RESUMEN
Although MDMA (3,4-methylendioxymethamphetamine, ecstasy) neurotoxicity in serotonin neurons is largely recognized in a wide variety of species including man, neurotoxicity in dopamine (DA) neurons is thought to be species-specific. MDMA is mainly consumed by adolescents, often in conjunction with caffeine (Energy Drinks) and this association has been reported to exacerbate MDMA toxic effects. In order to model these aspects of MDMA use, vis-à-vis their impact on DA neurons, we investigated the effects of adolescent exposure to low doses of MDMA (5 mg/kg for 10 days), alone or in combination with caffeine (10 mg/kg) on neuronal and functional DA indices and on recognition memory in adult rats. MDMA reduced density of tyrosine hydroxylase (TH) positive neurons in the ventral tegmental area and in the substantia nigra pars compacta, and immunoreactivity of TH and DA transporter in the nucleus accumbens (NAc) shell and core, and caudate-putamen. This same treatment caused a reduction of basal dialysate DA in the NAc core. MDMA-pretreated rats also showed behavioral sensitization to a MDMA challenge at adulthood and potentiation of MDMA-induced increase of dialysate DA in the NAc core, but not in the NAc shell. In addition, MDMA-treated rats displayed a deficit in recognition memory. Caffeine co-administration did not affect the above outcomes. Our results show that adolescent exposure of rats to low doses of MDMA induces long-lasting and widespread reduction of DA neurons indicative of a neurotoxic effect on DA neurons and suggestive of a degeneration of the same neurons.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Trastornos de la Memoria/inducido químicamente , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Animales , Encéfalo/metabolismo , Encéfalo/patología , Cafeína/toxicidad , Cuerpo Celular/efectos de los fármacos , Cuerpo Celular/patología , Recuento de Células , Neuronas Dopaminérgicas/metabolismo , Interacciones Farmacológicas , Técnica del Anticuerpo Fluorescente , Masculino , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/patología , Ratas Sprague-Dawley , Reconocimiento en Psicología/efectos de los fármacos , Reconocimiento en Psicología/fisiología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
3,4-methylenedyoxymethamphetamine (MDMA or "ecstasy"), a recreational drug of abuse, can induce glia activation and dopaminergic neurotoxicity. Since MDMA is often consumed in crowded environments featuring high temperatures, we studied how these factors influenced glia activation and dopaminergic neurotoxicity induced by MDMA. C57BL/6J adolescent (4 weeks old) and adult (12 weeks old) mice received MDMA (4×20mg/kg) in different conditions: 1) while kept 1, 5, or 10×cage at room temperature (21°C); 2) while kept 5×cage at either room (21°C) or high (27°C) temperature. After the last MDMA administration, immunohistochemistry was performed in the caudate-putamen for CD11b and GFAP, to mark microglia and astroglia, and in the substantia nigra pars compacta for tyrosine hydroxylase, to mark dopaminergic neurons. MDMA induced glia activation and dopaminergic neurotoxicity, compared with vehicle administration. Crowding (5 or 10 mice×cage) amplified MDMA-induced glia activation (in adult and adolescent mice) and dopaminergic neurotoxicity (in adolescent mice). Conversely, exposure to a high environmental temperature (27°C) potentiated MDMA-induced glia activation in adult and adolescent mice kept 5×cage, but not dopaminergic neurotoxicity. Crowding and exposure to a high environmental temperature amplified MDMA-induced hyperthermia, and a positive correlation between body temperature and activation of either microglia or astroglia was found in adult and adolescent mice. These results provide further evidence that the administration setting influences the noxious effects of MDMA in the mouse brain. However, while crowding amplifies both glia activation and dopaminergic neurotoxicity, a high environmental temperature exacerbates glia activation only.
Asunto(s)
Envejecimiento , Aglomeración/psicología , Dopamina/metabolismo , Alucinógenos/toxicidad , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Neuroglía/efectos de los fármacos , Síndromes de Neurotoxicidad , Envejecimiento/efectos de los fármacos , Análisis de Varianza , Animales , Temperatura Corporal/efectos de los fármacos , Antígeno CD11b/metabolismo , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/psicología , Temperatura , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
BACKGROUND: Mitochondrial dysfunction, oxidative stress and their interplay are core pathological features of Parkinson's disease. In dopaminergic neurons, monoamines and their metabolites provide an additional source of reactive free radicals during their breakdown by monoamine oxidase or auto-oxidation. Moreover, mitochondrial dysfunction and oxidative stress have a supraadditive impact on the pathological, cytoplasmic accumulation of dopamine and its subsequent release. Here we report the effects of a novel series of potent and selective MAO-B inhibitory (hetero)arylalkenylpropargylamine compounds having protective properties against the supraadditive effect of mitochondrial dysfunction and oxidative stress. RESULTS: The (hetero)arylalkenylpropargylamines were tested in vitro, on acute rat striatal slices, pretreated with the complex I inhibitor rotenone and in vivo, using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced acute, subchronic, and chronic experimental models of Parkinson's disease in mice. The compounds exhibited consistent protective effects against i) in vitro oxidative stress induced pathological dopamine release and the formation of toxic dopamine quinone in the rat striatum and rescued tyrosine hydroxylase positive neurons in the substantia nigra after rotenone treatment; ii) in vivo MPTP-induced striatal dopamine depletion and motor dysfunction in mice using acute and subchronic, delayed application protocols. One compound (SZV558) was also examined and proved to be protective in a chronic mouse model of MPTP plus probenecid (MPTPp) administration, which induces a progressive loss of nigrostriatal dopaminergic neurons. CONCLUSIONS: Simultaneous inhibition of MAO-B and oxidative stress induced pathological dopamine release by the novel propargylamines is protective in animal models and seems a plausible strategy to combat Parkinson's disease.
Asunto(s)
Cuerpo Estriado/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Pargilina/análogos & derivados , Enfermedad de Parkinson/metabolismo , Propilaminas/farmacología , Sustancia Negra/efectos de los fármacos , Animales , Cuerpo Estriado/efectos de los fármacos , Modelos Animales de Enfermedad , Dopamina/análogos & derivados , Dopamina/metabolismo , Masculino , Estrés Oxidativo/efectos de los fármacos , Pargilina/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/patología , Ratas Wistar , Sustancia Negra/metabolismo , Sustancia Negra/patologíaRESUMEN
Previous studies have demonstrated that caffeine administration to adult mice potentiates glial activation induced by 3,4-methylenedioxymethamphetamine (MDMA). As neuroinflammatory response seems to correlate with neurodegeneration, and the young brain is particularly vulnerable to neurotoxicity, we evaluated dopamine neuron degeneration and glial activation in the caudate-putamen (CPu) and substantia nigra pars compacta (SNc) of adolescent and adult mice. Mice were treated with MDMA (4 × 20 mg/kg), alone or with caffeine (10 mg/kg). Interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, neuronal nitric oxide synthase (nNOS) were evaluated in CPu, whereas tyrosine hydroxylase (TH), glial fibrillary acidic protein, and CD11b were evaluated in CPu and SNc by immunohistochemistry. MDMA decreased TH in SNc of both adolescent and adult mice, whereas TH-positive fibers in CPu were only decreased in adults. In CPu of adolescent mice, caffeine potentiated MDMA-induced glial fibrillary acidic protein without altering CD11b, whereas in SNc caffeine did not influence MDMA-induced glial activation. nNOS, IL-1ß, and TNF-α were increased by MDMA in CPu of adults, whereas in adolescents, levels were only elevated after combined MDMA plus caffeine. Caffeine alone modified only nNOS. Results suggest that the use of MDMA in association with caffeine during adolescence may exacerbate the neurotoxicity and neuroinflammation elicited by MDMA. Previous studies have demonstrated that caffeine potentiated glial activation induced by 3,4-methylenedioxymethamphetamine (MDMA) in adult mice. In this study, caffeine was shown to potentiate MDMA-induced dopamine neuron degeneration in substantia nigra pars compacta, astrogliosis, and TNF-α levels in caudate-putamen of adolescent mice. Results suggest that combined use of MDMA plus caffeine during adolescence may worsen the neurotoxicity and neuroinflammation elicited by MDMA.
Asunto(s)
Envejecimiento/efectos de los fármacos , Cafeína/toxicidad , Neuronas Dopaminérgicas/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Degeneración Nerviosa/inducido químicamente , Factores de Edad , Envejecimiento/patología , Animales , Cafeína/administración & dosificación , Neuronas Dopaminérgicas/patología , Sinergismo Farmacológico , Inflamación/inducido químicamente , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , N-Metil-3,4-metilenodioxianfetamina/administración & dosificación , Degeneración Nerviosa/patologíaRESUMEN
Several studies suggest that 50-kHz ultrasonic vocalizations (USVs) may indicate a positive affective state in rats, and these vocalizations are increasingly being used to investigate the properties of psychoactive drugs. Previous studies, however, have focused on dopaminergic psychostimulants and morphine, whereas little is known about how other drugs modulate 50-kHz USVs. To further elucidate the neuropharmacology of 50-kHz USVs, the present study characterized the direct and long-lasting effects of different drugs of abuse, by measuring the number of 50-kHz USVs and their 'trill' subtype emitted by adult male rats. Rats received repeated administrations of amphetamine (2 mg/kg, i.p.), 3,4-methylenedioxymethamphetamine (MDMA, 7.5 mg/kg, i.p.), morphine (7.5 mg/kg, s.c.), or nicotine (0.4 mg/kg, s.c.), on either consecutive or alternate days (five administrations in total) in a novel environment. Seven days later, rats were re-exposed to the drug-paired environment, subjected to USVs recording, and then challenged with the same drug. Finally, 7 d after the challenge, rats were repeatedly exposed to the drug-paired environment and vocalizations were measured. Amphetamine was the only drug to stimulate 50-kHz USVs and 'trill' subtype emission during administration and challenge. Conversely, all rats emitted 50-kHz USVs when re-exposed to the test cage, and this effect was most marked in morphine-treated rats, and less evident in nicotine-treated rats. This study demonstrates that the direct and long-lasting effects of drugs on 50-kHz USVs are regulated differently, providing a better understanding of the usefulness of these vocalizations in the study of psychoactive drugs.
Asunto(s)
Estimulantes del Sistema Nervioso Central/farmacología , Psicotrópicos/farmacología , Vocalización Animal/efectos de los fármacos , Anfetamina/farmacología , Animales , Esquema de Medicación , Masculino , Morfina/farmacología , Actividad Motora/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/farmacología , Nicotina/farmacología , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , UltrasonidoRESUMEN
Clinical observations report a greater propensity to develop Parkinson's disease (PD) in amphetamine users. 3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is an amphetamine-related drug that is largely consumed by adolescents and young adults, which may have neuroinflammatory and neurotoxic effects. Here, the objective was to evaluate in mice whether consumption of MDMA during adolescence might influence the neuroinflammatory and neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin known to induce PD in humans. The activation of astroglia and microglia by glial fibrillary acidic protein (GFAP) and complement receptor type 3 (CD11b) immunohistochemistry and the degeneration of dopaminergic neurons by tyrosine hydroxylase (TH) immunohistochemistry were evaluated. MPTP (20 mg/kg × 4) was administered to mice treated from ages 8 weeks to 17 weeks with MDMA (10 mg/kg twice daily, two times a week). In mice that were chronically treated with MDMA, administration of MPTP induced a higher microglial and astroglial response in both the striatum and the substantia nigra pars compacta (SNc) compared with vehicle-treated or vehicle + MPTP-treated mice. Inflammatory changes were associated with a decrease in TH immunoreactivity in the SNc of MDMA-treated mice and with a further decrease in the striatum and the SNc of MDMA + MPTP-treated mice compared with vehicle-treated, MDMA-treated, and MPTP-treated mice. The results demonstrate that chronic administration of MDMA during late adolescence in mice exacerbates the neurodegeneration and neuroinflammation caused by MPTP, suggesting that MDMA may constitute a risk factor for dopaminergic neuron degeneration.
Asunto(s)
Inhibidores de Captación Adrenérgica/toxicidad , Encéfalo/patología , Neuronas Dopaminérgicas/patología , Intoxicación por MPTP/patología , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Neuroglía/metabolismo , Animales , Antígeno CD11b/metabolismo , Recuento de Células , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Proteína Ácida Fibrilar de la Glía/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Neuroglía/efectos de los fármacos , Factores de Tiempo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Abnormal involuntary movements (AIMs) and dyskinesias elicited by drugs that stimulate dopamine receptors in the basal ganglia are a major issue in the management of Parkinson's disease (PD). Preclinical studies in dopamine-denervated animals have contributed to the modeling of these abnormal movements, but the precise neurochemical and functional mechanisms underlying these untoward effects are still elusive. It has recently been suggested that the performance of movement may itself promote the later emergence of drug-induced motor complications, by favoring the generation of aberrant motor memories in the dopamine-denervated basal ganglia. Our recent results from hemiparkinsonian rats subjected to the priming model of dopaminergic stimulation are in agreement with this. These results demonstrate that early performance of movement is crucial for the manifestation of sensitized rotational behavior, indicative of an abnormal motor response, and neurochemical modifications in selected striatal neurons following a dopaminergic challenge. Building on this evidence, this paper discusses the possible role of movement performance in drug-induced motor complications, with a look at the implications for PD management.
RESUMEN
A previous study of our group demonstrated that movement performance induced by dopamine agonist drugs in hemiparkinsonian rats unilaterally lesioned with 6-hydroxydopamine (6-OHDA), governs the occurrence of a sensitized motor response to a subsequent dopaminergic challenge (priming model). In the present study, we examined the influence of movement performance (rotational behavior) on the molecular events induced by priming in the striatum. To this end, unilaterally 6-OHDA-lesioned rats were primed with apomorphine (0.2 mg/kg) in immobilized or freely moving conditions (priming induction) and 3 days later the D1 receptor agonist SKF 38393 was administered (priming expression). Evaluation of striatal mRNA for enkephalin and dynorphin, markers of the indirect and direct striatonigral pathways, and of GAD67 showed an increase in dynorphin in primed SKF 38393-treated rats, no matter whether immobilized or freely moving during priming induction, whilst enkephalin and GAD67 did not show any changes. In contrast, evaluation of mRNA for the early gene zif-268 in the striatum showed a generalized increase after administration of SKF 38393, in both primed and unprimed rats. However, examination of zif-268 mRNA at the single-cell level, showed that only dynorphin(+) neurons of primed not immobilized rats displayed a significantly higher number of zif-268-positive silver grains in response to the SKF 38393 challenge. This selective activation of zif-268 in dynorphinergic striatonigral efferent neurons demonstrates that movement performance in response to dopaminergic drug administration under conditions of dopamine denervation is critical for the emergence of neurochemical modifications in selected striatal efferent neurons. Furthermore, these results may provide information on the first initial molecular events taking place in the complex processes that lead to dyskinetic movements in Parkinson's disease.
Asunto(s)
Cuerpo Estriado/metabolismo , Agonistas de Dopamina/farmacología , Dinorfinas/metabolismo , Movimiento/fisiología , Enfermedad de Parkinson/patología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Adrenérgicos/toxicidad , Análisis de Varianza , Animales , Apomorfina/farmacología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Encefalinas/genética , Encefalinas/metabolismo , Lateralidad Funcional/efectos de los fármacos , Lateralidad Funcional/fisiología , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Neuronas Motoras , Oxidopamina/toxicidad , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/fisiopatología , ARN Mensajero , Ratas , Ratas Sprague-DawleyRESUMEN
Evidence is accumulating to suggest that 3,4-methylenedioxymethamphetamine (MDMA) has neurotoxic and neuroinflammatory properties. MDMA is composed of two enantiomers with different biological activities. In this study, we evaluated the in vivo effects of S(+)-MDMA, R(-)-MDMA, and S(+)-MDMA in combination with R(-)-MDMA on microglial and astroglial activation compared with racemic MDMA, by assessment of complement type 3 receptor (CD11b) and glial fibrillary acidic protein (GFAP) immunoreactivity in the mouse striatum, nucleus accumbens, motor cortex, and substantia nigra. Motor activity and body temperature were also measured, to elucidate the physiological modifications paired with the observed glial changes. Similar to racemic MDMA (4 × 20 mg/kg), S(+)-MDMA (4 × 10 mg/kg) increased both CD11b and GFAP in the striatum, although to a lower degree, whereas R(-)-MDMA (4 × 10 mg/kg) did not induce any significant glial activation. Combined administration of S(+) plus R(-)-MDMA did not induce any further activation compared with S(+)-MDMA. In all other areas, only racemic MDMA was able to slightly activate the microglia, but not the astroglia, whereas enantiomers had no effect, either alone or in combination. Racemic MDMA and S(+)-MDMA similarly increased motor activity and raised body temperature, whereas R(-)-MDMA affected neither body temperature nor motor activity. Interestingly, the increase in body temperature was correlated with glial activation. The results show that no synergism, but only additivity of effects, is caused by the combined administration of S(+)- and R(-)-MDMA, and underline the importance of investigating the biochemical and behavioral properties of the two MDMA enantiomers to understand their relative contribution to the neuroinflammatory and neurotoxic effects of MDMA.
Asunto(s)
Astrocitos/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Alucinógenos/toxicidad , Microglía/efectos de los fármacos , Actividad Motora/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Animales , Encéfalo/citología , Encéfalo/efectos de los fármacos , Antígeno CD11b/metabolismo , Interacciones Farmacológicas , Alucinógenos/química , Masculino , Ratones , Ratones Endogámicos C57BL , N-Metil-3,4-metilenodioxianfetamina/química , EstereoisomerismoRESUMEN
Activation of the nuclear factor κB/c-Rel can increase neuronal resilience to pathological noxae by regulating the expression of pro-survival manganese superoxide dismutase (MnSOD, now known as SOD2) and Bcl-xL genes. We show here that c-Rel-deficient (c-rel(-/-)) mice developed a Parkinson's disease-like neuropathology with ageing. At 18 months of age, c-rel(-/-) mice exhibited a significant loss of dopaminergic neurons in the substantia nigra pars compacta, as assessed by tyrosine hydroxylase-immunoreactivity and Nissl staining. Nigral degeneration was accompanied by a significant loss of dopaminergic terminals and a significant reduction of dopamine and homovanillic acid levels in the striatum. Mice deficient of the c-Rel factor exhibited a marked immunoreactivity for fibrillary α-synuclein in the substantia nigra pars compacta as well as increased expression of divalent metal transporter 1 (DMT1) and iron staining in both the substantia nigra pars compacta and striatum. Aged c-rel(-/-) mouse brain were characterized by increased microglial reactivity in the basal ganglia, but no astrocytic reaction. In addition, c-rel(-/-) mice showed age-dependent deficits in locomotor and total activity and various gait-related deficits during a catwalk analysis that were reminiscent of bradykinesia and muscle rigidity. Both locomotor and gait-related deficits recovered in c-rel(-/-) mice treated with l-3,4-dihydroxyphenylalanine. These data suggest that c-Rel may act as a regulator of the substantia nigra pars compacta resilience to ageing and that aged c-rel(-/-) mice may be a suitable model of Parkinson's disease.
Asunto(s)
Envejecimiento/genética , Neuronas Dopaminérgicas/patología , FN-kappa B/genética , Trastornos Parkinsonianos/genética , Sustancia Negra/patología , Envejecimiento/metabolismo , Animales , Recuento de Células , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Ácido Homovanílico/metabolismo , Ratones , Ratones Noqueados , Actividad Motora/genética , FN-kappa B/metabolismo , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Sustancia Negra/metabolismo , alfa-Sinucleína/metabolismoRESUMEN
Adenosine A(2A) receptor antagonists are one of the most attractive classes of drug for the treatment of Parkinson's disease (PD) as they are effective in counteracting motor dysfunctions and display neuroprotective and anti-inflammatory effects in animal models of PD. In this study, we evaluated the neuroprotective and anti-inflammatory properties of the adenosine A(2A) receptor antagonist ST1535 in a subchronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. C57BL/6J mice were repeatedly administered with vehicle, MPTP (20 mg/kg), or MPTP + ST1535 (2 mg/kg). Mice were sacrificed three days after the last administration of MPTP. Immunohistochemistry for tyrosine hydroxylase (TH) and cresyl violet staining were employed to evaluate dopaminergic neuron degeneration in the substantia nigra pars compacta (SNc) and caudate-putamen (CPu). CD11b and glial fibrillary acidic protein (GFAP) immunoreactivity were, respectively, evaluated as markers of microglial and astroglial response in the SNc and CPu. Stereological analysis for TH revealed a 32% loss of dopaminergic neurons in the SNc after repeated MPTP administration, which was completely prevented by ST1535 coadministration. Similarly, CPu decrease in TH (25%) was prevented by ST1535. MPTP treatment induced an intense gliosis in both the SNc and CPu. ST1535 totally prevented CD11b immunoreactivity in both analyzed areas, but only partially blocked GFAP increase in the SNc and CPu. A(2A) receptor antagonism is a new opportunity for improving symptomatic PD treatment. With its neuroprotective effect on dopaminergic neuron toxicity induced by MPTP and its antagonism on glial activation, ST1535 represents a new prospect for a disease-modifying drug.
Asunto(s)
Adenina/análogos & derivados , Antagonistas del Receptor de Adenosina A2/uso terapéutico , Antiinflamatorios/uso terapéutico , Encéfalo/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Trastornos Parkinsonianos/tratamiento farmacológico , Triazoles/uso terapéutico , Adenina/uso terapéutico , Animales , Encéfalo/metabolismo , Encéfalo/patología , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/patología , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patologíaRESUMEN
In the dopamine-depleted striatum, an altered post-synaptic signalling of efferent neurons might underline the onset of variable dyskinetic responses to dopaminergic agonists. We have previously shown that a subchronic treatment with the D1 agonist SKF-38393 and the D2 agonist ropinirole induces a dyskinetic response of high and low intensities respectively, in 6-hydroxydopamine-lesioned rats. Here, zif-268 mRNA expression was evaluated in striatonigral and striatopallidal neurons to assess a neurochemical marker of these different dyskinetic responses upon drug administration. Acute and subchronic SKF-38393 (3mg/kg) increased zif-268 expression per neuron in the striatonigral pathway, albeit the number of neurons displaying high early-gene levels was reduced by the subchronic treatment. Zif-268 mRNA in striatopallidal neurons was not affected by SKF-38393 treatments. In contrast, ropinirole (5mg/kg) did not alter zif-268 mRNA in striatonigral neurons acutely, whereas ropinirole decreased zif-268 mRNA subchronically. Both acute and subchronic ropinirole decreased zif-268 levels in the striatopallidal pathway. The differential expression of zif-268 in striatonigral and striatopallidal neurons might provide a biochemical correlate of the dyskinetic outcome displayed by SKF-38393 and ropinirole treatments, suggesting that evaluation of neuronal responses upon drug administration provides a tool for the preclinical characterization of dyskinetic potential beyond behavioural tests.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Agonistas de Dopamina/efectos adversos , Discinesia Inducida por Medicamentos/metabolismo , Proteína 1 de la Respuesta de Crecimiento Precoz/biosíntesis , Sustancia Negra/efectos de los fármacos , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/efectos adversos , Animales , Cuerpo Estriado/metabolismo , Discinesia Inducida por Medicamentos/etiología , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Globo Pálido/efectos de los fármacos , Globo Pálido/metabolismo , Indoles/efectos adversos , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Oxidopamina , Enfermedad de Parkinson Secundaria/etiología , Enfermedad de Parkinson Secundaria/metabolismo , ARN Mensajero/biosíntesis , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/metabolismo , Sustancia Negra/metabolismoRESUMEN
Several reports suggest that 3,4-methylenedioxymethamphetamine (MDMA) induces neurotoxic effects and gliosis. Since recreational use of MDMA is often associated with caffeinated beverages, we investigated whether caffeine interferes with MDMA-induced astroglia and microglia activation, thus facilitating its neurotoxicity. MDMA (4 x 20 mg/kg) was acutely administered to mice alone or in combination with caffeine (10 mg/kg). CD11b and GFAP immunoreactivity were evaluated as markers of microglia and astroglia activation in the substantia nigra pars-compacta (SNc) and striatum. MDMA was associated with significantly higher CD11b and GFAP immunoreactivity in striatum, whereas only CD11b was significantly higher than vehicle in SNc. Caffeine potentiated the increase in CD11b and GFAP in the striatum but not in the SNc of MDMA-treated mice. The abuse of MDMA is a growing worldwide problem; the results of this study suggest that combination of MDMA plus caffeine by increasing glial activation might have harmful health consequences.
Asunto(s)
Astrocitos/efectos de los fármacos , Encéfalo/citología , Encéfalo/efectos de los fármacos , Cafeína/farmacología , Microglía/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Inhibidores de Fosfodiesterasa/farmacología , Animales , Antígeno CD11b/metabolismo , Interacciones Farmacológicas , Regulación de la Expresión Génica/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Parkinson's disease (PD) is characterized by a progressive degeneration of dopamine (DA) neurons and gradual worsening of motor symptoms. The investigation of progressive degenerative mechanisms and potential neuroprotective strategies relies on experimental models of the chronic neuropathology observed in human. The present study investigated the progressive nature of neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTPp) chronic mouse model of PD. MPTP (25 mg/kg) plus probenecid (250 mg/kg) were administered twice a week for 5 weeks. We evaluated behavioral deficits (olfactory and motor impairment), neurodegeneration (loss of tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta, SNc), biochemical markers of functional impairment in the caudate-putamen (CPu) (striatal enkephalin mRNA, DA and DOPAC levels), and glial reactivity (CD11b and GFAP immunoreactivity in the SNc and CPu) at progressive time-points (after 1, 3, 7, and 10 administrations of MPTPp). Olfactory dysfunction already appeared after the 1st MPTPp injection, whereas motor dysfunction appeared after the 3rd and worsened upon subsequent administrations. Moreover, starting after three MPTPp injections, we observed a gradual decline of TH-positive cells in the SNc, and a gradual raise of enkephalin mRNA in the CPu. Striatal DA levels reduction was not different among all time-points evaluated, whereas DOPAC levels were similarly reduced after 1-7 MPTP injections, but were further decreased after the 10th injection. Reactive microglia and astroglia were observed in both the SNc and CPu from the 1st MPTPp administration. In the SNc, gliosis displayed a gradual increase over the treatment. After 2 months, TH, DA, DOPAC, and reactive glia in the SNc were still altered in MPTPp-treated mice as compared to controls. By showing a progressive development of behavioral deficits and nigral neurodegeneration, together with impairment of biochemical parameters and gradual increase of glial response, results suggest that the chronic MPTPp protocol is a model of progressive PD, which may be suitable to investigate chronic pathological processes and neuroprotective strategies in PD.
Asunto(s)
Dopamina/metabolismo , Degeneración Nerviosa/etiología , Trastornos Parkinsonianos/complicaciones , Trastornos Parkinsonianos/patología , Análisis de Varianza , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Antígeno CD11b/metabolismo , Recuento de Células , Cromatografía Líquida de Alta Presión/métodos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Electroquímica/métodos , Encefalinas/genética , Encefalinas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Bulbo Olfatorio/fisiopatología , Factores de Tiempo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Rosiglitazone is a commonly prescribed insulin-sensitizing drug with a selective agonistic activity on the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). PPAR-gamma can modulate inflammatory responses in the brain, and agonists might be beneficial in neurodegenerative diseases. In the present study we used a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine plus probenecid (MPTPp) mouse model of progressive Parkinson's disease (PD) to assess the therapeutic efficacy of rosiglitazone on behavioural impairment, neurodegeneration and inflammation. Mice chronically treated with MPTPp displayed typical features of PD, including impairment of motor and olfactory functions associated with partial loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNc), decrease of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) content and dynorphin (Dyn) mRNA levels in the caudate-putamen (CPu), intense microglial and astroglial response in the SNc and CPu. Chronic rosiglitazone, administered in association with MPTPp, completely prevented motor and olfactory dysfunctions and loss of TH-positive cells in the SNc. In the CPu, loss of striatal DA was partially prevented, whereas decreases in DOPAC content and Dyn were fully counteracted. Moreover, rosiglitazone completely inhibited microglia reactivity in SNc and CPu, as measured by CD11b immunostaining, and partially inhibited astroglial response assessed by glial fibrillary acidic protein immunoreactivity. Measurement of striatal MPP+ levels 2, 4, 6 h and 3 days after chronic treatment indicated that MPTP metabolism was not altered by rosiglitazone. The results support the use of PPAR-gamma agonists as a putative anti-inflammatory therapy aimed at arresting PD progression, and suggest that assessment in PD clinical trials is warranted.
Asunto(s)
Intoxicación por MPTP/metabolismo , Intoxicación por MPTP/prevención & control , PPAR gamma/agonistas , Tiazolidinedionas/uso terapéutico , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Antígeno CD11b/metabolismo , Catalepsia , Cromatografía Líquida de Alta Presión/métodos , Enfermedad Crónica , Modelos Animales de Enfermedad , Dopamina/metabolismo , Interacciones Farmacológicas , Dinorfinas/genética , Dinorfinas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo , Globo Pálido/efectos de los fármacos , Globo Pálido/metabolismo , Locomoción/efectos de los fármacos , Intoxicación por MPTP/inducido químicamente , Intoxicación por MPTP/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , PPAR gamma/metabolismo , Desempeño Psicomotor/efectos de los fármacos , ARN Mensajero/metabolismo , Rosiglitazona , Olfato/efectos de los fármacos , Espectrometría de Masas en Tándem/métodos , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Clinical evidence suggests that stimulation of the D(1) rather than D(2) dopamine receptor is related to the development of dyskinesias in Parkinson's disease (PD). We evaluated, in the 6-hydroxydopamine rat model of PD, sensitization of contralateral turning (SCT) behaviour and abnormal involuntary movements (AIMs) as behavioural parameters of dyskinetic response, and changes in zif-268 mRNA expression in striatonigral and striatopallidal neurons on subchronic administration of the D(2)/D(3) agonist ropinirole, defined as a mild dyskinetic drug in the clinic. Results were compared with previous findings on repeated L-dopa treatment. Ropinirole displayed a mild dyskinetic response characterized by SCT only, which contrasted with the presence of SCT in association with AIMs elicited by repeated L-dopa. Zif-268 mRNA levels were decreased in both striatonigral and striatopallidal neurons by ropinirole, in contrast to hyper-expression of zif-268 mRNA selectively induced by L-dopa in striatonigral neurons. Unbalanced responsiveness of striatal efferent neurons might represent a molecular correlate of high dyskinetic potential and AIMs in rats; in contrast, a balanced striatal output might underlie the low dyskinetic potential displayed by ropinirole.
Asunto(s)
Antiparkinsonianos/farmacología , Conducta/efectos de los fármacos , Química Encefálica/fisiología , Cuerpo Estriado/efectos de los fármacos , Discinesia Inducida por Medicamentos , Levodopa/farmacología , Animales , Antiparkinsonianos/efectos adversos , Química Encefálica/efectos de los fármacos , Cuerpo Estriado/fisiología , Modelos Animales de Enfermedad , Discinesia Inducida por Medicamentos/metabolismo , Discinesia Inducida por Medicamentos/patología , Discinesia Inducida por Medicamentos/fisiopatología , Vías Eferentes/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Humanos , Levodopa/efectos adversos , Oxidopamina/toxicidad , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/etiología , RatasRESUMEN
Prolonged treatment with L-DOPA induces highly disabling dyskinesia in Parkinson's disease (PD) patients. In contrast, dopaminergic agonists display variably dyskinetic outcome, depending on pharmacokinetic/pharmacodynamic profile. The present study was aimed at assessing behavioral and biochemical correlates of intense or mild dyskinesia displayed by the different dopamine (DA) receptors stimulation in a rat model of PD. The effect of subchronic stimulation of the D(1) receptor by SKF38393, and the D(2)/D(3) receptor by ropinirole was evaluated in unilaterally 6-hydroxyDA-lesioned rats. Sensitization of contralateral turning (SCT) behavior and abnormal involuntary movements (AIMs) were assessed as behavioral correlates of dyskinetic responses. Opioid peptides mRNA in the dorsolateral striatum (dlStr) and glutamic acid decarboxylase (GAD67) mRNA content in globus pallidus (GP), were evaluated as an index of neuroadaptive changes occurring in the direct and indirect basal ganglia pathways. Subchronic SKF38393 caused AIMs and SCT whereas ropinirole elicited SCT only, indicating that both drugs induced some dyskinetic response, albeit of different type. Peptides mRNA evaluation in dlStr, showed that SKF38393 subchronic treatment was associated to an overexpression of both dynorphin (DYN) and enkephalin (ENK) mRNAs, in the direct and indirect striatal pathway respectively. In contrast, a decrease in DYN mRNA levels only was observed after treatment with ropinirole. Analysis of GAD67 mRNA levels in the GP showed an increase after both D(1) and D(2)/D(3) agonist treatments. Results suggest that presence of SCT alone or SCT plus AIMs might represent correlates of the differential severity of dyskinetic movements induced by treatment with low (ropinirole) or high (SKF38393) dyskinetic potential. Neuroadaptive increases in opioid peptide expression in both direct and indirect striatal pathways were associated to the appearance of AIMs alone. In contrast, increase of GAD67 mRNA in the GP was associated to both behavioral responses (SCT and AIMs), suggesting that neuroadaptive changes in this area were unrelated to the difference in dyskinetic potential of drugs.
Asunto(s)
Antiparkinsonianos/farmacología , Cuerpo Estriado/efectos de los fármacos , Agonistas de Dopamina/farmacología , Dopamina/metabolismo , Discinesia Inducida por Medicamentos/fisiopatología , Trastornos Parkinsonianos/tratamiento farmacológico , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Antiparkinsonianos/uso terapéutico , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiopatología , Agonistas de Dopamina/uso terapéutico , Dinorfinas/metabolismo , Discinesia Inducida por Medicamentos/metabolismo , Encefalinas/metabolismo , Glutamato Descarboxilasa/efectos de los fármacos , Glutamato Descarboxilasa/metabolismo , Indoles/farmacología , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/metabolismo , Vías Nerviosas/fisiopatología , Péptidos Opioides/genética , Oxidopamina , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/fisiopatología , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Dopaminérgicos/efectos de los fármacos , Receptores Dopaminérgicos/metabolismo , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Ácido gamma-Aminobutírico/biosíntesisRESUMEN
Antagonism of adenosine A2A receptor function has been proposed as an effective therapy in the treatment of Parkinson's disease. Thus, the study of new adenosine receptor antagonists is of great importance for the potential use of these drugs in clinical practice. The present study evaluated effects of the new preferential adenosine A2A receptor antagonist 2-butyl-9-methyl-8-(2H-1,2,3-triazol-2-yl)-9H-purin-6-ylamine (ST1535) in unilaterally 6-hydroxydopamine lesioned rats. Acute ST1535 dose-dependently potentiated contralateral turning behaviour induced by a threshold dose of l-3,4-dihydroxyphenylalanine (L-DOPA) (3 mg/kg i.p.), a classical test for antiparkinson drug screening. Subchronic (18 days, twice a day) ST1535 (20 mg/kg i.p.)+L-DOPA (3 mg/kg i.p.) did not induce sensitization to turning behaviour or abnormal involuntary movements during the course of treatment, indicating a low dyskinetic potential of the drug. Moreover, while subchronic administration of a fully effective dose of L-DOPA (6 mg/kg i.p.) significantly increased GABA synthesizing enzyme glutamic acid decardoxylase (GAD67), dynorphin and enkephalin mRNA levels in the lesioned striatum, subchronic ST1535 (20 mg/kg i.p.)+L-DOPA (3 mg/kg i.p.) did not modify any of these markers, although it induced a similar number of contralateral rotations at the beginning of treatment. Finally, acute administration of ST1535 (20 mg/kg i.p.) proved capable of reducing jaw tremors in tacrine model of Parkinson's disease tremor. Results showed that ST1535, in association with a low dose of L-DOPA, displayed antiparkinsonian activity similar to that produced by a full dose of L-DOPA without exacerbating abnormal motor side effects. Moreover, in agreement to other well characterized adenosine A2A receptor antagonists, ST1535 features antitremorigenic effects.