RESUMO
Reserpine (RES) is an irreversible inhibitor of VMAT2 used to study Parkinson's disease (PD) and screening for antiparkinsonian treatments in rodents. Recently, the repeated treatment with a low dose of reserpine was proposed as a model capable of emulating progressive neurochemical, motor and non-motor impairments in PD. Conversely, compared to Wistar rats, Spontaneously Hypertensive Rats (SHR) are resistant to motor changes induced by repeated treatment with a low dose of RES. However, such resistance has not yet been investigated for RES-induced non-motor impairments. We aimed to assess whether SHR would have differential susceptibility to the object recognition deficit induced by repeated low-dose reserpine treatment. We submitted male Wistar and SHR rats to repeated RES treatment (15 s.c. injections of 0.1 mg/kg, every other day) and assessed object memory acquisition and retrieval 48 h after the 6th RES injection (immediately before the appearance of motor impairments). Only RES Wistar rats displayed memory impairment after reserpine treatment. On the other hand, untreated SHR rats displayed object recognition memory deficit, but RES treatment restored such deficits. We also performed immunohistochemistry for tyrosine hydroxylase (TH) and α-synuclein (α-syn) 48 h after the last RES injection. In a different set of animals submitted to the same treatment, we quantified DA, 5-HT and products of lipid peroxidation in the prefrontal cortex (PFC) and hippocampus (HPC). SHR presented increased constitutive levels of DA in the PFC and reduced immunoreactivity to TH in the medial PFC and dorsal HPC. Corroborating the behavioral findings, RES treatment restored those constitutive alterations in SHR. These findings indicate that the neurochemical, molecular and genetic differences in the SHR strain are potentially relevant targets to the study of susceptibility to diseases related to dopaminergic alterations.
Assuntos
Transtornos Cognitivos/induzido quimicamente , Dopamina/metabolismo , Hipocampo , Doença de Parkinson Secundária/induzido quimicamente , Córtex Pré-Frontal , Reconhecimento Psicológico/efeitos dos fármacos , Reserpina/farmacologia , Tirosina 3-Mono-Oxigenase/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Endogâmicos SHR/metabolismo , Ratos Wistar/metabolismo , Reserpina/administração & dosagem , Transdução de Sinais/efeitos dos fármacosRESUMO
Reserpine (RES) is an irreversible inhibitor of VMAT2 used to study Parkinson’s disease (PD) and screening for antiparkinsonian treatments in rodents. Recently, the repeated treatment with a low dose of reserpine was proposed as a model capable of emulating progressive neurochemical, motor and non-motor impairments in PD. Conversely, compared to Wistar rats, Spontaneously Hypertensive Rats (SHR) are resistant to motor changes induced by repeated treatment with a low dose of RES. However, such resistance has not yet been investigated for RES-induced non-motor impairments. We aimed to assess whether SHR would have differential susceptibility to the object recognition deficit induced by repeated low-dose reserpine treatment. We submitted male Wistar and SHR rats to repeated RES treatment (15 s.c. injections of 0.1 mg/kg, every other day) and assessed object memory acquisition and retrieval 48 h after the 6th RES injection (immediately before the appearance of motor impairments). Only RES Wistar rats displayed memory impairment after reserpine treatment. On the other hand, untreated SHR rats displayed object recognition memory deficit, but RES treatment restored such deficits. We also performed immunohistochemistry for tyrosine hydroxylase (TH) and α-synuclein (α-syn) 48 h after the last RES injection. In a different set of animals submitted to the same treatment, we quantified DA, 5-HT and products of lipid peroxidation in the prefrontal cortex (PFC) and hippocampus (HPC). SHR presented increased constitutive levels of DA in the PFC and reduced immunoreactivity to TH in the medial PFC and dorsal HPC. Corroborating the behavioural findings, RES treatment restored those constitutive alterations in SHR. These findings indicate that the neurochemical, molecular and genetic differences in the SHR strain are potentially relevant targets to the study of susceptibility to diseases related to dopaminergic alterations.
RESUMO
Tityus serrulatus venom (Tsv)-induced pulmonary edema can occur in severe envenomation and the mechanisms involved are not completely understood. Therefore, we studied the effect of pharmacological modulation of the mast cell activation and the histamine antagonism on airways edema (investigated by Evans blue dye extravasation) and measured 5-hydroxytryptamine (5-HT) concentration in bronchoalveolar lavage fluid (BALF) in rats envenomed by Tsv. Additionally, the in vitro effect of Tsv on mast cells was studied using histological method and 5-HT release from mesenteric and peritoneal mast cells. We found that i.v. injection of Tsv increase vascular permeability in trachea, upper and lower bronchi and in lung parenchyma. This was not affected by ketotifen, a mast cell "stabilizer," or by pretreatment with pyrilamine (histamine H1 receptor antagonist). Moreover, 5-HT was not found in BALF of envenomed rats. In vitro experiments showed that Tsv did not induce mast cell degranulation nor release of 5-HT by mesenteric or peritoneal mast cells, in sharp contrast to preparations challenged by a mast cell activator, compound 48/80. In conclusion, our results show that Tsv causes strong edema in rat airways which is independent of mast cell activation and show that mast cells are not directly activated by Tsv.
Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Mordeduras e Picadas de Insetos/patologia , Mastócitos/efeitos dos fármacos , Sistema Respiratório/efeitos dos fármacos , Venenos de Escorpião/toxicidade , Animais , Líquido da Lavagem Broncoalveolar/citologia , Degranulação Celular/efeitos dos fármacos , Azul Evans , Indicadores e Reagentes , Mordeduras e Picadas de Insetos/fisiopatologia , Cetotifeno/farmacologia , Masculino , Mastócitos/fisiologia , Pirilamina/farmacologia , Ratos , Ratos Wistar , Sistema Respiratório/irrigação sanguínea , EscorpiõesRESUMO
1. The effects of the main component of the Tityus serrulatus scorpion venom, toxin TsTX-I, were studied on the contractility and release of neurotransmitters in the rat vas deferens. Since TsTX-I is known to act on sodium channels, we used veratridine, another sodium channel agent, for comparison. 2. Toxin TsTX-I induced concentration-dependent contractions with an EC(50) value of 47.8+/-0.1 nM and a maximum effect of 84.4+/-10.4% of that for BaCl(2). 3. Contractions by TsTX-I were abolished by denervation or tetrodotoxin (0.1 microM), showing that the toxin effects depend on the integrity of sympathetic nerve terminals. 4. To check for the presence of a noradrenergic component, experiments were conducted after removal of adrenergic stores in nerve terminals by reserpinization (10 mg kg(-1), 24 h prior to experiments) or blockade of alpha(1) adrenoceptors by prazosin (30 microM), showing that these procedures did not modify the response to TsTX-I, and therefore that adrenoceptors were not involved in contractions. 5. To check for the presence of a purinergic component, experiments were carried out after blockade of P(2X) receptors by suramin (0.1 mM) or desensitization by alpha,beta-methylene-ATP (30 microM). These agents greatly abolished the contractile response to TsTX-I (about 83% by desensitization and 96% by suramin), showing the involvement of purinergic receptors. 6. The release of noradrenaline and purinergic agents (ATP, ADP, AMP and adenosine) was detected by HPLC. Together, the total release of purines in the presence of TsTX-I was about 42 times higher than in the control group. In contrast, TsTX-I did not modify the overflow of noradrenaline, showing that the release was selective for purines. 7. The release of purinergic agents was reduced by the N-type calcium channel blocker omega-conotoxin GVIA (1 microM) and by the P/Q-type blocker omega-conotoxin MVIIC (1 microM), showing that the effects of TsTX-I are calcium-dependent. 8. The results show that TsTX-I produced a selective release of purines from postganglionic sympathetic nerves in the rat vas deferens.