RESUMEN
Extensive damage to nigrostriatal dopaminergic neurons leads to Parkinson's disease (PD). To date, the most effective treatment has been administration of levodopa (L-DOPA) to increase dopaminergic tone. This treatment leads to responses that vary widely among patients, from predominantly beneficial effects to the induction of disabling, abnormal movements (L-DOPA induced dyskinesia (LID)). Similarly, experimental studies have shown animals with widely different degrees of LID severity. In this study, unilateral injections of 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle (MFB) produced more than 90% depletion of dopamine in both the striatum and the substantia nigra reticulata (SNr) of rats. Population analysis showed that dopamine depletion levels were clustered in a single population. In contrast, analysis of abnormal involuntary movements (AIMs) induced by L-DOPA treatment of 6-OHDA-lesioned animals yielded two populations: one with mild LID, and the other with severe LID, which are also related to different therapeutic responses. We examined whether the severity of LID correlated with changes in dopamine 3 receptor (D3R) signaling because of the following: (a) D3R expression and the induction of LID are strongly correlated; and (b) dopaminergic denervation induces a qualitative change in D3R signaling in the SNr. We found that the effects of D3R activation on cAMP accumulation and depolarization-induced [3H]-gamma-aminobutyric acid ([3H]-GABA) release were switched. L-DOPA treatment normalized the denervation-induced changes in animals with mild LID. The D3R activation caused depression of both dopamine 1 receptor (D1R)-induced increases in cAMP production and depolarization-induced [3H]-GABA release, which were reversed to their pre-denervation state. In animals with severe LID, none of the denervation-induced changes were reversed. The finding that in the absence of identifiable differences in 6-OHDA and L-DOPA treatment, two populations of animals with different D3R signaling and LIDs severity implies that mechanisms intrinsic to the treated subject determine the segregation.
Asunto(s)
Discinesias/etiología , Discinesias/metabolismo , Levodopa/efectos adversos , Levodopa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Animales , AMP Cíclico/metabolismo , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Masculino , Haz Prosencefálico Medial/efectos de los fármacos , Haz Prosencefálico Medial/metabolismo , Oxidopamina/metabolismo , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacosRESUMEN
Parkinson's disease (PD) is characterized by the degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc). Clinical and experimental evidence suggest that the activation of the nicotinic acetylcholine receptor (nAChR) could be protective for PD. In this study, we investigated the neuroprotective capacity of nicotine in a rat PD model. Considering that iron metabolism has been implicated in PD pathophysiology and nicotine has been described to chelate this metal, we also studied the effect of nicotine on the cellular labile iron pool (LIP) levels. Rotenone (1 µg) was unilaterally injected into the median forebrain bundle to induce the degeneration of the nigrostriatal pathway. Nicotine administration (1 mg/K, s.c. daily injection, starting 5 days before rotenone and continuing for 30 days) attenuated the dopaminergic cell loss in the SNpc and the degeneration of the dopaminergic terminals provoked by rotenone, as assessed by immunohistochemistry. Furthermore, nicotine partially prevented the reduction on dopamine levels in the striatum and improved the motor deficits, as determined by HPLC-ED and the forelimb use asymmetry test, respectively. Studies in primary mesencephalic cultures showed that pretreatment with nicotine (50 µM) improved the survival of tyrosine hydroxylase-positive neurons after rotenone (20 nM) exposure. Besides, nicotine induced a reduction in the LIP levels assessed by the calcein dequenching method only at the neuroprotective dose. These effects were prevented by addition of the nAChRs antagonist mecamylamine (100 µM). Overall, we demonstrate a neuroprotective effect of nicotine in a model of PD in rats and that a reduction in iron availability could be an underlying mechanism.
Asunto(s)
Hierro/metabolismo , Nicotina/uso terapéutico , Agonistas Nicotínicos/uso terapéutico , Enfermedad de Parkinson/prevención & control , Porción Compacta de la Sustancia Negra/patología , Análisis de Varianza , Animales , Recuento de Células , Modelos Animales de Enfermedad , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Relación Dosis-Respuesta a Droga , Embrión de Mamíferos , Conducta Exploratoria/efectos de los fármacos , Fluoresceínas/farmacocinética , Miembro Anterior/fisiopatología , Insecticidas/toxicidad , Masculino , Haz Prosencefálico Medial/efectos de los fármacos , Haz Prosencefálico Medial/patología , Mesencéfalo/citología , Actividad Motora/efectos de los fármacos , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/patología , Ratas , Ratas Sprague-Dawley , Rotenona/toxicidad , Tubulina (Proteína)/metabolismo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Amantadine is the noncompetitive antagonist of N-methyl-D-aspartate, receptor activated by the excitatory neurotransmitter glutamate. It is the only effective medication used to alleviate dyskinesia induced by L-3,4-dihydroxyphenylalanine (L-DOPA) in Parkinson's disease patients. Unfortunately, adverse effects as abnormal involuntary movements (AIMs) known as L-DOPA-induced dyskinesia limit its clinical utility. Combined effective symptomatic treatment modalities may lessen the liability to undesirable events. Likewise drugs known to interfere with nitrergic system reduce AIMs in animal models of Parkinson's disease. We aimed to analyze an interaction between amantadine, neuronal nitric oxide synthase inhibitor (7-nitroindazole, 7NI), and nitric oxide donor (sodium nitroprusside, SNP) in 6-hydroxydopamine-(6-OHDA)-lesioned rats (microinjection in the medial forebrain bundle) presenting L-DOPA-induced dyskinesia (20 mg/kg, gavage, during 21 days). We confirm that 7NI-30 mg/kg, SNP-2/4 mg/kg and amantadine-40 mg/kg, individually reduced AIMs. Our results revealed that co-administration of sub-effective dose of amantadine (10 mg/kg) plus sub-effective dose of 7NI (20 mg/kg) potentiates the effect of reducing AIMs scores when compared to the effect of the drugs individually. No superior benefit on L-DOPA-induced AIMs was observed with the combination of amantadine and SNP. The results revealed that combination of ineffective doses of amantadine and 7NI represents a new strategy to increase antidyskinetic effect in L-DOPA-induced AIMs. It may provide additional therapeutic benefits to Parkinson's disease patients from these disabling complications at lower and thus safer and more tolerable doses than required when either drug is used alone. To close, we discuss the paradox of both nitric oxide synthase inhibitor and/or donor produced AIMs reduction by targeting nitric oxide synthase.
Asunto(s)
Amantadina/uso terapéutico , Discinesia Inducida por Medicamentos/complicaciones , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Indazoles/uso terapéutico , Levodopa/efectos adversos , Nitroprusiato/uso terapéutico , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Quimioterapia Combinada , Masculino , Haz Prosencefálico Medial/efectos de los fármacos , Microinyecciones , Oxidopamina/administración & dosificación , RatasRESUMEN
Parkinson's disease (PD) is characterized by a progressive neurodegeneration in the substantia nigra and a striatal dopamine decrease. Striatal extracellular adenosine and ATP modulate the dopaminergic neurotransmission whereas guanosine has a protective role in the brain. Therefore, the regulation of their levels by enzymatic activity may be relevant to the clinical feature of PD. Here it was evaluated the extracellular nucleotide hydrolysis from striatal slices 4 weeks after a unilateral infusion with 6-OHDA into the medial forebrain bundle. This infusion increased ADP, AMP, and GTP hydrolysis by 15, 25, and 41%, respectively, and decreased GDP hydrolysis by 60%. There was no change in NTPDases1, 2, 3, 5, 6, and 5'-nucleotidase transcription. Dopamine depletion changes nucleotide hydrolysis and, therefore, alters the regulation of striatal nucleotide levels. These changes observed in 6-OHDA-lesioned animals may contribute to the symptoms observed in the model and provide evidence to indicate that extracellular purine hydrolysis is a key factor in understanding PD, giving hints for new therapies.
Asunto(s)
Adenina/metabolismo , Adrenérgicos/farmacología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Guanina/metabolismo , Oxidopamina/farmacología , Enfermedad de Parkinson/metabolismo , 5'-Nucleotidasa/genética , 5'-Nucleotidasa/metabolismo , Ácido Anhídrido Hidrolasas/genética , Ácido Anhídrido Hidrolasas/metabolismo , Animales , Modelos Animales de Enfermedad , Isoenzimas/metabolismo , Masculino , Haz Prosencefálico Medial/efectos de los fármacos , Haz Prosencefálico Medial/metabolismo , Fosfatos/metabolismo , Ratas , Ratas WistarRESUMEN
Although, the mechanism of 2,4-dichlorophenoxyacetic acid (2,4-D) neurotoxicity remains unknown, the monoaminergic system appears to mediate some of its effects in rats as we previously reported. In this study; we examined the 2,4-D effects on locomotor activity, circling behavior and monoamine levels after the injection into the basal ganglia of male adult rats. These effects were compared with those induced after selective lesions of dopaminergic neurons with 6-hydroxydopamine (6-OHDA). 2,4-D-injected into one striatum (100 microg/rat) produced a marked depression in locomotor activity and elicited a moderate circling towards the ipsilateral side at 6 and 24 h postinjection. These behavioral changes were accompanied by a decrease and an increase of serotonin (5-HT) and homovanillic acid (HVA) levels, respectively. 2,4-D administration (100 microg/rat) into the nucleus accumbens, induced similar behavioral and neurochemical patterns to the intrastriatal 2,4-D injection, although rats did not present notorious turning. When 2,4-D was injected into one medial forebrain bundle (MFB, 50 microg/rat), animals presented ipsilateral circling, while locomotor activity was unchanged at 3 and 7 days post-injection. These last rats also exhibited diminished levels of striatal 5-HT, dopamine (DA) and their metabolites without changes in the substantia nigra (SN). Animals sacrificed 3 and 7 days after a 6-OHDA injection into one of the MFB, presented progressive depletion of dopamine in striatum and SN. 2,4-D as well as 6-OHDA-treated rats into one of the MFB were challenged with low dose (0.05 mg/kg s.c.) of apomorphine (only at 7 days post-injection) to evaluate a possible DA-receptor supersensitivity. Only 6-OHDA treated rats showing a vigorous contralateral rotation activity. These results indicate that 2,4-D induced a regionally-specific neurotoxicity in the basal ganglia of rats. The neurotoxic effects of 2,4-D on basal ganglia by interacting with the monoaminergic system depended not only on the exact location of the 2,4-D injection, but also on the dose and time period of post-injection. Toxicity produced by 2,4-D appears to be different in monoaminergic terminals, axonal fibers, and cell bodies.