RESUMO
Heavy metals, such as methylmercury, are key environmental pollutants that easily reach human beings by bioaccumulation through the food chain. Several reports have demonstrated that endocrine organs, and especially the pituitary gland, are potential targets for mercury accumulation; however, the effects on the regulation of hormonal release are unclear. It has been suggested that serum prolactin could represent a biomarker of heavy metal exposure. The aim of this study was to evaluate the effect of methylmercury on prolactin release and the role of the nitrergic system using prolactin secretory cells (the mammosomatotroph cell line, GH3B6). Exposure to methylmercury (0-100 μM) was cytotoxic in a time- and concentration-dependent manner, with an LC50 higher than described for cells of neuronal origin, suggesting GH3B6 cells have a relative resistance. Methylmercury (at exposures as low as 1 μM for 2 h) also decreased prolactin release. Interestingly, inhibition of nitric oxide synthase by N-nitro-L-arginine completely prevented the decrease in prolactin release without acute neurotoxic effects of methylmercury. These data indicate that the decrease in prolactin production occurs via activation of the nitrergic system and is an early effect of methylmercury in cells of pituitary origin.
Assuntos
Humanos , Animais , Bovinos , Ratos , Compostos de Metilmercúrio/toxicidade , Óxido Nítrico Sintase/antagonistas & inibidores , Nitroarginina/toxicidade , Hipófise/efeitos dos fármacos , Prolactina/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cavalos , Hipófise/metabolismo , Neoplasias HipofisáriasRESUMO
Heavy metals, such as methylmercury, are key environmental pollutants that easily reach human beings by bioaccumulation through the food chain. Several reports have demonstrated that endocrine organs, and especially the pituitary gland, are potential targets for mercury accumulation; however, the effects on the regulation of hormonal release are unclear. It has been suggested that serum prolactin could represent a biomarker of heavy metal exposure. The aim of this study was to evaluate the effect of methylmercury on prolactin release and the role of the nitrergic system using prolactin secretory cells (the mammosomatotroph cell line, GH3B6). Exposure to methylmercury (0-100 µM) was cytotoxic in a time- and concentration-dependent manner, with an LC50 higher than described for cells of neuronal origin, suggesting GH3B6 cells have a relative resistance. Methylmercury (at exposures as low as 1 µM for 2 h) also decreased prolactin release. Interestingly, inhibition of nitric oxide synthase by N-nitro-L-arginine completely prevented the decrease in prolactin release without acute neurotoxic effects of methylmercury. These data indicate that the decrease in prolactin production occurs via activation of the nitrergic system and is an early effect of methylmercury in cells of pituitary origin.
Assuntos
Compostos de Metilmercúrio/toxicidade , Óxido Nítrico Sintase/antagonistas & inibidores , Nitroarginina/toxicidade , Hipófise/efeitos dos fármacos , Prolactina/metabolismo , Animais , Bovinos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cavalos , Humanos , Hipófise/metabolismo , Neoplasias Hipofisárias , RatosRESUMO
The inferior colliculus (IC), a midbrain structure that processes acoustic information of aversive nature, is distinguished from other auditory nuclei in the brainstem by its connections with structures of the motor system. Recent evidence relating the IC to motor behavior shows that glutamate-mediated mechanisms in the neural circuits at the IC level modulate haloperidol-induced catalepsy. It has been shown that N(G)-nitro-L-arginine (L-NOARG), inhibitor of enzyme nitric oxide synthase (NOS), can induce catalepsy after intraperitoneal (ip), intracerebroventricular or intrastriatal administration. The present study examined whether the catalepsy induced by L-NOARG (ip) can be influenced by collicular glutamatergic mechanisms and if a NO-dependent neural substrate into the IC plays a role in this immobility state. L-NOARG-induced catalepsy was challenged with prior intracollicular microinjections of glutamate NMDA receptor antagonists, AP7 (20 or 40 nmol/0.5 µl), or of the NMDA receptor agonist N-methyl-D-aspartate (NMDA, 30 nmol/0.5 µl). Catalepsy was evaluated by positioning both forepaws of the rats on an elevated horizontal wooden bar and recording the time for which the animal maintained this position. The results showed that intracollicular microinjection of AP7 previous to systemic injections of L-NOARG (90 mg/kg) significantly attenuated the catalepsy. Conversely, intracollicular microinjection of NMDA increased the time of catalepsy when administered 10 min before systemic L-NOARG (10 or 45 mg/kg). The microinjection of L-NOARG (50 or 100 nmol) directly into the IC was not able to induce catalepsy. These findings suggest that glutamate-mediated mechanisms in the neural circuits of the IC modulate L-NOARG-induced catalepsy and participate in the regulation of motor activity.
Assuntos
Catalepsia/induzido quimicamente , Catalepsia/patologia , Inibidores Enzimáticos/toxicidade , Colículos Inferiores/metabolismo , Nitroarginina/toxicidade , Receptores de N-Metil-D-Aspartato/metabolismo , 2-Amino-5-fosfonovalerato/administração & dosagem , 2-Amino-5-fosfonovalerato/análogos & derivados , Animais , Catalepsia/prevenção & controle , Relação Dose-Resposta a Droga , Esquema de Medicação , Interações Medicamentosas , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Colículos Inferiores/efeitos dos fármacos , Masculino , Microinjeções , N-Metilaspartato/administração & dosagem , Ratos , Ratos Wistar , Estatísticas não Paramétricas , Fatores de TempoRESUMO
N(G)-(Nitro-L-arginine (L-NOARG), an inhibitor of nitric oxide synthase, induces catalepsy in mice. The objective of the present work was to investigate if serotonergic drugs are able to modulate this effect. Results showed that the cataleptogenic effect of L-NOARG (40 mg/kg) in male albino-Swiss mice was enhanced by pre-treatment with (+)-N-tert-butyl-3-(4-[2-methoxyphenyl]piperazin-1-yl)-2-phenylpro panamide ((+)-WAY-100135, 5 or 10 mg/kg), a 5-HT1A-selective receptor antagonist, and by ketanserin (5 or 10 mg/kg), a 5-HT2A receptor and alpha1-adrenoceptor antagonist. Prazosin (3 or 5 mg/kg), an alpha1-adrenoceptor antagonist, and endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3yl)-2,3-dihydro-3,3-dimet hyl-indole-1-carboxamide HCl (BRL-46470A, 0.05 or 0.5 mg/kg), a 5-HT3 receptor antagonist, did not interfere with L-NOARG-induced catalepsy. Ritanserin (3 or 10 mg/kg), a 5-HT2A and 5-HT2C receptor antagonist, tended to enhance the effect of L-NOARG. These results confirm that interference with the formation of nitric oxide induces catalepsy in mice, and suggest that this effect is modulated by 5-HT1A and 5-HT2A receptors.