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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Although the efficacy of racemate ketamine, a rapid onset and sustained antidepressant, for patients with treatment-resistant depression was a serendipitous finding, clinical use of ketamine is limited, due to psychotomimetic side effects and abuse liability. Behavioral and side-effect evaluation tests were applied to compare the two stereoisomers of ketamine. To elucidate their potential therapeutic mechanisms, we examined the effects of these stereoisomers on brain-derived neurotrophic factor (BDNF)-TrkB signaling, and synaptogenesis in selected brain regions. In the social defeat stress and learned helplessness models of depression, R-ketamine showed a greater potency and longer-lasting antidepressant effect than S-ketamine (esketamine). Furthermore, R-ketamine induced a more potent beneficial effect on decreased dendritic spine density, BDNF-TrkB signaling and synaptogenesis in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of the hippocampus from depressed mice compared with S-ketamine. However, neither stereoisomer affected these alterations in the nucleus accumbens of depressed mice. In behavioral tests for side effects, S-ketamine, but not R-ketamine, precipitated behavioral abnormalities, such as hyperlocomotion, prepulse inhibition deficits and rewarding effects. In addition, a single dose of S-ketamine, but not R-ketamine, caused a loss of parvalbumin (PV)-positive cells in the prelimbic region of the medial PFC and DG. These findings suggest that, unlike S-ketamine, R-ketamine can elicit a sustained antidepressant effect, mediated by increased BDNF-TrkB signaling and synaptogenesis in the PFC, DG and CA3. R-ketamine appears to be a potent, long-lasting and safe antidepressant, relative to S-ketamine, as R-ketamine appears to be free of psychotomimetic side effects and abuse liability.
Assuntos
Antidepressivos/farmacologia , Alucinógenos , Ketamina/farmacologia , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Western Blotting , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-DawleyAssuntos
Amantadina/uso terapêutico , Antiparkinsonianos/uso terapêutico , Quimioterapia Combinada , Mutismo/tratamento farmacológico , Mutismo/etiologia , Esquizofrenia Catatônica/complicações , Feminino , Haloperidol/análogos & derivados , Haloperidol/uso terapêutico , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Long-lasting insecticide-treated nets (LLITNs) are expected to be an important advance in malaria control, but operational experience is still scarce. This study presents some operational findings concerning the introduction of Olyset LLITNs (Sumitomo Chemical Co., Ltd, Japan) in Laos. The study site, Bourapar district, a remote district at high risk of malaria, received Olyset nets during 1999-2000. After distribution of the nets the number of malaria cases in the district hospital decreased for a time, however it began to rise again a year after the intervention. To sustain the effect of the nets, net users were given instructions on maintenance and use. This study aimed to investigate the condition of Olyset nets and the maintenance behaviour of net users after 2-3 years of use, and to examine the associations between maintenance behaviour and the number of malaria episodes during the previous year. METHODS: Questionnaire interviews and inspections of nets were conducted at 240 households during February-March 2003. RESULTS: About 40% of the observed nets had holes/were torn, and the maintenance instructions had not been followed sufficiently. Households following the recommended washing frequency (38.2%) reported fewer malaria episodes during the past year, which demonstrates the importance of the recommended washing frequency in the effective use of the nets. CONCLUSIONS: Our study promotes the idea that, in addition to pursuing high coverage of LLITNs, more effort should be made to ensure that nets are kept in good condition in future LLITN programmes.
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Roupas de Cama, Mesa e Banho/provisão & distribuição , Comportamentos Relacionados com a Saúde , Conhecimentos, Atitudes e Prática em Saúde , Inseticidas , Manutenção/normas , Malária/prevenção & controle , Controle de Mosquitos/instrumentação , Adulto , Roupas de Cama, Mesa e Banho/normas , Estudos Transversais , Cuidado Periódico , Características da Família , Educação em Saúde , Humanos , Higiene , Inseticidas/administração & dosagem , Manutenção/métodos , Malária/epidemiologia , Pessoa de Meia-Idade , Controle de Mosquitos/métodos , Controle de Mosquitos/normas , Fatores Socioeconômicos , Inquéritos e Questionários , Tailândia/epidemiologiaRESUMO
Learned helplessness rats are thought to be an animal model of depression. To study the role of synapse plasticity in depression, we examined the effects of learned helplessness and antidepressant treatments on synapsin I (a marker of presynaptic terminals), growth-associated protein-43 (GAP-43; a marker of growth cones), and microtubule-associated protein-2 (MAP-2; a marker of dendrites) in the hippocampus by immunolabeling. (1) Learned helplessness rats showed significant increases in the expression of synapsin I two days after the attainment of learned helplessness, and significant decreases in the protein expression eight days after the achievement of learned helplessness. Subchronic treatment of naïve rats with imipramine or fluvoxamine significantly decreased the expression of synapsin I. (2) Learned helplessness increased the expression of GAP-43 two days and eight days after learned helplessness training. Subchronic treatment of naïve rats with fluvoxamine but not imipramine showed a tendency to decrease the expression of synapsin I. (3) Learned helplessness rats showed increased expression of MAP-2 eight days after the attainment of learned helplessness. Naïve rats subchronically treated with imipramine showed a tendency toward increased expression of MAP-2, but those treated with fluvoxamine did not. These results indicate that the neuroplasticity-related proteins synapsin I, GAP-43, and MAP-2 may play a role in the pathophysiology of depression and the mechanisms of antidepressants.
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Antidepressivos/farmacologia , Proteína GAP-43/metabolismo , Desamparo Aprendido , Hipocampo/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Sinapsinas/metabolismo , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Fluvoxamina/farmacologia , Imipramina/farmacologia , Imuno-Histoquímica/métodos , Masculino , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Fatores de TempoRESUMO
It is well documented that neurosteroids administered during the neonatal period influence the development of several brain systems. In our previous study, pregnenolone administered to rats during the neonatal period altered adenosinergic and dopaminergic functions in the striatum and cerebral cortex. The present study examined the effects of the treatment with pregnenolone and dehydroepiandrosterone (DHEA) from the postnatal day (P) 3-P7 on synapsin I (a marker for presynaptic terminals) and glial fibrillary acidic protein (GFAP: a marker for astroglia) levels in the hippocampus of Sprague-Dawley rats at 3 and 7 weeks of age. In addition, neuropeptide Y and dynorphin A immunoreactivity was measured. The administration of pregnenolone and DHEA to neonatal rats significantly altered the expression of synapsin I in the dentate gyrus and CA3 region at post-puberty but not at pre-puberty. A significantly greater expression of GFAP-immunoreactive astrocytes or processes was demonstrated in the pregnenolone- and DHEA-treated groups at both pre-puberty and post-puberty. A significant increase in the number and size of GFAP-immunoreactive astrocytes and in the extension of arborization was seen in the overall hippocampus. The number of neuropeptide Y-positive cells in the hilus region was also significantly increased in the neurosteroid-treated group at post-puberty. No differences were detected in dynorphin A immunoreactivity among the experimental groups. These results of this study suggest that pregnenolone and DHEA play an important role in the development of hippocampus.
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Animais Recém-Nascidos/fisiologia , Desidroepiandrosterona/farmacologia , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/metabolismo , Neuropeptídeo Y/metabolismo , Pregnenolona/farmacologia , Sinapsinas/metabolismo , Animais , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Dinorfinas/metabolismo , Hipocampo/efeitos dos fármacos , Imuno-Histoquímica , Ratos , Ratos Sprague-Dawley , Maturidade Sexual/fisiologiaRESUMO
Steroid hormones synthesized in the brain, called 'neurosteroids', modulate neuronal activity. We treated neonatal rats with a main precursor of the neurosteroidogenesis, pregnenolone, and examined adenosine A2A receptor, 5- hydroxytryptamine (5-HT)1A and 5-HT7 receptor densities in the front-parietal cortex in juvenile and adult rats. In receptor binding assay using [3H]CGS21680 and [3H]8-OH-DPAT, it was shown that neonatal pregnenolone-treatment induced a significant decrease in the adenosine A2A receptor density with no significant effects on the 5-HT1A and 5-HT7 receptor densities.
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Adenosina/análogos & derivados , Córtex Cerebral/crescimento & desenvolvimento , Dopamina/metabolismo , Pregnenolona/metabolismo , Receptores Purinérgicos P1/metabolismo , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/metabolismo , Adenosina/metabolismo , Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Animais , Animais Recém-Nascidos , Anti-Hipertensivos/metabolismo , Ligação Competitiva/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Feminino , Masculino , Transtornos Mentais/metabolismo , Transtornos Mentais/fisiopatologia , Fenetilaminas/metabolismo , Gravidez , Pregnenolona/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptor A2A de Adenosina , Receptores Purinérgicos P1/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , Receptores 5-HT1 de Serotonina , Agonistas do Receptor de Serotonina/metabolismo , Caracteres Sexuais , Transmissão Sináptica/fisiologiaRESUMO
Subchronic treatment with MAP (4.6 mg/kg, i.p., once daily for 11 days) significantly decreased the Kd, but not Bmax, values of [3H]1,3-dipropyl-8-cyclopentylxanthine ([3H]DPCPX) binding to adenosine A1 receptors in the prefrontal cortex and hippocampus, but not striatum, of rat brain. However, subchronic treatment with PCP (10 mg/kg, i.p., once daily for 11 days) did not alter the Kd and Bmax values of [3H]DPCPX binding to adenosine A1 receptors in these three regions. Subchronic treatment with MAP or PCP did not alter the Bmax and Kd values of [3H]2-p-(2-carboxyehyl)phenethylamino-5'-N-ethylcarboxyamidoadenosine ([3H]CGS21680) binding to adenosine A2A receptors in the striatum. Furthermore, subchronic treatment with MAP or PCP significantly decreased the specific binding of [3H]CGS21680 to adenosine A2A receptors in the hippocampus, but not in the prefrontal cortex. Thus, these results suggest that MAP and PCP may produce differential effects on the adenosine A2A receptors, but not adenosine A1 receptors in rat brain.
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Adenosina/análogos & derivados , Corpo Estriado/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Metanfetamina/farmacologia , Fenciclidina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Receptores Purinérgicos P1/metabolismo , Adenosina/metabolismo , Animais , Corpo Estriado/metabolismo , Hipocampo/metabolismo , Masculino , Metanfetamina/administração & dosagem , Fenciclidina/administração & dosagem , Fenetilaminas/metabolismo , Córtex Pré-Frontal/metabolismo , Ensaio Radioligante , Ratos , Ratos Wistar , Xantinas/metabolismoRESUMO
Trimethyltin (TMT), an organic metal, has been known to induce behavioral abnormalities including seizures and aggression. We administered TMT to rats, then, behavioral changes as well as the changes of dynorphin and Met-enkephalin mRNA were observed with or without phenobarbital treatment in order to reveal the role of neuropeptides in seizure-generating mechanisms. Met-enkephalin mRNA was significantly increased at the 2nd to 6th day after TMT administration when seizure was frequently observed. Meanwhile, dynorphin mRNA was decreased significantly from the 2nd day to 16th day during aggression score remained high. Phenobarbital abolished not only seizures and aggression, but also the changes of neuropeptide expressions. These results suggest that the changes of dynorphin mRNA are more strongly associated with aggression than seizures, while Met-enkephalin changes correlate more with seizures.
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Anticonvulsivantes/farmacologia , Dinorfinas/genética , Encefalina Metionina/genética , Hipocampo/fisiologia , Fenobarbital/farmacologia , Compostos de Trimetilestanho/intoxicação , Animais , Epilepsia/tratamento farmacológico , Epilepsia/fisiopatologia , Expressão Gênica/efeitos dos fármacos , Hibridização In Situ , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Using in situ hybridization, we studied the effects of age and gender on the expression of brain-derived neurotrophic factor (BDNF) mRNA and heat shock protein hsp-70 mRNA in the rat retrosplenial cortex following administration of the noncompetitive NMDA receptor antagonist (+)-MK-801 (dizocilpine). Male and female Sprague-Dawley rats (5 weeks, 12 weeks, or 10 months old) were given a single intraperitoneal injection of saline (1 ml/kg) or dizocilpine (0.3, 1.0, or 3.0 mg/kg). No expression of BDNF mRNA and hsp-70 mRNA was detected in the rat retrosplenial cortex after administration of saline (1 ml/kg, IP). Administration of dizocilpine (0.3, 1.0, or 3.0 mg/kg, IP) caused a marked induction of BDNF mRNA and hsp-70 mRNA in the retrosplenial cortex of male and female rats, in a dose-dependent manner. Female rats were more sensitive to the induction of BDNF mRNA and hsp-70 mRNA in the retrosplenial cortex by dizocilpine as compared to male rats. It was also found that adult (12 weeks old) and aged (10 months old) rats were more sensitive to the induction of hsp-70 mRNA and BDNF mRNA in the retrosplenial cortex by dizocilpine as compared to young (5 weeks old) rats. These results suggest that the age and gender differences observed in the expression of BDNF mRNA and hsp-70 mRNA in the retrosplenial cortex by dizocilpine may be associated with the differences in dizocilpine-induced neurotoxicity observed with gender and age within the same region.
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Envelhecimento/fisiologia , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Córtex Cerebral/metabolismo , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , RNA Mensageiro/biossíntese , Caracteres Sexuais , Animais , Córtex Cerebral/efeitos dos fármacos , Feminino , Proteínas de Choque Térmico HSP70/biossíntese , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Recent studies have demonstrated that chronic antidepressant treatment increases the expression of the cyclic amp (cAMP) response element binding protein (CREB) in rat hippocampus. The study presented here was conducted to determine if CREB is a relevant target that produces an antidepressant-like effect. METHODS: We employed the herpes simplex virus (HSV)-mediated gene transfer technique to overexpress CREB and determined its effect on the learned helplessness and forced swim tests, two established models used for pharmacological screening of antidepressant drugs. RESULTS: In the learned helplessness model, rats that received bilateral microinjection of HSV-CREB into the dentate gyrus showed significantly fewer escape failures in the subsequent conditioned avoidance test than those injected with control vector (HSV-LacZ). In contrast, microinjection of HSV-CREB in either the CA1 pyramidal cell layer of hippocampus or the prefrontal cortex did not produce an antidepressant response. In the forced swim test, CREB expression in the dentate gyrus resulted in a significantly shorter immobility time than those injected with HSV-LacZ. CONCLUSIONS: These results demonstrate that over-expression of CREB in hippocampus results in an antidepressant effect and suggest that CREB may serve as a potential molecular target for novel therapeutic agents.
Assuntos
AMP Cíclico/metabolismo , Hipocampo/metabolismo , Proteínas Nucleares/metabolismo , Transativadores/metabolismo , Animais , Antidepressivos/farmacologia , Proteína de Ligação a CREB , Giro Denteado/metabolismo , Depressão/metabolismo , Genes Virais/efeitos dos fármacos , Genes Virais/genética , Vetores Genéticos/efeitos dos fármacos , Vetores Genéticos/genética , Desamparo Aprendido , Hipocampo/efeitos dos fármacos , Imipramina/farmacologia , Imuno-Histoquímica , Masculino , Proteínas Nucleares/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Simplexvirus/efeitos dos fármacos , Simplexvirus/genética , Simplexvirus/metabolismo , Transativadores/efeitos dos fármacosRESUMO
Using in situ hybridization and immunohistochemical techniques, we examined the expression pattern of egr-1 mRNA and Egr-1 protein in several brain regions following administration of 3, 4-methylenedioxymethamphetamine (MDMA). Furthermore, we also studied the role of N-methyl-D-aspartate (NMDA) receptor, dopamine D(1) receptor, 5-hydroxytryptamine (5-HT) transporter or 5-HT(2A) receptor in the induction of egr-1 mRNA by MDMA. Basal constitutive levels of egr-1 mRNA were detected in control rat brains. A single administration of MDMA (10 mg/kg) caused marked induction of egr-1 mRNA in the prefrontal cortex, striatum and hippocampal dentate gyrus. However, no changes in the egr-1 mRNA levels were detected in the CA1 region of hippocampus and occipital cortex after administration of MDMA (10 mg/kg). Furthermore, the expression of egr-1 mRNA in the prefrontal cortex, striatum and hippocampal dentate gyrus after administration of MDMA (10 mg/kg) was blocked significantly by pretreatment with NMDA receptor antagonist (5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]-cyclohepten-5, 10-imine ((+)-MK801; 1 mg/kg), dopamine D(1) receptor antagonist SCH 23390 (1 mg/kg) or 5-HT uptake inhibitor paroxetine (5 mg/kg), but not by 5-HT(2A) receptor antagonist SR46349B (5 mg/kg). However, high basal levels of Egr-1 immunoreactivity in the rat brain were not altered by administration of MDMA (10 mg/kg). These results suggest that MDMA alters the expression of egr-1 mRNA in several regions of rat brain, and that the expression of egr-1 mRNA by MDMA in the prefrontal cortex, striatum and hippocampal dentate gyrus appears to be mediated, at least in part, by NMDA receptor, dopamine D(1) receptor and 5-HT transporter.
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Química Encefálica/efeitos dos fármacos , Proteínas de Ligação a DNA/biossíntese , Alucinógenos/farmacologia , Proteínas Imediatamente Precoces , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , RNA Mensageiro/biossíntese , Fatores de Transcrição/biossíntese , Animais , Benzazepinas/farmacologia , Maleato de Dizocilpina/farmacologia , Antagonistas de Dopamina/farmacologia , Proteína 1 de Resposta de Crescimento Precoce , Antagonistas de Aminoácidos Excitatórios/farmacologia , Fluorbenzenos/farmacologia , Imuno-Histoquímica , Hibridização In Situ , Masculino , Paroxetina/farmacologia , Fenóis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Antagonistas da Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
We investigated the effects of a schizophrenomimetic drug, phencyclidine (PCP), on substance P (SP) contents in the discrete rat brain areas using an enzyme-immunoassay for SP. The acute intraperitoneal (i.p.) administration of PCP (10 mg/kg), which is a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) type glutamate receptor and a dopamine uptake inhibitor, reduced the concentration of the peptide in the prefrontal cortex, limbic forebrain, striatum, and substantia nigra, but not in the ventral tegmental area, at 60 or 120 min postinjection. A selective noncompetitive NMDA antagonist, dizocilpine hydrogen maleate ((+)-MK-801) (1 mg/kg, i.p.), also caused a decrease in the SP content in the prefrontal cortex and limbic forebrain but failed to alter the content in the other areas studied 30 min thereafter. Dopamine agonists, methamphetamine (4.8 mg/kg, i.p.) and apomorphine (4.4 mg/kg, i.p.), diminished the SP contents in the striatum and substantia nigra 60 min after their injection without effects in the prefrontal cortex, limbic forebrain, and ventral tegmental area. Furthermore, pretreatment with haloperidol (1 mg/kg, i.p.), a D2 preferable dopamine receptor antagonist and a typical antipsychotic, blocked the ability of PCP to decrease the SP concentrations in the substantia nigra but not in the prefrontal cortex. PCP, therefore, might diminish the SP levels by NMDA receptor-mediated and dopamine-independent mechanisms in the prefrontal cortex and limbic forebrain, but by NMDA receptor-independent and dopamine-dependent mechanisms in the striatum and substantia nigra. The haloperidol-insensitive reduction of the frontal SP could be involved in certain neuroleptic-resistant symptoms of PCP-treated animals, PCP psychosis, or schizophrenia.
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Encéfalo/metabolismo , Haloperidol/farmacologia , Fenciclidina/farmacologia , Substância P/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Interações Medicamentosas , Sistema Límbico/efeitos dos fármacos , Sistema Límbico/metabolismo , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/metabolismo , Ratos , Ratos Wistar , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismoRESUMO
Psychotic depression is reported and requires different pharmacological treatment from other mood disorders, however, sufficient studies to guide us in selecting successful treatment strategies have not been performed. In this study, algorithm for the treatment of psychotic depression was developed by the Japan Psychopharmacology Algorithm Project. The following three issues are emphasized: (1) risk of suicide; (2) agitation; and (3) oral intake ability. When patients show a high risk of suicide and/or agitation, prompt treatment strategies, such as tricyclic antidepressant (TCA)/neuroleptics therapy or electroconvulsive therapy (ECT), are necessary. If patients show no suicidal risk without agitation, TCA therapy is recommended. ECT is recommended as the first choice when the symptoms are severe or when there is an inability of oral intake.
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Transtornos Psicóticos Afetivos/tratamento farmacológico , Algoritmos , Antidepressivos/administração & dosagem , Antipsicóticos/administração & dosagem , Transtorno Depressivo/tratamento farmacológico , Transtornos Psicóticos Afetivos/diagnóstico , Transtornos Psicóticos Afetivos/psicologia , Antidepressivos/efeitos adversos , Antidepressivos Tricíclicos/administração & dosagem , Antidepressivos Tricíclicos/efeitos adversos , Antipsicóticos/efeitos adversos , Terapia Combinada , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/psicologia , Eletroconvulsoterapia , Humanos , Prevenção do SuicídioRESUMO
Phencyclidine (PCP) has been shown to cause neurotoxicity in rat retrosplenial cortex following a single administration, although the precise mechanism underlying PCP-induced neurotoxicity is unclear. Using in situ hybridization and immunohistochemistry, we studied the effects of PCP on expression of immediate early gene zif268 mRNA and zif268 protein in the rat brain. High constitutive levels of zif268 mRNA and zif268 immunoreactivity were observed in the brain of control rats. Administration of PCP (12.5, 25 or 50 mg/kg, i.p., 6 h) caused marked induction of zif268 mRNA in the rat retrosplenial cortex, in a dose-dependent manner. However, the basal levels of zif268 mRNA in the other regions of cerebral cortex were decreased by administration of PCP. Emulsion-autoradiographical study suggested that marked expression of zif268 mRNA was observed in the layers III and IV of retrosplenial cortex where the neurotoxicity of PCP was detected. Furthermore, zif268 immunoreactivity in the layer IV of retrosplenial cortex was not changed by administration of PCP (25 mg/kg, i.p., 5 h), but that in the other layers of retrosplenial cortex was reduced by PCP. These results suggest that immediate early gene zif268 may, in part, play a role in the neurotoxicity of NMDA receptor antagonists such as PCP.
Assuntos
Proteínas de Ligação a DNA/genética , Alucinógenos/farmacologia , Proteínas Imediatamente Precoces/genética , Sistema Límbico/efeitos dos fármacos , Fenciclidina/farmacologia , RNA Mensageiro/biossíntese , Fatores de Transcrição/genética , Animais , Proteína 1 de Resposta de Crescimento Precoce , Feminino , Imuno-Histoquímica , Hibridização In Situ , Sistema Límbico/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Kainic acid-induced seizures in rats represent an established animal model for human temporal lobe epilepsy. However, it is well-known that behavioral responses to the systemic administration of kainic acid are inconsistent between animals. In this study, we examined the relationship between expression of genes, neuropathological damage, and behavioral changes (seizure intensity and body temperature) in rats after systemic administration of kainic acid. The considerable differences in the response to kainic acid-induced seizures were observed in rats after a single administration of kainic acid (12 mg/kg i.p.). There was no detection of the expression of heat shock protein hsp-70 mRNA and HSP-70 protein in brain of vehicle-treated controls and in animals exhibiting weak behavioral changes (stage 1-2). A moderate expression of hsp-70 mRNA was detected throughout all regions (the pyramidal cell layers of CA1-3 and dentate gyrus) of the hippocampus, the basolateral, lateral, central and medial amygdala, the piriform cortex, and the central medial thalamic nucleus of rats that developed moderate seizures (stage 3-4). Marked expression of hsp-70 mRNA was detected in the all regions (cingulate, parietal, somatosensory, insular, entorhinal, piriform cortices) of cerebral cortex and all regions of hippocampus, and the central medial thalamic nucleus of the rats that developed severe seizures (stage 4-5). In addition, marked HSP-70 immunoreactivity was detected in the pyramidal cell layers of CA1 and CA3 regions of hippocampus, all regions (cingulate, parietal, somatosensory, insular, piriform cortices) of cerebral cortex, and the striatum of rats that developed severe seizures (stage 4-5). Furthermore, a marked expression of cyclooxygenase-2 (COX-2) mRNA and brain-derived neurotrophic factor (BDNF) mRNA levels by kainic acid-induced behavioral seizures (stage 3-4 or stage 4-5) was detected in all hippocampal pyramidal cell layers, granule layers of dentate gyrus, piriform cortex, neocortex, and amygdala. The present study suggest that the behavioral changes (seizure intensity and body temperature) and neuropathological damage after systemic administration of kainic acid are inconsistent between animals, and that these behavioral changes (severity of kainic acid-induced limbic seizures) might be correlated with gene expression of hsp-70 mRNA, COX-2 mRNA, and BDNF mRNA in rat brain.
Assuntos
Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Agonistas de Aminoácidos Excitatórios , Proteínas de Choque Térmico HSP70/biossíntese , Isoenzimas/biossíntese , Ácido Caínico , Prostaglandina-Endoperóxido Sintases/biossíntese , RNA Mensageiro/biossíntese , Convulsões/metabolismo , Convulsões/psicologia , Animais , Temperatura Corporal/efeitos dos fármacos , Ciclo-Oxigenase 2 , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino , Proteínas de Membrana , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Ratos , Ratos Sprague-Dawley , Convulsões/induzido quimicamenteRESUMO
The effect of the antitubulin agent colcemid on human glioma cells was investigated by sorting cells with different DNA content and subjecting them to confocal laser microscopy and transmission electron microscopy. The human glioma cell line U251MG was exposed to colcemid at a concentration of 0.05 microg for 16 h. Flow cytometric analysis revealed the accumulation of cells in S/G2M phase. Cells harvested from each of G0/G1 and S/G2M peaks were then analyzed by confocal laser microscopy and transmission electron microscopy. Confocal laser microscopy revealed that colcemid-treated cells harvested from the G0/G1 peak contained mitotic and apoptotic cells in addition to interphase cells. Electron microscopy confirmed that colcemid-treated cells in the G0/G1 peak had fragmented nuclei typical of apoptotic cells and mitotic cells with altered chromatin structure. Some mitotic cells obtained by mitotic shake-off after treatment with colcemid showed DNA strand breaks defined by in situ nick end labeling. The present study indicates that mitotic as well as interphase apoptosis occurs in U251MG cells following colcemid treatment.
Assuntos
Apoptose/efeitos dos fármacos , Demecolcina/farmacologia , Glioma/patologia , Ciclo Celular , Fragmentação do DNA/efeitos dos fármacos , Citometria de Fluxo , Glioma/metabolismo , Glioma/ultraestrutura , Humanos , Interfase , Microscopia Confocal , Microscopia Eletrônica , Mitose , Células Tumorais CultivadasRESUMO
Desipramine, imipramine, clomipramine, (-)-propranolol, (-)-alprenolol, (+/-)-pentazocine and risperidone caused a concentration-dependent inhibition of 6 nM [3H]DTG (1,3-di-o-tolylguanidine)-defined sigma (sigma) binding with Ki values of about 0.5-2.5 microM in well-washed homogenates obtained from rat cerebral cortex. The saturation studies revealed that the inhibition by desipramine (1-4 microM), (-)-propranolol (1 microM) and (-)-alprenolol (3 microM) resulted from a reduction of the Bmax value without alteration of the Kd of [3H]DTG binding to the cortex or hippocampus. In contrast, imipramine, (+/-)-pentazocine, clomipramine and risperidone competitively attenuated the cortical or hippocampal [3H]DTG binding. These findings demonstrate the uncompetitive inhibition of [3H]DTG binding by neuroactive drugs, thereby providing further support for the possible multiple regulation of cerebral sigma receptors.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Alprenolol/farmacologia , Antidepressivos Tricíclicos/farmacologia , Desipramina/farmacologia , Guanidinas/farmacologia , Propranolol/farmacologia , Receptores sigma/antagonistas & inibidores , Animais , Cinética , Masculino , Ratos , Ratos Wistar , Receptores sigma/metabolismoRESUMO
We investigated the effects of chronic treatment with food containing one of five antidepressants on substance P (SP) content in the rat brain using radioimmunoassay and enzyme-immunoassay. The antidepressants used were imipramine, desipramine, clomipramine, amoxapine and mianserin. Following 40 days of treatment, all the antidepressants decreased SP concentrations in the striatum, substantia nigra and amygdala. Only imipramine and desipramine reduced the peptide content in the hippocampus, and only mianserin reduced it in the septum. We further examined the acute effects of antidepressants one hour after a single intraperitoneal administration. Acute imipramine and desipramine treatment reduced SP in the striatum, whereas acute mianserin decreased it in the striatum and substantia nigra. These results demonstrate that all antidepressants on chronic treatment had a common effect, a reduction of SP content in the striatum, substantia nigra and amygdala. This raises the possibility that such a decrease may contribute to the therapeutic action of antidepressants in affective disorders.
Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Antidepressivos/farmacologia , Corpo Estriado/efeitos dos fármacos , Substância P/metabolismo , Substância Negra/efeitos dos fármacos , Amoxapina/farmacologia , Tonsila do Cerebelo/metabolismo , Animais , Clomipramina/farmacologia , Corpo Estriado/metabolismo , Desipramina/farmacologia , Imipramina/farmacologia , Masculino , Mianserina/farmacologia , Radioimunoensaio , Ratos , Ratos Wistar , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Substância Negra/metabolismo , Fatores de TempoRESUMO
In contrast to the inner structure, three-dimensional structure of psammona bodies in meningiomas is not well defined. This study examined three cultured meningiomas, in which surface observation of psammoma bodies might be easier than in the tumor tissues since influence of interposing connective tissue is minimized in tissue culture. Early culture revealed that psammoma bodies with frank calcification were suspended in the tissue culture medium, and so were they collected, centrifuged, and then processed for electron microscopy. Ultrastructurally, psammoma bodies were mostly spherical in shape and composed of a core of dense calcification and surrounding collagen fiber bundles. Apart from psammoma bodies, round bodies with concentric lamination like a transversely cut onion were frequently noted by light microscopy. These bodies were composed mainly of tangles of collagen fibers emerged from surrounding tumor cell processes. The results suggest that psammoma bodies in meningiomas arise in part from meningothelial whorls due to collagen production by tumor cells followed by obliteration and disappearance of tumor cell processes, although some of the alternative pathways for psammoma body formation proposed by other investigators cannot be ruled out by this study.