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1.
Glia ; 59(12): 1850-63, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21882243

RESUMO

Oxidative stress that correlates with damage to nigrostriatal dopaminergic neurons and reactive gliosis in the basal ganglia is a hallmark of methamphetamine (METH) toxicity. In this study, we analyzed the protective role of the transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2), a master regulator of redox homeostasis, in METH-induced neurotoxicity. We found that Nrf2 deficiency exacerbated METH-induced damage to dopamine neurons, shown by an increase in loss of tyrosine hydroxylase (TH)- and dopamine transporter (DAT)-containing fibers in striatum. Consistent with these effects, Nrf2 deficiency potentiated glial activation, indicated by increased striatal expression of markers for microglia (Mac-1 and Iba-1) and astroglia (GFAP) one day after METH administration. At the same time, Nrf2 inactivation dramatically potentiated the increase in TNFα mRNA and IL-15 protein expression in GFAP+ cells in the striatum. In sharp contrast to the potentiation of striatal damage, Nrf2 deficiency did not affect METH-induced dopaminergic neuron death or expression of glial markers or proinflammatory molecules in the substantia nigra. This study uncovers a new role for Nrf2 in protection against METH-induced inflammatory and oxidative stress and striatal degeneration.


Assuntos
Axônios/patologia , Corpo Estriado/patologia , Dopamina/fisiologia , Gliose/patologia , Metanfetamina/toxicidade , Fator 2 Relacionado a NF-E2/deficiência , Degeneração Walleriana/patologia , Inibidores da Captação Adrenérgica/antagonistas & inibidores , Inibidores da Captação Adrenérgica/toxicidade , Animais , Axônios/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Gliose/induzido quimicamente , Gliose/fisiopatologia , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/toxicidade , Masculino , Metanfetamina/antagonistas & inibidores , Camundongos , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Degeneração Walleriana/induzido quimicamente , Degeneração Walleriana/fisiopatologia
2.
Neurobiol Dis ; 42(3): 391-403, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21303698

RESUMO

Methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA), amphetamine derivatives widely used as recreational drugs, induce similar neurotoxic effects in mice, including a marked loss of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the striatum. Although the role of dopamine in these neurotoxic effects is well established and pharmacological studies suggest involvement of a dopamine D2-like receptor, the specific dopamine receptor subtype involved has not been determined. In this study, we used dopamine D2 receptor knock-out mice (D2R(-/-)) to determine whether D2R is involved in METH- and MDMA-induced hyperthermia and neurotoxicity. In wild type animals, both drugs induced marked hyperthermia, decreased striatal dopamine content and TH- and DAT-immunoreactivity and increased striatal GFAP and Mac-1 expression as well as iNOS and interleukin 15 at 1 and 7days after drug exposure. They also caused dopaminergic cell loss in the SNpc. Inactivation of D2R blocked all these effects. Remarkably, D2R inactivation prevented METH-induced loss of dopaminergic neurons in the SNpc. In addition, striatal dopamine overflow, measured by fast scan cyclic voltammetry in the presence of METH, was significantly reduced in D2R(-/-) mice. Pre-treatment with reserpine indicated that the neuroprotective effect of D2R inactivation cannot be explained solely by its ability to prevent METH-induced hyperthermia: reserpine lowered body temperature in both genotypes, and potentiated METH toxicity in WT, but not D2R(-/-) mice. Our results demonstrate that the D2R is necessary for METH and MDMA neurotoxicity and that the neuroprotective effect of D2R inactivation is independent of its effect on body temperature.


Assuntos
Estimulantes do Sistema Nervoso Central/toxicidade , Dopamina/metabolismo , Metanfetamina/toxicidade , N-Metil-3,4-Metilenodioxianfetamina/toxicidade , Neurônios/metabolismo , Síndromes Neurotóxicas/metabolismo , Receptores de Dopamina D2/metabolismo , Análise de Variância , Animais , Temperatura Corporal/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Neurônios/efeitos dos fármacos , Síndromes Neurotóxicas/genética , Receptores de Dopamina D2/genética , Tirosina 3-Mono-Oxigenase/metabolismo
3.
Neurotox Res ; 34(3): 627-639, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29934756

RESUMO

Methamphetamine (METH), an amphetamine derivate, may increase the risk of developing Parkinson's disease (PD). Human and animal studies have shown that METH produces persistent dopaminergic neurotoxicity in the nigrostriatal pathway, despite initial partial recovery. To determine the processes leading to early compensation, we studied the detailed morphology and distribution of tyrosine hydroxylase immunoreactive fibers (TH-ir) classified by their thickness (types I-IV) before and after METH. Applying three established neurotoxic regimens of METH: single high dose (1 × 30 mg/kg), multiple lower doses (3 × 5 mg/kg) or (3 × 10 mg/kg), we show that METH primarily damages type I fibers (the thinner ones), and to a much lesser extend types II-IV fibers including sterile axons. The striatal TH terminal partial recovery process, consisting of a progressive regrowth increases in types II, III, and IV fibers, demonstrated by co-localization of GAP-43, a sprouting marker, was observed 3 days post-METH treatment. In addition, we demonstrate the presence of growth-cone-like TH-ir structures, indicative of new terminal generation as well as improvement in motor functions after 3 days. A temporal relationship was observed between decreases in TH-expression and increases in silver staining, a marker of degeneration. Striatal regeneration was associated with an increase in astroglia and decrease in microglia expression, suggesting a possible role for the neuroimmune system in regenerative processes. Identification of regenerative compensatory mechanisms in response to neurotoxic agents could point to novel mechanisms in countering the neurotoxicity and/or enhancing the regenerative processes.


Assuntos
Estimulantes do Sistema Nervoso Central/toxicidade , Corpo Estriado/fisiopatologia , Dopamina/metabolismo , Metanfetamina/toxicidade , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/patologia , Animais , Proteínas de Ligação ao Cálcio , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/ultraestrutura , Modelos Animais de Doenças , Proteína GAP-43/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/patologia , Terminações Pré-Sinápticas/ultraestrutura , Transtornos Psicomotores/etiologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Coloração pela Prata , Fatores de Tempo , Tirosina 3-Mono-Oxigenase/metabolismo
4.
Neurotox Res ; 27(3): 209-16, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25492248

RESUMO

The indusium griseum (IG), a thin layer of gray matter in contact with the dorsal surface of the corpus callosum and the lateral gray matter of the cingulate gyrus, has a common origin with hippocampus and shows similar organization with the dentate gyrus. Although some studies have examined the effect of methamphetamine (METH), an addictive and an illegal psychostimulant on this structure, quantitative effects and possible mechanism of actions of METH in this area are lacking. By applying two different protocols of equivalent METH administration (i.e., a high dose of 1 × 30 mg/kg and a lower and repeated injection dose of 3 × 10 mg/kg) and using a specific silver staining method in mice, we demonstrate that this drug produces degeneration in IG with both protocols, without affecting the dopaminergic system. Moreover, we observed quantitative increases in labeling of GFAP and Iba-1, markers of astro- and microgliosis, respectively, which suggest astrogliosis and microgliosis. Thus, our study provides morphological and semi-quantitative evidence that METH induces neurodegeneration in IG and that this damage is associated with astrogliosis and microgliosis in this area.


Assuntos
Gliose/induzido quimicamente , Lobo Límbico/efeitos dos fármacos , Lobo Límbico/patologia , Metanfetamina/toxicidade , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Masculino , Metanfetamina/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/patologia
5.
Neuropsychopharmacology ; 39(5): 1066-80, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24169803

RESUMO

Methamphetamine is a widely abused illicit drug. Recent epidemiological studies showed that methamphetamine increases the risk for developing Parkinson's disease (PD) in agreement with animal studies showing dopaminergic neurotoxicity. We examined the effect of repeated low and medium doses vs single high dose of methamphetamine on degeneration of dopaminergic terminals and cell bodies. Mice were given methamphetamine in one of the following paradigms: three injections of 5 or 10 mg/kg at 3 h intervals or a single 30 mg/kg injection. The integrity of dopaminergic fibers and cell bodies was assessed at different time points after methamphetamine by tyrosine hydroxylase immunohistochemistry and silver staining. The 3 × 10 protocol yielded the highest loss of striatal dopaminergic terminals, followed by the 3 × 5 and 1 × 30. Some degenerating axons could be followed from the striatum to the substantia nigra pars compacta (SNpc). All protocols induced similar significant degeneration of dopaminergic neurons in the SNpc, evidenced by amino-cupric-silver-stained dopaminergic neurons. These neurons died by necrosis and apoptosis. Methamphetamine also killed striatal neurons. By using D1-Tmt/D2-GFP BAC transgenic mice, we observed that degenerating striatal neurons were equally distributed between direct and indirect medium spiny neurons. Despite the reduced number of dopaminergic neurons in the SNpc at 30 days after treatment, there was a partial time-dependent recovery of dopamine terminals beginning 3 days after treatment. Locomotor activity and motor coordination were robustly decreased 1-3 days after treatment, but recovered at later times along with dopaminergic terminals. These data provide direct evidence that methamphetamine causes long-lasting loss/degeneration of dopaminergic cell bodies in the SNpc, along with destruction of dopaminergic terminals in the striatum.


Assuntos
Corpo Estriado/efeitos dos fármacos , Dopaminérgicos/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Metanfetamina/farmacologia , Degeneração Neural/induzido quimicamente , Substância Negra/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Axônios/efeitos dos fármacos , Axônios/metabolismo , Axônios/patologia , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Relação Dose-Resposta a Droga , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Necrose/induzido quimicamente , Necrose/metabolismo , Necrose/patologia , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Vias Neurais/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Coloração pela Prata , Substância Negra/metabolismo , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismo
6.
Parkinsons Dis ; 2013: 308052, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23476887

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder predominantly affecting the elderly. The aetiology of the disease is not known, but age and environmental factors play an important role. Although more than a dozen gene mutations associated with familial forms of Parkinson's disease have been described, fewer than 10% of all cases can be explained by genetic abnormalities. The molecular basis of Parkinson's disease is the loss of dopamine in the basal ganglia (caudate/putamen) due to the degeneration of dopaminergic neurons in the substantia nigra, which leads to the motor impairment characteristic of the disease. Methamphetamine is the second most widely used illicit drug in the world. In rodents, methamphetamine exposure damages dopaminergic neurons in the substantia nigra, resulting in a significant loss of dopamine in the striatum. Biochemical and neuroimaging studies in human methamphetamine users have shown decreased levels of dopamine and dopamine transporter as well as prominent microglial activation in the striatum and other areas of the brain, changes similar to those observed in PD patients. Consistent with these similarities, recent epidemiological studies have shown that methamphetamine users are almost twice as likely as non-users to develop PD, despite the fact that methamphetamine abuse and PD have distinct symptomatic profiles.

7.
Neurotox Res ; 18(1): 48-58, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19760475

RESUMO

Methamphetamine (METH), a commonly abused psychostimulant, causes dopamine neurotoxicity in humans, rodents, and nonhuman primates. This study examined the selective neuroanatomical pattern of dopaminergic neurotoxicity induced by METH in the mouse striatum. We examined the effect of METH on tyrosine hydroxylase (TH) and dopamine transporter (DAT) immunoreactivity in the different compartments of the striatum and in the nucleus accumbens. The levels of dopamine and its metabolites, 3,4-dihidroxyphenylacetic acid and homovanillic acid, as well as serotonin (5-HT) and its metabolite, 5-hydroxyindolacetic acid, were also quantified in the striatum. Mice were given three injections of METH (4 mg/kg, i.p.) at 3 h intervals and sacrificed 7 days later. This repeated METH injection induced a hyperthermic response and a decrease in striatal concentrations of dopamine and its metabolites without affecting 5-HT concentrations. In addition, the drug caused a reduction in TH- and DAT-immunoreactivity when compared to saline-treated animals. Interestingly, there was a significantly greater loss of TH- and DAT-immunoreactivity in striosomes than in the matrix. The predominant loss of dopaminergic terminals in the striosomes occurred along the rostrocaudal axis of the striatum. In contrast, METH did not decrease TH- or DAT-immunoreactivity in the nucleus accumbens. These results provide the first evidence that compartments of the mouse striatum, striosomes and matrix, and mesolimbic and nigrostriatal pathways have different vulnerability to METH. This pattern is similar to that observed with other neurotoxins such as MPTP, the most widely used model of Parkinson's disease, in early Huntington's disease and hypoxic/ischemic injury, suggesting that these conditions might share mechanisms of neurotoxicity.


Assuntos
Corpo Estriado/efeitos dos fármacos , Dopaminérgicos/toxicidade , Dopamina/metabolismo , Metanfetamina/toxicidade , Substância Negra/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismo , Animais , Corpo Estriado/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Esquema de Medicação , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Homovanílico/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Substância Negra/metabolismo
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