RESUMEN
Although still a disorder of unknown etiology, Parkinson's disease (PD) has provided a number of clues that have led to clinical trials of neuroprotection. For example, defects in mitochondrial metabolism and evidence for oxidative stress in PD have fostered therapeutic interventions aimed at slowing disease progression. More than a dozen compounds already have been tested in PD for disease modification, and others are in planning stages for clinical trials. The challenge is to find a highly effective therapy halting disease progression (beyond the relatively modest clinical effect exemplified by recent findings with coenzyme Q-10 treatment administered at 1200mg/day). Clinical exam-based ratings and disability assessments still serve at providing the primary evidence of efficacy. However, with surrogate biomarkers such as radiotracer neuroimaging of the dopaminergic system, the pace of clinical investigation can be increased. Recent years have seen the utilization of more sensitive study methods in PD neuroprotection research, such as staggered wash-in, 2 x 2 factorial, and "futility" trial designs. The results of several ongoing PD neuroprotection trials are planned for release in the near future.
Asunto(s)
Redes y Vías Metabólicas/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/terapia , Animales , Coenzimas , Humanos , Mitocondrias/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Ubiquinona/análogos & derivados , Ubiquinona/farmacología , Ubiquinona/uso terapéuticoRESUMEN
Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of diseases such as Alzheimer's Disease (AD) and amyotrophic lateral sclerosis (ALS). Increased expression of MMP-9 and TIMPs has been reported in postmortem AD and ALS brain tissue, as well as in ALS cerebrospinal fluid (CSF) and plasma. Although individual studies of MMP and TIMP expression in CSF have included AD and ALS samples, there are no studies comparing the expression of these proteins between neurodegenerative diseases. We measured the levels of matrix metalloproteinases (MMPs)-2 and -9 and the tissue inhibitor of MMPs (e.g. TIMP-1 and TIMP-2) in CSF samples from patients with Parkinson's Disease (PD), Huntington's Disease (HD), AD and ALS as compared to age-matched control patients. There was constitutive expression of the proform of gelatinase A (proMMP-2) on zymography gels in all CSF samples. Unexpectedly, there was an additional gelatinolytic band at 130 kDa of unknown etiology in the CSF samples of patients with PD (61% of patients studied), AD (61%), HD (25%) and ALS (39%). Levels of TIMP-1 were significantly elevated in CSF samples from all disease groups. TIMP-2 was significantly increased in CSF of AD and HD patients. MMP-2 levels did not differ significantly between groups. These findings show that TIMPs are elevated in the CSF of patients with neurodegenerative diseases suggesting a potential role of these endogenous inhibitors of matrix metalloproteinases in neurodegenerative diseases.
Asunto(s)
Metaloproteinasas de la Matriz/líquido cefalorraquídeo , Enfermedades Neurodegenerativas/líquido cefalorraquídeo , Enfermedades Neurodegenerativas/enzimología , Inhibidor Tisular de Metaloproteinasa-1/líquido cefalorraquídeo , Inhibidor Tisular de Metaloproteinasa-2/líquido cefalorraquídeo , Adulto , Anciano , Regulación Enzimológica de la Expresión Génica/fisiología , Humanos , Persona de Mediana Edad , Estadísticas no Paramétricas , Inhibidores Tisulares de Metaloproteinasas/líquido cefalorraquídeoRESUMEN
Ceruloplasmin (CP) is a 132 kd cuproprotein which, together with transferrin, provides the majority of anti-oxidant capacity in serum. Increased iron deposition and lipid peroxidation in the basal ganglia of subjects with hereditary CP deficiency suggest that CP may serve as an anti-oxidant in the brain as well. The present study compared CP immunoreactivity in brain specimens from normal controls and subjects with neurodegenerative disorders (Alzheimer's disease [AD], Parkinson's disease [PD], progressive supranuclear palsy [PSP], and Huntington's disease [HD]) (n = 5 per group). The relative intensity of neuronal CP staining and the numbers of CP-stained neurons per 25x microscope field were determined in hippocampus (CA1, subiculum, and parahippocampal gyrus), parietal cortex, frontal cortex, substantia nigra, and caudate. CP was detected in both neurons and astrocytes in all specimens, and in senile plaques and occasional neurofibrillary tangles in AD brain. Neuronal CP staining intensity tended to increase in most AD brain regions, but was statistically significant vs controls only in the CA1 region of hippocampus (p = .016). Neuronal CP staining in brain specimens from other neurodegenerative disorders showed a slight but nonsignificant increase vs controls. The numbers of CP-stained neurons per field did not differ between the various neurodegenerative disorders and controls. These results suggest that a modest increase in neuronal CP content is present in the AD brain, and lesser elevations in neuronal CP occur in the other neurodegenerative disorders in this study. Though CP functions as both an acute phase protein and an anti-oxidant in peripheral tissues, whether it does so in the brain remains to be determined.
Asunto(s)
Encéfalo/metabolismo , Ceruloplasmina/inmunología , Ceruloplasmina/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Anciano , Anciano de 80 o más Años , Encéfalo/inmunología , Encéfalo/patología , Núcleo Caudado/inmunología , Núcleo Caudado/metabolismo , Núcleo Caudado/patología , Lóbulo Frontal/inmunología , Lóbulo Frontal/metabolismo , Lóbulo Frontal/patología , Hipocampo/inmunología , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Enfermedades Neurodegenerativas/inmunología , Neuronas/inmunología , Neuronas/metabolismo , Lóbulo Parietal/inmunología , Lóbulo Parietal/metabolismo , Lóbulo Parietal/patología , Sustancia Negra/inmunología , Sustancia Negra/metabolismo , Sustancia Negra/patologíaRESUMEN
OBJECTIVE: To assess the safety and efficacy of subcutaneous apomorphine hydrochloride administration for off-state (poor motor function) periods in patients with Parkinson disease with motor fluctuations under both inpatient titration and outpatient therapeutic conditions. PATIENTS AND METHODS: Twenty-nine patients had advanced Parkinson disease with 2 hours or more off time despite aggressive oral therapy. Patients randomly received titrated doses of subcutaneous apomorphine hydrochloride (2-10 mg, n = 20) or pH-matched vehicle placebo (n = 9) during an inpatient and 1-month outpatient phase. A change in the United Parkinson Disease Rating Scale motor score 20 minutes after inpatient dosing during a practically defined off-state event and the percentage of injections successfully aborting off-state events were the primary inpatient and outpatient efficacy factors. RESULTS: The average (SEM) levodopa equivalent dose of apomorphine hydrochloride was 5.4 +/- 0.5 mg and the mean placebo dose was 1.0 mL. Mean inpatient United Parkinson Disease Rating Scale motor scores were reduced by 23.9 and 0.1 points (62% and 1%) by apomorphine treatment and placebo, respectively (P<.001). The mean percentage of outpatient injections resulting in successful abortion of off-state events was 95% for apomorphine and 23% for placebo (P<.001). Inpatient response was significantly correlated with and predictive of outpatient efficacy (P<.001). The levodopa dose was not predictive of the apomorphine dose requirement. Frequent adverse events included dyskinesia, yawning, and injection site reactions. CONCLUSION: Apomorphine by intermittent subcutaneous injection is effective and safe for outpatient use to reverse off-state events that occur despite optimized oral therapy.
Asunto(s)
Antiparkinsonianos/administración & dosificación , Apomorfina/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Anciano , Antiparkinsonianos/efectos adversos , Apomorfina/efectos adversos , Método Doble Ciego , Femenino , Humanos , Inyecciones Subcutáneas , Pacientes Internos , Masculino , Persona de Mediana Edad , Pacientes AmbulatoriosRESUMEN
We performed a double-blind, placebo-controlled, randomized, crossover, multiple-dose study on entacapone in 25 patients with Parkinson's disease with levodopa (L-Dopa) treatment-related fluctuations. A run-in period was followed by four 2-week treatment periods during which the patients took 4 to 6 daily doses of L-Dopa concomitantly with 100, 200, or 400 mg of entacapone or with placebo. The effects were assessed at the end of each period; the inhibition of soluble catechol-O-methyltransferase (S-COMT) activity in red blood cells and the plasma concentrations of entacapone, L-Dopa, and 3-O-methyldopa (3-OMD) were measured and clinical effects assessed on an 18-hour home diary. Twenty-one patients completed the study. Entacapone decreased the COMT activity from predose level: 100 mg by 25%, 200 mg by 33%, and 400 mg by 32% (p < 0.001 vs. placebo for each dose). Correspondingly, the 3-OMD concentrations decreased by 39%, 54%, and 66% with 100-, 200-, and 400-mg doses, respectively. The elimination half-life of L-Dopa was prolonged by 23% (p < 0.05), 26% (p < 0.001), and 48% (p < 0.001), and the area under the curve of L-Dopa increased by 17% (p < 0.05), 27% (p < 0.001), and 37% (p < 0.001) with the increasing doses. Despite a significant decrease in the daily dose of L-Dopa, entacapone decreased the proportion of daily "off" time: 100 mg by 11%, 200 mg by 18%, and 400 mg by 20% compared with placebo. However, this decrease was not statistically significant for any of the doses in this small patient population. The dyskinetic "on" time did not increase with different doses of entacapone. All doses were well tolerated, and no severe adverse events were reported. The study showed that repeated dosing of entacapone inhibits the COMT activity in a dose-dependent manner and thereby reduces the loss of L-Dopa to 3-OMD. Therefore, the area under the curve of L-Dopa is increased and the patient's clinical condition improved.
Asunto(s)
Antiparkinsonianos/farmacocinética , Antiparkinsonianos/uso terapéutico , Inhibidores de Catecol O-Metiltransferasa , Catecoles/farmacología , Inhibidores Enzimáticos/farmacología , Levodopa/farmacocinética , Levodopa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Adulto , Anciano , Antiparkinsonianos/efectos adversos , Área Bajo la Curva , Catecol O-Metiltransferasa/sangre , Catecoles/efectos adversos , Catecoles/farmacocinética , Estudios Cruzados , Método Doble Ciego , Interacciones Farmacológicas , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Femenino , Humanos , Levodopa/efectos adversos , Masculino , Persona de Mediana Edad , NitrilosRESUMEN
N-0923 is a non-ergot, dopaminergic D(2) agonist designed to be transdermally available. It has anti-parkinsonian effects when infused intravenously. An adhesive matrix patch was developed to deliver N-0923 transdermally (N-0923 TDS). In this phase II trial, we evaluated the effectiveness of various doses of N-0923 TDS at replacing levodopa. Eighty-five Parkinson's disease (PD) patients were randomized to placebo or one of four doses of N-0923 TDS for 21 days. Change in daily levodopa dose was the primary efficacy measure. Significantly greater reductions in levodopa dose were achieved as compared to placebo for the two highest doses of N-0923 TDS. Patients treated with 33.5 mg and 67 mg N-0923 TDS decreased levodopa use by 26% and 28%, vs. 7% for placebo. N-0923 TDS was safe and well tolerated.
Asunto(s)
Agonistas de Dopamina/administración & dosificación , Levodopa/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Receptores de Dopamina D2/agonistas , Tetrahidronaftalenos/administración & dosificación , Tiofenos/administración & dosificación , Administración Cutánea , Anciano , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Equivalencia Terapéutica , Resultado del TratamientoRESUMEN
This study evaluated the feasibility and psychometric properties of self-completed and telephone interview versions of a patient health-related quality-of-life (HQL) questionnaire for Parkinson's disease that included the SF-36 Health Survey (SF-36), the Parkinson's Disease Questionnaire (PDQ-39), and the Medical Outcomes Study Sexual Function Survey. Parkinson's disease patients (n = 150) completed the questionnaire twice: once at the study site and once over the telephone in a randomized order. Ninety-four percent of enrolled patients completed the first HQL assessment and 88% completed both assessments. Cronbach's alpha exceeded 0.70 for all scales except for the self-completed PDQ-39 Social Support subscale (0.57) and the telephone interview PDQ-39 Social Support (0.60) and Cognitions (0.67) subscales and the SF-36 General Health (0.60) and Social Function (0.61) subscales. There were no statistically significant differences in mean HQL scale scores across the two modes of administration. Mean scores for 3 of the PDQ-39 subscales and the Summary Index were significantly poorer (p < 0.05) for patients at later clinical stages. Similarly, patients with dyskinesias reported significantly poorer scores for 4 of the PDQ-39 subscales and the Summary Index and patients with self-reported comorbidities reported poorer SF-36 Physical Function and General Health subscale scores than patients without dyskinesias and comorbidities, respectively. This study suggests that the self-completed and telephone interview versions of the patient HQL questionnaire are feasible and valid for future clinical trial applications.
Asunto(s)
Entrevistas como Asunto , Enfermedad de Parkinson/psicología , Psicometría/métodos , Calidad de Vida , Encuestas y Cuestionarios , Anciano , Análisis de Varianza , Estudios de Factibilidad , Femenino , Estado de Salud , Humanos , Masculino , Reproducibilidad de los Resultados , Teléfono , Estados UnidosRESUMEN
Studies with cerebrospinal fluid from subjects with Parkinson's disease suggest that purine abnormalities may be present in this disorder. The effects of purines on dopamine metabolism have not been characterized, though adenosine is known to inhibit dopaminergic neurotransmission. In this study, dopamine, its precursor 3,4-dihydroxyphenylalanine (DOPA), and its degradation products 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were measured in rat pheochromocytoma PC12 cells following 24-h incubation with 5, 50, and 500 microM adenosine, adenine, guanosine, guanine, hypoxanthine, xanthine, and uric acid. Incubation with adenosine increased DOPA, DOPAC, and HVA, while adenine treatment decreased DOPA. Guanosine (500 microM) decreased DOPA, dopamine, and DOPAC, while lower concentrations increased DOPAC and HVA. Incubation with guanine decreased dopamine, and xanthine decreased dopamine and DOPAC. Hypoxanthine and uric acid exerted minimal effects. These results indicate that purines exert a variety of effects on dopamine metabolism. The influence of purine metabolism on the dopaminergic deficit in the Parkinsonian brain merits further investigation.
Asunto(s)
Dopamina/metabolismo , Células PC12/efectos de los fármacos , Células PC12/metabolismo , Purinas/metabolismo , Purinas/farmacología , Adenina/metabolismo , Adenina/farmacología , Adenosina/metabolismo , Adenosina/farmacología , Animales , Modelos Animales de Enfermedad , Guanina/metabolismo , Guanina/farmacología , Guanosina/metabolismo , Guanosina/farmacología , Hipoxantina/metabolismo , Hipoxantina/farmacología , Neostriado/metabolismo , Neostriado/patología , Neostriado/fisiopatología , Vías Nerviosas/metabolismo , Vías Nerviosas/patología , Vías Nerviosas/fisiopatología , Neuronas/metabolismo , Neuronas/patología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Ratas , Sustancia Negra/metabolismo , Sustancia Negra/patología , Sustancia Negra/fisiopatología , Ácido Úrico/metabolismo , Ácido Úrico/farmacología , Xantina/metabolismo , Xantina/farmacologíaRESUMEN
The effect and clinical significance of tolcapone withdrawal on erythrocyte catechol-O-methyltransferase (COMT) activity, levodopa pharmacokinetics, and levodopa requirements were investigated in 59 patients with fluctuating parkinsonism who were randomized to receive placebo or tolcapone 100 or 200 mg three times daily for 6 weeks. Tolcapone withdrawal caused a transient elevation in COMT activity by 64% in patients receiving 100 mg three times daily and by 128% in those receiving 200 mg three times daily at approximately 1-2 weeks after discontinuation of drug. Thereafter, COMT activity was declining but did not reach baseline values by the 12-week study endpoint. However, this had no effect on plasma levodopa and 3-O-methyldopa (3-OMD) concentrations or on levodopa requirements. During treatment, tolcapone increased "on" time and decreased "off" time; after discontinuation of study medication and levodopa dose adjustment, on and off times were similar to baseline. Withdrawal was generally well tolerated; no patients withdrew from the trial during the posttreatment period, and no serious adverse events were observed. In conclusion, the transient increase in erythrocyte COMT activity observed after discontinuation oftolcapone is not associated with changes in peripheral levodopa metabolism and therefore has no significant clinical consequences in terms of levodopa requirements, clinical symptoms, or adverse events.
Asunto(s)
Antiparkinsonianos/efectos adversos , Antiparkinsonianos/uso terapéutico , Benzofenonas/efectos adversos , Levodopa/uso terapéutico , Enfermedad de Parkinson/fisiopatología , Síndrome de Abstinencia a Sustancias/fisiopatología , Anciano , Antiparkinsonianos/sangre , Benzofenonas/farmacocinética , Catecol O-Metiltransferasa/sangre , Método Doble Ciego , Eritrocitos/efectos de los fármacos , Eritrocitos/enzimología , Femenino , Humanos , Levodopa/sangre , Levodopa/farmacocinética , Masculino , Nitrofenoles , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/enzimología , Síndrome de Abstinencia a Sustancias/enzimología , Tolcapona , Tirosina/análogos & derivados , Tirosina/sangre , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BALB/c mice injected intravenously with a single, sub-lethal dose of Nocardia asteroides GUH-2 develop several levodopa responsive movement disorders. These included headshake, stooped posture, bradykinesia, and hesitation to forward movement. The changes in monoamine levels in the brain of these mice were determined. There was a significant loss of dopamine with greatly increased dopamine turnover in the neostriatum 7 to 29 days after infection. These effects were specific for dopaminergic neurons since minimal changes were found in neostriatal norepinephrine and serotonin even though serotonin turnover was increased. Changes in monoamine metabolism were not limited to the neostriatum. There were reduced levels of serotonin and norepinephrine with increased serotonin turnover in the cerebellum. One year after infection, dopamine metabolism had returned to near normal levels, but many of the movement disorders persisted. Specific changes in neurochemistry did not always appear to correspond with these impairments. Nevertheless, these data are similar to those reported in MPTP treated BALB/c mice.
Asunto(s)
Monoaminas Biogénicas/metabolismo , Encéfalo/metabolismo , Encéfalo/microbiología , Trastornos del Movimiento/metabolismo , Nocardiosis/metabolismo , Nocardia asteroides , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Encéfalo/patología , Cerebelo/metabolismo , Dopamina/metabolismo , Femenino , Ácido Homovanílico/metabolismo , Ácido Hidroxiindolacético/metabolismo , Ratones , Ratones Endogámicos BALB C , Trastornos del Movimiento/etiología , Trastornos del Movimiento/microbiología , Neostriado/metabolismo , Nocardiosis/patología , Nocardia asteroides/aislamiento & purificación , Nocardia asteroides/patogenicidad , Norepinefrina/metabolismo , Serotonina/metabolismo , Tasa de SupervivenciaRESUMEN
The debate about the toxicity of L-DOPA to dopaminergic neurons has not been resolved. Even though enzymatic and nonenzymatic metabolism of L-DOPA can produce hydrogen peroxide and oxygen free radicals, there has been controversy as to whether L-DOPA generates an oxidant stress in vivo. This study determined whether acute or repeated administration of L-DOPA caused in vivo production of hydroxyl radicals in striatum and other brain regions in rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal projections. Salicylate trapping combined with in vivo microdialysis provided measurements of extracellular 2,3-dihydroxybenzoic acid (2,3-DHBA) in striatum following L-DOPA administration systemically (100 mg/kg, i.p.) or by intrastriatal perfusion (1 mM, via the microdialysis probe). Tissue concentrations of 2,3-DHBA and salicylate were also measured in striatum, ventral midbrain, and cerebellum following repeated administration of L-DOPA (50 mg/kg, i.p., once daily for 16 days). In each instance, treatment with L-DOPA did not increase 2,3-DHBA concentrations, regardless of the nigrostriatal dopamine system's integrity. When added to the microdialysis perfusion medium, L-DOPA resulted in a significant decrease in the striatal extracellular concentration of 2,3-DHBA. These results suggest that administration of L-DOPA, even at high doses, does not induce hydroxyl radical formation in vivo and under some conditions may actually diminish hydroxyl radical activity. Furthermore, prior damage to the nigrostriatal dopamine system does not appear to predispose surviving dopaminergic neurons to increased hydroxyl radical formation following L-DOPA administration. Unlike L-DOPA, systemic administration of methamphetamine (10 mg/kg, s.c.) produced a significant increase in the concentration of 2,3-DHBA in striatal dialysate, suggesting that increased formation of hydroxyl radicals may contribute to methamphetamine neurotoxicity.
Asunto(s)
Cuerpo Estriado/metabolismo , Gentisatos , Radical Hidroxilo/metabolismo , Levodopa/farmacología , Oxidopamina/farmacología , Sustancia Negra/metabolismo , Animales , Cerebelo/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/patología , Hidroxibenzoatos/metabolismo , Hidroxibenzoatos/farmacología , Inyecciones , Masculino , Mesencéfalo/metabolismo , Metanfetamina/farmacología , Microdiálisis , Concentración Osmolar , Ratas , Ratas Sprague-Dawley , Salicilatos/metabolismo , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patologíaRESUMEN
Clinicians have a number of options when diagnosing and managing Parkinson's disease. The decision to start pharmacotherapy often depends on the particular needs of the patient and careful weighing of possible benefits, cost, and adverse outcomes. Even mild parkinsonism may require the input of a specialist to obtain the best results.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Agonistas de Dopamina/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Humanos , Enfermedad de Parkinson/diagnóstico , Índice de Severidad de la EnfermedadRESUMEN
Since the introduction of levodopa to treat Parkinson's disease (PD), several new therapies have been directed at improving symptom control, which can decline after a few years of levodopa therapy. Dopaminergic agents can serve as adjuncts or as alternatives to levodopa. In addition, a new class of drugs, catechol-O-methyltransferase inhibitors, can extend the duration of levodopa action. Although surgical options such as pallidotomy offer improvement of parkinsonism beyond the realm of pharmacologic treatment, judicious administration of drugs in combination can generally solve most problems of PD.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Inhibidores de Catecol O-Metiltransferasa , Agonistas de Dopamina/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Benzofenonas/uso terapéutico , Benzotiazoles , Cabergolina , Sinergismo Farmacológico , Ergolinas/uso terapéutico , Humanos , Indoles/uso terapéutico , Levodopa/uso terapéutico , Nitrofenoles , Pramipexol , Tiazoles/uso terapéutico , TolcaponaAsunto(s)
Antiparkinsonianos/administración & dosificación , Levodopa/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Antiparkinsonianos/efectos adversos , Encéfalo/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Humanos , Levodopa/efectos adversosRESUMEN
A localized acute phase response occurs in the brain in Alzheimer's disease. Acute phase proteins have previously been measured in brain homogenates to quantify this response. The extent to which measurements of these proteins reflect brain parenchymal contents, as opposed to vascular contents, is unknown. In this study, the acute phase proteins ceruloplasmin (CP), complement factor 3 (C3), haptoglobin (HP), and albumin were measured in regional brain homogenates from phosphate buffered saline-perfused and sham-perfused rats (n = 7-9/group). Interleukin 1-beta (IL1-beta) and copper were also measured. Mean CP, C3, HP, and albumin concentrations in perfused specimens decreased by 94%, 88%, 90%, and 81% vs. sham-perfused specimens (all p < 0.001), while IL1-beta and copper were unchanged. These results suggest that acute phase protein measurements in brain homogenates reflect primarily vascular contents. However, IL1-beta and copper concentrations in brain homogenates are minimally influenced by vascular contents.
Asunto(s)
Proteínas de Fase Aguda/metabolismo , Encéfalo/metabolismo , Circulación Cerebrovascular , Animales , Encéfalo/irrigación sanguínea , Masculino , Ratas , Ratas Endogámicas F344Asunto(s)
Antiparkinsonianos/administración & dosificación , Sistemas de Liberación de Medicamentos/tendencias , Administración Cutánea , Apomorfina/administración & dosificación , Preparaciones de Acción Retardada , Humanos , Levodopa/administración & dosificación , Lisurida/administración & dosificaciónAsunto(s)
Infarto Cerebral/fisiopatología , Cuerpo Estriado/fisiopatología , Dopamina/fisiología , Escritura Manual , Mesencéfalo/irrigación sanguínea , Tálamo/irrigación sanguínea , Infarto Cerebral/patología , Cuerpo Estriado/patología , Humanos , Imagen por Resonancia Magnética , Mesencéfalo/patología , Tálamo/patologíaRESUMEN
Some patients with an 18p- syndrome show dystonia, and a focal dystonia gene has been mapped to chromosome 18p. The authors evaluated the extent of the deletion in three patients with an 18p- syndrome and dystonia using 14 DNA markers on 18p. A common deleted area, covering the DYT7 locus, places the putative dystonia gene between the telomere of 18p and D18S1104 (49.6 cM). Dystonia in these patients may be caused by haploinsufficiency of the DYT7 gene, a new dystonia gene on 18p, or may result from developmental brain anomalies.
Asunto(s)
Cromosomas Humanos Par 18/genética , Distonía/genética , Adulto , Deleción Cromosómica , Mapeo Cromosómico , ADN/análisis , Femenino , Humanos , Cariotipificación , Masculino , SíndromeRESUMEN
Parkinson's disease (PD) is characterized by decreased striatal dopamine, but serotonin (5-HT) is also reduced. Because 5-HT decreases following a single levodopa injection, levodopa has been suggested to contribute to PD's serotonergic deficits. However, in a recent study, rat striatal serotonin levels were reported to increase following 15-day levodopa administration. To address this issue, we administered levodopa (50 mg/kg) to rabbits for 5 days, then measured serotonin, its precursors tryptophan and 5-hydroxytryptophan (5-HTP), and its major metabolite 5-hydroxyindole-acetic acid (5-HIAA) in striatum and CSF. Striatal serotonin and tryptophan were unchanged, while 5-HTP and 5-HIAA increased 4- and 7-fold, respectively. CSF 5-HTP and 5-HIAA were also significantly increased. In levodopa-treated animals, 5-HTP concentrations were moderately correlated (r = 0.679) between striatum and CSF, while weak correlations were present between striatal and CSF concentrations of both serotonin and 5-HIAA. These results suggest that repeated levodopa treatment increases striatal serotonin turnover without changing serotonin content. However, levodopa-induced alterations in striatal serotonin metabolism may not be accurately reflected by measurement of serotonin and 5-HIAA in CSF.