RESUMEN
Parkinson's Disease (PD), treated with the dopamine precursor l-3,4-dihydroxyphenylalanine (L-DOPA), displays motor and non-motor orofacial manifestations. We investigated the pathophysiologic mechanisms of the lateral pterygoid muscles (LPMs) and the trigeminal system related to PD-induced orofacial manifestations. A PD rat model was produced by unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. Abnormal involuntary movements (dyskinesia) and nociceptive responses were determined. We analyzed the immunodetection of Fos-B and microglia/astrocytes in trigeminal and facial nuclei and morphological markers in the LPMs. Hyperalgesia response was increased in hemiparkinsonian and dyskinetic rats. Hemiparkinsonism increased slow skeletal myosin fibers in the LPMs, while in the dyskinetic ones, these fibers decreased in the contralateral side of the lesion. Bilateral increased glycolytic metabolism and an inflammatory muscle profile were detected in dyskinetic rats. There was increased Fos-B expression in the spinal nucleus of lesioned rats and in the motor and facial nucleus in L-DOPA-induced dyskinetic rats in the contralateral side of the lesion. Glial cells were increased in the facial nucleus on the contralateral side of the lesion. Overall, spinal trigeminal nucleus activation may be associated with orofacial sensorial impairment in Parkinsonian rats, while a fatigue profile on LPMs is suggested in L-DOPA-induced dyskinesia when the motor and facial nucleus are activated.
Asunto(s)
Discinesia Inducida por Medicamentos , Enfermedad de Parkinson , Trastornos Parkinsonianos , Ratas , Animales , Levodopa/farmacología , Discinesia Inducida por Medicamentos/metabolismo , Cuerpo Estriado/metabolismo , Trastornos Parkinsonianos/metabolismo , Enfermedad de Parkinson/metabolismo , Oxidopamina/efectos adversos , Tronco Encefálico/metabolismo , Modelos Animales de Enfermedad , Antiparkinsonianos/efectos adversosRESUMEN
The dopamine content in cerebral structures has been related to neuronal excitability and several approaches have been used to study this phenomenon during seizure vulnerability period. In the present work, we describe the effects of dopamine depletion after the administration of 6-hidroxidopamine (6-OHDA) into the substantia nigra pars compacta of male rats submitted to the pilocarpine model of epilepsy. Susceptibility to pilocarpine-induced status epilepticus (SE), as well as spontaneous and recurrent seizures (SRSs) frequency during the chronic period of the model were determined. Since the hippocampus is one of main structures in the development of this experimental model of epilepsy, the dopamine levels in this region were also determined after drug administration. In the first experiment, 62% (15/24) of 6-OHDA pre-treated rats and 45% (11/24) of those receiving ascorbic acid as control solution progressed to motor limbic seizures evolving to SE, after the administration of pilocarpine. Severeness of seizures during the model´s the acute period, was significantly higher in epileptic experimental rats (56.52%), than in controls (4.16%). In the second experiment, the frequency of seizures in the model's chronic phase did not significantly change between groups. Our data show that dopamine may play an important role on seizure severity in the pilo's model acute period, which seems to be due to dopamine inhibitory action on motor expression of seizure.
Asunto(s)
Epilepsia , Estado Epiléptico , Animales , Dopamina/efectos adversos , Epilepsia/inducido químicamente , Masculino , Agonistas Muscarínicos/efectos adversos , Oxidopamina/efectos adversos , Pilocarpina/toxicidad , Ratas , Ratas Wistar , Convulsiones/inducido químicamente , Convulsiones/metabolismo , Estado Epiléptico/inducido químicamenteRESUMEN
AIMS: Parkinson's disease (PD) is a neurological disorder caused by environmental and genetic factors, characterized by the death of dopaminergic neurons of the substantia nigra pars compacta (SNpc), leading to a decrease of dopamine in the striatum. In addition to motor symptoms, PD has several abnormalities, among which are cardiovascular changes, such as orthostatic and postprandial hypotension, and blood pressure lability. Studies demonstrate gender differences in PD pathogenesis, indicating that female hormones have a protective role against disease development. However, no studies examining cardiovascular changes in a female rat model of parkinsonism exist. MAIN METHODS: Wistar female rats were subjected to ovariectomy (OVX) or sham surgery. After seven days, these animals were subjected to bilateral infusion of 6-hydroxydopamine (6-OHDA) or vehicle solution in their SNpc. On the 14th experimental day, a femoral artery catheterization was performed to record cardiovascular parameters after 24 h in conscious state. Analyses of cardiovascular variability and spontaneous baroreflex were performed. The nitrite (NO) concentration in the heart, thoracic aorta, abdominal aorta, and plasma was measured. KEY FINDINGS: The sham-6-OHDA group had no decrease in the mean arterial pressure compared to sham-saline group, whereas the OVX-6-OHDA group presented a baseline decrease in comparison to sham-6-OHDA. The OVX-6-OHDA group showed an NO increase in the heart and abdominal aorta, whereas the sham-6-OHDA group did not. The very low frequency variability component decreased in the sham-6-OHDA but not in the OVX-6-OHDA group. SIGNIFICANCE: We suggest a cardiovascular protection by ovarian hormones in PD with a possible NO involvement.
Asunto(s)
Sistema Cardiovascular/fisiopatología , Enfermedad de Parkinson/fisiopatología , Trastornos Parkinsonianos/fisiopatología , Animales , Presión Sanguínea , Cuerpo Estriado/fisiopatología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Neuronas Dopaminérgicas/patología , Femenino , Frecuencia Cardíaca , Neostriado/fisiopatología , Óxido Nítrico/análisis , Oxidopamina/efectos adversos , Oxidopamina/farmacología , Enfermedad de Parkinson/metabolismo , Ratas , Ratas Wistar , Sustancia Negra/fisiopatologíaRESUMEN
Degeneration of the locus coeruleus (LC), the main source of cerebral noradrenaline (NA), has been reported in diverse neurodegenerative diseases, including Parkinson's diseases (PD). There is increasing evidence indicating the role of NA deficiency in the prefrontal cortex (PFC) and the development of early cognitive impairments in PD. Here, we evaluated whether a selective noradrenergic lesion of LC caused by 6-hydroxydopamine (6-OHDA) may induce memory deficits and neurochemical alterations in the PFC. Adult male Wistar rats received stereotaxic bilateral injections of 6-OHDA (5 µg/2 µl) into the LC, and two stainless-steel guide cannulas were implanted in the PFC. The SHAM group received just vehicle. To induce a selective noradrenergic lesion, animals received nomifensine (10 mg/kg), a dopamine transporter blocker, one hour before surgery. 6-OHDA-lesioned rats displayed impairments of the short- and long-term object recognition memory associated to reduced content of tyrosine hydroxylase in the LC. Neurochemical analysis revealed an altered mitochondrial membrane potential in LC. Regarding the PFC, an increased ROS production, cell membrane damage, and mitochondrial membrane potential disruption were observed. Remarkably, bilateral NA (1 µg/0.2 µl) infusion into the PFC restored the recognition memory deficits in LC-lesioned rats. These findings indicate that a selective noradrenergic LC lesion induced by 6-OHDA deregulates a noradrenergic network in the PFC, which could be involved in the early memory impairments observed in nondemented PD patients.
Asunto(s)
Locus Coeruleus/patología , Trastornos de la Memoria/patología , Oxidopamina/efectos adversos , Corteza Prefrontal/fisiopatología , Animales , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas WistarRESUMEN
Patients with Parkinson's disease (PD) manifest nonmotor and motor symptoms. Autonomic cardiovascular dysregulation is a common nonmotor manifestation associated with increased morbimortality. Conventional clinical treatment alleviates motor signs but does not change disease progression and fails in handling nonmotor features. Nutrition is a key modifiable determinant of chronic disease. This study aimed to assess the effects of propolis on cardiological features, heart rate (HR) and heart rate variability (HRV) and on nigrostriatal dopaminergic damage, detected by tyrosine hydroxylase (TH) immunoreactivity, in the 6-hydroxydopamine (6-OHDA) rat model of PD. Male Wistar rats were injected bilaterally with 6-OHDA or saline into the striatum and were treated with propolis or water for 40 days. Autonomic function was assessed by time domain parameters (standard deviation of all normal-to-normal intervals (SDNN) and square root of the mean of the squared differences between adjacent normal RR intervals (RMSSD)) of HRV calculated from electrocardiogram recordings. Reductions in HR (p = 1.47×10-19), SDNN (p = 3.42×10-10) and RMSSD (p = 8.2×10-6) detected in parkinsonian rats were reverted by propolis. Propolis attenuated neuronal loss in the substantia nigra (p = 5.66×10-15) and reduced striatal fiber degeneration (p = 7.4×10-5) in 6-OHDA-injured rats, which also showed significant weight gain (p = 1.07×10-5) in comparison to 6-OHDA-lesioned counterparts. Propolis confers cardioprotection and neuroprotection in the 6-OHDA rat model of PD.
Asunto(s)
Cardiotónicos/farmacología , Fármacos Neuroprotectores/farmacología , Oxidopamina/efectos adversos , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Enfermedad de Parkinson/tratamiento farmacológico , Própolis/farmacología , Animales , Cuerpo Estriado/efectos de los fármacos , Modelos Animales de Enfermedad , Dopamina , Frecuencia Cardíaca , Masculino , Enfermedad de Parkinson/patología , Enfermedad de Parkinson Secundaria/inducido químicamente , Ratas , Ratas Wistar , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
After Alzheimer, Parkinson disease (PD) is the most frequently occurring progressive, degenerative neurological disease. It affects both sympathetic and parasympathetic nervous systems in a variable fashion. Cardiovascular symptoms are present in almost all stages of PD and narrower heart rate variability is the earliest sign. Administration of Levodopa to PD patients has proven to provide some degree of neurological protection. This drug, however, causes side effects including nausea and vomiting, lessened by the administration of domperidone. Autopsies in PD patients led some researchers to suggest the involvement of the ventricular arrhythmia induced by domperidone. The aim of the present study was to determine the impact of the adjusted human maximal dose of domperidone, on cardiological features of Wistar rats. domperidone was administered to both 6-hydroxydopamine Parkinsonism models and regular Wistar rats. Quantitative analysis of ranges of heart beat variation showed significant abnormal distribution in both groups receiving domperidone as compared with respective sham counterparts. However, qualitative analysis of Poincaré plots showed that 6-hydroxydopamine Parkinsonism models receiving domperidone had the narrowest full range of heart beat and the worst distribution heart beat ranges as compared with all study groups corroborating with previous suggestion that domperidone administration to PD patients is likely to play a role in sudden unexpected death in this group of patients.
Asunto(s)
Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/fisiopatología , Domperidona/farmacología , Antagonistas de Dopamina/farmacología , Oxidopamina/efectos adversos , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/complicaciones , Animales , Conducta Animal , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/tratamiento farmacológico , Modelos Animales de Enfermedad , Domperidona/administración & dosificación , Domperidona/efectos adversos , Antagonistas de Dopamina/administración & dosificación , Antagonistas de Dopamina/efectos adversos , Electrocardiografía , Frecuencia Cardíaca , Humanos , Inmunohistoquímica , Masculino , RatasRESUMEN
Red wine polyphenols are known for their implications for human health protection, although they suffer from high instability. For this reason, a red wine powder was prepared by freeze-drying encapsulation in maltodextrin/arabic gum matrix, and its composition was determined by means of high-performance liquid chromatography coupled quadrupole time-of-flight mass spectrometry (HPLC-MS-QTOF). More than thirty polyphenols, including anthocyanins, flavanols, flavonols, phenolic acids and stilbenoids, were identified. Some of the main quantified polyphenols were: malvidin-3-O-glucoside, malvidin 3-O-(6â³-acetyl-glucose), petunidin-3-O-glucoside, quercetin-3-O-glucuronide, syringenin-3-O-glucoside, epicatechin, gallic acid and syringic acid. The biological activity of this de-alcoholized and encapsulated red wine on human neuroblastoma SH-SY5Y cells was studied. The results showed that the encapsulated red wine powder has active redox properties, as verified by performing reactive oxygen species (ROS) analysis utilizing a neuronal model. This could help explain its action against the neurotoxicity induced by 6-hydroxydopamine (6-OHDA).
Asunto(s)
Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Polifenoles/farmacología , Vino/análisis , Cápsulas , Línea Celular , Supervivencia Celular , Cromatografía Líquida de Alta Presión , Goma Arábiga/química , Humanos , Espectrometría de Masas , Modelos Biológicos , Neuronas/citología , Neuronas/metabolismo , Fármacos Neuroprotectores/química , Oxidopamina/efectos adversos , Polifenoles/química , Polisacáridos/química , Polvos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Chrysin is a natural flavonoid which is found in bee propolis, honey and various plants, and neuroprotective effect of chrysin in mice was previously demonstrated by our group. Neuroinflammation, neurotrophic factors and neuronal recovery factors associated with the neuroprotective effect of this flavonoid require further investigations. Thus, now we investigated the possible involvement of inflammatory cytokines, neurotrophic factors and neuronal recovery in the effect of chrysin in 6-hydroxidopamine (6-OHDA), a well-established model of Parkinson's disease, in striatum of mice. The 6-OHDA microinjection induced behavioral alterations on the rotarod test and apomorphine-induced circling behavior in mice. 6-OHDA administration elevated levels of tumour necrosis factor-α, interferon-gamma, interleukin-1ß, interleukin-2, interleukin-6 and nuclear factor-kappa B and decreased the interleukin-10 levels, total reactive antioxidant potential and total antioxidant reactivity in striatum, as well as, modified the calcium-binding protein B (S100B), brain-derived neurotrophic factor, nerve growth factor and glial cell line-derived neurotrophic factor levels. The intrastriatal injection of 6-OHDA also induced an decrease of dopamine, 3,4-dihydroxyphenylacetic acid, homovanylic acid levels and tyrosine hydroxylase content. Oral treatment with chrysin (10 mg/kg, 28 days), culminated with the prevention of these alterations occasioned by 6-OHDA. These results corroborated with the neuroprotective effect of chrysin in the treatment of Parkinson's disease and, indicated the mechanism involved throught the inflammatory cytokines, neurotrophic factors and recovery of dopaminergic neurons in striatum.
Asunto(s)
Flavonoides/farmacología , Inflamación/prevención & control , Factores de Crecimiento Nervioso/metabolismo , Oxidopamina/efectos adversos , Enfermedad de Parkinson Secundaria/prevención & control , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Biomarcadores , Dopamina/metabolismo , Regulación de la Expresión Génica/fisiología , Ácido Homovanílico/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Factores de Crecimiento Nervioso/genética , Distribución AleatoriaRESUMEN
The present study evaluates the possible antinociceptive effect of chromosphere transplants in rats injected with 6-hydroxydopamine (6-OHDA), a model of Parkinson's disease. Male adult Wistar rats received 40µg/0.5µl of 6-OHDA or 0.5µl of vehicle into the left substantia nigra (SNc). Rats were evaluated for mechanical allodynia, cold allodynia, thermal hyperalgesia and formalin. Rats with altered nociceptive threshold were transplanted with chromospheres. After transplant, rats were evaluated every week. Our results confirm that 6-OHDA injection into rat's SNc reduces mechanical, thermal, and chemical thresholds. Interestingly, chromospheres' transplant reverted 6-OHDA-induced allodynia and hyperalgesia. The antinociceptive effect induced by chromospheres was dopamine D2- and opioid-receptor dependent since sulpiride or naltrexone reverted its effect.
Asunto(s)
Nocicepción/efectos de los fármacos , Nocicepción/fisiología , Trastornos Parkinsonianos/fisiopatología , Animales , Células Cultivadas , Masculino , Microinyecciones , Naltrexona/farmacología , Oxidopamina/efectos adversos , Dimensión del Dolor , Trastornos Parkinsonianos/inducido químicamente , Ratas , Sustancia Negra/efectos de los fármacos , Sulpirida/farmacologíaRESUMEN
The receptor for advanced glycation endproducts (RAGE) is a pattern-recognition receptor associated with inflammation in most cell types. RAGE up-regulates the expression of proinflammatory mediators and its own expression via activation of NF-kB. Recent works have proposed a role for RAGE in Parkinson's disease (PD). In this study, we used the multimodal blocker of RAGE FPS-ZM1, which has become available recently, to selectively inhibit RAGE in the substantia nigra (SN) of rats intracranially injected with 6-hydroxydopamine (6-OHDA). FPS-ZM1 (40 µg per rat), injected concomitantly with 6-OHDA (10 µg per rat) into the SN, inhibited the increase in RAGE, activation of ERK1/2, Src and nuclear translocation of NF-kB p65 subunit in the SN. RAGE inhibition blocked glial fibrillary acidic protein and Iba-1 upregulation as well as associated astrocyte and microglia activation. Circulating cytokines in serum and CSF were also decreased by FPS-ZM1 injection. The loss of tyrosine hydroxylase and NeuN-positive neurons was significantly inhibited by RAGE blocking. Finally, FPS-ZM1 attenuated locomotory and exploratory deficits induced by 6-OHDA. Our results demonstrate that RAGE is an essential component in the neuroinflammation and dopaminergic denervation induced by 6-OHDA in the SN. Selective inhibition of RAGE may offer perspectives for therapeutic approaches.
Asunto(s)
Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Oxidopamina/efectos adversos , Receptor para Productos Finales de Glicación Avanzada/antagonistas & inhibidores , Sustancia Negra/metabolismo , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/patología , Mediadores de Inflamación/metabolismo , Masculino , FN-kappa B/metabolismo , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Ratas , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patología , Familia-src Quinasas/metabolismoRESUMEN
PURPOSE: To investigate the role of adenosine A2A receptors on 6-OHDA-induced motor disorder in rat. METHODS: In order to induce experimental model of Parkinson's disease, 6-hydoxydopamine (8 µg/rat) was injected unilaterally into the SNc. After three weeks as a recovery period, 6-OHDA-induced bradykinesia and balance disturbances were assessed by using beam traversal test 10, 30 and 60 minutes after intraperitoneal injections of the drugs (caffeine, SCH58261). RESULTS: The results showed that 6-OHDA (8 µg/rat, Intra-SNc) induced motor disorders of Parkinson's disease and increased elapsed time in the beam test (p<0.001). Injection of caffeine (30 mg/kg, i.p.) and SCH58261 (2 mg/kg, i.p.) attenuated elapsed time on beam (p<0.01 and p<0.001). We showed that acute administration of caffeine and SCH 58261 can improve the 6-OHDA-induced bradykinesia and motor disturbance. CONCLUSION: Adenosine A2AR antagonists improve 6-OHDA-motor deficit and this effect seems to be mediated by the inhibition of A2A presynaptic receptors in substantia nigra pars compacta.
Asunto(s)
Antagonistas del Receptor de Adenosina A2/farmacología , Cafeína/farmacología , Oxidopamina/efectos adversos , Enfermedad de Parkinson Secundaria/inducido químicamente , Antagonistas de Receptores Purinérgicos P1/farmacología , Animales , Modelos Animales de Enfermedad , Hipocinesia/inducido químicamente , Masculino , Actividad Motora/efectos de los fármacos , Trastornos Motores/inducido químicamente , Ratas Wistar , Estudios de Tiempo y MovimientoRESUMEN
PURPOSE: To investigate the role of adenosine A2A receptors on 6-OHDA-induced motor disorder in rat. METHODS: In order to induce experimental model of Parkinson's disease, 6-hydoxydopamine (8 μg/rat) was injected unilaterally into the SNc. After three weeks as a recovery period, 6-OHDA-induced bradykinesia and balance disturbances were assessed by using beam traversal test 10, 30 and 60 minutes after intraperitoneal injections of the drugs (caffeine, SCH58261). RESULTS: The results showed that 6-OHDA (8 μg/rat, Intra-SNc) induced motor disorders of Parkinson's disease and increased elapsed time in the beam test (p<0.001). Injection of caffeine (30 mg/kg, i.p.) and SCH58261 (2 mg/kg, i.p.) attenuated elapsed time on beam (p<0.01 and p<0.001). We showed that acute administration of caffeine and SCH 58261 can improve the 6-OHDA-induced bradykinesia and motor disturbance. CONCLUSION: Adenosine A2AR antagonists improve 6-OHDA-motor deficit and this effect seems to be mediated by the inhibition of A2A presynaptic receptors in substantia nigra pars compacta.
Asunto(s)
Animales , Masculino , Enfermedad de Parkinson Secundaria/inducido químicamente , Cafeína/farmacología , Oxidopamina/efectos adversos , Antagonistas de Receptores Purinérgicos P1/farmacología , Antagonistas del Receptor de Adenosina A2/farmacología , Estudios de Tiempo y Movimiento , Ratas Wistar , Hipocinesia/inducido químicamente , Modelos Animales de Enfermedad , Trastornos Motores/inducido químicamente , Actividad Motora/efectos de los fármacosRESUMEN
In order to assess whether caffeine and theophylline have the same potency and efficacy to reverse the impairment of motor function caused by acute or chronic interruption of striatal dopamine transmission, a comparison of their dose-response relationship was made in the acute model of haloperidol-induced catalepsy, and the chronic model of unilateral lesion of the dopamine nigrostriatal pathway with 6-hydroxydopamine. At equimolar doses, both drugs reduced catalepsy intensity and increased its onset latency in a dose-dependent fashion, showing comparable potencies and attaining the maximal effect at similar doses. Catalepsy intensity: caffeine ED50 = 24.1 µmol/kg [95% CI, 18.4-31.5]; theophylline ED50 = 22.0 µmol/kg [95% CI, 17.0-28.4]. Catalepsy latency: caffeine ED50 = 27.0 µmol/kg [95% CI, 21.1-34.6]; theophylline ED50 = 28.8 µmol/kg [95% CI, 22.5-36.7]. In one group of hemiparkinsonian rats (n = 5), caffeine caused a dose-dependent recovery of the contralateral forepaw stepping: ED50 = 2.4 µmol/kg/day [95% CI, 1.9-3.1]), reaching its maximum at the dose of 5.15 µmol/kg/day. When the treatment of these same rats was switched to 5.15 µmol/kg/day of theophylline, the stepping recovery was only 51 ± 12% of that induced by caffeine. Assessing the dose-response relationship of theophylline in another group of hemiparkinsonian rats (n = 7) revealed that it caused stepping recovery in an all-or-none fashion. Thus, the three lower doses had no effect, but at the dose of 5.15 µmol/kg/day theophylline suddenly increased the stepping to 56 ± 5% of the maximal effect observed when the treatment of these same rats was switched to an equimolar dose of caffeine. Increasing the dose of theophylline up to 15.45 µmol/kg/day caused no further stepping improvement since it was only 41 ± 6% of the maximal effect produced by caffeine at the dose of 5.15 µmol/kg/day. Given that theophylline showed less potency and efficacy than caffeine to reverse the motor impairment caused by chronic, but not acute, interruption of striatal dopaminergic transmission in rats, it is suggested that caffeine would provide more benefits than theophylline to improve the motor function in patients with Parkinson's disease.
Asunto(s)
Cafeína/farmacología , Cuerpo Estriado/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , Destreza Motora/efectos de los fármacos , Teofilina/farmacología , Animales , Catalepsia/inducido químicamente , Relación Dosis-Respuesta a Droga , Haloperidol/efectos adversos , Haloperidol/antagonistas & inhibidores , Masculino , Oxidopamina/efectos adversos , Oxidopamina/antagonistas & inhibidores , Trastornos Parkinsonianos/inducido químicamente , RatasRESUMEN
Striatal cholinergic interneurons show tonic spiking activity in the intact and sliced brain, which stems from intrinsic mechanisms. Because of it, they are also known as "tonically active neurons" (TANs). Another hallmark of TAN electrophysiology is a pause response to appetitive and aversive events and to environmental cues that have predicted these events during learning. Notably, the pause response is lost after the degeneration of dopaminergic neurons in animal models of Parkinson's disease. Moreover, Parkinson's disease patients are in a hypercholinergic state and find some clinical benefit in anticholinergic drugs. Current theories propose that excitatory thalamic inputs conveying information about salient sensory stimuli trigger an intrinsic hyperpolarizing response in the striatal cholinergic interneurons. Moreover, it has been postulated that the loss of the pause response in Parkinson's disease is related to a diminution of I(sAHP), a slow outward current that mediates an afterhyperpolarization following a train of action potentials. Here we report that I(sAHP) induces a marked spike-frequency adaptation in adult rat striatal cholinergic interneurons, inducing an abrupt end of firing during sustained excitation. Chronic loss of dopaminergic neurons markedly reduces I(sAHP) and spike-frequency adaptation in cholinergic interneurons, allowing them to fire continuously and at higher rates during sustained excitation. These findings provide a plausible explanation for the hypercholinergic state in Parkinson's disease. Moreover, a reduction of I(sAHP) may alter synchronization of cholinergic interneurons with afferent inputs, thus contributing to the loss of the pause response in Parkinson's disease.
Asunto(s)
Acetilcolina/metabolismo , Potenciales de Acción/fisiología , Cuerpo Estriado/patología , Interneuronas/fisiología , Trastornos Parkinsonianos/patología , Análisis de Varianza , Animales , Antracenos/farmacología , Apamina/farmacología , Ácido Ascórbico/efectos adversos , Bario/farmacología , Simulación por Computador , Cuerpo Estriado/lesiones , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica/métodos , Técnicas In Vitro , Indoles/farmacología , Masculino , Modelos Neurológicos , Fármacos Neuroprotectores/farmacología , Oxidopamina/efectos adversos , Trastornos Parkinsonianos/inducido químicamente , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Sustancia Negra/lesiones , Sustancia Negra/fisiologíaRESUMEN
Enriched environment (EE) is neuroprotective in several animal models of neurodegeneration. It stimulates the expression of trophic factors and modifies the astrocyte cell population which has been said to exert neuroprotective effects. We have investigated the effects of EE on 6-hydroxydopamine (6-OHDA)-induced neuronal death after unilateral administration to the medial forebrain bundle, which reaches 85-95% of dopaminergic neurons in the substantia nigra after 3 weeks. Continuous exposure to EE 3 weeks before and after 6-OHDA injection prevents neuronal death (assessed by tyrosine hydroxylase staining), protects the nigrostriatal pathway (assessed by Fluorogold retrograde labeling) and reduces motor impairment. Four days after 6-OHDA injection, EE was associated with a marked increase in glial fibrillary acidic protein staining and prevented neuronal death (assessed by Fluoro Jade-B) but not partial loss of tyrosine hydroxylase staining in the anterior substantia nigra. These results robustly demonstrate that EE preserves the entire nigrostriatal system against 6-OHDA-induced toxicity, and suggests that an early post-lesion astrocytic reaction may participate in the neuroprotective mechanism.
Asunto(s)
Astrocitos/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Ambiente , Oxidopamina/efectos adversos , Enfermedad de Parkinson Secundaria , Sustancia Negra/metabolismo , Anfetamina , Análisis de Varianza , Animales , Astrocitos/patología , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Proteína Ácida Fibrilar de la Glía/metabolismo , Masculino , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/patología , Enfermedad de Parkinson Secundaria/prevención & control , Ratas , Ratas Wistar , Prueba de Desempeño de Rotación con Aceleración Constante/métodos , Estilbamidinas , Sustancia Negra/patología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Oxidation of catecholamines is suggested to contribute to oxidative stress in Parkinson's disease. Nitric oxide (*NO) is able to oxidize cyclic compounds like ubiquinol; moreover, recent lines of evidence proposed a direct role of *NO and its by-product peroxynitrite in the pathophysiology of Parkinson's disease. The aim of this study was to analyze the potential reaction between 6-hydroxydopamine, a classic inducer of Parkinson's disease, and *NO. The results showed that *NO reacts with the deprotonated form of 6-hydroxydopamine at pH 7 and 37 degrees C with a second-order rate constant of 1.5 x 10(3) M(-1) x s(-1) as calculated by the rate of *NO decay measured with an amperometric sensor. Accordingly, the rates of formation of 6-hydroxy-dopamine quinone were dependent on *NO concentration. The coincubation of *NO and 6-hydroxydopamine with either bovine serum albumin or alpha-synuclein led to tyrosine nitration of the protein, in a concentration dependent-manner and sensitive to superoxide dismutase. These findings suggest the formation of peroxynitrite during the redox reactions following the interaction of 6-hydroxydopamine with *NO. The implications of this reaction for in vivo models are discussed in terms of the generation of reactive nitrogen and oxygen species within a propagation process that may play a significant role in neurodegenerative diseases.
Asunto(s)
Óxido Nítrico/metabolismo , Oxidopamina/metabolismo , Enfermedad de Parkinson/metabolismo , Ácido Peroxinitroso/metabolismo , Tirosina/análogos & derivados , Tirosina/biosíntesis , Animales , Bovinos , Proteínas del Tejido Nervioso/metabolismo , Oxidación-Reducción , Oxidopamina/efectos adversos , Enfermedad de Parkinson Secundaria/inducido químicamente , Albúmina Sérica Bovina/metabolismo , Superóxido Dismutasa/farmacología , Sinucleínas , Tirosina/antagonistas & inhibidores , alfa-SinucleínaRESUMEN
Astroglial and microglial activation was analyzed in adult male Wistar rats after a unilateral striatal injection of different doses (8, 4 and 1 micrograms) of 6-hydroxydopamine (6-OHDA). Control animals received the injection of the same volume of the solvent. The rotational behavior was registered by a rotometer 24 and 72 hours, 7, 10, 14 and 22 days after lesion. Following, animals were sacrificed and the tyrosine hydroxylase (TH) positive dopamine cells, the glial fibrillary acidic protein (GFAP) immunolabeled astrocytes and the OX42 immunoreactive microglia were visualized by mean of immunohistochemistry and quantified by stereologic method employing the optical disector and the point intercepts. The apomorphine (0.5 mg/kg)-induced circling behavior was seen only after 8 micrograms of 6-OHDA from 72 hours postlesion until sacrifice. Decreases of the TH immunoreactive terminals and cell bodies were found in the sampled fields of the striatum and pars compacta of the substantia nigra (SNc), respectively, after 8 and 4 micrograms of 6-OHDA. The GFAP immunohistochemistry revealed increases in the number/density of astroglial cells in the ipsilateral neostriatum (137% of control) and ipsilateral SNc (83% of control) and also in the volumeal fraction of the astroglial processes in the ipsilateral neostriatum (30% of control) and ipsilateral SNc (38% of control) in the rats with higher dose of the neurotoxin. Increases in the number of OX42 microglial labeled profiles and in the volumeal fraction of microglial processes were found in the ipsilateral neostriatum (67% and 27%, respectively, of control) and ipsilateral SNc (100% and 50%, respectively, of control) in the 8 micrograms 6-OHDA injected rats. These results suggest that the retrograde degeneration induced by a intrastriatal injection of a small dose of the 6-OHDA leads to an astroglial and microglial reaction in the nigrostriatal dopamine pathway. The interaction between activated glial cells may be involved in the wounding and repair events in the partial lesioned nigrostriatal system as well as in the paracrine responses to surviving dopamine neurons.
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Astrocitos/metabolismo , Astrocitos/patología , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Microglía/metabolismo , Microglía/patología , Degeneración Nerviosa , Oxidopamina/efectos adversos , Oxidopamina/farmacocinética , Sustancia Negra/metabolismo , Sustancia Negra/patología , Simpaticolíticos/efectos adversos , Simpaticolíticos/farmacocinética , Animales , Conducta Animal/fisiología , Relación Dosis-Respuesta a Droga , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunohistoquímica , Masculino , Degeneración Nerviosa/inducido químicamente , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Oxidopamina/administración & dosificación , Ratas , Ratas Wistar , Simpaticolíticos/administración & dosificación , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
El objetivo del presente trabajo fue evaluar el efecto del microtrasplante de células dopaminérgicas fetales "sembradas" en substancia negra pars reticulata (Snr) simultáneamente con el striatum (Est). Los animales recibieron trasplante o microtrasplante de células en el Est y la Snr ipsilateral a la lesión de la sustancia negra pars compacta o en ambos. De acuerdo al sitio y a la técnica utilizada se consideraron los grupos experimentales siguientes: I macrotrasplante en Est (n=20), II microtrasplante en Est (n=20), III macrotrasplante en Est + Snr (n=20), IV microtrasplante en Est + Snr (n=20), V macrotrasplante en Snr (n=20), VI microtrasplante en Snr (n=20), VII Control (Solo lesión) (n=20). Las rotaciones inducidas por d-anfetamina (5mg/Kg i.p) y por apomorfina fueron estudiadas 1,2,3, y 6 meses y 3 y 6 meses respectivamente después del trasplante. Tres meses después del trasplante se estudió la asimetría motora que presentaban los animales a través de la prueba de la escalera. Las rotaciones disminuyeron significativamente en los grupos de trasplante intraestriatal. La comparación entre las técnicas quirúrgicas mostró diferencias no significativas entre ellas. La prueba de la escalera arrojó diferencias significativas en la utilización de las extremidades en todos los grupos experimentales. La utilización de la extremidad izquierda disminuyó significativamente en todos los grupos. Las rotaciones no parecen ser sensibles a modificar su comportamiento con el microtrasplante aunque son más dependientes del sitio de trasplante en cuestión.
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Animales , Ratas , Conducta Animal/efectos de los fármacos , Mesencéfalo/trasplante , Trastornos Parkinsonianos , Sustancia Negra/trasplante , Trasplante de Tejido Fetal , Oxidopamina/efectos adversos , Ratas Wistar , Proyectos de InvestigaciónRESUMEN
INTRODUCTION: Studies of neural transplants in experimental models of Parkinson's disease have concentrated their attention on ectopic transplants of foetal mesencephalic cells to denervated striatum. However, the external globus pallidus has recently been shown to play an important part in the physiopathology of this disease. OBJECTIVE: Bearing in mind the importance of loss of extra-striatal dopamine in the genesis of the clinical signs found in parkinsonism, the objective of this study was to evaluate the effect of foetal mesencephalic transplantation to the globus pallidus of hemiparkinsonian rats. MATERIAL AND METHODS: Following conventional transplantation methodolgy, suspensions of cells from the ventral mesencephalum of rat embryos (E-14) were implanted. The tissue was grafted into the striatum, pallidum-striatum and pallidum areas of rats with unilateral lesions of the striatonigral bundle. One, two, three and six months after transplantation, the rotatory activity induced by D-amphetamine was evaluated. The rotatory behaviour induced by apomorphine was evaluated at three months. Motor ability of the front legs was evaluated in all experimental groups three months after transplantation using the 'ladder test'. RESULTS: In the experimental groups in which a transplant was made to the globus pallidus there was a significant reduction (p < 0.01) in rotatory activity induced by D-amphetamine and by apomorphine as compared with the non-transplanted groups. CONCLUSIONS: Transplants of foetal dopaminergic cells survive in the globus pallidus of hemiparkinsonian rats and can improve the rotational activity induced by dopaminergic agonists.