Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 8.412
Filtrar
1.
J Med Life ; 13(2): 206-210, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32742515

RESUMO

Nausea is a mental sensation of unease and discomfort before vomiting. Vomiting refers to the return of the contents of the upper gastrointestinal tract to the mouth caused by contractions of chest and abdomen muscles. Postoperative nausea and vomiting is an unpleasant experience with high treatment costs. Therefore, this study aimed to compare the effects of haloperidol, metoclopramide, dexmedetomidine, and ginger on postoperative nausea and vomiting after laparoscopy. This double-blind clinical trial was performed on all laparoscopy candidates at Valiasr hospital, Arak, Iran. The patients were randomly divided into four groups (haloperidol, metoclopramide, dexmedetomidine and ginger), and all patients underwent general anesthesia using fentanyl, midazolam, atracurium, and propofol. After intubation, tube fixation, and stable hemodynamic conditions, the patients received four ginger capsules with a hint of lemon. A group of patients received 25 µg of dexmedetomidine. In the Plasil group, 10 mg of metoclopramide was given 30 minutes before the completion of surgery. In addition, 0.5 cc of haloperidol (5 mg) was administered to a group of patients. Heart rate, blood pressure, and oxygen saturation were recorded from the beginning of surgery, every 15 minutes until the end of the surgery. Furthermore, the occurrence of nausea and vomiting was recorded during recovery, 2 and 4 hours after surgery. Data were then analyzed using the SPSS software v.23. Eighty-eight patients were enrolled in the study. The youngest and the oldest were 30 years and 70 years old, respectively, and the mean age was 48.02 ± 9.31 years. Moreover, the number of women in the four groups was higher than that of men. Blood pressure in the dexmedetomidine group was lower than the other four groups (P <0.05). The lowest heart rate was observed in the haloperidol group, while the highest heart rate was seen in the plasil group (P <0.05). The occurrence of vomiting and nausea was not significantly different between the four groups (P <0.05). Our results showed no significant difference in postoperative nausea and vomiting between the four drugs. Due to the hemodynamic changes induced by each drug, it is best to use these drugs based on the patient's condition. Ginger is also a herbal remedy that has fewer side effects, and this drug can be a good option for patients when there is no contraindication.


Assuntos
Colecistectomia Laparoscópica/efeitos adversos , Dexmedetomidina/uso terapêutico , Gengibre/química , Haloperidol/uso terapêutico , Metoclopramida/uso terapêutico , Extratos Vegetais/uso terapêutico , Náusea e Vômito Pós-Operatórios/tratamento farmacológico , Náusea e Vômito Pós-Operatórios/etiologia , Adulto , Idoso , Pressão Sanguínea/efeitos dos fármacos , Dexmedetomidina/farmacologia , Método Duplo-Cego , Feminino , Haloperidol/farmacologia , Humanos , Irã (Geográfico) , Masculino , Metoclopramida/farmacologia , Pessoa de Meia-Idade , Oxigênio/metabolismo
2.
In Vivo ; 34(3 Suppl): 1629-1632, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: covidwho-534630

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense single-stranded RNA virus. It is contagious in humans and is the cause of the coronavirus disease 2019 (COVID-19) pandemic. In the current analysis, we searched for SARS-CoV-2 sequences within the human genome. To compare the SARS-CoV-2 genome to the human genome, we used the blast-like alignment tool (BLAT) of the University of California, Santa Cruz Genome Browser. BLAT can align a user sequence of 25 bases or more to the genome. BLAT search results revealed a 117-base pair SARS-CoV-2 sequence in the human genome with 94.6% identity. The sequence was in chromosome 1p within an intronic region of the netrin G1 (NTNG1) gene. The sequence matched a sequence in the SARS-CoV-2 orf1b (open reading frames) gene. The SARS-CoV-2 human sequence lies within non-structural proteins 14 and 15 (NSP14 and NSP15), and is quite close to the viral spike sequence, separated only by NSP16, a 904-base pair sequence. The mechanism for SARS-CoV-2 infection is the binding of the virus spike protein to the membrane-bound form of angiotensin-converting enzyme 2 and internalization of the complex by the host cell. It is probably no accident that a sequence from the SARS-CoV-2 orf1b gene is found in the human NTNG1 gene, implicated in schizophrenia, and that haloperidol, used to treat schizophrenia, may also be a treatment for COVID-19. We suggest, therefore, that it is important to investigate other haloperidol analogs. Among them are benperidol, bromperidol, bromperidol decanoate, droperidol, seperidol hydrochloride, and trifluperidol. These analogs might be valuable in the treatment of COVID-19 and other coronavirus infections.


Assuntos
Betacoronavirus/genética , Cromossomos Humanos Par 1/genética , Genes Virais , Netrina-1/genética , Proteínas Virais/genética , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Sequência de Bases , Infecções por Coronavirus/tratamento farmacológico , DNA Complementar/genética , Endorribonucleases/genética , Exorribonucleases/genética , Haloperidol/análogos & derivados , Haloperidol/farmacologia , Haloperidol/uso terapêutico , Humanos , Íntrons/genética , Pan troglodytes/genética , Pandemias , Pneumonia Viral/tratamento farmacológico , RNA Viral/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Alinhamento de Sequência , Homologia de Sequência do Ácido Nucleico , Especificidade da Espécie , Proteínas não Estruturais Virais/genética
3.
In Vivo ; 34(3 Suppl): 1629-1632, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32503821

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense single-stranded RNA virus. It is contagious in humans and is the cause of the coronavirus disease 2019 (COVID-19) pandemic. In the current analysis, we searched for SARS-CoV-2 sequences within the human genome. To compare the SARS-CoV-2 genome to the human genome, we used the blast-like alignment tool (BLAT) of the University of California, Santa Cruz Genome Browser. BLAT can align a user sequence of 25 bases or more to the genome. BLAT search results revealed a 117-base pair SARS-CoV-2 sequence in the human genome with 94.6% identity. The sequence was in chromosome 1p within an intronic region of the netrin G1 (NTNG1) gene. The sequence matched a sequence in the SARS-CoV-2 orf1b (open reading frames) gene. The SARS-CoV-2 human sequence lies within non-structural proteins 14 and 15 (NSP14 and NSP15), and is quite close to the viral spike sequence, separated only by NSP16, a 904-base pair sequence. The mechanism for SARS-CoV-2 infection is the binding of the virus spike protein to the membrane-bound form of angiotensin-converting enzyme 2 and internalization of the complex by the host cell. It is probably no accident that a sequence from the SARS-CoV-2 orf1b gene is found in the human NTNG1 gene, implicated in schizophrenia, and that haloperidol, used to treat schizophrenia, may also be a treatment for COVID-19. We suggest, therefore, that it is important to investigate other haloperidol analogs. Among them are benperidol, bromperidol, bromperidol decanoate, droperidol, seperidol hydrochloride, and trifluperidol. These analogs might be valuable in the treatment of COVID-19 and other coronavirus infections.


Assuntos
Betacoronavirus/genética , Cromossomos Humanos Par 1/genética , Exorribonucleases/genética , Genes Virais , Netrina-1/genética , Proteínas não Estruturais Virais/genética , Proteínas Virais/genética , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Sequência de Bases , Infecções por Coronavirus/tratamento farmacológico , DNA Complementar/genética , Endorribonucleases/genética , Haloperidol/análogos & derivados , Haloperidol/farmacologia , Haloperidol/uso terapêutico , Humanos , Íntrons/genética , Pan troglodytes/genética , Pandemias , Pneumonia Viral/tratamento farmacológico , RNA Viral/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Alinhamento de Sequência , Homologia de Sequência do Ácido Nucleico , Especificidade da Espécie
4.
Nat Commun ; 11(1): 1074, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-32103023

RESUMO

The D2 dopamine receptor (DRD2) is one of the most well-established therapeutic targets for neuropsychiatric and endocrine disorders. Most clinically approved and investigational drugs that target this receptor are known to be subfamily-selective for all three D2-like receptors, rather than subtype-selective for only DRD2. Here, we report the crystal structure of DRD2 bound to the most commonly used antipsychotic drug, haloperidol. The structures suggest an extended binding pocket for DRD2 that distinguishes it from other D2-like subtypes. A detailed analysis of the structures illuminates key structural determinants essential for DRD2 activation and subtype selectivity. A structure-based and mechanism-driven screening combined with a lead optimization approach yield DRD2 highly selective agonists, which could be used as chemical probes for studying the physiological and pathological functions of DRD2 as well as promising therapeutic leads devoid of promiscuity.


Assuntos
Antipsicóticos/farmacologia , Haloperidol/farmacologia , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/ultraestrutura , Cristalografia por Raios X , Humanos , Conformação Proteica/efeitos dos fármacos , Receptores de Dopamina D2/agonistas , Risperidona/metabolismo , Risperidona/farmacologia
5.
Fluids Barriers CNS ; 16(1): 38, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31842924

RESUMO

BACKGROUND: Research into amisulpride use in Alzheimer's disease (AD) implicates blood-brain barrier (BBB) dysfunction in antipsychotic sensitivity. Research into BBB transporters has been mainly directed towards the ABC superfamily, however, solute carrier (SLC) function in AD has not been widely studied. This study tests the hypothesis that transporters for organic cations contribute to the BBB delivery of the antipsychotics (amisulpride and haloperidol) and is disrupted in AD. METHODS: The accumulation of [3H]amisulpride (3.7-7.7 nM) and [3H]haloperidol (10 nM) in human (hCMEC/D3) and mouse (bEnd.3) brain endothelial cell lines was explored. Computational approaches examined molecular level interactions of both drugs with the SLC transporters [organic cation transporter 1 (OCT1), plasma membrane monoamine transporter (PMAT) and multi-drug and toxic compound extrusion proteins (MATE1)] and amisulpride with the ABC transporter (P-glycoprotein). The distribution of [3H]amisulpride in wildtype and 3×transgenic AD mice was examined using in situ brain perfusion experiments. Western blots determined transporter expression in mouse and human brain capillaries . RESULTS: In vitro BBB and in silico transporter studies indicated that [3H]amisulpride and [3H]haloperidol were transported by the influx transporter, OCT1, and efflux transporters MATE1 and PMAT. Amisulpride did not have a strong interaction with OCTN1, OCTN2, P-gp, BCRP or MRP and could not be described as a substrate for these transporters. Amisulpride brain uptake was increased in AD mice compared to wildtype mice, but vascular space was unaffected. There were no measurable changes in the expression of MATE1, MATE2, PMAT OCT1, OCT2, OCT3, OCTN1, OCTN2 and P-gp in capillaries isolated from whole brain homogenates from the AD mice compared to wildtype mice. Although, PMAT and MATE1 expression was reduced in capillaries obtained from specific human brain regions (i.e. putamen and caudate) from AD cases (Braak stage V-VI) compared to age matched controls (Braak stage 0-II). CONCLUSIONS: Together our research indicates that the increased sensitivity of individuals with Alzheimer's to amisulpride is related to previously unreported changes in function and expression of SLC transporters at the BBB (in particular PMAT and MATE1). Dose adjustments may be required for drugs that are substrates of these transporters when prescribing for individuals with AD.


Assuntos
Doença de Alzheimer/metabolismo , Amissulprida/farmacologia , Antipsicóticos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Proteínas de Membrana Transportadoras/farmacologia , Idoso de 80 Anos ou mais , Animais , Sítios de Ligação , Linhagem Celular , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Feminino , Haloperidol/farmacologia , Humanos , Masculino , Proteínas de Membrana Transportadoras/química , Camundongos , Camundongos Transgênicos , Modelos Biológicos
6.
Bull Exp Biol Med ; 168(1): 48-51, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31745682

RESUMO

We studied antidepressant and antiparkinsonian properties of N-(5-hydroxynicotinoyl)-Lglutamic acid calcium salt (Ampasse) in rodents. It was found that Ampasse in a dose of 30 mg/kg exhibited antidepressant activity in the forced swimming test in mice and in a dose of 0.1 mg/kg maximally alleviates the symptoms of parkinsonian syndrome induced by systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in C57Bl/6 mice, and haloperidol-induced catalepsy in rats.


Assuntos
Antidepressivos/uso terapêutico , Cálcio/química , Depressão/tratamento farmacológico , Ácido Glutâmico/química , Ácido Glutâmico/uso terapêutico , Transtornos Parkinsonianos/tratamento farmacológico , Animais , Catalepsia/induzido quimicamente , Haloperidol/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
7.
Environ Toxicol Pharmacol ; 72: 103244, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31557707

RESUMO

The glucose metabolism in the pentose cycle is essential to the source of NADPH. Deficiency of these enzymes have been linked to depression and psychotic disorders. Depression is an increasingly prevalent mental disorder which may cause loss of labor. Antidepressant drugs are commonly employed in treatments of mood disorders and anxiety treatment. The purpose of this study is to investigate the effects of aripiprazole, mirtazapine, risperidone, escitalopram and haloperidol on the activity of 6-phosphogluconate dehydrogenase (6PGD) and glucose-6-phosphate dehydrogenase (G6PD) enzymes purified from human erythrocytes. It was found that aripiprazole, mirtazapine, risperidone, escitalopram and haloperidol show effective inhibitor properties on purified G6PD and 6PGD enzymes. The IC50 values of these drugs were found in the range of 26.34 µM-5.78 mM for 6PGD and 16.26 µM-3.85 mM for G6PD. The Ki values of the drugs were found in the range of 30.21 ± 4.31 µM-4.51 ± 1.83 mM for 6PGD and 14.12 ± 3.48 µM-4.98 ± 1.14 mM for G6PD. Usage of drugs with significant biological effects may be a hazard in some conditions.


Assuntos
Antidepressivos/farmacologia , Eritrócitos/efeitos dos fármacos , Glucosefosfato Desidrogenase/antagonistas & inibidores , Via de Pentose Fosfato/efeitos dos fármacos , Fosfogluconato Desidrogenase/antagonistas & inibidores , Aripiprazol/farmacologia , Citalopram/farmacologia , Eritrócitos/enzimologia , Haloperidol/farmacologia , Humanos , Mirtazapina/farmacologia
8.
Neurosci Res ; 147: 39-47, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31446906

RESUMO

Perinatal virus infection is an environmental risk factor for neurodevelopmental disorders such as schizophrenia. We previously demonstrated that neonatal treatment with a viral mimetic, polyriboinosinic-polyribocytidilic acid (polyI:C), in mice leads to emotional and cognitive deficits in adolescence. Here, we investigated the effects of antipsychotics on polyI:C-induced behavioral abnormalities. We also performed a proteomic analysis in the hippocampus of polyI:C-treated adult mice using two-dimensional electrophoresis to understand the changes in protein expression following neonatal immune activation. Neonatal mice were subcutaneously injected with polyI:C for 5 days (postnatal day 2-6). At 10 weeks, sensorimotor gating, emotional and cognitive function were analyzed in behavioral tests. Clozapine improved PPI deficit and emotional and cognitive dysfunction in polyI:C-treated mice. However, haloperidol improved only PPI deficit. Proteomic analysis revealed that two candidate proteins were obtained in the hippocampus of polyI:C-treated mice, including aldehyde dehydrogenase family 1 member L1 (ALDH1L1) and collapsin response mediator protein 5 (CRMP5). These data suggest that the neonatal polyI:C-treated mouse model may be useful for evaluating antipsychotic activity of compounds. Moreover, changes in the protein expression of ALDH1L1 and CRMP5 support our previous findings that astrocyte-neuron interaction plays a role in the pathophysiology of neurodevelopmental disorders induced by neonatal immune activation.


Assuntos
Antipsicóticos/farmacologia , Poli I-C/farmacologia , Proteômica , Esquizofrenia/induzido quimicamente , Aldeído Desidrogenase 1/metabolismo , Animais , Animais Recém-Nascidos , Clozapina/farmacologia , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Feminino , Haloperidol/farmacologia , Hipocampo/efeitos dos fármacos , Hidrolases/metabolismo , Relações Interpessoais , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas do Tecido Nervoso , Gravidez , Inibição Pré-Pulso , Reconhecimento Psicológico , Filtro Sensorial/efeitos dos fármacos
9.
Folia Med (Plovdiv) ; 61(2): 258-265, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31301661

RESUMO

BACKGROUND: Parkinson's disease (PD) is the second most common neurode-generative disease, usually detected by its motor symptoms. The non-motor symptoms, including cognitive deficits, have been of great interest to researchers in the last few decades. AIM: To assess the effect of pramipexole on learning and memory in naïve and haloperidol-challenged rats. MATERIALS AND METHODS: Male Wistar rats divided into 9 groups (n=8): naïve - saline, pramipexole 0.5; 1 and 3 mg/kg bw; Haloperidol groups - saline, haloperidol, haloperidol + pramipexole 0.5; 1 and 3 mg/kg bw. Two-way active avoidance test (TWAA) and activity cage were performed. The studied parameters were: number of conditioned and unconditioned responses, vertical and horizontal movements. Statistical analysis was done using SPSS 19. RESULTS: The naïve experimental groups significantly increased the number of conditioned responses during the tests for short- and long-term memory, compared with the saline groups (p<0.05). During the short-memory test only the animals with the lowest dose of PMX significantly increased the number of unconditioned responses whereas during the long-term memory test all experimental groups increased the number of escapes in comparison with the saline groups (p<0.05). Challenge dose of haloperidol attenuates learning and memory in pramipexol treated rats. Only the highest dose of pramipexol showed significant increase in conditioned and unconditioned responses compared with the haloperidol group (p<0.05). CONCLUSION: Pramipexole improves learning and memory in naïve rats by enhancing dopaminergic neurotransmission. This is probably not the only mechanism involved. This is confirmed by the decrease in learning and memory ability in rats with haloperidol-challenge.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Memória/efeitos dos fármacos , Pramipexol/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Haloperidol/farmacologia , Aprendizagem/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar
10.
Mol Pharmacol ; 96(3): 308-319, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31266815

RESUMO

The dopamine D2 receptor (D2R) mediates ligand-biased signaling with potential therapeutic implications. However, internalization, choice of endocytic routes, and degradation of the D2R in lysosomes may also participate in agonist-directed trafficking. We developed bioluminescence resonance energy transfer (BRET) assays that measure relative distances between Renilla luciferase8-tagged D2R and green fluorescent protein 2 (GFP2)-tagged K-Ras (plasma membrane marker), and between luciferase8-tagged D2R and GFP2-Rab5 (early), GFP2-Rab4 (recycling), or GFP2-Rab7 (late) endosomal markers. The BRET signal between D2R-Luc and GFP2-K-Ras was robustly diminished after receptor internalization induced by dopamine, with subsequent BRET signals increasing when luciferase8-tagged D2R approached GFP2-Rab proteins in endosomal compartments. All BRET signals were blocked by the selective D2R antagonist haloperidol and were decreased by low temperature and high sucrose blocks, two parameters interfering with internalization. Some antipsychotic drugs, such as aripiprazole, are less efficacious in internalizing D2R than most of the antiparkinsonian agents. However, antipsychotics were nearly as efficacious as antiparkinsonians in directing the D2R toward early and recycling endosomes. The Rab7 marker for the late endosome/lysosome route was also capable of discriminating between D2R compounds. We could show that some drugs engaged the D2R either to interact preferentially with arrestin-3 or to internalize. Our study revealed that D2R trafficking in cells was differentially regulated by antipsychotic and antiparkinsonian drugs. Taken together, the BRET assays reported here could further help decipher D2R ligand-induced arrestin-3 recruitment and trafficking, with potentially more selective therapeutic profiles and fewer undesired side effects.


Assuntos
Arrestinas/metabolismo , Técnicas de Transferência de Energia por Ressonância de Bioluminescência , Proteínas de Fluorescência Verde/metabolismo , Receptores de Dopamina D2/agonistas , Animais , Células CHO , Cricetulus , Antagonistas de Dopamina/farmacologia , Haloperidol/farmacologia , Lisossomos/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais , Proteínas rab de Ligação ao GTP/metabolismo
11.
Oxid Med Cell Longev ; 2019: 7417561, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31205589

RESUMO

Both c-Jun N-terminal kinase (JNK) and reactive oxygen species (ROS) play important roles in myocardial ischemia/reperfusion (I/R) injury. Our previous studies suggest that N-n-butyl haloperidol iodide (F2) exerts cardioprotection by reducing ROS production and JNK activation caused by I/R. In this study, we hypothesized that there is a JNK/Sab/Src/ROS pathway in the mitochondria in H9c2 cells following hypoxia/reoxygenation (H/R) that induces oxidative stress in the mitochondria and that F2 exerts mitochondrial protective effects during H/R injury by modulating this pathway. The results showed that H/R induced higher-level ROS in the cytoplasm on the one hand and JNK activation and translocation to the mitochondria by colocalization with Sab on the other. Moreover, H/R resulted in mitochondrial Src dephosphorylation, and subsequently, oxidative stress evidenced by the increase in ROS generation and oxidized cardiolipin in the mitochondrial membranes and by the decrease in mitochondrial superoxide dismutase activity and membrane potential. Furthermore, treatment with a JNK inhibitor or Sab small interfering RNA inhibited the mitochondrial translocation of p-JNK, decreased colocalization of p-JNK and Sab on the mitochondria, and reduced Src dephosphorylation and mitochondrial oxidative stress during H/R. In addition, Src dephosphorylation by inhibitor PP2 increased mitochondrial ROS production. F2, like inhibitors of the JNK/Sab/Src/ROS pathway, downregulated the H/R-induced mitochondrial translocation of p-JNK and the colocalization of p-JNK and Sab on the mitochondria, increased Src phosphorylation, and alleviated the above-mentioned mitochondrial oxidative stress. In conclusion, F2 could ameliorate H/R-associated oxidative stress in mitochondria in H9c2 cells through the mitochondrial JNK/Sab/Src/ROS pathway.


Assuntos
Haloperidol/análogos & derivados , Hipóxia/fisiopatologia , Mitocôndrias/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Animais , Células Cultivadas , Haloperidol/farmacologia , Oxigenação Hiperbárica , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas Mitocondriais/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Substâncias Protetoras/farmacologia , Ratos , Quinases da Família src/metabolismo
12.
PLoS One ; 14(6): e0218200, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31181134

RESUMO

Antipsychotic drugs haloperidol and clozapine have been reported to increase the sensitivity of retinal ganglion cells (RGCs) to flashes of light in the P23H rat model of retinitis pigmentosa. In order to better understand the effects of these antipsychotic drugs on the visual responses of P23H rat RGCs, I examined the responses of RGCs to a drifting sinusoidal grating of various contrasts. In-vitro multielectrode array recordings were made from P23H rat RGCs and healthy Sprague-Dawley (SD) rat RGCs. Retinas were stimulated with a drifting sinusoidal grating with eight values of contrast (0, 4, 6, 8.5, 13, 26, 51, and 83%). Contrast response functions based on response amplitudes were fitted with a hyperbolic ratio function and contrast thresholds were determined from the fitted curves. SD rat RGCs were divided into two categories, saturating and non-saturating cells, based on whether they showed saturation of responses at high contrast levels. Most SD rat RGCs (58%) were saturating cells. Haloperidol and clozapine decreased the responses of saturating SD rat RGCs to all grating contrasts, except for the highest contrast tested. Clozapine also decreased the responses of non-saturating SD rat RGCs to all grating contrasts, except for the highest contrast tested. Haloperidol did not however significantly affect the responses of non-saturating SD rat RGCs. Haloperidol and clozapine increased the contrast thresholds of both saturating and non-saturating cells in SD rat retinas. Most (73%) P23H rat RGCs could be categorized as either saturating or non-saturating cells. The remaining 'uncategorized' cells were poorly responsive to the drifting grating and were analyzed separately. Haloperidol and clozapine increased the responses of non-saturating and uncategorized P23H rat RGCs to most grating contrasts, including the highest contrast tested. Haloperidol and clozapine also increased the responses of saturating P23H rat RGCs to most grating contrasts but these increases were not statistically significant. Haloperidol and clozapine decreased the contrast thresholds of saturating cells, non-saturating cells and uncategorized cells in P23H rat retinas, although the decrease in contrast thresholds of saturating cells was not found to be statistically significant. Overall, the findings show that haloperidol and clozapine have differential effects on the contrast response functions of SD and P23H rat RGCs. In contrast to the effects observed on SD rat RGCs, both haloperidol and clozapine increased the responsiveness of P23H rat RGCs to both low and high contrast visual stimuli and decreased contrast thresholds.


Assuntos
Antipsicóticos/farmacologia , Células Ganglionares da Retina/efeitos dos fármacos , Retinite Pigmentosa/tratamento farmacológico , Animais , Clozapina/farmacologia , Modelos Animais de Doenças , Haloperidol/farmacologia , Masculino , Estimulação Luminosa , Ratos , Ratos Sprague-Dawley , Retina/efeitos dos fármacos , Retina/fisiologia
13.
Behav Processes ; 165: 1-3, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31185264

RESUMO

The nematode Phasmarhabditis hermaphrodita can infect and kill many species of slugs and has been formulated into a biological control agent for farmers and gardeners. P. hermaphrodita can manipulate the behaviour of slugs, making those infected move to areas where the nematode is present. Research suggests P. hermaphrodita uses manipulation of biogenic amines to achieve this, however the exact role of serotonin and dopamine needs further elucidation. Here we fed slugs Deroceras invadens (uninfected and infected with P. hermaphrodita) apomorphine, sertraline and haloperidol and observed their behaviour when given a choice between a P. hermaphrodita infested habitat, or a parasite free area of soil. In contrast to their usual P. hermaphrodita avoidance behaviour, uninfected D. invadens fed sertraline were attracted to the nematodes and conversely those fed haloperidol avoided the nematodes. D. invadens fed apomorphine were recorded equally on the control and nematode side. D. invadens pre-infected with P. hermaphrodita fed sertraline and apomorphine were found significantly more on the side with the nematodes. However, suppressing dopaminergic signalling through feeding with haloperidol abrogated this attraction and slugs were found on both sides. These results demonstrate that serotonin and dopamine are potential regulators of behavioural manipulation by P. hermaphrodita.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Agentes de Controle Biológico/farmacologia , Gastrópodes/efeitos dos fármacos , Gastrópodes/parasitologia , Rhabditoidea , Animais , Apomorfina/farmacologia , Aprendizagem da Esquiva/fisiologia , Dopamina/fisiologia , Haloperidol/farmacologia , Serotonina/fisiologia , Sertralina/farmacologia , Solo/parasitologia
14.
Am J Psychiatry ; 176(9): 730-743, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31055969

RESUMO

OBJECTIVE: The mechanisms leading to schizophrenia are likely to be diverse. However, there may be common pathophysiological pathways for subtypes of the disease. The authors tested the hypothesis that increased protein insolubility and ubiquitination underlie the pathophysiology for a subtype of schizophrenia. METHODS: Prefrontal cortex and superior temporal gyrus from postmortem brains of individuals with and without schizophrenia were subjected to cold sarkosyl fractionation, separating proteins into soluble and insoluble fractions. Protein insolubility and ubiquitin levels were quantified for each insoluble fraction, with normalization to total homogenate protein. Mass spectrometry analysis was then performed to identify the protein contents of the insoluble fractions. The potential biological relevance of the detected proteins was assessed using Gene Ontology enrichment analysis and Ingenuity Pathway Analysis. RESULTS: A subset of the schizophrenia brains showed an increase in protein insolubility and ubiquitination in the insoluble fraction. Mass spectrometry of the insoluble fraction revealed that brains with increased insolubility and ubiquitination exhibited a similar peptide expression by principal component analysis. The proteins that were significantly altered in the insoluble fraction were enriched for pathways relating to axon target recognition as well as nervous system development and function. CONCLUSIONS: This study suggests a pathological process related to protein insolubility for a subset of patients with schizophrenia. Determining the molecular mechanism of this subtype of schizophrenia could lead to a better understanding of the pathways underlying the clinical phenotype in some patients with major mental illness as well as to improved nosology and identification of novel therapeutic targets.


Assuntos
Encéfalo/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Esquizofrenia/metabolismo , Animais , Antipsicóticos/farmacologia , Western Blotting , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Estudos de Casos e Controles , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Haloperidol/farmacologia , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Ratos , Ratos Sprague-Dawley , Risperidona/farmacologia , Esquizofrenia/etiologia , Esquizofrenia/fisiopatologia , Solubilidade , Lobo Temporal/metabolismo , Lobo Temporal/patologia , Ubiquitinação
15.
Behav Pharmacol ; 30(6): 521-528, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31058657

RESUMO

Haloperidol (HAL) was developed in 1958 for the treatment of schizophrenia and is classified as a typical antipsychotic drug (APD). Effective in treating positive symptoms of schizophrenia, it does not treat negative symptoms and produces extrapyramidal motor side-effects. Atypical APDs like clozapine treat both positive and negative symptoms of schizophrenia, have reduced extrapyramidal motor side-effects and possess other clinical advantages. This study used a drug discrimination assay to allow a direct comparison between the subjective effects of HAL and other APDs. Eleven C57BL/6 mice were trained to discriminate 0.05 mg/kg HAL from the vehicle in a two-lever drug discrimination task. The HAL generalization curve (0.001563-0.2 mg/kg) yielded an ED50=0.0024 mg/kg (95% confidence interval: 0.0012-0.0048 mg/kg). The typical APD chlorpromazine produced full substitution at 4.0 mg/kg with 82.7% drug-lever responding (%DLR) with significant rate suppression and partial substitution (73.9% DLR) at 1.0 mg/kg with no rate suppression. The atypical APD clozapine produced partial substitution at 2.5 mg/kg (64.8% DLR) with significant rate suppression. The atypical APD amisulpride failed to substitute for HAL with a maximum %DLR of 57.9% at 40 mg/kg with no rate suppression. The atypical APD aripiprazole partially substituted with a maximum of 75.9% DLR at 1.25 mg/kg with significant rate suppression. These results demonstrate that HAL can be trained as a discriminative stimulus in C57BL/6 mice, and its discriminative cue appears to be unique and distinct from that of atypical APDs.


Assuntos
Aprendizagem por Discriminação/efeitos dos fármacos , Haloperidol/farmacologia , Amissulprida/farmacologia , Animais , Antipsicóticos/farmacologia , Aripiprazol/farmacologia , Clozapina/farmacologia , Discriminação Psicológica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL
16.
J Anesth ; 33(3): 416-425, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31049689

RESUMO

PURPOSE: Neuroinflammation may contribute to the pathogenesis of the cognitive symptoms of postoperative delirium (POD) and its subsequent long-term cognitive impairment. Haloperidol (HAL), a dopamine receptor antagonist, is widely used to treat POD, whereas the effects of HAL on postoperative neuroinflammation and related cognitive deficits have been underdetermined. METHODS: Aged rats underwent sham or abdominal surgery and were subcutaneously treated with either vehicle, low-dose (0.5 mg/kg bolus, then 0.5 mg/kg/day infusion), or high-dose (2.0 mg/kg bolus, then 2.0 mg/kg/day infusion) HAL. All treatments were initiated immediately after surgery and continued for 48 h. On either postoperative day 2 (early) or 7 (late), all rats were tested for trace and context fear memory retention after acquisition of trace fear conditioning. Following the cognitive testing, the levels of pro-inflammatory cytokines, as well as dopamine and its metabolite, in hippocampus and medial prefrontal cortex (mPFC) were measured. RESULTS: In the early postoperative period, surgery induced acute neuroinflammation along with related trace and context memory dysfunction. Dopamine turnover was increased in both hippocampus and mPFC, whereas no relationship with memory functions was observed. However, HAL even at high-dose failed to restore the surgery-induced neuroinflammation and related cognitive deficits. In the late postoperative period, chronic neuroinflammation was detected only in hippocampus, which was associated with context, but not trace memory dysfunction. Neither low- nor high-dose HAL could prevent the development of these late-phase neurocognitive deficits. CONCLUSION: Our findings indicate that perioperative administration with HAL may have no effects on postoperative neuroinflammation and related cognitive impairment.


Assuntos
Cognição/efeitos dos fármacos , Disfunção Cognitiva/etiologia , Haloperidol/farmacologia , Animais , Citocinas/metabolismo , Delírio/prevenção & controle , Medo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Memória/fisiologia , Período Pós-Operatório , Ratos , Ratos Wistar , Fatores de Tempo
17.
World Neurosurg ; 128: e468-e477, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31048057

RESUMO

OBJECTIVE: The current standard treatment of malignant glioma is maximal resection followed by chemotherapy and radiotherapy. Temozolomide (TMZ) has been the first-line chemotherapeutic agent used, although to achieve a satisfactory clinical effect. TMZ chemoresistance could result from glioblastoma stem cells, which are critical for tumor initiation, recurrence, and therapeutic resistance and are potential targets. Moreover, signals mediated by the dopamine D2 receptor (DRD2) can positively regulate proliferation and tumorigenesis of glioma cells. RESULTS: To enhance TMZ's antitumor effect, we treated glioma cells with combinations of TMZ and DRD2 antagonists (DDRAs). The combined application of TMZ and DDRAs (haloperidol or risperidone) had synergistic effects and inhibited proliferation of glioma cells more significantly than did monotherapy. The combined treatment increased the levels of γH2AX (a marker of DNA damage) more significantly than did TMZ alone, although DDRAs alone had no effect on γH2AX levels. Moreover, the expression of DRD2 transcripts in U251 glioma cells and glioblastoma stem cells were significantly elevated after TMZ treatment, suggesting crosstalk between TMZ- and DRD2-mediated signaling. To explore the underlying mechanisms, we measured the expression of prosurvival proteins after treatment with either TMZ or DDRAs alone or combined. The results showed that DDRAs could inhibit the extracellular signal-related kinase signaling pathway and block TMZ-induced protective autophagy, which could explain why DDRAs increased the cytotoxicity of TMZ. CONCLUSIONS: We have provided evidence showing the synergistic effects of TMZ and DDRAs on suppressing glioma cell growth. Our study has provided novel insights on enhancing the effectiveness of chemotherapy against malignant glioma and eventually improving the clinical outcomes of patients with glioblastoma multiforme.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Autofagia/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2/farmacologia , Glioblastoma/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Temozolomida/farmacologia , Animais , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Sinergismo Farmacológico , Glioblastoma/metabolismo , Haloperidol/farmacologia , Histonas/efeitos dos fármacos , Histonas/metabolismo , Humanos , Técnicas In Vitro , Camundongos , Camundongos Nus , Transplante de Neoplasias , Células-Tronco Neoplásicas/efeitos dos fármacos , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/genética , Risperidona/farmacologia
18.
J Vis Exp ; (145)2019 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-30933076

RESUMO

The present article provides a guide for the conduction and analysis of three conditioning-based protocols to evaluate impulsivity in rats. Impulsivity is a meaningful concept because it is associated with psychiatric conditions in humans and with maladaptive behavior in non-human animals. It is believed that impulsivity is composed of separate factors. There are laboratory protocols devised to assess each of these factors using standardized automated equipment. Delay discounting is associated with the incapacity to be motivated by delayed outcomes. This factor is evaluated through intertemporal choice protocols, which consist of presenting the individual with a choice situation involving an immediate reward and a larger but delayed reward. Response inhibition deficit is associated with the incapacity to withhold prepotent responses. Differential reinforcement of low rates (DLR) and feature-negative discrimination protocols assess the response inhibition deficit factor of impulsivity. The former imposes a condition to a motivated individual in which most wait a minimum period of time for a response to be rewarded. The latter evaluates the capacity of individuals to refrain from food seeking responses when a signal of the absence of food is presented. The purpose of these protocols is to construct an objective quantitative measure of impulsivity, which serves to make cross-species comparisons, allowing the possibility of translational research. The advantages of these particular protocols include their easy set-up and application, which stems from the relatively small amount of equipment needed and the automated nature of these protocols.


Assuntos
Comportamento Impulsivo/fisiologia , Laboratórios , Animais , Comportamento de Escolha , Desvalorização pelo Atraso/fisiologia , Discriminação Psicológica , Alimentos , Haloperidol/farmacologia , Masculino , Ratos Endogâmicos SHR , Ratos Wistar , Reforço Psicológico
19.
Exp Neurol ; 318: 61-70, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31034808

RESUMO

GNAL encodes guanine nucleotide-binding protein subunit Gα(olf) which plays a key role in striatal medium spiny neuron (MSN)-dopamine signaling. GNAL loss-of-function mutations are causally-associated with isolated dystonia, a movement disorder characterized by involuntary muscle contractions leading to abnormal postures. Dopamine D2 receptor (D2R) blockers such as haloperidol are mainstays in the treatment of psychosis but may contribute to the development of secondary acute and tardive dystonia. Administration of haloperidol promotes cAMP-dependent signaling in D2R-expressing indirect pathway MSNs. At present, little is known about the cellular relationships among isolated, acute, and tardive dystonia. Herein, we report the effects of acute D2R blockade on motor behavior, DNA repair, cAMP-mediated histone H3 phosphorylation (Ser10), and cell death in Gnal+/- mice and their isogenic Gnal+/+ littermates. In comparison to Gnal+/+ littermates, Gnal+/- mice exhibited increased catalepsy responses, persistent DNA breaks, decreased cAMP-dependent histone H3 phosphorylation (Ser10), and increased cell death in response to haloperidol. In striatum, aged Gnal+/- mice exhibited increased global DNA methylation, increased euchromatin, and dendritic structural abnormalities. Our results provide evidence that Gα(olf) deficiency intensifies the effects of D2R antagonism and suggests that loss-of-function variants in GNAL may increase risk for movement disorders associated with D2R blockers. We hypothesize that the effects of Gα(olf) dysfunction and/or long-term D2R antagonism may lead to epigenetic silencing, transcriptional dysregulation, and, ultimately, cellular senescence and/or apoptosis in human brain.


Assuntos
Antagonistas de Dopamina/farmacologia , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Instabilidade Genômica/efeitos dos fármacos , Haloperidol/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Feminino , Haploinsuficiência , Masculino , Camundongos , Discinesia Tardia/genética
20.
Dokl Biochem Biophys ; 484(1): 63-65, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31012016

RESUMO

Using voltage-clamp technique, the involvement of sigma-1 receptors in the regulation of Na+ transport in frog skin by the immunomodulatory drug glutoxim was investigated. We have shown for the first time that preincubation of the frog skin with the sigma-1 receptor antagonists haloperidol and chlorpromazine attenuates the stimulatory effect of glutoxim on the Na+ transport. The results suggest the possible involvement of the sigma-1 receptors in the regulation of Na+ transport in frog skin epithelium by glutoxim.


Assuntos
Proteínas de Anfíbios/antagonistas & inibidores , Clorpromazina/farmacologia , Haloperidol/farmacologia , Oligopeptídeos/farmacologia , Receptores sigma/antagonistas & inibidores , Pele/metabolismo , Sódio/metabolismo , Proteínas de Anfíbios/metabolismo , Animais , Transporte de Íons/efeitos dos fármacos , Rana temporaria , Receptores sigma/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA