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1.
J Gerontol A Biol Sci Med Sci ; 73(3): 299-307, 2018 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-28575152

RESUMO

Alzheimer's disease (AD) is rarely addressed in the context of aging even though there is an overlap in pathology. We previously used a phenotypic screening platform based on old age-associated brain toxicities to identify the flavonol fisetin as a potential therapeutic for AD and other age-related neurodegenerative diseases. Based on earlier results with fisetin in transgenic AD mice, we hypothesized that fisetin would be effective against brain aging and cognitive dysfunction in rapidly aging senescence-accelerated prone 8 (SAMP8) mice, a model for sporadic AD and dementia. An integrative approach was used to correlate protein expression and metabolite levels in the brain with cognition. It was found that fisetin reduced cognitive deficits in old SAMP8 mice while restoring multiple markers associated with impaired synaptic function, stress, and inflammation. These results provide further evidence for the potential benefits of fisetin for the treatment of age-related neurodegenerative diseases.


Assuntos
Envelhecimento/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Flavonoides/farmacologia , Envelhecimento/metabolismo , Animais , Western Blotting , Modelos Animais de Doenças , Eicosanoides/metabolismo , Flavonóis , Imuno-Histoquímica , Aprendizagem em Labirinto/efeitos dos fármacos , Metabolômica/métodos , Camundongos , Camundongos Transgênicos , Percepção Visual/efeitos dos fármacos
2.
Sci Rep ; 6: 31692, 2016 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-27558862

RESUMO

Several lines of evidence suggest that neuregulin 1 (NRG1) signaling may influence cognitive function and neuropathology in Alzheimer's disease (AD). To test this possibility, full-length type I or type III NRG1 was overexpressed via lentiviral vectors in the hippocampus of line 41 AD mouse. Both type I and type III NRG1 improves deficits in the Morris water-maze behavioral task. Neuropathology was also significantly ameliorated. Decreased expression of the neuronal marker MAP2 and synaptic markers PSD95 and synaptophysin in AD mice was significantly reversed. Levels of Aß peptides and plaques were markedly reduced. Furthermore, we showed that soluble ectodomains of both type I and type III NRG1 significantly increased expression of Aß-degrading enzyme neprilysin (NEP) in primary neuronal cultures. Consistent with this finding, immunoreactivity of NEP was increased in the hippocampus of AD mice. These results suggest that NRG1 provides beneficial effects in candidate neuropathologic substrates of AD and, therefore, is a potential target for the treatment of AD.


Assuntos
Doença de Alzheimer/terapia , Neuregulina-1/fisiologia , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Animais , Células Cultivadas , Cognição , Feminino , Hipocampo/patologia , Humanos , Aprendizagem em Labirinto , Camundongos Transgênicos , Neprilisina/metabolismo , Ratos
3.
Alzheimers Dement ; 12(6): 678-86, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27149904

RESUMO

INTRODUCTION: Neurons die in Alzheimer's disease (AD) and are not effectively replaced. An alternative approach to maintain nerve cell number is to identify compounds that stimulate the proliferation of endogenous neural stem cells in old individuals to replace lost neurons. However, unless a neurogenic drug is also neuroprotective, the replacement of lost neurons will not be sufficient to stop disease progression. METHODS: The neuroprotective AD drug candidate J147 is shown to enhance memory, improve dendritic structure, and stimulate cell division in germinal regions of the brains of very old mice. Based on the potential neurogenic potential of J147, a neuronal stem cell screening assay was developed to optimize derivatives of J147 for human neurogenesis. RESULTS: The best derivative of J147, CAD-031, maintains the neuroprotective and memory enhancing properties of J147, yet is more active in the human neural stem cell assays. DISCUSSION: The combined properties of neuroprotection, neurogenesis, and memory enhancement in a single drug are more likely to be effective for the treatment of age-associated neurodegenerative disorders than any individual activity alone.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Curcumina/farmacologia , Curcumina/uso terapêutico , Descoberta de Drogas , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Células Cultivadas , Curcumina/química , Modelos Animais de Doenças , Células-Tronco Embrionárias/efeitos dos fármacos , Feminino , Fator 2 de Crescimento de Fibroblastos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Fármacos Neuroprotetores/química , Presenilina-1/genética
4.
Aging (Albany NY) ; 7(11): 937-55, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26564964

RESUMO

Because age is the greatest risk factor for sporadic Alzheimer's disease (AD), phenotypic screens based upon old age-associated brain toxicities were used to develop the potent neurotrophic drug J147. Since certain aspects of aging may be primary cause of AD, we hypothesized that J147 would be effective against AD-associated pathology in rapidly aging SAMP8 mice and could be used to identify some of the molecular contributions of aging to AD. An inclusive and integrative multiomics approach was used to investigate protein and gene expression, metabolite levels, and cognition in old and young SAMP8 mice. J147 reduced cognitive deficits in old SAMP8 mice, while restoring multiple molecular markers associated with human AD, vascular pathology, impaired synaptic function, and inflammation to those approaching the young phenotype. The extensive assays used in this study identified a subset of molecular changes associated with aging that may be necessary for the development of AD.


Assuntos
Envelhecimento , Doença de Alzheimer/etiologia , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/análise , Animais , Comportamento Animal/efeitos dos fármacos , Barreira Hematoencefálica , Eicosanoides/metabolismo , Glutationa/metabolismo , Hipocampo/metabolismo , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , Aprendizagem em Labirinto/efeitos dos fármacos , Metabolômica , Camundongos , Transcriptoma
5.
Toxicol Appl Pharmacol ; 268(3): 318-30, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23403069

RESUMO

Adenoviral vectors (Ads) are promising gene delivery vehicles due to their high transduction efficiency; however, their clinical usefulness has been hampered by their immunogenicity and the presence of anti-Ad immunity in humans. We reported the efficacy of a gene therapy approach for glioma consisting of intratumoral injection of Ads encoding conditionally cytotoxic herpes simplex type 1 thymidine kinase (Ad-TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Ad-Flt3L). Herein, we report the biodistribution, efficacy, and neurological and systemic effects of a bicistronic high-capacity Ad, i.e., HC-Ad-TK/TetOn-Flt3L. HC-Ads elicit sustained transgene expression, even in the presence of anti-Ad immunity, and can encode large therapeutic cassettes, including regulatory elements to enable turning gene expression "on" or "off" according to clinical need. The inclusion of two therapeutic transgenes within a single vector enables a reduction of the total vector load without adversely impacting efficacy. Because clinically the vectors will be delivered into the surgical cavity, normal regions of the brain parenchyma are likely to be transduced. Thus, we assessed any potential toxicities elicited by escalating doses of HC-Ad-TK/TetOn-Flt3L (1×10(8), 1×10(9), or 1×10(10) viral particles [vp]) delivered into the rat brain parenchyma. We assessed neuropathology, biodistribution, transgene expression, systemic toxicity, and behavioral impact at acute and chronic time points. The results indicate that doses up to 1×10(9) vp of HC-Ad-TK/TetOn-Flt3L can be safely delivered into the normal rat brain and underpin further developments for its implementation in a phase I clinical trial for glioma.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Ensaios Clínicos Fase I como Assunto/métodos , Citotoxinas/administração & dosagem , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Glioblastoma/tratamento farmacológico , Imunização/métodos , Adenoviridae/metabolismo , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Citotoxinas/efeitos adversos , Citotoxinas/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Quimioterapia Combinada , Terapia Genética/efeitos adversos , Vetores Genéticos/efeitos adversos , Vetores Genéticos/metabolismo , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Masculino , Ratos , Ratos Endogâmicos Lew , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologia , Resultado do Tratamento
6.
Hum Gene Ther Methods ; 23(4): 271-84, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22950971

RESUMO

Adenoviral vectors (Ads) have been evaluated in clinical trials for glioma. However, systemic immunity against the vectors can hamper therapeutic efficacy. We demonstrated that combined immunostimulation and cytotoxic gene therapy provides long-term survival in preclinical glioma models. Because helper-dependent high-capacity Ads (HC-Ads) elicit sustained transgene expression, in the presence of antiadenoviral immunity, we engineered HC-Ads encoding conditional cytotoxic herpes simplex type 1 thymidine kinase and immunostimulatory cytokine Fms-like tyrosine kinase ligand-3 under the control of the TetOn system. Escalating doses of combined HC-Ads (1×10(8), 1×10(9), and 1×10(10) viral particles [VP]) were delivered into the rat brain. We assessed neuropathology, biodistribution, transgene expression, systemic toxicity, and behavioral impact at acute and chronic time points after vector delivery. Histopathological analysis did not reveal any evidence of toxicity or long-term inflammation at the lower doses tested. Vector genomes were restricted to the injection site. Serum chemistry did not uncover adverse systemic side effects at any of the doses tested. Taken together, our data indicate that doses of up to 1×10(9) VP of each HC-Ad can be safely administered into the normal brain. This comprehensive toxicity and biodistribution study will lay the foundations for implementation of a phase 1 clinical trial for GBM using HC-Ads.


Assuntos
Adenoviridae/genética , Encéfalo/metabolismo , Vetores Genéticos/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Análise Química do Sangue , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Ensaios Clínicos Fase I como Assunto , Modelos Animais de Doenças , Vetores Genéticos/genética , Vetores Genéticos/toxicidade , Glioma/terapia , Herpesvirus Humano 1/enzimologia , Humanos , Masculino , Ratos , Ratos Endogâmicos Lew , Timidina Quinase/genética , Distribuição Tecidual , Transdução Genética , Tirosina Quinase 3 Semelhante a fms/genética
7.
PLoS One ; 6(11): e27290, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22076148

RESUMO

The relationships among hippocampal neurogenesis, depression and the mechanism of action of antidepressant drugs have generated a considerable amount of controversy. The cyclin-dependent kinase (Cdk) inhibitor p21(Cip1) (p21) plays a crucial role in restraining cellular proliferation and maintaining cellular quiescence. Using in vivo and in vitro approaches the present study shows that p21 is expressed in the subgranular zone of the dentate gyrus of the hippocampus in early neuronal progenitors and in immature neurons, but not in mature neurons or astroglia. In vitro, proliferation is higher in neuronal progenitor cells derived from p21-/- mice compared to cells derived from wild-type mice. Proliferation is increased in neuronal progenitor cells after suppression of p21 using lentivirus expressing short hairpin RNA against p21. In vivo, chronic treatment with the non-selective antidepressant imipramine as well as the norepinephrine-selective reuptake inhibitor desipramine or the serotonin-selective reuptake inhibitor fluoxetine all decrease p21 expression, and this was associated with increased neurogenesis. Chronic antidepressant treatment did not affect the expression of other Cdk inhibitors. Untreated p21-/- mice exhibit a higher degree of baseline neurogenesis and decreased immobility in the forced swim test. Although chronic imipramine treatment increased neurogenesis and reduced immobility in the forced swim test in wild-type mice, it reduced neurogenesis and increased immobility in p21-/- mice. These results demonstrate the unique role of p21 in the control of neurogenesis, and support the hypothesis that different classes of reuptake inhibitor-type antidepressant drugs all stimulate hippocampal neurogenesis by inhibiting p21 expression.


Assuntos
Antidepressivos/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/fisiologia , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Animais , Western Blotting , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/antagonistas & inibidores , Depressão/tratamento farmacológico , Feminino , Fluoxetina/farmacologia , Hipocampo/metabolismo , Imipramina/farmacologia , Técnicas Imunoenzimáticas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , RNA Interferente Pequeno/genética , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Natação
8.
Behav Pharmacol ; 22(3): 222-7, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21522053

RESUMO

Acamprosate is used in the treatment of alcoholism; however, there is little information on its effects on nicotine addiction. The objective of this study was to determine whether acamprosate inhibits cue-induced relapse to nicotine self-administration in the rat. Rats were trained to press a lever to obtain intravenous infusions of nicotine (0.03 mg/kg/infusion) that were associated with the illumination of a cue light. After 29 days of nicotine self-administration sessions, extinction sessions were run during which responses on the active lever did not result in the infusion of nicotine or the illumination of the cue light. After 14 days of extinction sessions the rats received twice-daily injections of saline or acamprosate (50, 100, or 200 mg/kg/intraperitoneally). Seven days later the response to the previously conditioned cue was tested, but only saline infusions were delivered. Pretreatment with all doses of acamprosate reduced responding to a cue previously associated with nicotine. The lowest dose of acamprosate (50 mg/kg) reduced responding for the cue previously associated with nicotine infusions, but had no effect on food-rewarded behavior. These results show that acamprosate reduced cue-induced nicotine-seeking behavior and suggest that acamprosate might be efficacious in treating nicotine addiction in humans.


Assuntos
Sinais (Psicologia) , Comportamento de Procura de Droga/efeitos dos fármacos , Nicotina/administração & dosagem , Taurina/análogos & derivados , Acamprosato , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/fisiologia , Autoadministração , Taurina/farmacologia
9.
Proc Natl Acad Sci U S A ; 107(32): 14443-8, 2010 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-20660723

RESUMO

Soluble antigens diffuse out of the brain and can thus stimulate a systemic immune response, whereas particulate antigens (from infectious agents or tumor cells) remain within brain tissue, thus failing to stimulate a systemic immune response. Immune privilege describes how the immune system responds to particulate antigens localized selectively within the brain parenchyma. We believe this immune privilege is caused by the absence of antigen presenting dendritic cells from the brain. We tested the prediction that expression of fms-like tyrosine kinase ligand 3 (Flt3L) in the brain will recruit dendritic cells and induce a systemic immune response against exogenous influenza hemagglutinin in BALB/c mice. Coexpression of Flt3L with HA in the brain parenchyma induced a robust systemic anti-HA immune response, and a small response against myelin basic protein and proteolipid protein epitopes. Depletion of CD4(+)CD25+ regulatory T cells (Tregs) enhanced both responses. To investigate the autoimmune impact of these immune responses, we characterized the neuropathological and behavioral consequences of intraparenchymal injections of Flt3L and HA in BALB/c and C57BL/6 mice. T cell infiltration in the forebrain was time and strain dependent, and increased in animals treated with Flt3L and depleted of Tregs; however, we failed to detect widespread defects in myelination throughout the forebrain or spinal cord. Results of behavioral tests were all normal. These results demonstrate that Flt3L overcomes the brain's immune privilege, and supports the clinical development of Flt3L as an adjuvant to stimulate clinically effective immune responses against brain neo-antigens, for example, those associated with brain tumors.


Assuntos
Encéfalo/imunologia , Sistema Imunitário/imunologia , Tirosina Quinase 3 Semelhante a fms/imunologia , Adjuvantes Imunológicos , Animais , Antígenos/imunologia , Células Dendríticas/imunologia , Hemaglutininas/imunologia , Imunidade , Ligantes , Camundongos , Camundongos Endogâmicos BALB C , Prosencéfalo/imunologia , Medula Espinal/imunologia , Linfócitos T Reguladores/imunologia
10.
J Virol ; 84(12): 6007-17, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20375153

RESUMO

Glioblastoma multiforme (GBM) is a deadly primary brain tumor. Conditional cytotoxic/immune-stimulatory gene therapy (Ad-TK and Ad-Flt3L) elicits tumor regression and immunological memory in rodent GBM models. Since the majority of patients enrolled in clinical trials would exhibit adenovirus immunity, which could curtail transgene expression and therapeutic efficacy, we used high-capacity adenovirus vectors (HC-Ads) as a gene delivery platform. Herein, we describe for the first time a novel bicistronic HC-Ad driving constitutive expression of herpes simplex virus type 1 thymidine kinase (HSV1-TK) and inducible Tet-mediated expression of Flt3L within a single-vector platform. We achieved anti-GBM therapeutic efficacy with no overt toxicities using this bicistronic HC-Ad even in the presence of systemic Ad immunity. The bicistronic HC-Ad-TK/TetOn-Flt3L was delivered into intracranial gliomas in rats. Survival, vector biodistribution, neuropathology, systemic toxicity, and neurobehavioral deficits were assessed for up to 1 year posttreatment. Therapeutic efficacy was also assessed in animals preimmunized against Ads. We demonstrate therapeutic efficacy, with vector genomes being restricted to the brain injection site and an absence of overt toxicities. Importantly, antiadenoviral immunity did not inhibit therapeutic efficacy. These data represent the first report of a bicistronic vector platform driving the expression of two therapeutic transgenes, i.e., constitutive HSV1-TK and inducible Flt3L genes. Further, our data demonstrate no promoter interference and optimum gene delivery and expression from within this single-vector platform. Analysis of the efficacy, safety, and toxicity of this bicistronic HC-Ad vector in an animal model of GBM strongly supports further preclinical testing and downstream process development of HC-Ad-TK/TetOn-Flt3L for a future phase I clinical trial for GBM.


Assuntos
Adenoviridae/genética , Técnicas de Transferência de Genes , Glioma/genética , Glioma/terapia , Herpesvirus Humano 1/enzimologia , Timidina Quinase/uso terapêutico , Proteínas Virais/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/uso terapêutico , Adenoviridae/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Regulação da Expressão Gênica , Terapia Genética , Vetores Genéticos/genética , Vetores Genéticos/metabolismo , Glioma/metabolismo , Herpesvirus Humano 1/genética , Humanos , Ratos , Ratos Endogâmicos Lew , Timidina Quinase/genética , Timidina Quinase/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo
11.
Psychoneuroendocrinology ; 35(6): 887-95, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20036073

RESUMO

CRF receptor subtype 1 (CRF1), abundantly expressed in the central nervous system, has been implicated in defensive behavior in rodents. Pharmacological activation of CRF1 by peptidic agonists results in enhancement of anxiety-like behavior. However, receptor specificity of commonly used agonists was confounded by significant affinity to other receptors and widely used laboratory tests of experimental anxiety suffer from artificial aversive stimulation (e.g. electric shock), and limited measures of anxiety-like behavior. We used the recently developed, CRF1-selective agonist cortagine in a mouse model of defensive behaviors under semi-natural conditions, the rat exposure test (RET). Cortagine was injected bilaterally into the cerebral ventricles (i.c.v.) of male C57Bl/6J mice, 20min before exposure to a rat in specifically designed box that evokes a wide variety of defensive behaviors such as active/passive avoidance, freezing, risk assessment, and burying. Pre-injection of the CRF receptor antagonist acidic astressin was used to test for receptor specificity of the observed cortagine effects. A control experiment with no rat present was performed to test for baseline effects of cortagine in the exposure setup. Cortagine dose-dependently enhanced passive avoidance and freezing while burying was decreased. CRF receptor antagonism reliably blocked the effects of cortagine. Our results confirm previous findings of anxiogenic-like effects of cortagine, and demonstrate the usefulness of the RET in investigating differential pattering of drug-induced anxiety-like behavior in mice. In conclusion, our results suggest that CRF1 activation in forebrain areas promotes passive coping with the natural threat presented in the RET.


Assuntos
Adaptação Psicológica/efeitos dos fármacos , Comportamento Agonístico/efeitos dos fármacos , Hormônio Liberador da Corticotropina/farmacologia , Receptores de Hormônio Liberador da Corticotropina/agonistas , Proteínas Recombinantes de Fusão/farmacologia , Animais , Hormônio Liberador da Corticotropina/administração & dosagem , Relação Dose-Resposta a Droga , Interações Medicamentosas , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Long-Evans , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Proteínas Recombinantes de Fusão/administração & dosagem
12.
Curr Gene Ther ; 9(5): 409-21, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19860655

RESUMO

Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults. Despite significant advances in treatment and intensive research, the prognosis for patients with GBM remains poor. Therapeutic challenges for GBM include its invasive nature, the proximity of the tumor to vital brain structures often preventing total resection, and the resistance of recurrent GBM to conventional radiotherapy and chemotherapy. Gene therapy has been proposed as a useful adjuvant for GBM, to be used in conjunction with current treatment. Work from our laboratory has shown that combination of conditional cytotoxic with immunotherapeutic approaches for the treatment of GBM elicits regression of large intracranial tumor masses and anti-tumor immunological memory in syngeneic rodent models of GBM. In this review we examined the currently available animal models for GBM, including rodent transplantable models, endogenous rodent tumor models and spontaneous GBM in dogs. We discuss non-invasive surrogate end points to assess tumor progression and therapeutic efficacy, such as behavioral tests and circulating biomarkers. Growing preclinical and clinical data contradict the old dogma that cytotoxic anti-cancer therapy would lead to an immune-suppression that would impair the ability of the immune system to mount an anti-tumor response. The implications of the findings reviewed indicate that combination of cytotoxic therapy with immunotherapy will lead to synergistic antitumor efficacy with reduced neurotoxicity and supports the clinical implementation of combined cytotoxic-immunotherapeutic strategies for the treatment of patients with GBM.


Assuntos
Neoplasias Encefálicas/terapia , Terapia Genética , Glioblastoma/terapia , Animais , Comportamento Animal , Terapia Combinada , Modelos Animais de Doenças , Cães , Humanos , Ratos
13.
CNS Drug Rev ; 13(4): 423-43, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18078427

RESUMO

Corticotropin-releasing factor (CRF) is a neuropeptide and mediating component of neuroendocrine, autonomic, and behavioral processes associated with the stress response. The two receptor subtypes identified in the mammalian brain, CRF receptor subtype 1 (CRF1) and CRF2, are suggested to differentially modulate these processes. Manipulation of these receptors with selective CRF compounds and transgenic models has revealed, in most studies, a clear potentiation of the stress response through central activation of CRF1. However, pharmacological activation of CRF restricted to CRF1 has been limited by the availability of selective peptidic compounds. Recently, a highly selective CRF1 agonist, cortagine, has been developed. It was synthesized from chimeric intermediate sequences of ovine CRF, sauvagine, and human/rat CRF into a highly soluble peptide with strong affinity for CRF1 (IC(50) < 5 nM) and a very low binding preference for CRF2 (IC(50) > 500 nM). Affinity for the CRF binding protein (IC(50) > 1,000 nM) can be abolished by the addition of a glutamate residue on position 21 of the cortagine peptide sequence. Cortagine has recently been tested in a variety of preclinical models of behavior including the elevated-plus-maze (EPM), forced swim test (FST), homecage, and rat exposure test (RET). Preliminary characterization in the EPM and FST suggested that this compound elicits anxiogenic and antidepressant-like effects, respectively. Additional testing in the homecage and RET, which targets various elements of behavior, directs to a more potent anxiogenic profile of cortagine. In this review, we discuss the behavioral findings and the tests used to measure these effects. Finally, we also discuss preliminary findings of autonomic activation obtained by central injection of cortagine that support CRF1 involvement in the modulation of heart rate and heart rate variability.


Assuntos
Sistema Nervoso Autônomo/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Hormônio Liberador da Corticotropina/farmacologia , Receptores de Hormônio Liberador da Corticotropina/agonistas , Proteínas Recombinantes de Fusão/farmacologia , Animais , Humanos
14.
Behav Brain Res ; 171(1): 1-8, 2006 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-16621042

RESUMO

Following intracerebroventricular (i.c.v.) injection of ovine CRF (oCRF), an endogenous peptide agonist at both CRF1 and CRF2 receptors, defensive behaviors of CD-1 mice were evaluated in the Mouse Defensive Test Battery (MDTB). Behavioral measures taken before, during, and after predator (a hand-held anesthetized rat) confrontation included exploratory activity, risk assessment, avoidance, flight, freezing, defensive threat/attack, and residual emotional responses. Both low (0.1 nmol) and high (0.2 nmol) doses of oCRF robustly suppressed exploratory activities and increased risk assessment during the initial familiarization period. Flight speed and jump escapes when the mouse was chased were significantly elevated by the 0.2 nmol dose. Both doses enhanced freezing and avoidance to a distant predator when the escape route was blocked. The 0.2 nmol dose also potentiated flight responses to a contacting predator in a highly confined space. Both oCRF groups traveled shorter distances and exhibited less escape attempts following the removal of the threat stimulus. These findings indicate that non-selective activation of corticotropin-releasing factor (CRF) receptors via ventricular infusion of oCRF potentiates defensive behaviors relevant to the demand of specific challenges, generally enhancing the predominant defensive behavior in each specific situation.


Assuntos
Aprendizagem da Esquiva/fisiologia , Comportamento Animal/fisiologia , Hormônio Liberador da Corticotropina/fisiologia , Reação de Fuga/fisiologia , Comportamento Exploratório/fisiologia , Análise de Variância , Animais , Hormônio Liberador da Corticotropina/administração & dosagem , Relação Dose-Resposta a Droga , Injeções Intraventriculares , Masculino , Camundongos , Ratos , Receptores de Hormônio Liberador da Corticotropina/agonistas , Ovinos
15.
Pharmacol Biochem Behav ; 80(1): 189-94, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15652395

RESUMO

Arginine vasopressin (AVP) has been implicated in a variety of physiological and behavioral responses to stress. Synthesis of receptor-selective AVP agonist and antagonist compounds allows differential analysis of the specific roles of particular receptor subtypes with respect to these responses. Here, effects of the recently synthesized AVP V1b selective antagonist, SSR149415, were examined for offensive aggression in male Syrian hamsters, using a resident-intruder paradigm. Oral administration of vehicle or 1, 10, or 30 mg/kg of SSR149415 to resident hamsters was followed by evaluation of a range of aggression-related measures of residents confronted by intruders. The 10 and 30 mg/kg doses significantly reduced the duration of offensive sideways and chase behaviors, and the 30 mg/kg dose also reduced chase frequency. The 10 and 30 mg/kg dose also significantly reduced frequency and duration of olfactory investigation and duration of flank marking. These findings suggest a link between activity of the V1b receptor and the modulation of offensive aggression. These findings agree with previous research on V1b receptor effects in suggesting that antagonism of this receptor may be useful in modulating a range of emotional responses to highly stressful or threatening conditions.


Assuntos
Agressão/efeitos dos fármacos , Antagonistas dos Receptores de Hormônios Antidiuréticos , Indóis/farmacologia , Pirrolidinas/farmacologia , Agressão/fisiologia , Agressão/psicologia , Animais , Arginina Vasopressina/antagonistas & inibidores , Arginina Vasopressina/fisiologia , Cricetinae , Relação Dose-Resposta a Droga , Masculino , Receptores de Vasopressinas/fisiologia
16.
Pharmacol Biochem Behav ; 77(3): 465-9, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15006456

RESUMO

Corticotropin-releasing factor (CRF) and its receptor subtypes have been implicated in endocrine and behavioral responsivity to stress and emotion, including fear, anxiety, and aggression. SSR125543A is a new nonpeptide selective antagonist at the CRF1 receptor that has been shown to produce an anxiolytic-like effect in a number of animal models of anxiety. The present study investigated effects of an oral dose of 10, or 30 mg/kg of SSR125543A on aggressive behaviors of resident male Syrian hamsters toward male intruders. The high dose (30 mg/kg) of the CRF1 receptor antagonist produced a higher latency to bite and lower lateral attack frequencies and chase durations, indicating a reduction in aggression toward intruders in resident hamsters. The same dose of SSR125543A also enhanced frequency and duration of olfactory investigation, indicating that neither avoidance of the opponent nor deficiency in social activity is responsible for the reduction in aggression seen in these animals.


Assuntos
Agressão/efeitos dos fármacos , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Receptores de Hormônio Liberador da Corticotropina/fisiologia , Tiazóis/farmacologia , Agressão/fisiologia , Animais , Cricetinae , Relação Dose-Resposta a Droga , Masculino , Mesocricetus
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