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1.
Int J Mol Sci ; 23(5)2022 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-35269853

RESUMO

Some selective serotonin reuptake inhibitors (SSRIs), primarily sertraline, demonstrate anti-proliferative activity in malignant cell-lines and in xenografted mouse models of colorectal tumor. There is, however, a paucity of comparative studies on the anti-tumor effects of SSRIs. We compared the in vitro and in vivo effects of sertraline and citalopram on murine 4T1 breast cancer. Grafted mice were used to determine the rate of tumor growth and survival as well as the impact of stress and antidepressant treatment on tumor progression and mortality and on pro-inflammatory cytokines. Sertraline, in the micromolar range, but not citalopram, induced a significant in vitro concentration-dependent inhibition of murine 4T1 cell proliferation and splenocyte viability. In contrast, sertraline (10 mg/kg/d), enhanced in vivo tumor growth. Contrary to the study's hypothesis, chronic mild stress did not modify tumor growth in grafted mice. The in vitro effects of sertraline on tumor growth seem to be the opposite of its in vivo effects. The impact of sertraline treatment on humans with breast cancer should be further investigated.


Assuntos
Neoplasias , Sertralina , Animais , Ansiedade/tratamento farmacológico , Proliferação de Células , Citalopram/farmacologia , Citalopram/uso terapêutico , Camundongos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Sertralina/farmacologia , Sertralina/uso terapêutico
2.
PLoS One ; 15(1): e0227879, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929603

RESUMO

Accumulating evidence suggests that Alzheimer's disease is associated with brain insulin resistance, as are some other types of dementia. Intranasal insulin administration has been suggested as a potential approach to overcoming brain insulin resistance and improving cognitive functions. Islet transplantation into the cranial subarachnoid cavity was used as an alternative route for insulin delivery into the brain. Recently, the authors showed the short-term beneficial cognitive effect of a small number of intracranially grafted islets in rats with cognitive dysfunction induced by intracerebroventricular administration of streptozotocin (icv-STZ). This was associated with continuous and safe insulin delivery to the rat brain. The current study investigated the long-term effect of intracranial grafting of islets on cognitive functioning in icv-STZ rats. Severe dementia, associated with obesity and cerebral amyloid-ß angiopathy, was induced in Lewis inbred rats by icv-STZ. Two months after icv-STZ, one hundred syngeneic islets were transplanted into the cranial subarachnoid space. Two and six months later, cognitive alterations were assessed by Morris water-maze tests. Islet graft survival was evaluated by immunohistochemical and biochemical assays. Improvement was found in spatial learning and memory of grafted rats as opposed to the sham-operated icv-STZ rats. The grafted islets showed intact morphology, intensive expression of insulin, glucagon and glucose transporter 2. Normoglycemic obesity and cerebral amyloid-ß angiopathy were found in both grafted and sham-operated icv-STZ rats. In conclusion, islet grafting into cranial subarachnoid space provides an efficient and safe approach for insulin delivery to the brain, leading to a long-term attenuation of icv-STZ-induced cognitive dysfunction.


Assuntos
Doença de Alzheimer/terapia , Transtornos Cognitivos/terapia , Insulina/biossíntese , Transplante das Ilhotas Pancreáticas/métodos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/cirurgia , Cognição/fisiologia , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/cirurgia , Humanos , Ilhotas Pancreáticas/metabolismo , Aprendizagem em Labirinto , Memória/fisiologia , Ratos
4.
J Alzheimers Dis ; 65(4): 1445-1458, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30175977

RESUMO

BACKGROUND: Alzheimer's disease (AD) is often associated with brain insulin resistance and peripheral metabolic dysfunctions. Recently, we developed a model of sporadic AD associated with obesity-related peripheral metabolic abnormalities in Lewis rats using intracerebroventricular administration of streptozotocin (icv-STZ). OBJECTIVE: We aimed to assess the effect of intracranially grafted pancreatic islets on cognitive and peripheral metabolic dysfunctions in the icv-STZ Lewis rats. METHODS: AD-like dementia associated with obesity was induced in inbred Lewis rats using a single icv-STZ. Two months after icv-STZ, syngeneic islets (100 islets per recipient) were implanted in the cranial subarachnoid cavity of icv-STZ rats. Morris water maze and marble burying tests were used for studying cognitive and behavioral functions. Central and peripheral metabolic alterations were assessed by histological and biochemical assays. RESULTS: The icv-STZ induced increases in food intake, body weight, and blood levels of insulin and leptin without alteration of glucose homeostasis. Grafted islets reduced body weight gain, food consumption, peripheral insulin resistance, and hyperleptinemia. Biochemical and histological analysis of the brain revealed viable grafted islets expressing insulin and glucagon. The grafted islets did not affect expression of brain insulin receptors and peripheral glucose homeostasis. Two months after islet transplantation, cognitive and behavioral functioning in transplanted rats were significantly better than the sham-operated icv-STZ rats. No significant differences in the locomotor activity between transplanted and non-transplanted icv-STZ rats were found. CONCLUSIONS: Intracranial islet transplantation attenuates cognitive decline and peripheral metabolic dysfunctions providing a novel therapeutic approach for sporadic AD associated with peripheral metabolic dysfunctions.


Assuntos
Doença de Alzheimer/complicações , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/cirurgia , Doenças Metabólicas/etiologia , Doenças Metabólicas/cirurgia , Doença de Alzheimer/induzido quimicamente , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Peso Corporal , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Líquidos/fisiologia , Ingestão de Alimentos/efeitos dos fármacos , Seguimentos , Transplante das Ilhotas Pancreáticas , Masculino , Metabolismo/fisiologia , Pâncreas/patologia , Ratos , Ratos Endogâmicos Lew , Ratos Wistar , Estreptozocina
5.
J Alzheimers Dis ; 60(1): 121-136, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28800326

RESUMO

BACKGROUND: Animal models of dementia associated with metabolic abnormalities play an important role in understanding the bidirectional relationships between these pathologies. Rodent strains develop cognitive dysfunctions without alteration of peripheral metabolism following intracerebroventricular administration of streptozotocin (icv-STZ). OBJECTIVE: We aimed to estimate the effect of icv-STZ on cognitive functions and peripheral metabolism in Lewis rats, which are rarely used for the induction of cognitive abnormalities. METHODS: Inbred adult Lewis rats were treated with single icv-STZ (3 mg/kg). Cognitive functions were assessed using Morris water maze (MWM) test and locomotion by the Open Field test. Metabolic alterations were studied using histological and biochemical analysis of brain and peripheral tissues. RESULTS: The icv-STZ induced rapid weight decline during the first two weeks. Thereafter, the rats showed an accelerated weight gain. Three months after the icv-STZ treatment, the rats were severely obese and revealed fatty liver, pancreatic islet hypertrophy, significantly elevated levels of blood insulin, leptin, and adiponectin, but intact peripheral glucose homeostasis. The icv-STZ rats expressed amyloid-ß deposits in blood vessels of leptomeningeal area, microgliosis, astrogliosis, and spongiosis in fimbria-fornix area of hippocampus. Locomotor activities of icv-STZ treated and sham-operated rats were similar. In the MWM test, the icv-STZ treated rats demonstrated severely impaired spatial learning during both acquisition and reversal phases. CONCLUSIONS: Icv-STZ treated Lewis rats develop severe dementia associated with obesity and peripheral metabolic abnormalities. This animal model may be useful for exploring the pathophysiological relationship between obesity and dementia and provides a new tool for development of effective therapy.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Demência/induzido quimicamente , Obesidade/induzido quimicamente , Estreptozocina/toxicidade , Peptídeos beta-Amiloides/metabolismo , Animais , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Demência/patologia , Demência/fisiopatologia , Modelos Animais de Doenças , Encefalite/induzido quimicamente , Comportamento Exploratório/efeitos dos fármacos , Hormônios/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Obesidade/patologia , Obesidade/fisiopatologia , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Ratos , Ratos Endogâmicos Lew
6.
Hum Mol Genet ; 26(13): 2462-2471, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28402427

RESUMO

Cannabis abuse in adolescence is associated with increased risk of psychotic disorders. Δ-9-tetrahydrocannabinol (THC) is the primary psychoactive component of cannabis. Disrupted-In-Schizophrenia-1 (DISC1) protein is a driver for major mental illness by influencing neurodevelopmental processes. Here, utilizing a unique mouse model based on host (DISC1) X environment (THC administration) interaction, we aimed at studying the pathobiological basis through which THC exposure elicits psychiatric manifestations. Wild-Type and dominant-negative-DISC1 (DN-DISC1) mice were injected with THC (10 mg/kg) or vehicle for 10 days during mid-adolescence-equivalent period. Behavioral tests were conducted to assess exploratory activity (open field test, light-dark box test) and cognitive function (novel object recognition test). Electrophysiological effect of THC was evaluated using acute hippocampal slices, and hippocampal cannabinoid receptor type 1 and brain-derived neurotrophic factor (BDNF) protein levels were measured. Our results indicate that THC exposure elicits deficits in exploratory activity and recognition memory, together with reduced short-term synaptic facilitation and loss of BDNF surge in the hippocampus of DN-DISC mice, but not in wild-type mice. Over-expression of BDNF in the hippocampus of THC-treated DN-DISC1 mice prevented the impairment in recognition memory. The results of this study imply that induction of BDNF following adolescence THC exposure may serve as a homeostatic response geared to maintain proper cognitive function against exogenous insult. The BDNF surge in response to THC is perturbed in the presence of mutant DISC1, suggesting DISC1 may be a useful probe to identify biological cascades involved in the neurochemical, electrophysiological, and behavioral effects of cannabis related psychiatric manifestations.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Dronabinol/efeitos adversos , Proteínas do Tecido Nervoso/efeitos dos fármacos , Adolescente , Animais , Animais Recém-Nascidos , Cannabis/efeitos adversos , Cognição/efeitos dos fármacos , Transtornos Cognitivos/metabolismo , Modelos Animais de Doenças , Dronabinol/metabolismo , Hipocampo/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Transtornos Psicóticos
7.
Behav Brain Res ; 323: 141-145, 2017 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-28167336

RESUMO

BACKGROUND: Schizophrenia patients who do not respond to clozapine treatment represent the most debilitating type of schizophrenia with unmet needs for novel interventions. To date there is no validated animal model for clozapine-refractory schizophrenia. METHODS: We used poor performance in the social preference (SP) test of C57/BL mice exposed to subchronic phencyclidine (PCP) as a correlate of negative signs of schizophrenia. Subsequently the mice were treated with clozapine and according to their SP they were defined as responding (i.e. clozapine/PCP ratio>1.5 SD) or non-responsive to clozapine. In each generation the responding mice were mated to produce the next generation. Unfortunately, the clozapine- non-responsive mice failed to proliferate and were thus excluded from the analyses. This forward genetic paradigm was used to produce the next generation of clozapine-responding mice. We assessed brain glutamic acid decarboxylase-67 (GAD67) protein levels, as a GABA-ergic marker, in the F2 and F3 generations. RESULTS: Already in the F1 generation of male mice, but not females, it was possible to discriminate between clozapine-responders and non-responders. The rate of responders within each consecutive generation, increased. The increase was more pronounced in females. Up-regulation of GAD67 levels was detected between F2 and F3 only in male clozapine-responder mice, but not in females. CONCLUSIONS: This preliminary proof-of-concept study succeeded in producing a trans-generation enrichment of clozapine-responsiveness trait in a hypo-glutamatergic animal model of negative signs of schizophrenia. This model may serve as a platform to better characterize the clozapine responsiveness trait and offer a model for clozapine-responsive schizophrenia.


Assuntos
Antipsicóticos/administração & dosagem , Clozapina/administração & dosagem , Modelos Animais de Doenças , Esquizofrenia/metabolismo , Esquizofrenia/prevenção & controle , Seleção Artificial , Animais , Feminino , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Glutamato Descarboxilase/metabolismo , Ácido Glutâmico/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenciclidina/administração & dosagem , Esquizofrenia/induzido quimicamente , Comportamento Social
8.
J Tissue Eng Regen Med ; 11(11): 3263-3272, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28127888

RESUMO

There is increasing evidence supporting a link between cognitive dysfunctions and impaired brain insulin signalling. Insulin therapy has previously been tested as an approach to ameliorate brain insulin resistance and deficiency in patients with various brain disorders. However, current strategies for insulin delivery to the brain may induce severe hypoglycaemia when injected peripherally or show poor uptake when delivered intranasally. Recently, we have shown that intracranial transplantation of naked pancreatic islets increased insulin content in the brain and attenuated cognitive dysfunctions without altering peripheral glucose homeostasis in rats with schizophrenia-like syndrome. In this study, we show that intracranial implantation of 50 pancreatic islets encapsulated in disc-shaped alginate is sufficient to elevate insulin content in the rat brain. Three weeks after implantation, the islets displayed intact morphology, intensive hormone staining and glucose-sensitive insulin release. The ultrapure alginate with high guluronic acid content used for islet encapsulation demonstrated good biocompatibility and stability after intracranial implantation. All implanted animals were normoglycaemic and normoinsulinaemic. In conclusion, the intracranial implantation of a small amount of alginate-encapsulated islets is an efficient tool for metabolically regulated insulin delivery to the brain. Copyright © 2017 John Wiley & Sons, Ltd.


Assuntos
Alginatos , Encéfalo/metabolismo , Células Imobilizadas , Hipoglicemia , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Alginatos/química , Alginatos/farmacologia , Animais , Células Imobilizadas/metabolismo , Células Imobilizadas/transplante , Ácido Glucurônico/química , Ácido Glucurônico/farmacologia , Ácidos Hexurônicos/química , Ácidos Hexurônicos/farmacologia , Hipoglicemia/metabolismo , Hipoglicemia/patologia , Hipoglicemia/terapia , Transplante das Ilhotas Pancreáticas , Masculino , Ratos , Transplante Isogênico
9.
J Mol Neurosci ; 58(1): 66-73, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26572534

RESUMO

Olanzapine-induced weight gain is associated with atherosclerosis, hypertension, dyslipidemia, and diabetes. We synthesized a novel antipsychotic drug (PGW5) possessing an olanzapine moiety linked to sarcosine, a glycine transporter 1 inhibitor. In this study, we compared the metabolic effects of PGW5 and olanzapine in a female rat model of weight gain. Female rats were treated daily with oral olanzapine (4 mg/kg), PGW5 (25 mg/kg), or vehicle for 16 days. Behavioral tests were conducted on days 12-14. Biochemical analyses were performed at the end of the treatment. A significant increase in body weight was observed in the olanzapine-treated group, while the PGW5 group did not differ from the controls. The open field test showed hypo-locomotion in the olanzapine-treated animals as compared to PGW5 and control groups. A significant increase in hypothalamic protein expression of the neuropeptide Y5 receptor and a decrease in pro-opiomelanocortin messenger ribonucleic acid (mRNA) levels were detected following PGW5 treatment, but not after olanzapine administration. PGW5 appears to possess minor metabolic effects compared with the parent compound olanzapine. The differential modulation of brain peptides associated with appetite regulation is possibly involved in the attenuation of metabolic effects by PGW5.


Assuntos
Alanina/análogos & derivados , Antipsicóticos/farmacologia , Benzodiazepinas/farmacologia , Aumento de Peso/efeitos dos fármacos , Alanina/química , Alanina/farmacologia , Animais , Antipsicóticos/química , Benzodiazepinas/química , Feminino , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Olanzapina , Ratos , Ratos Wistar , Receptores de Neuropeptídeo Y/genética , Receptores de Neuropeptídeo Y/metabolismo , Sarcosina/química
11.
Horm Behav ; 72: 1-11, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25943974

RESUMO

The treatment of rodents with non-competitive antagonist of the N-Methyl-D-aspartate (NMDA) receptor, MK-801 (dizocilpine), induces symptoms of psychosis, deficits in spatial memory and impairment of synaptic plasticity. Recent studies have suggested that insulin administration might attenuate the cognitive dysfunctions through the modulatory effect on the expression of NMDA receptors and on the brain insulin signaling. Intrahepatic pancreatic islet transplantation is known as an efficient tool for correcting impaired insulin signaling. We examined the capacity of syngeneic islets grafted into the cranial subarachnoid cavity to attenuate behavioral dysfunctions in rats exposed to MK-801. Animals were examined in the open field (OF) and the Morris Water Maze (MWM) tests following acute or subchronic administration of MK-801. We found well-vascularized grafted islets expressing insulin, glucagon and somatostatin onto the olfactory bulb and prefrontal cortex. Significantly higher levels of insulin were detected in the hippocampus and prefrontal cortex of transplanted animals compared to the non-transplanted rats. All animals expressed normal peripheral glucose homeostasis for two months after transplantation. OF tests revealed that rats exposed to MK-801 treatment, showed hyper-responsiveness in motility parameters and augmented center field exploration compared to intact controls and these effects were attenuated by the grafted islets. Moreover, in the MWM, the rats treated with MK-801 showed impairment of spatial memory that were partially corrected by the grafted islets. In conclusion, intracranial islet transplantation leads to the expression of islet hormones in the brain and attenuates behavioral and cognitive dysfunctions in rats exposed to MK-801 administration without altering the peripheral glucose homeostasis.


Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Maleato de Dizocilpina/farmacologia , Transplante das Ilhotas Pancreáticas , Ilhotas Pancreáticas/metabolismo , Hormônios Pancreáticos/metabolismo , Transplante Heterotópico , Animais , Células Cultivadas , Hipocampo/efeitos dos fármacos , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Endogâmicos Lew
12.
J Mol Neurosci ; 55(2): 552-60, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25064496

RESUMO

Laquinimod is a novel oral immunomodulatory drug for the treatment of multiple sclerosis (MS). Considering the frequent co-morbidity of MS with anxiety and depression, we sought to assess the antidepressant and anxiolytic effects of laquinimod in mouse models. Laquinimod (0.5-25 mg/kg), fluoxetine (10 mg/kg) or vehicle were administered for 4-14 days to adult Balb/c mice, followed by behavioral tests and brain BDNF analysis. Following a 4-day administration of laquinimod (5 and 25 mg/kg), an increase in motivated behavior was observed in the forced swim test (p < 0.01 vs. controls). In the open field test, laquinimod (0.5-5 mg/kg), but not fluoxetine, significantly increased motility (p < 0.05), whereas both decreased anxiety behavior (p < 0.01), evident only for laquinimod (5 mg/kg) in the elevated plus maze (p < 0.05). Following 7 days of administration, both drugs decreased anxiety behavior in the elevated plus maze and marble burying tests (p < 0.001 and p < 0.02, respectively). After 14 days, only laquinimod (5 mg/kg) demonstrated anxiolytic efficacy in the open field test (p < 0.05), with evidence of increased BDNF in response to 5-25 mg/kg in the hippocampus, but not frontal cortex (p < 0.05). In conclusion, laquinimod may possess anxiolytic and antidepressant effects, possibly associated with hippocampal BDNF increase, offering promise for MS patients suffering from psychiatric co-morbidity.


Assuntos
Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Quinolonas/uso terapêutico , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Hipocampo/metabolismo , Fatores Imunológicos/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Quinolonas/farmacologia
13.
Eur Neuropsychopharmacol ; 24(3): 425-36, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24389121

RESUMO

UNLABELLED: Schizophrenia is a chronic mental disorder related to hypo-functioning of glutamatergic neurotransmission. N-methyl-D-aspartate-receptor (NMDA-R) positive modulators were reported to reduce schizophrenia symptoms. However, their efficacy is low and inconsistent. We developed a novel antipsychotic possessing an olanzapine moiety linked to the positive modulator of glutamate NMDA-R sarcosine (PGW5) and characterized the pharmacodynamic properties of the novel molecule in-vivo using MK-801 and in-vitro using receptor binding analysis. We investigated the pharmacological activity of PGW5 (olanzapine linked to sarcosinyl moiety) in male mice (BALB/c or C57BL). In an open field test, up to 50mg/kg PGW5 did not affect motility while higher doses were sedative. PGW5 (25-50mg/kg po) antagonized MK-801 (0.15 mg/kg ip) and amphetamine-induced (5mg/kg ip) hyperactivity. PGW5 (25mg/kg po/d) treatment for 15 or 22 days exhibited antidepressant and anxiolytic activity in mice. Moreover, PGW5, but not olanzapine, attenuated phencyclidine (PCP)-induced deficits of social preference in mice and promoted the expression of brain derived neurotrophic factor (BDNF) in the hippocampus and the frontal cortex and glutamic acid decarboxylase (GAD67) in the hippocampus. Mice treated with PGW5 (25 and 50mg/kg/d) for 28 days did not show toxic effects in terms of weight gain and blood-chemistry analysis. CONCLUSIONS: PGW5 is a novel and safe antipsychotic, efficacious against schizophrenia-like positive and negative symptoms at nonsedative doses. The drug shows anxiolytic and antidepressant activity, and improves impaired social performance in phencyclidine (PCP) treated mice. The mechanism underlying its activity seems to involve potentiation of NMDA receptor as well as stimulation of brain BDNF and GAD67 expression.


Assuntos
Alanina/análogos & derivados , Antipsicóticos/farmacologia , Benzodiazepinas/farmacologia , Esquizofrenia/tratamento farmacológico , Alanina/administração & dosagem , Alanina/efeitos adversos , Alanina/farmacologia , Anfetamina/farmacologia , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Ansiedade/tratamento farmacológico , Benzodiazepinas/administração & dosagem , Benzodiazepinas/efeitos adversos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Depressão/tratamento farmacológico , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Olanzapina , Fenciclidina/farmacologia , Agitação Psicomotora/tratamento farmacológico , Agitação Psicomotora/etiologia , Comportamento Social
14.
World J Biol Psychiatry ; 15(1): 76-82, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24219803

RESUMO

UNLABELLED: OBJECTIVES. Disrupted in schizophrenia 1 (DISC1) is considered the most prominent candidate gene for schizophrenia. In this study, we aimed to characterize behavioural and brain biochemical traits in a mouse expressing a dominant negative DISC1mutant (DN-DISC1). METHODS: DN-DISC1 mice underwent behavioural tests to evaluate object recognition, social preference and social novelty seeking. ELISA was conducted on brain tissue to evaluate BDNF levels. Western blot was employed to measure BDNF receptor (TrkB) and cannabinoid receptor CB1. RESULTS: The mutant DISC1 mice displayed deficits in preference to social novelty while both social preference and object recognition were intact. Biochemical analysis of prefrontal cortex and hippocampus revealed a modest reduction in cortical TrkB protein levels of male mice while no differences in BDNF levels were observed. We found sex dependent differences in the expression of cannabinoid-1 receptors. CONCLUSIONS: We describe novel behavioural and biochemical abnormalities in the DN-DISC1 mouse model of schizophrenia. The data shows for the first time a possible link between DISC1 mutation and the cannabinoid system.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Proteínas do Tecido Nervoso/genética , Córtex Pré-Frontal/metabolismo , Receptor CB1 de Canabinoide/genética , Esquizofrenia/genética , Comportamento Social , Animais , Modelos Animais de Doenças , Genes Dominantes/genética , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Mutação , Córtex Pré-Frontal/patologia , Receptor trkB/genética , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia
15.
Psychopharmacology (Berl) ; 230(1): 23-7, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23828160

RESUMO

RATIONALE: We previously demonstrated that the addition of the selective norepinephrine reuptake inhibitor reboxetine attenuates olanzapine-induced weight gain. Using the same study sample, we also sought to determine whether reboxetine's weight-attenuating effect was accompanied by a beneficial effect on metabolic and endocrine parameters relevant to antipsychotic-induced weight gain and obesity. METHOD: Blood samples at baseline and at the end of the 6-week trial were available for 54 participants who participated in previous double-blind, placebo-controlled studies of reboxetine (4 mg BID) addition to olanzapine-treated schizophrenia patients. Fasting glucose, lipid profile, insulin, leptin, cortisol, dehydroepiandrosterone (DHEA), prolactin, and thyroid-stimulating hormone (TSH) were analyzed. RESULTS: In contrast to the olanzapine/placebo group, the olanzapine/reboxetine group exhibited a reduction in blood triglyceride (p < 0.05) and leptin (p < 0.05) levels, and elevation in cortisol (p < 0.05) and DHEA (p < 0.008) levels. No significant between-group differences were detected in the changes in cholesterol, glucose, insulin, TSH, and prolactin. CONCLUSIONS: Reboxetine addition resulted in meaningful improvement of some metabolic and endocrine measures associated with olanzapine-induced weight gain. The potential role of reboxetine in the prevention of olanzapine-induced weight gain and cardio-metabolic morbidity merits further large-scale, long-term investigation.


Assuntos
Antipsicóticos/efeitos adversos , Benzodiazepinas/efeitos adversos , Morfolinas/farmacologia , Esquizofrenia/tratamento farmacológico , Inibidores da Captação Adrenérgica/administração & dosagem , Inibidores da Captação Adrenérgica/farmacologia , Inibidores da Captação Adrenérgica/uso terapêutico , Adulto , Antipsicóticos/administração & dosagem , Antipsicóticos/uso terapêutico , Benzodiazepinas/administração & dosagem , Benzodiazepinas/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Morfolinas/administração & dosagem , Morfolinas/uso terapêutico , Olanzapina , Reboxetina , Aumento de Peso/efeitos dos fármacos , Adulto Jovem
16.
Neurosci Lett ; 550: 93-7, 2013 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-23827216

RESUMO

Selective serotonin reuptake inhibitors (SSRIs) stimulate synaptic plasticity and neurogenesis, most likely via the MAP-kinase signal transduction pathway (by phosphorilation of ERK) and by stimulating neurotrophic factors such as brain derived neurotrophic factor (BDNF) and the neuroprotective protein (Bcl-2). Using human neuroblastoma cells (SHSY5Y), we found that sertraline and its derivative, desmethylsertraline, at low concentrations (1-10 µM), induced potent neurotrophic activity. Subsequently, we have treated for 21 days young and aged mice with sertraline. Sertraline in certain doses improved significantly spatial memory learning, in both young and old mice. Sertraline treatment resulted in up-regulation of brain BDNF, phospho-ERK and Bcl-2 that may be involved in the pro-cognitive effect of sertraline.


Assuntos
Hipocampo/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Sertralina/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Linhagem Celular Tumoral , Hipocampo/metabolismo , Humanos , Camundongos , Neurônios/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Regulação para Cima/efeitos dos fármacos
17.
J Mol Neurosci ; 50(1): 88-97, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-22968760

RESUMO

Chronic mild stress (CMS) in rats is an established rodent depression model. Antidepressants attenuate the depression-like symptoms and prevent the biochemical changes caused by stress. In the present study, we examined the effect of CMS and the selective norepinephrine reuptake inhibitor (NRI) reboxetine (REB) treatment on behavioral parameters in rats and on hippocampal and cortical neurotrophic factors. Male Sprague Dawley rats were exposed for 5 weeks to a variety of mild stressors. REB (5 mg/kg/i.p.) was daily injected to half of the stressed and unstressed groups. Animal behavior following CMS was tested using the Morris Water Maze (MWM) cognitive paradigm and by monitoring sucrose intake and weight gain. After 5 weeks of CMS, stressed rats showed decreased sucrose intake, and REB treatment normalized this decrease. CMS reduced hippocampal brain-derived neurotrophic factor (BDNF) levels, and REB treatment reversed this alteration and increased BDNF receptor (TrkB) levels. REB elevated hippocampal extracellular signal-regulated kinase (ERK) phosphorylation of both stressed and unstressed rats. In conclusion, our study shows that BDNF, its receptor TrkB, and ERK participate in the neurobiological response to chronic stress and in the molecular and cellular activities of REB in the hippocampus.


Assuntos
Inibidores da Captação Adrenérgica/uso terapêutico , Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtorno Depressivo/tratamento farmacológico , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Morfolinas/uso terapêutico , Estresse Psicológico/complicações , Inibidores da Captação Adrenérgica/farmacologia , Animais , Antidepressivos/farmacologia , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Transtorno Depressivo/etiologia , Transtorno Depressivo/metabolismo , Sacarose Alimentar , MAP Quinases Reguladas por Sinal Extracelular/genética , Preferências Alimentares/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Masculino , Morfolinas/farmacologia , Fosforilação , Ratos , Ratos Sprague-Dawley , Reboxetina , Receptor trkB/genética , Receptor trkB/metabolismo , Aumento de Peso/efeitos dos fármacos
18.
Eur Neuropsychopharmacol ; 23(9): 1115-23, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23116946

RESUMO

Mesenchymal stem cells (MSCs) are an attractive cell source for regenerative medicine strategies in brain diseases. Experimental studies have shown that repeated administration of phencyclidine (PCP) leads to schizophrenia-like behavioral changes in mice. The aim of the present study was to explore the effectiveness of MSC transplantation into the hippocampus in attenuating PCP-induced social behavior deficits. PCP was administered subcutaneously to C57bl mice (10mg/kg daily) for 2 weeks. On the first day of PCP administration, adult human MSCs were transplanted into the hippocampus. A week after the last PCP dose, the mice underwent social preference testing. MSC transplantation was associated with a significant reduction in the adverse social behavior induced by PCP. Immunohistochemical analysis revealed that the stem cells survived in the mouse brain, and hippocampal Western blot analysis revealed a statistical trend towards a decrease in cleaved caspase 3 protein levels in the stem cell treated group. Upon in vitro co-culture of astrocytes and MSCs, the MSCs, in the presence of PCP, positively regulated astrocyte expression of genes involved in glutamate metabolism and antioxidant defenses. These findings suggest that MSC transplantation into the hippocampus may serve as a novel neuroprotective tool for the treatment of the PCP-induced schizophrenia-like social endophenotype. The mechanism underlying the beneficial behavioral effect may involve modulation of host astrocyte functioning, including glutamate processing and antioxidant capacity.


Assuntos
Astrócitos/metabolismo , Regulação da Expressão Gênica , Transplante de Células-Tronco Mesenquimais/métodos , Fenciclidina/toxicidade , Esquizofrenia/induzido quimicamente , Esquizofrenia/cirurgia , Animais , Animais Recém-Nascidos , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Células Cultivadas , Técnicas de Cocultura , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/cirurgia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Esquizofrenia/patologia
19.
Neuroimmunomodulation ; 19(5): 309-18, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22797111

RESUMO

OBJECTIVE: Previous studies suggest that selective serotonin reuptake inhibitors (SSRIs) modulate immune system functionality. SSRIs are the preferred treatment for major depressive disorder (MDD). A high rate of MDD is observed in rheumatoid arthritis (RA) patients. The aim of this study was to evaluate immunological effects of SSRIs in a rat model of RA. METHODS: Adjuvant arthritis was induced in 8-week-old Lewis rats; in the first set of experiments following the induction, 15.3 or 30.6 mg/kg of sertraline was daily injected into the ankle joint of the left rear leg. Clinical disease activity was evaluated and the findings compared with the 3 untreated legs and with control groups given methotrexate (MTX) or vehicle only at the same site. In a second set of experiments, the effect of 5, 25 and 50 mg/kg daily oral sertraline was evaluated in the same rat model. Splenocyte viability and inflammatory mediators were evaluated. RESULTS: The sertraline-treated rats showed a significant reduction in clinical arthritis compared to controls, at all doses given, accompanied by a significant increase in interleukin 10 and a decrease in tumor necrosis factor-α levels and cycloxygenase-2 production, without lymphotoxicity. There was no significant difference from MTX, the first-line treatment for RA patients. Oral sertraline had a significant anti-inflammatory effect at all doses. There was no treatment × time effect. CONCLUSION: The beneficial effects of sertraline in this rat model of arthritis have clinical implications for its use in humans. Large-scale clinical efficacy trials are needed.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Fatores Imunológicos/uso terapêutico , Sertralina/uso terapêutico , Análise de Variância , Animais , Artrite Reumatoide/induzido quimicamente , Concanavalina A/imunologia , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Testes Imunológicos de Citotoxicidade , Avaliação da Deficiência , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Adjuvante de Freund/toxicidade , Metotrexato/uso terapêutico , Ratos , Ratos Endogâmicos Lew , Baço/efeitos dos fármacos , Baço/imunologia , Timidina/metabolismo
20.
J Mol Neurosci ; 45(2): 246-55, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21479508

RESUMO

Depression is associated with hippocampus (HC) volume loss. Chronic mild stress (CMS) in rats is a model of depression. Antidepressants attenuate HC volume loss and reverse the depression-like symptoms of stressed animals. We evaluated the effect of CMS and the selective serotonin reuptake inhibitor, fluoxetine (FLX) treatment on behavioral and cognitive parameters in rats, and on HC and frontal cortex (FC) neurotrophic factors levels. Male rats were exposed sequentially, over a period of 5 weeks, to a variety of mild stressors. FLX (5 mg/kg/day ip) was administered to the stressed group and controls (unstressed). After 5 of CMS, animals were tested using the Morris Water Maze (MWM). In the MWM, we observed that FLX had a transitory effect on unstressed rats. CMS reduced insulin-like growth factor-1 receptor (IGF-1R) levels in the HC whereas after FLX treatment these levels reverted to normal range. CMS rats revealed a significant decrease in extracellular signal-regulated kinase (ERK) phosphorylation in both HC and FC regions, while FLX normalized these levels. This study suggests that IGF-1R and ERK may have a role in mediating the neural stress response and the mode of action of FLX. This role seems to be independent of the BDNF alterations.


Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Depressão/tratamento farmacológico , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fluoxetina , Fatores de Crescimento Neural/metabolismo , Inibidores Seletivos de Recaptação de Serotonina , Estresse Psicológico/fisiopatologia , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/anatomia & histologia , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Aprendizagem/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico
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