RESUMO
Galanin, a neuropeptide widely expressed in the central and peripheral nervous systems and in the endocrine system, has been shown to regulate numerous physiological and pathological processes through interactions with three G-protein-coupled receptors, GalR1 through GalR3. Over the past decade, some of the receptor subtype-specific effects have been elucidated through pharmacological studies using subtype selective ligands, as well as through molecular approaches involving knockout animals. In this chapter, we summarize the current data which constitute the basis of targeting GalR1, GalR2, and GalR3 for the treatment of various human diseases and pathological conditions, including seizure, Alzheimer's disease, mood disorders, anxiety, alcohol intake in addiction, metabolic diseases, pain and solid tumors.
Assuntos
Galanina/fisiologia , Receptores de Galanina/agonistas , Receptores de Galanina/fisiologia , Afeto , Consumo de Bebidas Alcoólicas , Doença de Alzheimer/fisiopatologia , Animais , Cognição/fisiologia , Comportamento Alimentar , Galanina/metabolismo , Humanos , Ligantes , Neoplasias/fisiopatologia , Dor/fisiopatologia , Receptores de Galanina/metabolismo , Convulsões/fisiopatologiaRESUMO
The neuropeptide galanin has been shown to play a role in psychiatric disorders as well as in other biological processes including regulation of pain threshold through interactions with three G-protein coupled receptors, galanin receptor subtypes 1-3 (GalR1-3). While most of the pharmacological studies on galanin in stress-related disorders have been done with rats, the continuous development of genetically engineered mice involving galanin or its receptor subtype(s) validates the importance of mouse pharmacological studies. The present study on mice examined the homeostatic, endocrinological and neuroanatomical effects of the galanin, injected intracerebroventricularly (i.c.v.), in regulation of stress responses after restraint stress. Furthermore, the roles of GalR1 on these effects were studied using GalR1 knockout (KO) mice. The core body temperature and the locomotor activity were monitored with radio telemetry devices. Galanin (i.c.v.) decreased locomotor activity and exerted a bidirectional effect on the restraint stress-induced hyperthermia; a high dose of galanin significantly attenuated the stress-induced hyperthermic response, while a low dose of galanin moderately enhanced this response. The bidirectional effect of galanin was correlated with changes in stress hormone levels (adrenocorticotropic hormone and corticosterone). To neuroanatomically localize the effects of galanin on stress response, cFos immunoreactivity was assessed in galanin receptor rich areas; paraventricular nucleus (PVN) of the hypothalamus and the locus coeruleus (LC), respectively. A high dose of galanin significantly induced cFos activity in the LC but not in the PVN. In GalR1KO mice, a high dose of galanin failed to induce any of the above effects, suggesting the pivotal role of GalR1 in decreased locomotor activity and stress-resistant effects caused by galanin i.c.v. injection studied here.
Assuntos
Encéfalo/metabolismo , Galanina/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Receptor Tipo 1 de Galanina/genética , Estresse Psicológico/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Corticosterona/metabolismo , Relação Dose-Resposta a Droga , Febre/tratamento farmacológico , Febre/metabolismo , Febre/fisiopatologia , Galanina/farmacologia , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Injeções Intraventriculares , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/metabolismo , Camundongos , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Sistemas Neurossecretores/efeitos dos fármacos , Sistemas Neurossecretores/metabolismo , Sistemas Neurossecretores/fisiopatologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptor Tipo 1 de Galanina/efeitos dos fármacos , Restrição Física , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/fisiopatologiaRESUMO
Galanin, a neuropeptide widely expressed in the central and peripheral nervous systems and in the endocrine system, has been shown to regulate numerous physiological and pathological processes through interactions with three G-protein-coupled receptors, GalR1 through GalR3. Over the past decade, some of the receptor subtype-specific effects have been elucidated through pharmacological studies using subtype selective ligands, as well as through molecular approaches involving knockout animals. In the present review, we summarize the current data which constitute the basis of targeting GalR1, GalR2 and GalR3 for the treatment of various human diseases and pathological conditions, including seizure, Alzheimer's disease, mood disorders, anxiety, alcohol intake in addiction, metabolic diseases, pain and solid tumors.
Assuntos
Galanina/metabolismo , Receptores de Galanina/agonistas , Receptores de Galanina/antagonistas & inibidores , Alcoolismo/tratamento farmacológico , Doença de Alzheimer/tratamento farmacológico , Animais , Depressão/tratamento farmacológico , Comportamento Alimentar , Humanos , Neoplasias/metabolismo , Dor/tratamento farmacológico , Receptores de Galanina/fisiologia , Convulsões/etiologiaRESUMO
Formation and extinction of aversive memories in the mammalian brain are insufficiently understood at the cellular and molecular levels. Using the novel metabotropic glutamate receptor 7 (mGluR7) agonist AMN082, we demonstrate that mGluR7 activation facilitates the extinction of aversive memories in two different amygdala-dependent tasks. Conversely, mGluR7 knockdown using short interfering RNA attenuated the extinction of learned aversion. mGluR7 activation also blocked the acquisition of Pavlovian fear learning and its electrophysiological correlate long-term potentiation in the amygdala. The finding that mGluR7 critically regulates extinction, in addition to acquisition of aversive memories, demonstrates that this receptor may be relevant for the manifestation and treatment of anxiety disorders.
Assuntos
Tonsila do Cerebelo/fisiologia , Aprendizagem da Esquiva/fisiologia , Extinção Psicológica/fisiologia , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Receptores de Glutamato Metabotrópico/fisiologia , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Compostos Benzidrílicos/química , Compostos Benzidrílicos/farmacologia , Células CHO , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Estimulação Elétrica , Extinção Psicológica/efeitos dos fármacos , Ácido Glutâmico/farmacologia , Guanosina 5'-O-(3-Tiotrifosfato)/farmacocinética , Humanos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Técnicas de Patch-Clamp , Ligação Proteica/efeitos dos fármacos , RNA Interferente Pequeno/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , TransfecçãoRESUMO
OBJECTIVE: To investigate the effect of recombinant human lactoferrin (rhLF) on cervical ripening using a rabbit model in which preterm labor was induced by bacterial endotoxin lipopolysaccharide (LPS). STUDY DESIGN: Timed pregnant rabbits (New Zealand White, 3-4 kg, day 14) were randomly assigned to the following treatment groups: Group A, LPS + rhLF (n = 4); Group B, LPS (n = 4); and Group C, control (n = 4). Recombinant human lactoferrin (10 microg) was administrated to pregnant rabbits in Group A and not in Group B. Lipopolysaccharide (100 microg) was given to the rabbits in both groups for 3 days (days14-16). Drugs were administered as a vaginal suppository. On day 18, the rabbits were anesthetized with intramuscular ketamine hydrochloride (20 mg/kg) and diazepam (4 mg/kg). Both cervices of the rabbit uterus, which is bicorpus-bicolli, were taken out. One cervix was placed in 10% formalin solution for a histological study with standard hematoxylin-eosin staining. The other was used for an extension test to assess the grade of ripening. Extension was measured after a 5-mm length of cervical tissue was loaded with 5.8 g. RESULTS: The histological study showed remarkably loose and edematous connective tissue in Group B cervices. Cervical tissues in Group A was not different from those in Group C. Extension lengths were 2.2 +/- 0.2 mm in Group A, 7.0 +/- 2.7 mm in Group B, and 1.7 +/- 0.3 mm in Group C. CONCLUSION: These results suggest that rhLF inhibits cervical maturation induced by LPS in a rabbit model and may have a potential to prevent preterm delivery caused by cervical infection and ripening.
Assuntos
Maturidade Cervical/efeitos dos fármacos , Lactoferrina/farmacologia , Nascimento Prematuro/prevenção & controle , Proteínas Recombinantes/farmacologia , Administração Intravaginal , Animais , Colo do Útero/efeitos dos fármacos , Colo do Útero/patologia , Feminino , Humanos , Lipopolissacarídeos/farmacologia , Modelos Animais , Gravidez , Coelhos , Distribuição AleatóriaRESUMO
OBJECTIVE: To evaluate concentrations of interleukin (IL)-6, IL-8, lactoferrin (LF), and alpha defencine (alpha-DF) in the cervical mucus of pregnant women and analyze their relation to cervicitis and bacterial vaginosis (BV). METHODS: Cervical mucus samples were obtained from August 2003 through May 2004 from 157 women who were between the 6th and 36th week of an uncomplicated singleton pregnancy. All women were delivered at term, 69 without BV or cervicitis, 9 with BV, and 79 with cervicitis. RESULTS: Interleukin 8, LF, and mu-DF concentrations were higher in women with cervicitis (0.81 +/- 0.36 pg/mL, 14.8+/-12.3 microg/mL, and 0.60 +/- 0.49 microg/mL) than in women without BV or cervicitis (0.35 +/- 0.34 pg/mL, 8.0 +/- 11.0 microg/mL, and 0.15 +/- 0.12 microg/mL). Interleukin 6 concentration was higher in women with BV (0.26 +/- 0.32 pg/mL) than in women without BV or cervicitis (0.09 +/- 0.15 pg/mL) or in women with cervicitis (0.12 +/- 0.18 pg/mL). CONCLUSIONS: Higher levels of inflammatory cytokines in the cervical mucus of pregnant women may lead to early detection of lower genital tract infection.