RESUMO
BACKGROUND: The release of calcitonin gene-related peptide (CGRP) from trigeminal nerves plays a central role in the pathophysiology of migraine and clinical evidence shows an antimigraine effect for CGRP receptor antagonists. Systemic administration of nitroglycerin (NTG), a nitrovasodilator, consistently provokes spontaneous-like migraine attacks in migraine sufferers; in the rat, systemic NTG induces a condition of hyperalgesia, probably through the activation of cerebral/spinal structures involved in nociceptive transmission. AIM: The aim of this article is to test the analgesic effect of the CGRP receptor antagonist MK-8825 in two animal models of pain that may be relevant for migraine: the tail flick test and the formalin test performed during NTG-induced hyperalgesia. RESULTS: MK-8825 showed analgesic activity when administered alone at both the tail flick test and the formalin test. Furthermore, the CGRP antagonist proved effective in counteracting NTG-induced hyperalgesia in both tests. MK-8825 indeed reduced the nociceptive behavior when administered either simultaneously or prior to (30-60 minutes before) NTG. CONCLUSION: These data suggest that MK-8825 may represent a potential therapeutic tool for the treatment of migraine.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Modelos Animais de Doenças , Hiperalgesia/induzido quimicamente , Hiperalgesia/fisiopatologia , Transtornos de Enxaqueca/fisiopatologia , Nitroglicerina/farmacologia , Piridinas/farmacologia , Compostos de Espiro/farmacologia , Animais , Masculino , Nociceptores/efeitos dos fármacos , Nociceptores/fisiologia , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologia , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacosRESUMO
CHF5074 is a non-steroidal anti-inflammatory derivative holding disease-modifying potential for the treatment of Alzheimer's disease. The aim of the present study was to characterize the electrophysiological and metabolic profile of CHF5074 in the hippocampus. Electrophysiological recordings show that CHF5074 inhibits in a dose-dependent manner the current-evoked repetitive firing discharge in CA1 pyramidal neurons. This result is paralleled by a dose-dependent reduction of field excitatory post-synaptic potentials with no effect on the paired-pulse ratio. The effects of CHF5074 were not mediated by AMPA or NMDA receptors, since the inward currents induced by local applications of AMPA and NMDA remained constant in the presence of this compound. We also suggest a possible activity of CHF5074 on ASIC1a receptor since ASIC1a-mediated current, evoked by application of a pH 5.5 solution, is reduced by pretreatment with this compound. Moreover, we demonstrate that CHF5074 treatment is able to counteract in hippocampal slices the OGD-induced increase in alanine, lactate and acetate levels. Finally, CHF5074 significantly reduced the apoptosis in hippocampal neurons exposed to OGD, as revealed by cleaved-caspase-3 immunoreactivity and TUNEL staining. Overall, the present work identifies novel mechanisms for CHF5074 in reducing metabolic acidosis, rendering this compound potentially useful also in conditions of brain ischemia.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Ciclopropanos/farmacologia , Flurbiprofeno/análogos & derivados , Hipocampo/efeitos dos fármacos , Isquemia/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Acetatos/metabolismo , Alanina/metabolismo , Animais , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Células Cultivadas , Fenômenos Eletrofisiológicos , Flurbiprofeno/farmacologia , Hipocampo/irrigação sanguínea , Hipocampo/fisiologia , Técnicas In Vitro , Isquemia/fisiopatologia , Ácido Láctico/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos WistarRESUMO
Homocysteine, a sulphur-containing amino acid formed by demethylation of methionine, is involved in numerous processes of methyl group transfer, all playing pivotal roles in the biochemistry of the human body. Increased levels of plasma homocysteine (hyperhomocysteinemia) - which may result from a deficiency of folate, vitamin B6 or B12 or mutations in enzymes regulating the catabolism of homocysteine - are associated with a wide range of clinical manifestations, mostly affecting the central nervous system (e.g., mental retardation, cerebral atrophy and epileptic seizures). Recent evidence suggests that changes in the metabolic fate of homocysteine, leading to hyperhomocysteinemia, may also play a role in the pathophysiology of neurodegenerative disorders, particularly Parkinson's disease (PD). The nervous system might be particularly sensitive to homocysteine, due to the excitotoxic-like properties of the amino acid. However, experimental findings have shown that homocysteine does not seem to posses direct, cytotoxic activity, while the amino acid has proven able to synergize with more specific neurotoxic insults. Hyperhomocysteinemia has been repeatedly reported in PD patients; the increase, however, seems mostly related to the methylated catabolism of l-Dopa, the main pharmacological treatment of PD. Therefore, hyperhomocysteinemia may not be specific to movement disorders or other neurological diseases, the condition being, in fact, rather the result of the combinations of different factors, mainly metabolic, but also genetic and pharmacological, intervening in the neurodegenerative process.
Assuntos
Encéfalo/metabolismo , Homocisteína/metabolismo , Hiper-Homocisteinemia/complicações , Degeneração Neural/metabolismo , Doença de Parkinson/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Encefalopatias Metabólicas/complicações , Encefalopatias Metabólicas/fisiopatologia , Causalidade , Humanos , Hiper-Homocisteinemia/fisiopatologia , Levodopa/metabolismo , Degeneração Neural/etiologia , Degeneração Neural/fisiopatologia , Doença de Parkinson/etiologia , Doença de Parkinson/fisiopatologiaRESUMO
INTRODUCTION: The mainstay therapy for Parkinson's disease (PD) relies on L-3,4-dihydroxyphenylalanine (L-DOPA) plus a DOPA-decarboxylase inhibitor. However, their effects on colonic dysmotility and inflammation observed in PD are undetermined. This study examined the effects of L-DOPA plus benserazide (BE) on colonic motility and inflammation in rats with central nigrostriatal dopaminergic denervation. METHODS: Neurodegeneration was induced by 6-hydroxydopamine (6-OHDA) injection into the medial forebrain bundle (MFB). 6-OHDA animals were treated orally with L-DOPA/BE for 28 days, starting 28 days after 6-OHDA injection. At the end of treatment, in vivo colonic transit was evaluated by a radiologic assay. Electrically stimulated (ES) cholinergic contractions were recorded in vitro from colonic preparations, while acetylcholine release was measured in the incubation medium. Choline acetyltransferase (ChAT) and glial fibrillary acidic protein (GFAP) expression as well as eosinophil and mast cell density were examined in the colonic wall by immunohistochemistry. Colonic TNF and IL-1ß levels were also assayed. RESULTS: 6-OHDA animals displayed: 1) decrease in in vivo colonic transit; 2) impairment of ES-stimulated cholinergic contractions; 3) decreased acetylcholine release from myenteric nerves; 4) decrease in ChAT and increase in GFAP myenteric immunopositivity; 5) increase in eosinophil and mast cell density; 6) increase in TNF and IL-1ß levels. Treatment with L-DOPA/BE elicited an improvement of in vivo and in vitro colonic motor activity, a normalization of acetylcholine release, ChAT immunopositivity, as well as pro-inflammatory cytokine patterns, ganglionic GFAP levels, eosinophil and mast cell density. CONCLUSION: Under dopaminergic nigrostriatal denervation, treatment with L-DOPA/BE ameliorated colonic motility through a normalization of myenteric cholinergic neurotransmission, along with an improvement of colonic inflammation.
Assuntos
Antiparkinsonianos/farmacologia , Benserazida/farmacologia , Colo/efeitos dos fármacos , Inflamação/tratamento farmacológico , Levodopa/farmacologia , Transtornos Parkinsonianos/tratamento farmacológico , Acetilcolina/metabolismo , Administração Oral , Animais , Colina O-Acetiltransferase/metabolismo , Colo/patologia , Colo/fisiopatologia , Trânsito Gastrointestinal/efeitos dos fármacos , Trânsito Gastrointestinal/fisiologia , Inflamação/patologia , Inflamação/fisiopatologia , Interleucina-1beta/metabolismo , Masculino , Músculo Liso/efeitos dos fármacos , Músculo Liso/patologia , Músculo Liso/fisiopatologia , Oxidopamina , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/fisiopatologia , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Técnicas de Cultura de Tecidos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The basal ganglia circuitry processes the signals that flow from the cortex, allowing the correct execution of voluntary movements. In Parkinson's disease, the degeneration of dopaminergic neurons of the substantia nigra pars compacta triggers a cascade of functional changes affecting the whole basal ganglia network. The most relevant alterations affect the output nuclei of the circuit, the medial globus pallidus and substantia nigra pars reticulata, which become hyperactive. Such hyperactivity is sustained by the enhanced glutamatergic inputs that the output nuclei receive from the subthalamic nucleus. The mechanisms leading to the subthalamic disinhibition are still poorly understood. According to the current model of basal ganglia organization, the phenomenon is due to a decrease in the inhibitory control exerted over the subthalamic nucleus by the lateral globus pallidus. Recent data, however, suggest that additional if not alternative mechanisms may underlie subthalamic hyperactivity. In particular, given the reciprocal innervation of the substantia nigra pars compacta and the subthalamic nucleus, the dopaminergic deficit might influence the subthalamic activity, directly. In addition, the increased excitatory drive to the dopaminergic nigral neurons originating from the hyperactive subthalamic nucleus might sustain the progression of the degenerative process. The identification of the role of the subthalamic nucleus and, more in general, of the glutamatergic mechanisms in the pathophysiology of Parkinson's disease might lead to a new approach in the pharmacological treatment of the disease. Current therapeutic strategies rely on the use of L-DOPA and/or dopamine agonists to correct the dopaminergic deficit. Drugs capable of antagonizing the effects of glutamate might represent, in the next future, a valuable tool for the development of new symptomatic and neuroprotective strategies for therapy of Parkinson's disease.
Assuntos
Gânglios da Base/fisiopatologia , Encéfalo/fisiopatologia , Doença de Parkinson/fisiopatologia , Animais , Córtex Cerebral/fisiopatologia , Humanos , Degeneração NeuralRESUMO
BACKGROUND: Constipation is extremely common in patients with Parkinson's disease (PD) and has been described in PD animal models. In this study, we investigated whether a PD-like degeneration of dopaminergic neurons of the substantia nigra can influence peristalsis in colonic segments of rats by impacting on enteric dopaminergic transmission. METHODS: Male, Sprague-Dawley rats received a unilateral injection of neurotoxin 6-hydroxydopamine (6-OHDA), or saline, into the medial-forebrain-bundle. Peristaltic activity was recorded in isolated colonic segments, in baseline conditions and following exposure to combinations of D2 receptor (DRD2) agonist sumanirole and antagonist L-741626. Dopamine levels and DRD2 expression were assessed in the ileum and colon of animals. We also investigated the involvement of the dorsal motor nucleus of the vagus (DMV) - a potential relay station between central dopaminergic denervation and gastrointestinal (GI) dysfunction - by analyzing cytochrome c oxidase activity and FosB/DeltaFosB expression in DMV neurons. KEY RESULTS: We observed profound alterations in the response of colonic segments of 6-OHDA lesioned animals to DRD2 stimulation. In fact, the inhibition of colonic peristalsis elicited by sumanirole in control rats was absent in 6-OHDA-lesioned animals. These animals also showed reduced DRD2 expression in the colon, along with elevation of dopamine levels. No significant changes were detected within the DMV. CONCLUSIONS & INFERENCES: Our results demonstrate that selective lesion of the nigrostriatal dopaminergic pathway subverts the physiological response of the colon to dopaminergic stimulation, opening new perspectives in the comprehension and treatment of GI dysfunctions associated with PD.
Assuntos
Colo/metabolismo , Gastroenteropatias/fisiopatologia , Transtornos Parkinsonianos/fisiopatologia , Receptores de Dopamina D2/biossíntese , Substância Negra/lesões , Animais , Cromatografia Líquida de Alta Pressão , Constipação Intestinal/etiologia , Constipação Intestinal/fisiopatologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos , Regulação para Baixo , Imunofluorescência , Gastroenteropatias/etiologia , Motilidade Gastrointestinal/efeitos dos fármacos , Motilidade Gastrointestinal/fisiologia , Processamento de Imagem Assistida por Computador , Masculino , Oxidopamina/administração & dosagem , Oxidopamina/toxicidade , Transtornos Parkinsonianos/complicações , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Substância Negra/efeitos dos fármacosRESUMO
Inactivation of the subthalamic nucleus (STN) has attracted interest as a therapeutic tool in Parkinson's disease. The functional consequences of the inactivation, however, are uncertain. In this study definition of the pattern of changes of cerebral functional activity associated with lesion of the STN and dopaminergic stimulation, by using the [14C]deoxyglucose method, was sought. Six or 7 days following unilateral lesion of the STN, the animals were divided into two groups: One group (n = 10) was administered apomorphine (1 mg/kg) subcutaneously; the second group (n = 10) received saline. The [14C]deoxyglucose procedure was initiated 10 minutes following the drug or saline injection. The results show that systemic administration of apomorphine to rats with unilateral lesion of the STN causes ipsiversive rotational behavior and asymmetries of glucose utilization of defined brain areas, including the substantia nigra reticulata, globus pallidus, and entopeduncular nucleus. These nuclei are the main targets of the subthalamic excitatory projections. Lesion of the nucleus per se (without challenge with apomorphine) has no significant consequences on glucose utilization. The findings indicate that the STN is involved in the activation of the basal ganglia output nuclei induced by systemic dopaminergic stimulation.
Assuntos
Encéfalo/metabolismo , Glucose/metabolismo , Atividade Motora/fisiologia , Núcleos Talâmicos/fisiologia , Animais , Apomorfina/farmacologia , Encéfalo/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual/efeitos dos fármacosRESUMO
Altered glutamatergic neurotransmission and neuronal metabolic dysfunction appear to be central to the pathophysiology of Parkinson's disease (PD). The substantia nigra pars compacta--the area where the primary pathological lesion is located--is particularly exposed to oxidative stress and toxic and metabolic insults. A reduced capacity to cope with metabolic demands, possibly related to impaired mitochondrial function, may render nigral highly vulnerable to the effects of glutamate, which acts as a neurotoxin in the presence of impaired cellular energy metabolism. In this way, glutamate may participate in the pathogenesis of PD. Degeneration of dopamine nigral neurons is followed by striatal dopaminergic denervation, which causes a cascade of functional modifications in the activity of basal ganglia nuclei. As an excitatory neurotransmitter, glutamate plays a pivotal role in normal basal ganglia circuitry. With nigrostriatal dopaminergic depletion, the glutamatergic projections from subthalamic nucleus to the basal ganglia output nuclei become overactive and there are regulatory changes in glutamate receptors in these regions. There is also evidence of increased glutamatergic activity in the striatum. In animal models, blockade of glutamate receptors ameliorates the motor manifestations of PD. Therefore, it appears that abnormal patterns of glutamatergic neurotransmission are important in the symptoms of PD. The involvement of the glutamatergic system in the pathogenesis and symptomatology of PD provides potential new targets for therapeutic intervention in this neurodegenerative disorder.
Assuntos
Encéfalo/fisiopatologia , Ácido Glutâmico/fisiologia , Neurônios/fisiologia , Neurotoxinas , Neurotransmissores/fisiologia , Doença de Parkinson/fisiopatologia , Animais , Gânglios da Base/fisiologia , Encéfalo/metabolismo , Canais de Cálcio/fisiologia , Metabolismo Energético , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Humanos , Modelos Neurológicos , Neurônios/metabolismo , Estresse Oxidativo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Receptores de AMPA/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Substância Negra/fisiopatologia , Transmissão SinápticaRESUMO
Oxidative stress plays a central role in the pathogenesis of Parkinson's disease (PD). L-DOPA, the gold standard in PD therapy, may paradoxically contribute to the progression of the disease because of its pro-oxidant properties. The issue, however, is controversial. In this study, we evaluated peripheral markers of oxidative stress in normal subjects, untreated PD patients and PD patients treated only with L-DOPA. We also measured platelet and plasma levels of L-DOPA, 3-O-methyldopa (the long-lasting metabolite of the drug), and dopamine. We found that isolated platelets of treated PD patients form higher amounts of 2,3-dihydroxybenzoate, an index of hydroxyl radical generation, than platelets of controls or untreated patients. In treated patients, platelet levels of 2,3-dihydroxybenzoate were positively correlated with platelet levels of L-DOPA, 3-O-methyldopa, and with the score of disease severity. Disease severity was correlated with platelet and plasma levels of L-DOPA, as well as with the daily intake of the drug. No significant differences in platelet levels of cytosolic and mitochondrial isoforms of the antioxidant enzyme superoxide dismutase were found between PD patients, either treated or untreated, and controls. Our findings lend further support to the hypothesis that L-DOPA might promote free radical formation in PD patients.
Assuntos
Antiparkinsonianos/uso terapêutico , Gentisatos , Levodopa/uso terapêutico , Estresse Oxidativo/fisiologia , Doença de Parkinson/tratamento farmacológico , Biomarcadores , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Dopamina/sangue , Feminino , Humanos , Hidroxibenzoatos/sangue , Radical Hidroxila , Técnicas In Vitro , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Salicilato de Sódio/farmacologia , Superóxido Dismutase/sangue , Tirosina/análogos & derivados , Tirosina/sangueRESUMO
Although the involvement of nitric oxide (NO) in mediating pain and neurovascular coupling is well established, the precise mechanisms sustaining these effects are still unclear. Cyclic GMP (cGMP) probably represents the main effector of the biological effects of NO at the vascular and neuronal levels. Nitroglycerin is a NO donor, which easily crosses the blood brain barrier. Several reports have suggested that the study of nitroglycerin effects upon neuronal and cerebrovascular elements is a useful animal model for investigating the pathophysiological mechanisms underlying migraine. In this study, the anatomic distribution of cGMP in the rat brain was evaluated at serial time-points after systemic administration of nitroglycerin or vehicle. The results show an increase in cGMP immunoreactivity in the nucleus trigeminalis caudalis and in the superficial cortical arterioles 2, 3 and 4h after the drug administration. The data obtained sustains the idea that cGMP is an important mediator of nitroglycerin effect in vascular and neuronal structures that are critical elements for the transmission of cephalic pain.
Assuntos
Arteríolas/efeitos dos fármacos , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , GMP Cíclico/biossíntese , Animais , Arteríolas/metabolismo , Encéfalo/metabolismo , Circulação Cerebrovascular/efeitos dos fármacos , Modelos Animais de Doenças , Imuno-Histoquímica , Masculino , Transtornos de Enxaqueca/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Nitroglicerina/farmacologia , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Vasodilatadores/farmacologiaRESUMO
RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative, which is neurotoxic to both serotonin (5HT) and dopamine (DA) nerve terminals. Previous reports, carried out in rodents and non-human primates, demonstrated neurotoxicity to monoamine axon terminals, although no study has analyzed nigral and striatal cell bodies at the sub-cellular level. OBJECTIVE: In this study, we examined intrinsic nigral and striatal cells, and PC12 cell cultures to evaluate whether, in mice, MDMA might affect nigral and striatal cell bodies. METHODS: After administering MDMA, we analyzed effects induced in vivo and in vitro using high-performance liquid chromatography (HPLC) analysis, light- and electron microscopy with immunocytochemistry, and DNA comet assay. RESULTS: We found that MDMA (5 mg/kg x4, 2 h apart), besides a decrease of nigrostriatal DA innervation and 5HT loss, produces neuronal inclusions within nigral and intrinsic striatal neurons consisting of multi-layer ubiquitin-positive whorls extending to the nucleus of the cell. These fine morphological changes are associated with clustering of heat shock protein (HSP)-70 in the nucleus, very close to chromatin filaments. In the same experimental conditions, we could detect oxidation of DNA bases followed by DNA damage. The nature of inclusions was further investigated using PC12 cell cultures. CONCLUSIONS: The present findings lead to re-consideration of the neurotoxic consequences of MDMA administration. In fact, occurrence of ubiquitin-positive neuronal inclusions and DNA damage both in nigral and striatal cells sheds new light into the fine alterations induced by MDMA, also suggesting the involvement of nuclear and cytoplasmic components of the ubiquitin-proteasome pathway in MDMA toxicity.
Assuntos
Corpo Estriado/efeitos dos fármacos , Dano ao DNA , N-Metil-3,4-Metilenodioxianfetamina/toxicidade , Neurônios/metabolismo , Serotoninérgicos/toxicidade , Substância Negra/efeitos dos fármacos , Ubiquitina/metabolismo , Animais , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Dopamina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/ultraestrutura , Células PC12 , Ratos , Substância Negra/metabolismo , Substância Negra/patologiaRESUMO
In this study, we measured the lymphocyte levels of proteins involved in apoptosis regulation, such as Bcl-2, the peripheral benzodiazepine receptor (PBR), caspase-3, and Cu/Zn superoxide dismutase (Cu/Zn SOD), in patients with Parkinson's disease (PD), either untreated or under therapy with dopaminergic agents (l-Dopa alone or l-dopa + dopamine agonists) and in healthy volunteers. All PD groups showed increased activity of caspase-3, compared to controls, particularly those under treatment only with l-Dopa. In this latter group, the increase in caspase-3 activity was also paralleled by an increase in the concentration of Cu/Zn SOD. In addition, patients taking l-Dopa + dopamine agonists showed marked decrease in Bcl-2 levels and increased PBR expression, which seems in keeping with the hypothesis that PBR may be functionally related to Bcl-2. In conclusion, we found clear modifications in the levels of proteins involved in the control of apoptosis in lymphocytes of PD patients. These changes were disease related but also modulated by the pharmacological treatment, which confirms the potential role of apoptosis in PD pathogenesis and the modulatory influence of dopaminergic agents.
Assuntos
Antiparkinsonianos/uso terapêutico , Apoptose , Biomarcadores/análise , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Análise de Variância , Caspase 3 , Caspases/análise , Agonistas de Dopamina/uso terapêutico , Humanos , Levodopa/uso terapêutico , Valores de Referência , Superóxido Dismutase/análiseRESUMO
The subthalamic nucleus (STN) plays a major role in the control of basal ganglia output, and its overactivity may be central to the symptoms of Parkinson's disease. In order to elucidate the functional relationship between STN and its projection nuclei, we studied the short-term (1 week) effect of a selective lesion of STN on the activity of succinate dehydrogenase (SDH) and cytochrome oxidase (CO), two markers of neuronal activity, in the basal ganglia of rats. STN ablation induced a discrete reduction of oxidative metabolism, ipsilaterally to the lesion, in substantia nigra pars reticulata and globus pallidus, the rodent homologue of lateral globus pallidus. Such changes, ascribable to the interruption of the STN excitatory output to these nuclei, were present after 24 h and remained stable, or increased, throughout the observation period. A transitory, ipsilateral decrease was also observed in the caudate-putamen and the somato-sensory cortex, likely due to involvement of polysynaptic pathways. SDH and CO activity were always altered in the same areas, but SDH changes were more pronounced and occurred more rapidly. These results shed further light on the role played by STN in the control of basal ganglia output.
Assuntos
Gânglios da Base/fisiologia , Mitocôndrias/enzimologia , Succinato Desidrogenase/metabolismo , Tálamo/fisiologia , Animais , Córtex Cerebral/enzimologia , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Masculino , Mitocôndrias/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
A unilateral lesion of the subthalamic nucleus (STN) induced, in the short-term (< or = 1 week), an ipsilateral decrease in [3H]dihydrorotenone binding to complex I in entopeduncular nucleus and substantia nigra pars reticulata (SNr). A slight reduction of [3H]MK-801 binding to N-methyl-D-aspartate (NMDA) receptors in the ipsilateral SNr was also found, whereas no changes in [3H]alpha-amino-3-hydroxy-5-methylisoxazole propionic acid binding were observed. The complex I decrease likely reflects a reduction in neuronal activity subsequent to the interruption of excitatory signaling from STN. The unexpected decrease in [3H]MK-801 binding in SNr may be related to presynaptic NMDA receptor modifications.
Assuntos
Gânglios da Base/enzimologia , Mitocôndrias/enzimologia , NAD(P)H Desidrogenase (Quinona)/metabolismo , Receptores de Glutamato/metabolismo , Núcleos Talâmicos/fisiologia , Animais , Autorradiografia , Maleato de Dizocilpina/metabolismo , Histocitoquímica , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/metabolismo , Rotenona/análogos & derivados , Rotenona/metabolismoRESUMO
Two distinct pathways are thought to connect the striatum to the basal ganglia output nuclei: a direct pathway, originating from neurons bearing dopamine, D(1) receptors and an indirect pathway, originating from neurons expressing D(2) receptors. It has been recently suggested, however, that dopamine receptor sub-types may co-localize and co-operate in the striatum. We sought to verify the functional segregation of the two pathways by measuring cerebral glucose utilization following intrastriatal injection of selective D(1) (SKF 38393), D(2) (quinpirole), or non-selective indirect (amphetamine) and direct (apomorphine) dopamine agonists, in freely-moving rats. All drugs -- regardless of receptor selectivity -- reduced glucose utilization in nuclei of both the direct and indirect pathways, thus lending further support to the existence of a functional co-operation of striatal D(1) and D(2) receptors.
Assuntos
Corpo Estriado/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Glucose/metabolismo , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Anfetamina/farmacologia , Animais , Apomorfina/farmacologia , Gânglios da Base/efeitos dos fármacos , Gânglios da Base/metabolismo , Corpo Estriado/metabolismo , Núcleo Entopeduncular/efeitos dos fármacos , Núcleo Entopeduncular/metabolismo , Globo Pálido/efeitos dos fármacos , Globo Pálido/metabolismo , Masculino , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Quimpirol/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/biossíntese , Receptores de Dopamina D2/biossíntese , Núcleo Subtalâmico/efeitos dos fármacos , Núcleo Subtalâmico/metabolismoRESUMO
Platelet catecholamines (CAs) do not seem to reflect the acute increases in plasma CAs observed during stress, at least over short periods of time. However, it is well known that stress, via the release of plasma CAs, is capable of affecting platelet function. To better address this issue, we studied platelet and plasma levels of free noradrenaline (NA), adrenaline (A), and dopamine (DA) in 10 healthy subjects undergoing three different stress tests: insulin tolerance test (ITT), cold pressor test (CPT) and handgrip test (HT). We also evaluated platelet count and platelet mean volume (MPV). ITT caused a considerable increase in plasma NA and a massive release of plasma A, while CPT and HT induced discrete increases only in plasma NA. ITT induced a significant decrease in platelet DA and a trend toward a decrease in platelet NA, along with a significant increase in MPV. All these changes occurred in coincidence with the peak levels of plasma CAs. No changes in platelet variables were observed in response to both CPT and HT. The modifications observed during ITT are likely to represent signs of an initial platelet activation in response to the acute plasma CA elevations this test was able to elicit. Our data show that platelet CA content does not represent a mere reflection of the circulating concentrations of plasma CAs, but it is the result of a dynamic balance between these two compartments.
Assuntos
Plaquetas/metabolismo , Catecolaminas/sangue , Estresse Fisiológico/sangue , Adulto , Idoso , Análise de Variância , Glicemia/metabolismo , Temperatura Baixa/efeitos adversos , Dopamina/sangue , Epinefrina/sangue , Exercício Físico , Feminino , Humanos , Insulina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Norepinefrina/sangue , Estresse Fisiológico/etiologiaRESUMO
The platelet and plasma levels of catecholamines (CA) were simultaneously studied in a group of normal subjects in order to find possible sex-related changes in the distribution of CA in these two compartments. No significant differences between males and females were observed, but a marked platelet noradrenaline increase was found in the luteal phase as compared to the follicular phase. Furthermore, the platelet and plasma CA levels were strongly correlated in the male group but not in the female group. These results, while confirming the existence of a menstrual-related variability in noradrenergic activity, suggest a sex-related difference in the dynamic balance between platelet and plasma CA levels. The simultaneous assay of platelet and plasma CA enabled this phenomenon to be revealed, whereas the separate evaluation of platelet or plasma CA levels would not have done so.
Assuntos
Plaquetas/metabolismo , Dopamina/sangue , Epinefrina/sangue , Norepinefrina/sangue , Caracteres Sexuais , Adulto , Idoso , Plaquetas/química , Feminino , Fertilidade , Humanos , Masculino , Menopausa/sangue , Ciclo Menstrual/sangue , Pessoa de Meia-Idade , Fatores SexuaisRESUMO
It has been suggested that the excitatory amino acid glutamate, acting as both a neurotoxin and a neurotransmitter, might play a central role in the pathophysiology of Parkinson's disease (PD). Intrinsic energetic defects of the neurons of the substantia nigra pars compacta, the brain area where the degenerative process of PD takes place, may render nigral neurons highly vulnerable to the effects of glutamate, which acts as a neurotoxin in the presence of impaired cellular energy metabolism. Degeneration of dopamine nigral neurons and striatal dopaminergic denervation cause a cascade of functional modifications in the activity of basal ganglia nuclei. Due to the close relationship that links dopaminergic and glutamatergic neurotransmission, glutamate is directly involved in the functional alterations of basal ganglia circuitry that lead to the development of parkinsonian motor symptoms. Drugs counteracting the effects of glutamate might therefore provide new protective and symptomatic strategies for therapy of PD.
Assuntos
Antiparkinsonianos/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Gânglios da Base/efeitos dos fármacos , Gânglios da Base/metabolismo , Gânglios da Base/fisiopatologia , Ácido Glutâmico/metabolismo , Humanos , Neurotransmissores/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica/efeitos dos fármacosRESUMO
The effects of the psychotropic drug etoperidone on the response to laboratory stressors was investigated in a controlled study. Cardiovascular and hormonal (catecholamines, corticotropin, and cortisol) measurements were made in a group of young, healthy volunteers during a cold pressor test (CPT), a mental arithmetic test (MAT), and insulin-induced hypoglycaemia (ITT). One-week treatment with etoperidone (ETO) (150 mg/day, orally) reduced basal and stress-induced values of systolic and diastolic blood pressure (BP) on CPT, while it did not alter catecholamine output in response to the stressor. Cardiovascular response was also attenuated after ETO on MAT, in the absence of any hormone changes. Adrenocorticotropic hormone (ACTH) and cortisol secretions were markedly reduced on ITT after ETO, whereas catecholamine outflow and cardiovascular parameters were substantially unaffected. These findings on ITT suggest that the anti-serotoninergic and anti-alpha 1-adrenergic activities of ETO may be used in the pharmacological control of the potentially detrimental consequences of the stress response.
Assuntos
Antidepressivos/farmacologia , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Estresse Psicológico/fisiopatologia , Sistema Nervoso Simpático/efeitos dos fármacos , Trazodona/análogos & derivados , Hormônio Adrenocorticotrópico/sangue , Adulto , Pressão Sanguínea/efeitos dos fármacos , Temperatura Baixa , Epinefrina/sangue , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hidrocortisona/sangue , Insulina/farmacologia , Masculino , Processos Mentais/efeitos dos fármacos , Norepinefrina/sangue , Sistema Hipófise-Suprarrenal/fisiopatologia , Pressão , Escalas de Graduação Psiquiátrica , Estresse Psicológico/psicologia , Sistema Nervoso Simpático/fisiopatologia , Trazodona/farmacologiaRESUMO
The hemodynamic and biochemical effects of cabergoline, a new ergoline derivative with selective, potent, and long-lasting dopamine (DA) agonistic properties, were evaluated in 19 parkinsonian patients, all previously identified as stable responders to levodopa plus L-Dopa decarboxylase inhibitor. The purpose of the study was to find markers capable of predicting the development of cardiopressor side effects during DA-agonistic therapy. Blood pressure (BP), heart rate, and plasma catecholamine responses to a standard meal and a tilt table test were evaluated before and during cabergoline therapy. Cabergoline (1.0 mg/day x os) in this open study significantly reduced the BP response to standing exclusively in the subgroup of patients who exhibited marked postprandial hypotension in baseline conditions. The patients subsequently experienced a partial recovery at day 7 of treatment. This finding indicates that postprandial hypotension is an early marker of autonomic failure in patients with Parkinson's disease (PD) and suggests the usefulness of evaluating cardiopressor response to a standard meal before starting new DA-agonist therapy in PD.