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1.
J Neurosci Res ; 91(10): 1292-302, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23907992

RESUMO

We previously showed that, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), vaccination with bacillus Calmette-Guerin (BCG) prior to MPTP exposure limited the loss of striatal dopamine (DA) and dopamine transporter (DAT) and prevented the activation of nigral microglia. Here, we conducted BCG dose studies and investigated the mechanisms underlying BCG vaccination's neuroprotective effects in this model. We found that a dose of 1 × 10(6) cfu BCG led to higher levels of striatal DA and DAT ligand binding (28% and 42%, respectively) in BCG-vaccinated vs. unvaccinated MPTP-treated mice, but without a significant increase in substantia nigra tyrosine hydroxylase-staining neurons. Previous studies showed that BCG can induce regulatory T cells (Tregs) and that Tregs are neuroprotective in models of neurodegenerative diseases. However, MPTP is lymphotoxic, so it was unclear whether Tregs were maintained after MPTP treatment and whether a relationship existed between Tregs and the preservation of striatal DA system integrity. We found that, 21 days post-MPTP treatment, Treg levels in mice that had received BCG prior to MPTP were threefold greater than those in MPTP-only-treated mice and elevated above those in saline-only-treated mice, suggesting that the persistent BCG infection continually promoted Treg responses. Notably, the magnitude of the Treg response correlated positively with both striatal DA levels and DAT ligand binding. Therefore, BCG vaccine-mediated neuroprotection is associated with Treg levels in this mouse model. Our results suggest that BCG-induced Tregs could provide a new adjunctive therapeutic approach to ameliorating pathology associated with PD and other neurodegenerative diseases.


Assuntos
Vacina BCG/imunologia , Fármacos Neuroprotetores/imunologia , Transtornos Parkinsonianos/imunologia , Transtornos Parkinsonianos/prevenção & controle , Linfócitos T Reguladores/imunologia , Animais , Vacina BCG/administração & dosagem , Encéfalo/imunologia , Encéfalo/patologia , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Citometria de Fluxo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/administração & dosagem
2.
Synapse ; 67(8): 476-88, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23417852

RESUMO

The continuing spread of methamphetamine (METH) abuse has stimulated research aimed at understanding consequences of its prolonged exposure. Alterations in nigrostriatal dopamine (DA) system parameters have been characterized in experimental studies after discontinuation of long-term METH but fewer studies have included similar assessments during METH exposure. Here, we report METH plasma pharmacokinetics and striatal DA system alterations in rat after noncontingent and contingent METH administration for 7.5 weeks. Escalating METH exposure was delivered by dynamic infusion (DI) that incorporated a "humanized" plasma METH half life or by intravenous self-administration (IVSA) that included binge intakes. Kinetic modeling of DI and IVSA for 24 h periods during the final week of METH exposure showed that plasma METH levels remained between 0.7 and 1.5 µM. Animals were sacrificed during their last METH administration for autoradiography assessment using [³H]ligands and D2 agonist-induced [³5S]GTPγS binding. DA transporter binding was decreased (DI, 34%; IVSA, 15%) while vesicular monoamine transporter binding and substantia nigra DA cell numbers were unchanged. Decreases were measured for D2 receptor (DI and IVSA, 15-20%) and [³5S]GTPγS binding (DI, 35%; IVSA, 18%). These similar patterns of DI and IVSA associated decreases in striatal DA markers reflect consequences of cumulative METH exposure and not the drug delivery method. For METH IVSA, individual differences were observed, yet each animal's total intake was similar within and across three 24-h binges. IVSA rodent models may be useful for identifying molecular mechanisms that are associated with METH binges in humans.


Assuntos
Corpo Estriado/efeitos dos fármacos , Dopaminérgicos/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Metanfetamina/farmacologia , Receptores de Dopamina D2/metabolismo , Animais , Corpo Estriado/metabolismo , Dopaminérgicos/administração & dosagem , Dopaminérgicos/farmacocinética , Agonistas de Dopamina/farmacologia , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Infusões Intravenosas , Injeções Intravenosas , Masculino , Metanfetamina/administração & dosagem , Metanfetamina/farmacocinética , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Radioisótopos de Enxofre , Trítio , Proteínas Vesiculares de Transporte de Monoamina/metabolismo
3.
Stud Health Technol Inform ; 173: 297-303, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22357005

RESUMO

A prototype Low Intensity Focused Ultrasound (LIFU) stimulator system was developed to evaluate non-invasive neuromodulation in a large animal model. We conducted a feasibility study on a Göttingen minipig, demonstrating reversible, targeted transcranial neuromodulation. The hypothalamus of the minipig was repeatedly stimulated with LIFU which evoked temporally correlated increases in both heart rate and blood pressure.


Assuntos
Simulação por Computador , Hipotálamo/diagnóstico por imagem , Ultrassom/métodos , Ultrassonografia/métodos , Animais , Estudos de Viabilidade , Modelos Animais , Suínos
4.
J Neurosci ; 29(9): 2867-75, 2009 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-19261882

RESUMO

The area and volume of brain structural features, as assessed by high-resolution three-dimensional magnetic resonance imaging (MRI), are among the most heritable measures relating to the human CNS. We have conducted MRI scanning of all available monkeys >2 years of age (n = 357) from the extended multigenerational pedigree of the Vervet Research Colony (VRC). Using a combination of automated and manual segmentation we have quantified several correlated but distinct brain structural phenotypes. The estimated heritabilities (h(2)) for these measures in the VRC are higher than those reported previously for such features in humans or in other nonhuman primates: total brain volume (h(2) = 0.99, SE = 0.06), cerebral volume (h(2) = 0.98, SE = 0.06), cerebellar volume (h(2) = 0.86, SE = 0.09), hippocampal volume (h(2) = 0.95, SE = 0.07) and corpus callosum cross-sectional areas (h(2) = 0.87, SE = 0.07). These findings indicate that, in the controlled environment and with the inbreeding structure of the VRC, additive genetic factors account for almost all of the observed variance in brain structure, and suggest the potential of the VRC for genetic mapping of quantitative trait loci underlying such variance.


Assuntos
Encéfalo/anatomia & histologia , Envelhecimento/fisiologia , Animais , Atlas como Assunto , Encéfalo/crescimento & desenvolvimento , Mapeamento Encefálico , Cerebelo/anatomia & histologia , Cerebelo/crescimento & desenvolvimento , Chlorocebus aethiops , Corpo Caloso/anatomia & histologia , Corpo Caloso/crescimento & desenvolvimento , Feminino , Variação Genética , Hipocampo/anatomia & histologia , Hipocampo/crescimento & desenvolvimento , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Linhagem , Fenótipo , Predomínio Social
5.
J Proteome Res ; 9(3): 1496-509, 2010 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-20155936

RESUMO

Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration in the nigrostriatal region of the brain; however, the neurodegeneration extends well beyond dopaminergic neurons. To gain a better understanding of the molecular changes relevant to PD, we applied two-dimensional LC-MS/MS to comparatively analyze the proteome changes in four brain regions (striatum, cerebellum, cortex, and the rest of brain) using a MPTP-induced PD mouse model with the objective to identify potential nigrostriatal-specific and other region-specific protein abundance changes. The combined analyses resulted in the identification of 4,895 nonredundant proteins with at least two unique peptides per protein. The relative abundance changes in each analyzed brain region were estimated based on the spectral count information. A total of 518 proteins were observed with substantial MPTP-induced abundance changes across different brain regions. A total of 270 of these proteins were observed with specific changes occurring either only in the striatum and/or in the rest of the brain region that contains substantia nigra, suggesting that these proteins are associated with the underlying nigrostriatal pathways. Many of the proteins that exhibit changes were associated with dopamine signaling, mitochondrial dysfunction, the ubiquitin system, calcium signaling, the oxidative stress response, and apoptosis. A set of proteins with either consistent change across all brain regions or with changes specific to the cortex and cerebellum regions were also detected. Ubiquitin specific protease (USP9X), a deubiquination enzyme involved in the protection of proteins from degradation and promotion of the TGF-beta pathway, exhibited altered abundance in all brain regions. Western blot validation showed similar spatial changes, suggesting that USP9X is potentially associated with neurodegeneration. Together, this study for the first time presents an overall picture of proteome changes underlying both nigrostriatal pathways and other brain regions potentially involved in MPTP-induced neurodegeneration. The observed molecular changes provide a valuable reference resource for future hypothesis-driven functional studies of PD.


Assuntos
Encéfalo/metabolismo , Intoxicação por MPTP/metabolismo , Proteômica/métodos , Animais , Apoptose/fisiologia , Química Encefálica , Modelos Animais de Doenças , Dopamina/metabolismo , Intoxicação por MPTP/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Especificidade de Órgãos , Fosforilação Oxidativa , Transdução de Sinais , Substância Negra/metabolismo , Espectrometria de Massas em Tandem
6.
Neuropsychopharmacology ; 33(6): 1441-52, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-17625500

RESUMO

Methamphetamine (METH)-associated alterations in the human striatal dopamine (DA) system have been identified with positron emission tomography (PET) imaging and post-mortem studies but have not been well correlated with behavioral changes or cumulative METH intake. Animal studies that model some aspects of human long-term METH abuse can establish dose-dependency profiles of both behavioral changes and potential brain neurotoxicities for identifying consequences of particular cumulative exposures. Based on parameters from human and our monkey pharmacokinetic studies, we modeled a prevalent human METH exposure of daily multiple doses in socially housed vervet monkeys. METH doses were escalated over 33 weeks, with final dosages resulting in estimated peak plasma METH concentrations of 1-3 microM, a range measured in human abusers. With larger METH doses, progressive increases in abnormal behavior and decreases in social behavior were observed on 'injection' days. Anxiety increased on 'no injection' days while aggression decreased throughout the study. Thereafter, during 3 weeks abstinence, differences in baseline vs post-METH behaviors were not observed. Post-mortem analysis of METH brains showed 20% lower striatal DA content while autoradiography studies of precommissural striatum showed 35% lower [3H]WIN35428 binding to the DA transporter. No statistically significant changes were detected for [3H]dihydrotetrabenazine binding to the vesicular monoamine transporter (METH-lower by 10%) or for [3H]SCH 23390 and [3H]raclopride binding to DA D1 and D2 receptors, respectively. Collectively, this long-term, escalating dose METH exposure modeling a human abuse pattern, not associated with high-dose binges, resulted in dose-dependent behavioral effects and caused persistent changes in presynaptic striatal DA system integrity.


Assuntos
Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/administração & dosagem , Metanfetamina/administração & dosagem , Síndromes Neurotóxicas , Análise de Variância , Animais , Autorradiografia , Benzazepinas/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Química Encefálica/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/sangue , Chlorocebus aethiops , Cocaína/análogos & derivados , Cocaína/farmacocinética , Modelos Animais de Doenças , Antagonistas de Dopamina/farmacocinética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacocinética , Relação Dose-Resposta a Droga , Masculino , Metanfetamina/sangue , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/fisiopatologia , Ligação Proteica/efeitos dos fármacos , Racloprida/farmacocinética , Comportamento Social , Trítio/farmacocinética
7.
Eur J Nucl Med Mol Imaging ; 35(12): 2256-66, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18604533

RESUMO

PURPOSE: Pretreatment with cyclosporine, a P-glycoprotein (P-gp) modulator increases brain uptake of 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[(18)F]fluorobenzamido]ethylpiperazine ([(18)F]MPPF) for binding to hydroxytryptamine(1A) (5-HT(1A)) receptors. Those increases were quantified in rat brain with in vivo microPET and ex vivo tissue studies. MATERIALS AND METHODS: Each Sprague-Dawley rat (n = 4) received a baseline [(18)F]MPPF microPET scan followed by second scan 2-3 weeks later that included cyclosporine pretreatment (50 mg/kg, i.p.). Maximum a posteriori reconstructed images and volumetric ROIs were used to generate dynamic radioactivity concentration measurements for hippocampus, striatum, and cerebellum, with simplified reference tissue method (SRTM) analysis. Western blots were used to semiquantify P-gp regional distribution in brain. RESULTS: MicroPET studies showed that hippocampus uptake of [(18)F]MPPF was increased after cyclosporine; ex vivo studies showed similar increases in hippocampus and frontal cortex at 30 min, and for heart and kidney at 2.5 and 5 min, without concomitant increases in [(18)F]MPPF plasma concentration. P-gp content in cerebellum was twofold higher than in hippocampus or frontal cortex. CONCLUSIONS: These studies confirm and extend prior ex vivo results (J. Passchier, et al., Eur J Pharmacol, 2000) that showed [(18)F]MPPF as a substrate for P-gp. Our microPET results showed that P-gp modulation of [(18)F]MPPF binding to 5-HT(1A) receptors can be imaged in rat hippocampus. The heterogeneous brain distribution of P-gp appeared to invalidate the use of cerebellum as a nonspecific reference region for SRTM modeling. Regional quantitation of P-gp may be necessary for accurate PET assessment of 5-HT(1A) receptor density when based on tracer uptake sensitive to P-gp modulation.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ciclosporina/farmacologia , Piperazinas/farmacocinética , Piridinas/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/agonistas , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Animais , Encéfalo/diagnóstico por imagem , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Ciclosporina/metabolismo , Hipocampo/diagnóstico por imagem , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Técnicas In Vitro , Masculino , Tomografia por Emissão de Pósitrons , Ratos , Receptor 5-HT1A de Serotonina/metabolismo , Distribuição Tecidual
8.
J Neurosurg ; 108(2): 336-42, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18240931

RESUMO

OBJECT: Deep brain stimulation (DBS) has become an effective therapy for an increasing number of brain disorders. Recently demonstrated DBS of the posterior hypothalamus as a safe treatment for chronic intractable cluster headaches has drawn attention to this target, which is involved in the regulation of diverse autonomic functions and feeding behavior through complex integrative mechanisms. In this study, the authors assessed the feasibility of ventromedial hypothalamus (VMH) DBS in freely moving vervet monkeys to modulate food intake as a model for the potential treatment of eating disorders. METHODS: Deep brain stimulation electrodes were bilaterally implanted into the VMH of 2 adult male vervet monkeys by using the stereotactic techniques utilized in DBS in humans. Stimulators were implanted subcutaneously on the upper back, allowing ready access to program stimulation parameters while the animal remained conscious and freely moving. In anesthetized animals, intraoperatively and 6-10 weeks postsurgery, VMH DBS parameters were selected according to minimal cardiovascular and autonomic nervous system responses. Thereafter, conscious animals were subjected to 2 cycles of VMH DBS for periods of 8 and 3 days, and food intake and behavior were monitored. Animals were then killed for histological verification of probe placement. RESULTS: During VMH DBS, total food consumption increased. The 3-month bilateral implant of electrodes and subsequent periods of high-frequency VMH stimulation did not result in significant adverse behavioral effects. CONCLUSIONS: This is the first study in which techniques of hypothalamic DBS in humans have been applied in freely moving nonhuman primates. Future studies can now be conducted to determine whether VMH DBS can change hypothalamic responsivity to endocrine signals associated with adiposity for long-term modulation of food intake.


Assuntos
Estimulação Encefálica Profunda/métodos , Ingestão de Alimentos/fisiologia , Hipotálamo Médio/fisiologia , Animais , Pressão Sanguínea/fisiologia , Chlorocebus aethiops , Estimulação Encefálica Profunda/instrumentação , Eletrodos Implantados , Estudos de Viabilidade , Comportamento Alimentar/fisiologia , Proteína Glial Fibrilar Ácida/análise , Frequência Cardíaca/fisiologia , Masculino , Modelos Animais , Técnicas Estereotáxicas , Núcleo Hipotalâmico Ventromedial/fisiologia
9.
Neuroreport ; 18(16): 1741-5, 2007 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-17921879

RESUMO

Increases in basal ganglia iron are well documented for neurodegenerative diseases but have not been associated with methamphetamine (METH). In this study, vervet monkeys that received two doses of METH (2 mg/kg, intramuscularly, 6 h apart) showed at 1 month, iron increases in substantia nigra pars reticulata and globus pallidus, with concurrent increases of ferritin-immunoreactivity and decreases of tyrosine hydroxylase-immunoreactivity in substantia nigra. At 1.5 years, substantia nigra tyrosine hydroxylase-immunoreactivity had recovered while iron and ferritin-immunoreactivity increases persisted. Globus pallidus and substantia nigra iron levels of the adult METH-exposed animals (age 5-9 years) were now comparable with those of drug-naive, aged animals (19-22 years), suggesting an aging-related condition that might render those regions more vulnerable to oxidative stress.


Assuntos
Envelhecimento/metabolismo , Doenças dos Gânglios da Base/induzido quimicamente , Gânglios da Base/efeitos dos fármacos , Distúrbios do Metabolismo do Ferro/induzido quimicamente , Ferro/metabolismo , Metanfetamina/toxicidade , Envelhecimento/patologia , Animais , Gânglios da Base/metabolismo , Gânglios da Base/patologia , Doenças dos Gânglios da Base/metabolismo , Doenças dos Gânglios da Base/fisiopatologia , Estimulantes do Sistema Nervoso Central/toxicidade , Chlorocebus aethiops , Modelos Animais de Doenças , Dopamina/metabolismo , Ferritinas/efeitos dos fármacos , Ferritinas/metabolismo , Globo Pálido/efeitos dos fármacos , Globo Pálido/metabolismo , Globo Pálido/patologia , Distúrbios do Metabolismo do Ferro/metabolismo , Distúrbios do Metabolismo do Ferro/fisiopatologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Especificidade da Espécie , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismo
10.
Psychopharmacology (Berl) ; 180(3): 501-12, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15959831

RESUMO

The translational value of preclinical models of methamphetamine abuse depends in large part on the degree to which the drug regimens used in animals produce methamphetamine exposure patterns similar to those experienced by human methamphetamine abusers. To approximate one common form of methamphetamine abuse, we studied the effects of a schedule of intravenous methamphetamine administration in rats which included 2 weeks of progressively more frequent drug injections (0.125 mg/kg/injection) followed by 40 maintenance days during which animals received 40 daily injections (at 15-min intervals), with the dose gradually increasing (0.125-0.25 mg/kg per injection) every 5-10 days. This treatment produced an emerging behavioral profile characterized by gradually more continuous periods of activation consisting of progressively more intense, focused stereotypy interrupted by episodic bursts of locomotion. We also assessed markers of dopamine neurotransmission (dopamine transporter, vesicular monoamine transporter, and dopamine D1 and D2 receptors) at 15 min and (including dopamine levels) at 6 and 30 days following cessation of methamphetamine treatment. All dopamine components measured in caudate-putamen were significantly reduced at 15 min and 6 days after the final methamphetamine injection. Dopamine D1 and D2 receptors fully recovered after 30 days of drug abstinence, whereas dopamine and the dopamine transporter exhibited significant but incomplete recovery by this time point. In contrast, only the vesicular monoamine transporter exhibited no evidence of recovery over the 30-day withdrawal period. These data are discussed in terms of damage to dopamine terminals and compensatory adjustments in mechanisms maintaining functional dopaminergic transmission.


Assuntos
Núcleo Caudado/efeitos dos fármacos , Metanfetamina/administração & dosagem , Putamen/efeitos dos fármacos , Comportamento Estereotipado/efeitos dos fármacos , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Núcleo Caudado/química , Núcleo Caudado/metabolismo , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/farmacocinética , Dopamina/metabolismo , Ácido Homovanílico/metabolismo , Injeções Intravenosas , Masculino , Metanfetamina/sangue , Metanfetamina/farmacocinética , Atividade Motora/efeitos dos fármacos , Terminações Nervosas/química , Terminações Nervosas/efeitos dos fármacos , Putamen/química , Putamen/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
11.
Neuropsychopharmacology ; 28(10): 1730-40, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12865898

RESUMO

The neurotoxic effects of methamphetamine (METH) have been characterized primarily from the study of high-dose binge regimens in rodents. However, this drug administration paradigm does not include a potentially important feature of stimulant abuse in humans, that is, the gradual escalation of stimulant doses that frequently occurs prior to high-dose exposure. We have argued that pretreatment with escalating doses (EDs) might significantly alter the neurotoxic profile produced by a single high-dose binge. In the present study, we tested this hypothesis by pretreating rats with saline or gradually increasing doses of METH (0.1-4.0 mg/kg over 14 days), prior to an acute METH binge (4 x 6 mg/kg at 2 h intervals). These animals, whose behavior was continuously monitored throughout drug treatment, were then killed 3 days later for determination of caudate-putamen dopamine (DA) content, levels of [(3)H]WIN 35,428 binding to the DA transporter, and levels of [(3)H]dihydrotetrabenazine ([(3)H]DTBZ) binding to the vesicular monoamine transporter. ED pretreatment markedly attenuated the stereotypy response, as well as the hyperthermia and indices of sympathetic activation associated with the acute binge. In addition, ED pretreatment prevented the decline in [(3)H]WIN 35,428 binding, and significantly diminished the decrease in DA levels, but did not affect the decrease in [(3)H]DTBZ binding associated with the acute binge. We suggest that further study of the effects produced by a regimen which includes a gradual escalation of doses prior to high-dose METH binge exposure could more accurately identify the neurochemical and behavioral changes relevant to those that occur as a consequence of high-dose METH abuse in humans.


Assuntos
Comportamento Animal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Cocaína/análogos & derivados , Metanfetamina/farmacologia , Comportamento Estereotipado/efeitos dos fármacos , Tetrabenazina/análogos & derivados , Ácido 3,4-Di-Hidroxifenilacético/análise , Animais , Sítios de Ligação , Temperatura Corporal/efeitos dos fármacos , Cocaína/farmacocinética , Dopamina/análise , Inibidores da Captação de Dopamina/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação/veterinária , Ácido Homovanílico/análise , Masculino , Atividade Motora/efeitos dos fármacos , Neostriado/anatomia & histologia , Neostriado/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Tetrabenazina/farmacocinética , Fatores de Tempo , Trítio/farmacocinética
12.
Brain Res Dev Brain Res ; 136(2): 101-10, 2002 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-12101027

RESUMO

The protein neuronatin is expressed in the nervous system of the fetus and neonate at a much higher level than in the adult. Its function is unknown. As a result of variable splicing, neuronatin mRNA exists in two forms, alpha and beta. Wild type PC12 cells express neuronatin-alpha. We have isolated a PC12 variant, called 1.9, that retains many of the neuron-like properties of wild type PC12 cells, but it does not express neuronatin and it exhibits markedly increased sensitivity to the toxic effects of nigericin, rotenone and valinomycin. Pretreatment of the 1.9 cells with alpha-methyltyrosine, which inhibits dopamine synthesis, had little effect on the cells' sensitivity to nigericin, rotenone or valinomycin indicating that dopamine-induced oxidative stress was not involved in the toxicity of these compounds. However, flattened cell subvariants of the 1.9 cells, which do not have any neuron-specific characteristics, did not exhibit increased sensitivity to nigericin indicating that some neuronal characteristic of the 1.9 cells contributed to the toxicity of nigericin. After the neuronatin-beta gene was transfected into and expressed in the 1.9 cells, they regained wild type PC12 levels of resistance to nigericin, rotenone and valinomycin. These studies suggest that the function of neuronatin during development could be to protect developing cells from toxic insult occurring during that period.


Assuntos
Animais Recém-Nascidos/metabolismo , Encéfalo/metabolismo , Morte Celular/genética , Resistência a Medicamentos/genética , Feto/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso/metabolismo , Neurotoxinas/metabolismo , Animais , Animais Recém-Nascidos/crescimento & desenvolvimento , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Proteínas de Transporte/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Proteínas da Membrana Plasmática de Transporte de Catecolaminas , Morte Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Tamanho Celular/efeitos dos fármacos , Tamanho Celular/fisiologia , Meios de Cultivo Condicionados/farmacologia , Dopamina/metabolismo , Feto/embriologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Ionóforos/farmacologia , Melaninas/metabolismo , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/ultraestrutura , Nigericina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Células PC12 , Ratos , Espécies Reativas de Oxigênio/metabolismo , Rotenona/farmacologia , Desacopladores/farmacologia , Valinomicina/farmacologia , alfa-Metiltirosina/farmacologia
13.
J Addict Dis ; 21(1): 21-34, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-11831497

RESUMO

The abuse of methamphetamine (METH) continues to increase throughout all age groups in different regions of the United States. "Ice," the popularized jargon for (+) methamphetamine hydrochloride, is the predominant drug form that is now consumed. "Ice" is effectively absorbed after either smoking or snorting and it is this rapid influx of drug that produces effects similar to those after intravenous administration. The intensity of METH actions in the central and peripheral nervous system shows tolerance after chronic administration, indicating that neuroadaptations have occurred. Thus, the physiological processes and corresponding biochemical mechanisms that regulate neuronal function have been changed by METH exposure. These biological alterations contribute to the craving and dependence associated with METH abuse and the withdrawal syndrome upon abstinence. However, these changes in behavior may also result from METH-induced neurotoxicity. This article reviews aspects of METH pharmacokinetics and related molecular pharmacodynamics that represent METH pharmacology and then relates those actions to their potential to produce neurotoxicity in humans.


Assuntos
Estimulantes do Sistema Nervoso Central/efeitos adversos , Metanfetamina/efeitos adversos , Transtornos Relacionados ao Uso de Substâncias/etiologia , Anfetaminas/química , Anfetaminas/metabolismo , Estimulantes do Sistema Nervoso Central/farmacocinética , Humanos , Metanfetamina/farmacocinética , Metanfetamina/farmacologia , Modelos Químicos , Síndromes Neurotóxicas/etiologia
14.
PLoS One ; 7(1): e30672, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22295102

RESUMO

Prior studies of appetite regulatory networks, primarily in rodents, have established that targeted electrical stimulation of ventromedial hypothalamus (VMH) can alter food intake patterns and metabolic homeostasis. Consideration of this method for weight modulation in humans with severe overeating disorders and morbid obesity can be further advanced by modeling procedures and assessing endpoints that can provide preclinical data on efficacy and safety. In this study we adapted human deep brain stimulation (DBS) stereotactic methods and instrumentation to demonstrate in a large animal model the modulation of weight gain with VMH-DBS. Female Göttingen minipigs were used because of their dietary habits, physiologic characteristics, and brain structures that resemble those of primates. Further, these animals become obese on extra-feeding regimens. DBS electrodes were first bilaterally implanted into the VMH of the animals (n = 8) which were then maintained on a restricted food regimen for 1 mo following the surgery. The daily amount of food was then doubled for the next 2 mo in all animals to produce obesity associated with extra calorie intake, with half of the animals (n = 4) concurrently receiving continuous low frequency (50 Hz) VMH-DBS. Adverse motoric or behavioral effects were not observed subsequent to the surgical procedure or during the DBS period. Throughout this 2 mo DBS period, all animals consumed the doubled amount of daily food. However, the animals that had received VMH-DBS showed a cumulative weight gain (6.1±0.4 kg; mean ± SEM) that was lower than the nonstimulated VMH-DBS animals (9.4±1.3 kg; p<0.05), suggestive of a DBS-associated increase in metabolic rate. These results in a porcine obesity model demonstrate the efficacy and behavioral safety of a low frequency VMH-DBS application as a potential clinical strategy for modulation of body weight.


Assuntos
Estimulação Encefálica Profunda/métodos , Hipotálamo , Obesidade/fisiopatologia , Obesidade/terapia , Aumento de Peso , Animais , Comportamento Animal , Glicemia/metabolismo , Dieta , Modelos Animais de Doenças , Feminino , Humanos , Imageamento por Ressonância Magnética , Obesidade/sangue , Obesidade/cirurgia , Reprodutibilidade dos Testes , Suínos
15.
PLoS One ; 6(1): e16610, 2011 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-21304945

RESUMO

There is a growing interest in using vaccination with CNS antigens to induce autoreactive T cell responses that home to damaged areas in the CNS and ameliorate neurodegenerative disease. Neuroprotective vaccine studies have focused on administering oligodendrocyte antigens or Copaxone® in complete Freund's adjuvant (CFA). Theoretical considerations, however, suggest that vaccination with a neuronal antigen may induce more robust neuroprotective immune responses. We assessed the neuroprotective potential of vaccines containing tyrosine hydroxylase (a neuronal protein involved in dopamine synthesis) or Copaxone® in CFA in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Surprisingly, we observed that the main beneficial factor in these vaccines was the CFA. Since the major immunogenic component in CFA is Mycobacterium tuberculosis, which closely related to the bacille Calmette-Guérin (BCG) that is used in human vaccines, we tested BCG vaccination in the MPTP mouse model. We observed that BCG vaccination partially preserved markers of striatal dopamine system integrity and prevented an increase in activated microglia in the substantia nigra of MPTP-treated mice. These results support a new neuroprotective vaccine paradigm in which general (nonself-reactive) immune stimulation in the periphery can limit potentially deleterious microglial responses to a neuronal insult and exert a neurorestorative effect in the CNS. Accordingly, BCG vaccination may provide a new strategy to augment current treatments for a wide range of neuropathological conditions.


Assuntos
Vacina BCG/farmacologia , Fármacos Neuroprotetores , Doença de Parkinson/terapia , Animais , Vacina BCG/uso terapêutico , Corpo Estriado , Modelos Animais de Doenças , Dopamina , Camundongos , Substância Negra , Tirosina 3-Mono-Oxigenase/uso terapêutico , Vacinação
16.
Brain Stimul ; 4(3): 125-36, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21777872

RESUMO

With the recent approval by the Food and Drug Administration (FDA) of Deep Brain Stimulation (DBS) for Parkinson's Disease, dystonia and obsessive compulsive disorder (OCD), vagus nerve stimulation (VNS) for epilepsy and depression, and repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression, neuromodulation has become increasingly relevant to clinical research. However, these techniques have significant drawbacks (eg, lack of special specificity and depth for the rTMS, and invasiveness and cumbersome maintenance for DBS). This article reviews the background, rationale, and pilot studies to date, using a new brain stimulation method-low-intensity focused ultrasound pulsation (LIFUP). The ability of ultrasound to be focused noninvasively through the skull anywhere within the brain, together with concurrent imaging (ie, functional magnetic resonance imaging [fMRI]) techniques, may create a role for research and clinical use of LIFUP. This technique is still in preclinical testing and needs to be assessed thoroughly before being advanced to clinical trials. In this study, we review over 50 years of research data on the use of focused ultrasound (FUS) in neuronal tissue and live brain, and propose novel applications of this noninvasive neuromodulation method.


Assuntos
Encéfalo/fisiopatologia , Terapia por Ultrassom/métodos , Humanos
17.
Neuropsychopharmacology ; 34(11): 2430-41, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19571794

RESUMO

Bingeing is one pattern of high-dose methamphetamine (METH) abuse, which involves continuous drug taking over several days and can result in psychotic behaviors for which the brain pathology remains poorly defined. A corresponding animal model of this type of METH exposure may provide novel insights into the neurochemical and behavioral sequelae associated with this condition. Accordingly, to simulate the pharmacokinetic profile of a human METH binge exposure in rats, we used a computer-controlled, intravenous METH procedure (dynamic infusion, DI) to overcome species differences in METH pharmacokinetics and to replicate the human 12-h plasma METH half-life. Animals were treated over 13 weeks with escalating METH doses, using DI, and then exposed to a binge in which drug was administered every 3 h for 72 h. Throughout the binge, behavioral effects included unabated intense oral stereotypies in the absence of locomotion and in the absence of sleep. Decrements in regional brain dopamine, norepinephrine, and serotonin levels, measured at 1 and 10 h after the last injection of the binge, had, with the exception of caudate-putamen dopamine and frontal cortex serotonin, recovered by 48 h. At 10 h after the last injection of the binge, [(3)H]ligand binding to dopamine and vesicular monoamine transporters in caudate-putamen were reduced by 35 and 13%, respectively. In a separate METH binge-treated cohort, post-binge behavioral alterations were apparent in an attenuated locomotor response to a METH challenge infusion at 24 h after the last injection of the binge. Collectively, the changes we characterized during and after a METH binge suggest that for human beings under similar exposure conditions, multiple time-dependent neurochemical deficits contribute to their behavioral profiles.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Estimulantes do Sistema Nervoso Central/farmacocinética , Metanfetamina/farmacocinética , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/farmacologia , Modelos Animais de Doenças , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Humanos , Masculino , Metanfetamina/administração & dosagem , Metanfetamina/farmacologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Norepinefrina/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Sono/efeitos dos fármacos , Sono/fisiologia , Fatores de Tempo , Proteínas Vesiculares de Transporte de Monoamina/metabolismo
18.
J Acquir Immune Defic Syndr ; 48(5): 531-40, 2008 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-18645521

RESUMO

BACKGROUND: Kaposi's sarcoma-associated herpesvirus (KSHV) possesses two distinct life cycles, lytic replication and latency. An immediate early viral protein, Replication and transcription activator (RTA), is responsible for the virus switch from latency to active replication. METHODS: To identify cellular pathways that reactivate KSHV replication, an RTA-responsive viral early promoter, PAN, coupled with an enhanced green fluorescent protein (EGFP) reporter was delivered into a KSHV latently infected B cell line. Five different chemical libraries with defined cellular targets were screened for their ability to induce the PAN promoter as an indication of lytic replication. RESULTS: We identified seven chemicals that disrupted latency in KSHV latently infected B cells, five being N-acyl-dopamine derivatives. We showed that these chemicals reactivate KSHV through interacting with dopamine receptors, and that KSHV utilizes dopamine receptors and the associated PKA and MAP kinase pathways to detect and transmit stress signals for reactivation. CONCLUSION: Our study identified two cellular signaling pathways that mediate KSHV reactivation and provided a chemical genetics approach to identify new endogenous activators with therapeutic potential against herpesvirus associated malignancies.


Assuntos
Linfócitos B/virologia , Herpesvirus Humano 8/fisiologia , Receptores Dopaminérgicos/metabolismo , Transdução de Sinais , Ativação Viral , Linfócitos B/metabolismo , Linhagem Celular , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dopamina/análogos & derivados , Dopamina/metabolismo , Dopamina/farmacologia , Herpesvirus Humano 8/isolamento & purificação , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Transfecção , Latência Viral , Replicação Viral
19.
J Proteome Res ; 7(2): 666-77, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18173235

RESUMO

The molecular mechanisms underlying the changes in the nigrostriatal pathway in Parkinson's disease (PD) are not completely understood. Here, we use mass spectrometry and microarrays to study the proteomic and transcriptomic changes in the striatum of two mouse models of PD, induced by the distinct neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and methamphetamine (METH). Proteomic analyses resulted in the identification and relative quantification of 912 proteins with two or more unique peptides and 86 proteins with significant abundance changes following neurotoxin treatment. Similarly, microarray analyses revealed 181 genes with significant changes in mRNA, following neurotoxin treatment. The combined protein and gene list provides a clearer picture of the potential mechanisms underlying neurodegeneration observed in PD. Functional analysis of this combined list revealed a number of significant categories, including mitochondrial dysfunction, oxidative stress response, and apoptosis. These results constitute one of the largest descriptive data sets integrating protein and transcript changes for these neurotoxin models with many similar end point phenotypes but distinct mechanisms.


Assuntos
Apoptose/fisiologia , Perfilação da Expressão Gênica , Mitocôndrias/patologia , Neostriado/metabolismo , Estresse Oxidativo/fisiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Proteômica , Animais , Apoptose/genética , Modelos Animais de Doenças , Dopamina/deficiência , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/genética , Mitocôndrias/metabolismo , Neostriado/efeitos dos fármacos , Neostriado/patologia , Neurotoxinas/farmacologia , Estresse Oxidativo/genética , Doença de Parkinson/genética , Proteoma/genética , Proteoma/metabolismo , RNA/metabolismo
20.
Synapse ; 61(4): 216-20, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17230548

RESUMO

Characterization of methamphetamine's (METH) dose-dependent effects on brain neurochemistry may represent a critical component for better understanding the range of resultant behavioral pathologies. Most human studies, however, have assessed only the effects of long term, high dose METH abuse (e.g., greater than 1000 mg/day) in individuals meeting DSM-IV criteria for METH dependence. Yet, for the majority of METH abusers, their patterns of METH exposure that consist of lower doses remain less well-characterized. In this study, blood samples were obtained from 105 individuals detained by police for possible criminal activity and testing positive for stimulants by EMIT assay. METH blood concentrations were subsequently quantified by GC-MS and were predominantly in the low micromolar range (0.1-11.1 microM), with median and mean values of 1.3 microM (0.19 mg/l) and 2 microM (0.3 mg/l), respectively. Pharmacokinetic calculations based on these measured values were used to estimate initial METH body burdens, the median value being 52 mg. Modeling a 52 mg dose for a 4 day-METH maintenance exposure pattern of 4 doses/day at 4 h intervals showed that blood concentrations remained between 1 and 4 microM during this period. Collectively, these data present evidence for a METH exposure pattern distinct from high dose-METH abuse and provide the rationale for assessing potential brain pathology associated with such lower dose-METH exposure.


Assuntos
Estimulantes do Sistema Nervoso Central/sangue , Estimulantes do Sistema Nervoso Central/farmacocinética , Metanfetamina/sangue , Metanfetamina/farmacocinética , Transtornos Relacionados ao Uso de Substâncias/sangue , Anfetamina/sangue , Anfetamina/farmacocinética , Relação Dose-Resposta a Droga , Medicina Legal , Humanos , Fatores de Tempo
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