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Acta Pharmacol Sin ; 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34522005


Behavioral sensitization is a progressive increase in locomotor or stereotypic behaviours in response to drugs. It is believed to contribute to the reinforcing properties of drugs and to play an important role in relapse after cessation of drug abuse. However, the mechanism underlying this behaviour remains poorly understood. In this study, we showed that mTOR signaling was activated during the expression of behavioral sensitization to cocaine and that intraperitoneal or intra-nucleus accumbens (NAc) treatment with rapamycin, a specific mTOR inhibitor, attenuated cocaine-induced behavioural sensitization. Cocaine significantly modified brain lipid profiles in the NAc of cocaine-sensitized mice and markedly elevated the levels of phosphatidylinositol-4-monophosphates (PIPs), including PIP, PIP2, and PIP3. The behavioural effect of cocaine was attenuated by intra-NAc administration of LY294002, an AKT-specific inhibitor, suggesting that PIPs may contribute to mTOR activation in response to cocaine. An RNA-sequencing analysis of the downstream effectors of mTOR signalling revealed that cocaine significantly decreased the expression of SynDIG1, a known substrate of mTOR signalling, and decreased the surface expression of GluA2. In contrast, AAV-mediated SynDIG1 overexpression in NAc attenuated intracellular GluA2 internalization by promoting the SynDIG1-GluA2 interaction, thus maintaining GluA2 surface expression and repressing cocaine-induced behaviours. In conclusion, NAc SynDIG1 may play a negative regulatory role in cocaine-induced behavioural sensitization by regulating synaptic surface expression of GluA2.

Exp Biol Med (Maywood) ; 234(3): 306-13, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19144870


Traditional medical extracts are commonly used as complex mixtures, which may contain naturally occurring contact sensitizers. In this investigation, the mice local lymph node assay (LLNA) was performed to evaluate the dermal sensitization potential of Myrrh, Borneolum, Olibanum, Moschus and Cassia Bark, which are widely used in topical traditional medication. In the radioactive LLNA, the stimulation index (SI) values were calculated for each medical extract. Myrrh, Borneolum, Olibanum and Moschus induced dose-dependent cell proliferation and SI was more than 3. Cassia Bark showed no positive response over the range of test concentrations. In the flow cytometry analysis, the total number of CD3(+), CD4(+), and CD8(+) cells in local lymph nodes was increased in Moschus-, Olibanum-, Myrrh- and Borneolum-treated mice. The ratio of the B220(+)/CD3(+) (B/T cell ratio) and the percentage of I-A(k+) cells that was also positive for the CD69 marker (I-A(k+)/ CD69(+)) were increased in the Moschus-, Olibanum- and Myrrh-treated mice. However, no ofbvious change was observed in Borneolum-treated mice. Cassia Bark did not induce changes in the lymphocyte subpopulations. These results indicate that Moschus, Olibanum and Myrrh can be regarded as sensitizers, and Borneolum regarded as an irritant. Cassia Bark is neither a sensitizer nor an irritant. The combination of radioactive and flow cytometric LLNA can be used for the prediction of sensitizing potential of medical extracts which lead to allergic contact dermatitis in humans.

Derme/efeitos dos fármacos , Derme/imunologia , Irritantes/farmacologia , Ensaio Local de Linfonodo , Extratos Vegetais/farmacologia , Plantas Medicinais/metabolismo , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Proliferação de Células/efeitos dos fármacos , Orelha/anatomia & histologia , Citometria de Fluxo , Lectinas Tipo C , Linfonodos/citologia , Linfonodos/efeitos dos fármacos , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos CBA , Tamanho do Órgão/efeitos dos fármacos
Brain Res ; 956(2): 246-53, 2002 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-12445692


The effect of Shiga-like toxin II (SLT-II), which was derived from Escherichia coli O157:H7, on doxorubicin transport across the blood-brain barrier (BBB) and P-glycoprotein function, was investigated in ddY mice. Doxorubicin (30 mg kg(-1)) was administered intravenously or fluorescein isothiocyanate labeled dextran (FD-4) was infused (20 microg min(-1)) to the mice, who had received an intravenous injection of SLT-II (0.2 microg/animal) 6 or 24 h earlier. Blood and brain were removed 4 h after injection of doxorubicin or 60 min after infusion of FD-4. SLT-II significantly elevated the brain concentration and brain-to-plasma concentration ratio (K(p)) of doxorubicin and FD-4 24 h after injection, but did not alter 6 h after. Cyclosporin A (200 mg kg(-1)) significantly increased the K(p) value of doxorubicin in the control mice, but did not alter it in mice treated 24 h earlier with SLT-II. Pentoxifylline (100 mg kg(-1)) a TNF-alpha production inhibitor, ameliorated SLT-II-induced increases in the brain concentrations of both drugs and the K(p) value of FD-4, suggesting that TNF-alpha, at least in part, causes damage to the brain capillaries. Western blot analysis revealed that SLT-II increased the protein level of P-glycoprotein in the brain of mice 6 h after injection and the increased level remained unchanged for 24 h. SLT-II did not change ATP content in the brain of mice. These results suggest that the increased P-glycoprotein level cannot explain SLT-II-induced increase in the doxorubicin accumulation in brain. The present findings indicate that SLT-II impairs the BBB function and doxorubicin transport across the BBB, while it overexpresses P-glycoprotein.

Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antibióticos Antineoplásicos/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Doxorrubicina/metabolismo , Toxina Shiga II/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/efeitos dos fármacos , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/sangue , Western Blotting , Ciclosporina/farmacologia , Dextranos/administração & dosagem , Dextranos/sangue , Doxorrubicina/administração & dosagem , Doxorrubicina/sangue , Inibidores Enzimáticos/farmacologia , Escherichia coli O157 , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Pentoxifilina/farmacologia , Fatores de Tempo
Antimicrob Agents Chemother ; 46(5): 1522-8, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-11959591


The effect of Shiga-like toxin II (SLT-II) (2 microg/animal), which was derived from Escherichia coli O157:H7, on renal handling of levofloxacin (LVX), a model drug for quinolone antimicrobial agents, was investigated in rats 24 h after intravenous injection. In histopathological examination, acute tubular injury was observed in SLT-II-treated rats, but the glomeruli were not injured. SLT-II significantly increased the steady-state concentration of LVX in plasma to 1.5-fold that of control rats. SLT-II induced significant decreases in the glomerular filtration rate (GFR) and renal clearance (CL(R)) of LVX. SLT-II slightly, but significantly, increased the unbound fraction and decreased renal plasma flow with no change in the extraction ratio of p-aminohippurate. SLT-II significantly increased concentrations of tumor necrosis factor alpha (TNF-alpha) and nitrite and nitrate (NOx) in plasma. The TNF-alpha inhibitor pentoxifylline partly, but significantly, inhibited SLT-II-induced decreases in the GFR and CL(R) of LVX; in contrast, S-methylisothiourea, a selective inhibitor of inducible nitric oxide synthase, did not. Western blotting analysis revealed that SLT-II did not alter the levels of multidrug resistance-associated protein 2 (Mrp2) and P-glycoprotein in kidneys 24 h after injection, assuming the lack of involvement of Mrp2 and P-glycoprotein in SLT-II-induced acute renal tubular injury and renal handling of LVX observed 24 h after SLT-II injection. The present study suggests that SLT-II impairs the renal handling of LVX by decreasing GFR and causing decreased renal plasma flow.

Transportadores de Cassetes de Ligação de ATP , Anti-Infecciosos/farmacocinética , Escherichia coli O157/metabolismo , Rim/metabolismo , Levofloxacino , Ofloxacino/farmacocinética , Toxina Shiga II/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Anti-Infecciosos/urina , Proteínas de Transporte/metabolismo , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Ofloxacino/administração & dosagem , Ofloxacino/urina , Ratos , Ratos Wistar , Toxina Shiga II/metabolismo