RESUMO
BACKGROUND: Insulin-like growth factor-1 (IGF-1) function is impaired in Parkinson disease. Cyclic glycine-proline (cGP), a metabolite of IGF-1, is neuroprotective through improving IGF-1 function. Parkinson disease patients score lower on Hospital-associated Anxiety and Depression Scale after supplementing blackcurrant anthocyanins (BCA), which may be associated with IGF-1 function. We evaluated the changes of cGP and IGF-1 before and after the supplementation. METHODS: Plasma and cerebrospinal fluid (CSF) were collected from 11 male patients before and after 28 day supplementation of BCA. The concentrations of IGF-1, IGF binding protein (IGFBP)-3, and cGP were measured using ELISA and HPLC-MS assays. The presence of cGP in the BCA was evaluated. RESULTS: cGP presented in the BCA. BCA supplementation increased the concentration of cGP (p < 0.01), but not IGF-1 and IGFBP-3 in the CSF. CSF concentration of cGP was correlated with plasma concentration of cGP (R = 0.68, p = 0.01) and cGP/IGF-1 molar ratio (R = 0.66, p = 0.01). The CSF/plasma ratio was high in cGP and low in IGF-1 and IGFBP-3. CONCLUSION: cGP is a natural nutrient to the BCA. The increased CSF cGP in Parkinson disease patients may result from the central uptake of plasma cGP. Given neurotrophic function, oral availability, and effective central uptake of cGP, the BCA has the potential to be developed to treat neurological conditions with IGF-1 deficiency.
Assuntos
Antocianinas/uso terapêutico , Antiparkinsonianos/uso terapêutico , Fator de Crescimento Insulin-Like I/líquido cefalorraquidiano , Doença de Parkinson/tratamento farmacológico , Peptídeos Cíclicos/líquido cefalorraquidiano , Ribes/química , Idoso , Idoso de 80 Anos ou mais , Antocianinas/isolamento & purificação , Antiparkinsonianos/isolamento & purificação , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Frutas/química , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/líquido cefalorraquidiano , Fator de Crescimento Insulin-Like I/deficiência , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Doença de Parkinson/sangue , Doença de Parkinson/líquido cefalorraquidiano , Doença de Parkinson/fisiopatologia , Peptídeos Cíclicos/sangue , Fatores de Tempo , Resultado do TratamentoRESUMO
Invasive aspergillosis has an extremely high mortality rate. In Japan, micafungin, an echinocandin drug that has a new mechanism of action as an antifungal agent and has a clinical effect against Aspergillus species, became available in 2002. However, little is known about its penetration into the central nervous system (CNS), or its efficacy for the treatment of invasive CNS aspergillosis. We report a 65-y-old female with diabetes mellitus and CNS aspergillosis who was treated with micafungin. During treatment, micafungin concentrations were measured in the cerebrospinal fluid and plasma. On a dose of 300 mg/d, the ratio of the micafungin concentration in the cerebrospinal fluid to that in plasma was extremely low (0.2%-0.05%); nevertheless, the patient did not have a relapse of invasive CNS aspergillosis after micafungin treatment.
Assuntos
Antifúngicos/uso terapêutico , Lipoproteínas/uso terapêutico , Neuroaspergilose/tratamento farmacológico , Peptídeos Cíclicos/uso terapêutico , Idoso , Anfotericina B/efeitos adversos , Antifúngicos/líquido cefalorraquidiano , Equinocandinas , Feminino , Humanos , Lipopeptídeos , Lipoproteínas/líquido cefalorraquidiano , Micafungina , Neuroaspergilose/prevenção & controle , Neuroaspergilose/cirurgia , Peptídeos Cíclicos/líquido cefalorraquidiano , RecidivaRESUMO
Thirty-one monkeys were randomly divided into three groups to undergo baseline cerebral angiography followed by induction of subarachnoid hemorrhage by placement of autologous blood clot along the right-sided arteries of the anterior circle of Willis (Day 0). The monkeys were then given drug vehicle or one of two endothelin (ET) antagonists, BQ-123 (6 mg/kg/day) or bosentan (5 mg/kg/day) intracisternally. The BQ-123 was administered by continuous infusion from a subcutaneous pump and the bosentan was given by twice-daily injections into an Ommaya reservoir in the subcutaneous space with a catheter along the right middle cerebral artery (MCA). Seven days later (Day 7), angiography was repeated and the animals were killed. Comparison of arterial diameters shown on angiograms between Day 0 and Day 7 groups given placebo and bosentan showed significant reductions in the diameters of the right intradural internal carotid (28% +/- 6% and 30% +/- 6%, respectively, paired t-test, p < 0.05), anterior cerebral artery (29% +/- 8% and 32% +/- 6% respectively +/- 6%, respectively) and MCA (34% +/- 6% and 46% +/- 4%, respectively). Animals injected with BQ-123 had significant narrowing of the right extradural internal carotid artery (7% +/- 6%) and the basilar artery (11% +/- 3%), but not of the right MCA. Comparison of arterial diameters between groups at Day 7 showed significant variance in the right extradural internal carotid, both intradural internal carotid, right middle cerebral, and left anterior cerebral arteries; the animals injected with BQ-123 developed significantly less arterial narrowing these those receiving bosentan and placebo. Bosentan was not detected in the cerebrospinal fluid aspirated from the cisterna magna on Day 7, whereas BQ-123 was detected in two animals. We can infer from these results that BQ-123 prevents vasospasm following subarachnoid hemorrhage in monkeys, that further investigations of ET antagonists are warranted, and that ET may be an important pathophysiological mediator of vasospasm. The lack of efficacy of bosentan may be related to inadequate cerebrospinal fluid levels obtained by administration twice-daily through an Ommaya reservoir.
Assuntos
Endotelinas/antagonistas & inibidores , Ataque Isquêmico Transitório/prevenção & controle , Peptídeos Cíclicos/uso terapêutico , Hemorragia Subaracnóidea/tratamento farmacológico , Sulfonamidas/uso terapêutico , Análise de Variância , Animais , Velocidade do Fluxo Sanguíneo , Bosentana , Artéria Carótida Interna/diagnóstico por imagem , Artéria Carótida Interna/efeitos dos fármacos , Angiografia Cerebral , Artérias Cerebrais/diagnóstico por imagem , Artérias Cerebrais/efeitos dos fármacos , Método Duplo-Cego , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos , Ataque Isquêmico Transitório/diagnóstico por imagem , Macaca fascicularis , Peptídeos Cíclicos/líquido cefalorraquidiano , Peptídeos Cíclicos/farmacologia , Estudos Prospectivos , Distribuição Aleatória , Sulfonamidas/metabolismo , Sulfonamidas/farmacologia , Ultrassonografia Doppler Transcraniana , Vasodilatação/efeitos dos fármacosRESUMO
The authors investigated the roles of endothelin (ET)-1 and the ETA receptor in the pathogenesis of delayed cerebral vasospasm following subarachnoid hemorrhage (SAH). A study was made of the preventive effect of a novel ETA receptor antagonist, BQ-123, on vasospasm and the expression of the ETA receptor messenger ribonucleic acid (mRNA) using a canine two-hemorrhage SAH model. Continuous intrathecal administration of BQ-123 (5 x 10(-6) mol/day) prevented narrowing of the basilar artery on Day 7 after SAH in 97.6% of cases in the study group versus 70.7% of cases in the control group (p < 0.05). While expression of the mRNA-coding ETA receptor was not detected in the control animals, it markedly increased on Day 3 after SAH and was also detected on Day 7. The results suggest that endothelin-1 and the ETA receptor participate in the pathogenesis of delayed cerebral vasospasm following SAH.
Assuntos
Vasoespasmo Coronário/prevenção & controle , Antagonistas dos Receptores de Endotelina , Peptídeos Cíclicos/uso terapêutico , RNA Mensageiro/genética , Receptores de Endotelina/genética , Hemorragia Subaracnóidea/complicações , Animais , Artéria Basilar/efeitos dos fármacos , Artéria Basilar/patologia , Northern Blotting , Vasoespasmo Coronário/genética , Vasoespasmo Coronário/patologia , Sondas de DNA , DNA Complementar , Modelos Animais de Doenças , Cães , Endotelinas/antagonistas & inibidores , Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/líquido cefalorraquidiano , Receptor de Endotelina A , Hemorragia Subaracnóidea/genéticaRESUMO
1. The effects of central administration of omega-conotoxin GVIA (omega-CTX), an N-type calcium channel blocker, were examined in conscious rabbits implanted with lateral intracerebroventricular (i.c.v.) cannulae. 2. Experiments were performed over 4 consecutive days. On day 1, the baroreceptor heart rate (induced by glyceryl trinitrate and phenylephrine) and Bezold-Jarisch like (elicited by serotonin) reflexes were measured before (0 h) and 2 h after central administration of omega-CTX (3 or 30 pmol/kg, i.c.v.) or vehicle. On days 2-4, resting parameters and reflexes were again monitored but no further omega-CTX was administered. 3. No change in heart rate (HR) was observed in any rabbit treatment group during the experimental period. In the vehicle (n = 6) and omega-CTX 3 pmol/kg (n = 6) groups, small falls in mean arterial pressure (MAP) of 6 +/- 2 and 10 +/- 3 mmHg, respectively, occurred between 0 and 24 h; MAP then remained stable. Baroreceptor-heart rate reflex curve parameters did not change in either of these groups during the 4 day period. 4. Following administration of omega-CTX 30 pmol/kg (n = 7), MAP decreased progressively and by 48 h had fallen by 19 +/- 4 mmHg. Also at 48 h, a 20% decrease in HR range of the baroreceptor-heart rate reflex curve was seen without any change in the lower HR plateau from the 0 h control. This indicates that there was an attenuation of the sympathetically mediated upper component of the curve while the vagally mediated component was unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Sistema Nervoso Autônomo/efeitos dos fármacos , Conotoxinas , Frequência Cardíaca/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Reflexo/efeitos dos fármacos , Animais , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Injeções Intravenosas , Injeções Intraventriculares , Peptídeos Cíclicos/líquido cefalorraquidiano , Coelhos , Serotonina/farmacologiaRESUMO
Cyclo(His-Pro) (CHP) is a peptide endogenous to human brain and cerebrospinal fluid (CSF). In animal studies administration of exogenous CHP augments dopaminergic neurotransmission. To explore the role of this peptide in schizophrenia, a disease characterized by a hyperdopaminergic state, we have measured CSF CHP levels in control, never-medicated schizophrenics and medicated schizophrenics. Our data show a 53% increase in CSF levels of CHP in never-medicated schizophrenics (p = 0.015), and a 25% increase in medicated schizophrenics when compared to controls. We speculate that CHP may contribute to the expression of hyperdopaminergic symptoms in schizophrenia.
Assuntos
Peptídeos Cíclicos/líquido cefalorraquidiano , Piperazinas/líquido cefalorraquidiano , Esquizofrenia/líquido cefalorraquidiano , Adulto , Dopamina/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/tratamento farmacológicoRESUMO
Levels of thyrotropin-releasing hormone (TRH) - and cyclo(His-Pro) (CHP)-like immunoreactivities and the activity of enzyme Pyroglutamate aminopeptidase (PAPase) were measured in cerebrospinal fluid (CSF) of over 100 normal adults (NA) and infants, and adult patients with various neurologic and neuropsychiatric disorders (NNDA). Levels of TRH and CHP in CSF of over 70% of the NA group were below 50 and 500 pg/ml respectively. The TRH- and CHP-like immunoreactivities in the remainder of the 30% of NA specimens exhibiting higher peptide concentrations were enzymatically and chromatographically characterized and were found to behave like authentic peptides. The levels of both of these peptides were significantly elevated in the CSF of most of the NNDA patients. An elevation in the CSF level of CHP was significantly correlated with the level of TRH, but not PAPase. Results from this study suggest that CSF elevation of TRH level may be due to a nonspecific response to stress that may be associated with hospitalization, myelogram procedure, and/or the neurologic and neuropsychiatric diseases for which the patients were admitted.
Assuntos
Transtornos Mentais/líquido cefalorraquidiano , Doenças do Sistema Nervoso/líquido cefalorraquidiano , Peptídeos Cíclicos/líquido cefalorraquidiano , Piperazinas/líquido cefalorraquidiano , Hormônio Liberador de Tireotropina/líquido cefalorraquidiano , Adulto , Idoso , Feminino , Humanos , Lactente , Masculino , Transtornos Mentais/enzimologia , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/enzimologia , Piroglutamil-Peptidase I/líquido cefalorraquidiano , Radioimunoensaio , Valores de ReferênciaRESUMO
In spinal cords from seven amyotrophic lateral sclerosis (ALS) patients and four controls, we found no difference in thyrotropin-releasing hormone (TRH) concentration relative to protein content, but there was a reduction per tissue wet weight in ALS. Immunohistochemical localization of TRH in ALS cord was unaltered. Histidyl proline diketopiperazine (HisPro-DKP), a possible metabolite of TRH, was significantly elevated per protein content in ALS. CSF levels of TRH and HisPro-DKP were unchanged. These findings suggest that TRH neurons are not primarily affected in ALS, but TRH and tissue protein are lost together as the disease progresses.
Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Peptídeos Cíclicos/análise , Piperazinas/análise , Hormônio Liberador de Tireotropina/análise , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos Cíclicos/líquido cefalorraquidiano , Piperazinas/líquido cefalorraquidiano , Medula Espinal/análise , Hormônio Liberador de Tireotropina/líquido cefalorraquidianoRESUMO
The distribution of cyclo(His-Pro), thyrotropin-releasing hormone and pyroglutamate aminopeptidase activity was examined in the CSF of human and a number of other mammalian species. Cyclo(His-Pro)-like immunoreactivity was present in the CSF of all species examined, and was immunologically and chromatographically identical with the authentic cyclo(His-Pro). Cyclo(His-Pro) concentration in CSF had no significant correlation with CSF TRH or pyroglutamate aminopeptidase.