time spent in the reciprocal social interaction test; decreased grooming and bedding behaviors; and enhanced brain CD38, oxytocin, oxytocin receptor, BDNF, retinoic acid gene expression, and serum oxytocin levels. No changes in neurological score were observed. Beta-carotene oral supplementation to BALB/c and BTBR mice at birth significantly reduced restricted and stereotyped behaviors and interests, increased social interactions and communication, CD38, and oxytocin, probably by enhancing brain neuroplasticity without toxicity. Thus, beta-carotene administered after birth to newborns of families predisposed to "autism" has the potential to prevent/ameliorate" autistic like behavior". These results support further clinical studies.


Assuntos
Transtorno Autístico/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , beta Caroteno/farmacologia , ADP-Ribosil Ciclase 1/metabolismo , Animais , Animais Recém-Nascidos , Transtorno do Espectro Autista/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Relações Interpessoais , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Ocitocina/metabolismo , Receptores do Ácido Retinoico/metabolismo , Comportamento Social , beta Caroteno/metabolismo
6.
J Nutr Biochem ; 22(8): 766-76, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21109417

RESUMO

Severe malnutrition resulting from anorexia nervosa or involuntary starvation leads to low weight, cognitive deficits and increased mortality rates. In the present study, we examined whether fish oil supplementation, compared with that of canola oil, would ameliorate the morbidity and mortality associated with these conditions by normalizing endocannabinoid and monoaminergic systems as well as other systems involved in satiety and cognitive function within the hypothalamus and hippocampus. Female Sabra mice restricted to 40% of their daily food intake exhibited decreased body weight, were sickly in appearance, displayed cognitive deficits and had increased mortality rates. Strikingly, fish oil supplementation that contains high omega-3 fatty acids levels decreased mortality and morbidity, and normalized the expression of genes and neurotransmitters in the hippocampus and hypothalamus. Fish oil supplementation, but not canola oil, increased survival rates, improved general appearance and prevented cognitive decline, despite the facts that both diets contained an equivalent number of calories and that there were no differences in weight between mice maintained on the two diets in 100% but decrease in the 40%. In the hypothalamus, the beneficial effects of fish oil supplementation were related to normalization of the endocannabinoid 2-arachidonylglycerol, serotonin (5-HT) (P<.056), dopamine, neuropeptide Y (NPY) and Ca(2+)/calmodulin (CaM)-dependent protein kinase (Camkk2). In the hippocampus, fish oil supplementation normalized 5-HT, Camkk2, silent mating type information regulation 1 and brain-derived neurotrophic factor. In conclusion, dietary supplements of fish oil, as source of omega-3 fatty acids, may alleviate cognitive impairments associated with severe diet restriction and prolong survival independently of weight gain by normalizing neurochemical systems.


Assuntos
Transtornos Cognitivos/tratamento farmacológico , Óleos de Peixe/farmacologia , Desnutrição/tratamento farmacológico , Saciação/efeitos dos fármacos , Animais , Peso Corporal , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Dopamina/metabolismo , Ácidos Graxos Monoinsaturados/farmacologia , Feminino , Expressão Gênica , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Camundongos , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , Reação em Cadeia da Polimerase , Óleo de Brassica napus , Receptor CB1 de Canabinoide/metabolismo , Receptores 5-HT1 de Serotonina/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo
7.
J Hepatol ; 51(3): 528-34, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19596476

RESUMO

BACKGROUND/AIMS: The endocannabinoid system in mice plays a role in models of human cirrhosis and hepatic encephalopathy (HE), induced by a hepatotoxin. We report now the therapeutic effects of cannabidiol (CBD), a non-psychoactive constituent of Cannabis sativa, on HE caused by bile duct ligation (BDL), a model of chronic liver disease. METHODS: CBD (5mg/kg; i.p.) was administered over 4weeks to mice that had undergone BDL. RESULTS: Cognitive function in the eight arm maze and the T-maze tests, as well as locomotor function in the open field test were impaired by the ligation and were improved by CBD. BDL raised hippocampal expression of the TNF-alpha-receptor 1 gene, which was reduced by CBD. However, BDL reduced expression of the brain-derived neurotrophic factor (BDNF) gene, which was increased by CBD. The effects of CBD on cognition, locomotion and on TNF-alpha receptor 1 expression were blocked by ZM241385, an A(2)A adenosine receptor antagonist. BDL lowers the expression of this receptor. CONCLUSIONS: The effects of BDL apparently result in part from down-regulation of A(2)A adenosine receptor. CBD reverses these effects through activation of this receptor, leading to compensation of the ligation effect.


Assuntos
Canabidiol/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Transtornos Neurológicos da Marcha/tratamento farmacológico , Transtornos Neurológicos da Marcha/etiologia , Encefalopatia Hepática/complicações , Hepatopatias/complicações , Antagonistas do Receptor A2 de Adenosina , Animais , Ductos Biliares/fisiopatologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Canabidiol/farmacologia , Doença Crônica , Cognição/efeitos dos fármacos , Cognição/fisiologia , Transtornos Cognitivos/metabolismo , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Feminino , Transtornos Neurológicos da Marcha/metabolismo , Encefalopatia Hepática/etiologia , Ligadura/efeitos adversos , Hepatopatias/etiologia , Camundongos , Camundongos Endogâmicos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , RNA Mensageiro/metabolismo , Receptor A2A de Adenosina/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Resultado do Tratamento , Triazinas/farmacologia , Triazóis/farmacologia
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