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1.
Eur J Nucl Med Mol Imaging ; 51(8): 2193-2203, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38441662

RESUMO

PURPOSE: Histone deacetylase 6 (HDAC6) has emerged as a therapeutic target for neurodegenerative diseases such as Alzheimer's disease. Noninvasive imaging of HDAC6 in the brain by positron emission tomography (PET) would accelerate research into its roles in these diseases. We recently discovered an 18F-labeled derivative of the selective HDAC6 inhibitor SW-100 ([18F]FSW-100) as a potential candidate for brain HDAC6 radioligand. As a mandatory step prior to clinical translation, we performed preclinical validation of [18F]FSW-100. METHODS: Process validation of [18F]FSW-100 radiosynthesis for clinical use and assessment of preclinical toxicity and radiation dosimetry estimated from mouse distribution data were performed. In vitro selectivity of FSW-100 for 28 common receptors in the brain and HDAC isoforms was characterized. [18F]FSW-100 PET imaging was performed in non-human primates in a conscious state to estimate the feasibility of HDAC6 imaging in humans. RESULTS: Three consecutive validation runs of the automated radiosynthesis gave [18F]FSW-100 injections with radiochemical yields of 12%, and the injections conformed to specified quality control criteria for batch release. No acute toxicity was observed for non-radiolabeled FSW-100 or radioactivity decayed [18F]FSW-100 injection, and the former was negative in the Ames test. The whole-body effective dose estimated from biodistribution in mice was within the range of that of previously reported 18F-radioligands in humans. In vitro selectivity against common receptors and other HDAC isoforms was confirmed. [18F]FSW-100 demonstrated good penetration in monkey brain, and in vivo blocking studies suggested that the uptake was specific. CONCLUSION: These results support the clinical utility of [18F]FSW-100 for in vivo imaging of HDAC6 in the brain.


Assuntos
Encéfalo , Desacetilase 6 de Histona , Tomografia por Emissão de Pósitrons , Animais , Tomografia por Emissão de Pósitrons/métodos , Camundongos , Desacetilase 6 de Histona/metabolismo , Desacetilase 6 de Histona/antagonistas & inibidores , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Ligantes , Doenças Neurodegenerativas/diagnóstico por imagem , Masculino , Humanos , Distribuição Tecidual , Radioquímica , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/química , Radioisótopos de Flúor
2.
J Neuroinflammation ; 14(1): 69, 2017 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-28356120

RESUMO

BACKGROUND: Upregulated levels of 18-kDa translocator proteins (TSPO) and type 2 endocannabinoid receptors (CB2) are considered to reflect different aspects of microglia-related neuroinflammatory responses in the brain. Relative to the increase in the TSPO expression that occurs slightly later during neuroinflammation in a proinflammatory fashion, CB2 activation is considered to relate to the neuroprotective responses that occurs predominantly at an early stage of brain disorders. These findings, however, were deduced from studies with different animal samples under different experimental settings. Here, we aimed to examined the differences in TSPO binding and CB2 availability at an early stage of stroke in the same animal using positron emission tomography (PET). METHODS: We used a total of eight Sprague-Dawley rats that underwent photothrombotic stroke surgery. The binding levels of a TSPO tracer [11C](R)PK11195 and a CB2 tracer [11C]NE40 were measured at 24 h after the surgery in the same animal using PET in combination with immunohistochemistry for CB2 and several other markers. A morphological inspection was also performed with X-ray computed tomography for small animals. RESULTS: The levels of [11C]NE40 binding potential (BPND) were significantly higher in the cerebral cortical region on the lesion side than those on the non-lesion side, whereas no difference was found in the levels of [11C](R)PK11195 BPND between hemispheres. The tracer influx index (R1) data were all reduced on the lesion side irrespective of tracers. This increase in [11C]NE40 BPND was concomitant with an elevation in CB2 expression mainly within the microglia in the peri-infarct area, as shown by immunohistochemical examinations with Iba-1, CD11b/c+, and NG2+ staining. CONCLUSIONS: The present results provide in vivo evidence of different responses of microglia occurring in the acute state of stroke. The use of the CB2 tracer [11C]NE40 allows us to evaluate the roles played by the neuroprotective aspect of microglia in acute neuroinflammatory processes.


Assuntos
Proteínas de Transporte/biossíntese , Tomografia por Emissão de Pósitrons/métodos , Receptor CB2 de Canabinoide/biossíntese , Receptores de GABA-A/biossíntese , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/metabolismo , Animais , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/metabolismo , Inflamação/diagnóstico por imagem , Inflamação/metabolismo , Masculino , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/metabolismo , Ratos , Ratos Sprague-Dawley
3.
EMBO Mol Med ; 15(5): e17052, 2023 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-36994913

RESUMO

We propose a new therapeutic strategy for Alzheimer's disease (AD). Brain peptide p3-Alcß37 is generated from the neuronal protein alcadein ß through cleavage of γ-secretase, similar to the generation of amyloid ß (Aß) derived from Aß-protein precursor/APP. Neurotoxicity by Aß oligomers (Aßo) is the prime cause prior to the loss of brain function in AD. We found that p3-Alcß37 and its shorter peptide p3-Alcß9-19 enhanced the mitochondrial activity of neurons and protected neurons against Aßo-induced toxicity. This is due to the suppression of the Aßo-mediated excessive Ca2+ influx into neurons by p3-Alcß. Successful transfer of p3-Alcß9-19 into the brain following peripheral administration improved the mitochondrial viability in the brain of AD mice model, in which the mitochondrial activity is attenuated by increasing the neurotoxic human Aß42 burden, as revealed through brain PET imaging to monitor mitochondrial function. Because mitochondrial dysfunction is common in the brain of AD patients alongside increased Aß and reduced p3-Alcß37 levels, the administration of p3-Alcß9-19 may be a promising treatment for restoring, protecting, and promoting brain functions in patients with AD.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Camundongos , Animais , Humanos , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Neurônios/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo
4.
Synapse ; 66(10): 909-17, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22807129

RESUMO

The acute and subacute ischemic neuronal damage in rat brain caused by photochemically induced thrombosis (PIT) was imaged using [¹8F]BMS-747158-02 ([¹8F]BMS) for mitochondrial complex-1 (MC-1) and [¹¹C](R)-PK11195 ([¹¹C](R)-PK) for peripheral benzodiazepine receptor [PBR; translocator protein] at preischemic "Normal," 1 (day 1), and 7 days (day 7) after ischemic insult. When [¹8F]BMS was intravenously injected into "Normal" rat, it was rapidly taken up into the brain, in which it showed a homogeneous distribution, and the uptake was suppressed by rotenone, a specific MC-1 inhibitor. The specificity of [¹8F]BMS binding to MC-1 was also confirmed by living brain slice imaging. At day 1, [¹8F]BMS uptake was low in infarct and peri-infarct regions where neuronal damage was detected by 2,3,5-triphenyltetrazolium chloride (TTC) staining. At day 7, the damaged areas determined using [¹8F]BMS revealed some discrepancy from those detected by TTC staining, suggesting that TTC stained not only surviving cells but also activated microglial cells in the peri-infarct region. This was also confirmed by [¹¹C](R)-PK imaging and immunohistochemical assessment with Iba1 antibody. In contrast, the uptake pattern of [¹8F]BMS was consistent with immunohistochemical assessment with NeuN antibody at both days 1 and 7. These results demonstrated that [¹8F]BMS could be a promising positron emission tomography ligand to assess the neuronal damage induced by ischemic insult in both acute and subacute phases.


Assuntos
Isquemia Encefálica/diagnóstico por imagem , Complexo I de Transporte de Elétrons/análise , Neurônios/diagnóstico por imagem , Piridazinas , Amidas , Animais , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Radioisótopos de Flúor , Isoquinolinas , Ligantes , Masculino , Neuroglia/química , Neuroglia/patologia , Neurônios/química , Neurônios/patologia , Tomografia por Emissão de Pósitrons , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/análise , Rotenona/farmacologia , Sais de Tetrazólio/farmacologia
5.
Neuroimage ; 58(1): 1-9, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-21712096

RESUMO

Although antimuscarinic agents are widely used to treat overactive bladder (OAB), they have been shown to induce side effects including dry mouth and cognitive impairment. The present study was aimed to investigate the effects of antimuscarinic agents, oxybutynin and imidafenacin, on temporal changes in cognitive function and central mAChR occupancy in conscious monkeys (Macaca mulatta). Three conscious monkeys underwent positron emission tomography (PET) scans with a mAChR radioligand N-[(11)C]methyl-3-piperidyl benzilate ([(11)C](+)3-MPB). The scan sequence was pre, and 1, 4, and 24h post oral administration of oxybutynin (0.1-1.0mg/kg) or imidafenacin (0.01-0.1mg/kg). Maximum cognitive impairment was observed 1h post-oxybutynin at oral doses of 0.3 and 1.0mg/kg, in a dose-dependent manner, and oxybutynin produced significant positive correlations between mAChR occupancy and cognitive impairment in the cortices, thalamus, brainstem, and striatum. The most significant correlation was observed in the brainstem, and then cortices. In contrast, imidafenacin did not induce discernible cognitive impairment, despite having obtained some lesser occupancy in cortices and brainstem. We propose that the thresholds of mAChR occupancy to produce cognitive impairment by antimuscarinic agents are ca. 30-40% in cortices and ca. 20-30% in brainstem, and a desirable drug for OAB treatment should not occupy central mAChR above these thresholds.


Assuntos
Química Encefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Cognição/efeitos dos fármacos , Imidazóis/farmacologia , Lisina/análogos & derivados , Maleimidas , Ácidos Mandélicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Compostos Radiofarmacêuticos , Receptores Muscarínicos/metabolismo , Algoritmos , Animais , Relação Dose-Resposta a Droga , Percepção de Forma/fisiologia , Macaca mulatta , Masculino , Estimulação Luminosa , Tomografia por Emissão de Pósitrons , Desempenho Psicomotor/fisiologia , Receptores Muscarínicos/efeitos dos fármacos
6.
Synapse ; 65(6): 548-51, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21064187

RESUMO

N-[¹¹C]methyl-3-piperidyl benzilate ([¹¹C]+3-MPB) was developed as a positron emission tomography (PET) ligand for muscarinic cholinergic receptor (mAChR). The aim of the present study was to validate a Logan reference tissue method as an analytical method for in vivo binding of [¹¹C]+3-MPB to mAChR. Seven monkeys (Macaca mulatta) underwent [¹¹C]+3-MPB PET scans with an arterial blood sampling. Logan plot with arterial input function (Logan arterial input method) was performed to determine the binding potential (BP(ND)). The BP(ND) was also determined by Logan plot with the cerebellum as the reference region (Logan reference tissue method). BP(ND) values determined by Logan arterial input method and Logan reference tissue method showed a significant linear relationship. The present study suggests that the cerebellum is a suitable reference region for quantification of mAChR in the living brain with [¹¹C]+3-MPB and PET.


Assuntos
Radioisótopos de Carbono , Cerebelo/irrigação sanguínea , Cerebelo/diagnóstico por imagem , Lisina/análogos & derivados , Maleimidas/metabolismo , Modelos Moleculares , Tomografia por Emissão de Pósitrons/métodos , Receptores Muscarínicos/sangue , Animais , Cerebelo/metabolismo , Ligantes , Lisina/metabolismo , Macaca mulatta
7.
Synapse ; 65(3): 207-14, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20665726

RESUMO

We evaluated sequential changes in rat brain function up to 14 days after focal ischemic insult with a small animal positron emission tomography (PET). Unilateral focal ischemic cerebral damage was induced by left middle cerebral artery occlusion with a photochemically induced thrombosis (PIT) method. PET scans were conducted with [(11)C](R)-PK11195 ([(11)C](R)-PK) for peripheral benzodiazepine receptor (PBR), [(11)C]flumazenil ([(11)C]FMZ) for central benzodiazepine receptor (CBR), and [(18)F]fluoro-2-deoxy-D-glucose ([(18)F]FDG) for glucose metabolism at before (as "Normal") and after PIT. At 1 and 3 days after PIT, [(18)F]FDG indicated lower uptake in the infarct area. Interestingly, unexpectedly high-[(18)F]FDG uptake was observed in the peri-infarct area surrounding the infarct area at day 7. The high-[(18)F]FDG uptake region completely overlapped with the high-[(11)C](R)-PK uptake region at day 7, which resulted in the underestimation of neuronal damage. Immunohistochemical data also suggested that the high-[(18)F]FDG uptake peak at day 7 was caused by inflammation including microglial cell activation. In contrast, imaging with [(11)C]FMZ indicated cortical neuronal damage on days 7 and 14 without any disturbance by microglial formation. These results indicated that [(18)F]FDG might not be a suitable ligand for ischemic neuronal damage detection from acute to subacute phases.


Assuntos
Fluordesoxiglucose F18 , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Isoquinolinas , Neurônios/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Animais , Radioisótopos de Carbono , Imuno-Histoquímica , Infarto da Artéria Cerebral Média/patologia , Neurônios/patologia , Ratos
8.
Am J Med Genet B Neuropsychiatr Genet ; 153B(6): 1221-7, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20468077

RESUMO

The FXYD domain-containing ion transport regulator 6 (FXYD6) gene encodes phosphohippolin that regulates cellular ion transport by altering the kinetic properties of Na,K-ATPase. Phosphohippolin is highly expressed in brain regions that are relevant to schizophrenia. The FXYD6 gene is located at chromosome 11q22-24, one of the most established linkage regions for schizophrenia. Therefore, it may be possible that genetic variants in FXYD6, including the regulatory genomic elements could cause abnormal function or expression of phosphohippolin and increase the genetic risk for schizophrenia. A previous study suggested that polymorphisms in FXYD6 are associated with schizophrenia in UK samples. However, conflicting results have been reported in the Japanese population. In this study, we aimed to test the prior genetic association findings using different samples from the ethnically homogeneous Japanese population (1,060 schizophrenic patients and 1,060 age- and sex-matched controls). From the FXYD6 gene, we examined six single nucleotide polymorphisms (rs11216573, rs555577, rs1815774, rs4938445, rs4938446, and rs497768), all of which were previously analyzed for association. We did not detect any significant allelic, genotypic or haplotypic association in our Japanese samples. Meta-analysis incorporating previous and the present studies also showed that the FXYD6 gene is not associated with schizophrenia. We conclude that the FXYD6 gene does not have a major influence on susceptibility to schizophrenia across populations.


Assuntos
Povo Asiático/genética , Canais Iônicos/genética , Esquizofrenia/genética , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/etnologia , ATPase Trocadora de Sódio-Potássio/metabolismo
9.
J Neurosci ; 28(22): 5756-61, 2008 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-18509037

RESUMO

Methamphetamine is a popular addictive drug whose use is associated with multiple neuropsychiatric adverse events and toxic to the dopaminergic and serotonergic systems of the brain. Methamphetamine-induced neuropathology is associated with increased expression of microglial cells that are thought to participate in either pro-toxic or protective mechanisms in the brain. Although reactive microgliosis has been observed in animal models of methamphetamine neurotoxicity, no study has reported on the status of microglial activation in human methamphetamine abusers. The present study reports on 12 abstinent methamphetamine abusers and 12 age-, gender-, and education-matched control subjects who underwent positron emission tomography using a radiotracer for activated microglia, [(11)C](R)-(1-[2-chlorophenyl]-N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide) ([(11)C](R)-PK11195). Compartment analysis was used to estimate quantitative levels of binding potentials of [(11)C](R)-PK11195 in brain regions with dopaminergic and/or serotonergic innervation. The mean levels of [(11)C](R)-PK11195 binding were higher in methamphetamine abusers than those in control subjects in all brain regions (>250% higher; p < 0.01 for all). In addition, the binding levels in the midbrain, striatum, thalamus, and orbitofrontal and insular cortices (p < 0.05) correlated inversely with the duration of methamphetamine abstinence. These results suggest that chronic self-administration of methamphetamine can cause reactive microgliosis in the brains of human methamphetamine abusers, a level of activation that appears to subside over longer periods of abstinence.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/etiologia , Transtornos Relacionados ao Uso de Anfetaminas/patologia , Encéfalo/patologia , Estimulantes do Sistema Nervoso Central/efeitos adversos , Metanfetamina/efeitos adversos , Microglia/efeitos dos fármacos , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/diagnóstico por imagem , Antineoplásicos/farmacocinética , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Isótopos de Carbono/farmacocinética , Estudos de Casos e Controles , Feminino , Humanos , Isoquinolinas/farmacocinética , Imageamento por Ressonância Magnética/métodos , Masculino , Microglia/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Ligação Proteica/efeitos dos fármacos
10.
PLoS One ; 10(6): e0129828, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26068663

RESUMO

Delay eyeblink conditioning, a cerebellum-dependent learning paradigm, has been applied to various mammalian species but not yet to monkeys. We therefore developed an accurate measuring system that we believe is the first system suitable for delay eyeblink conditioning in a monkey species (Macaca mulatta). Monkey eyeblinking was simultaneously monitored by orbicularis oculi electromyographic (OO-EMG) measurements and a high-speed camera-based tracking system built around a 1-kHz CMOS image sensor. A 1-kHz tone was the conditioned stimulus (CS), while an air puff (0.02 MPa) was the unconditioned stimulus. EMG analysis showed that the monkeys exhibited a conditioned response (CR) incidence of more than 60% of trials during the 5-day acquisition phase and an extinguished CR during the 2-day extinction phase. The camera system yielded similar results. Hence, we conclude that both methods are effective in evaluating monkey eyeblink conditioning. This system incorporating two different measuring principles enabled us to elucidate the relationship between the actual presence of eyelid closure and OO-EMG activity. An interesting finding permitted by the new system was that the monkeys frequently exhibited obvious CRs even when they produced visible facial signs of drowsiness or microsleep. Indeed, the probability of observing a CR in a given trial was not influenced by whether the monkeys closed their eyelids just before CS onset, suggesting that this memory could be expressed independently of wakefulness. This work presents a novel system for cognitive assessment in monkeys that will be useful for elucidating the neural mechanisms of implicit learning in nonhuman primates.


Assuntos
Piscadela , Condicionamento Clássico , Memória , Tempo de Reação , Animais , Eletromiografia , Macaca mulatta , Masculino , Gravação em Vídeo
11.
Neuroreport ; 15(17): 2571-4, 2004 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-15570154

RESUMO

To assess the involvement of serotonin in the symptoms of chronic fatigue syndrome, we investigated the serotonergic neurotransmitter system of chronic fatigue syndrome patients by the positron emission tomography (PET). Here we show that the density of serotonin transporters (5-HTTs) in the brain, as determined by using a radiotracer, [C](+)McN5652, was significantly reduced in the rostral subdivision of the anterior cingulate as compared with that in normal volunteers. This subdivision is different from that in the dorsal anterior cingulate in which binding potential values of individual patient showed a weak negative correlation with self-reported pain score of the patients. Therefore, an alteration of serotonergic system in the rostral anterior cingulate plays a key role in pathophysiology of chronic fatigue syndrome.


Assuntos
Síndrome de Fadiga Crônica/metabolismo , Giro do Cíngulo/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Adulto , Mapeamento Encefálico , Isótopos de Carbono/metabolismo , Estudos de Casos e Controles , Síndrome de Fadiga Crônica/patologia , Feminino , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/patologia , Humanos , Isoquinolinas/metabolismo , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Medição da Dor/métodos , Tomografia por Emissão de Pósitrons/métodos , Proteínas da Membrana Plasmática de Transporte de Serotonina
12.
Neuropsychopharmacology ; 38(13): 2666-74, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23880871

RESUMO

Subanesthetic doses of ketamine, an N-methyl-D-aspartic acid (NMDA) antagonist, have a rapid antidepressant effect which lasts for up to 2 weeks. However, the neurobiological mechanism regarding this effect remains unclear. In the present study, the effects of subanesthetic doses of ketamine on serotonergic systems in conscious monkey brain were investigated. Five young monkeys underwent four positron emission tomography measurements with [(11)C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzonitrile ([(11)C]DASB) for the serotonin transporter (SERT), during and after intravenous infusion of vehicle or ketamine hydrochloride in a dose of 0.5 or 1.5 mg/kg for 40 min, and 24 h post infusion. Global reduction of [(11)C]DASB binding to SERT was observed during ketamine infusion in a dose-dependent manner, but not 24 h later. The effect of ketamine on the serotonin 1A receptor (5-HT1A-R) and dopamine transporter (DAT) was also investigated in the same subjects studied with [(11)C]DASB. No significant changes were observed in either 5-HT1A-R or DAT binding after ketamine infusion. Microdialysis analysis indicated that ketamine infusion transiently increased serotonin levels in the extracellular fluid of the prefrontal cortex. The present study demonstrates that subanesthetic ketamine selectively enhanced serotonergic transmission by inhibition of SERT activity. This action coexists with the rapid antidepressant effect of subanesthetic doses of ketamine. Further studies are needed to investigate whether the transient combination of SERT and NMDA reception inhibition enhances each other's antidepressant actions.


Assuntos
Analgésicos/farmacologia , Encéfalo/efeitos dos fármacos , Estado de Consciência , Ketamina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Análise de Variância , Animais , Benzilaminas/farmacocinética , Encéfalo/diagnóstico por imagem , Isótopos de Carbono/farmacocinética , Cocaína/análogos & derivados , Cocaína/farmacocinética , Inibidores da Captação de Dopamina/farmacocinética , Relação Dose-Resposta a Droga , Fluordesoxiglucose F18/farmacocinética , Processamento de Imagem Assistida por Computador , Macaca mulatta , Imageamento por Ressonância Magnética , Masculino , Microdiálise , Tomografia por Emissão de Pósitrons
13.
PLoS One ; 7(12): e51515, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23240035

RESUMO

BACKGROUND: Numerous associations between brain-reactive antibodies and neurological or psychiatric symptoms have been proposed. Serum autoantibody against the muscarinic cholinergic receptor (mAChR) was increased in some patients with chronic fatigue syndrome (CFS) or psychiatric disease. We examined whether serum autoantibody against mAChR affected the central cholinergic system by measuring brain mAChR binding and acetylcholinesterase activity using positron emission tomography (PET) in CFS patients with positive [CFS(+)] and negative [CFS(-)] autoantibodies. METHODOLOGY: Five CFS(+) and six CFS(-) patients, as well as 11 normal control subjects underwent a series of PET measurements with N-[(11)C]methyl-3-piperidyl benzilate [(11)C](+)3-MPB for the mAChR binding and N-[(11)C]methyl-4-piperidyl acetate [(11)C]MP4A for acetylcholinesterase activity. Cognitive function of all subjects was assessed by neuropsychological tests. Although the brain [(11)C](+)3-MPB binding in CFS(-) patients did not differ from normal controls, CFS(+) patients showed significantly lower [(11)C](+)3-MPB binding than CFS(-) patients and normal controls. In contrast, the [(11)C]MP4A index showed no significant differences among these three groups. Neuropsychological measures were similar among groups. CONCLUSION: The present results demonstrate that serum autoantibody against the mAChR can affect the brain mAChR without altering acetylcholinesterase activity and cognitive functions in CFS patients.


Assuntos
Autoanticorpos/sangue , Mapeamento Encefálico , Síndrome de Fadiga Crônica , Receptores Muscarínicos , Acetilcolinesterase/metabolismo , Adulto , Autoanticorpos/imunologia , Radioisótopos de Carbono , Síndrome de Fadiga Crônica/sangue , Síndrome de Fadiga Crônica/imunologia , Síndrome de Fadiga Crônica/patologia , Feminino , Humanos , Lisina/análogos & derivados , Imageamento por Ressonância Magnética , Masculino , Maleimidas , Receptores Muscarínicos/sangue , Receptores Muscarínicos/imunologia , Tomografia Computadorizada de Emissão
14.
Neuropsychopharmacology ; 36(7): 1455-65, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21430646

RESUMO

The muscarinic cholinergic receptor (mAChR) antagonist scopolamine was used to induce transient cognitive impairment in monkeys trained in a delayed matching to sample task. The temporal relationship between the occupancy level of central mAChRs and cognitive impairment was determined. Three conscious monkeys (Macaca mulatta) were subjected to positron emission tomography (PET) scans with the mAChR radioligand N-[(11)C]methyl-3-piperidyl benzilate ([(11)C](+)3-MPB). The scan sequence was pre-, 2, 6, 24, and 48 h post-intramuscular administration of scopolamine in doses of 0.01 and 0.03 mg/kg. Occupancy levels of mAChR were maximal 2 h post-scopolamine in cortical regions innervated primarily by the basal forebrain, thalamus, and brainstem, showing that mAChR occupancy levels were 43-59 and 65-89% in doses of 0.01 and 0.03 mg/kg, respectively. In addition, dose-dependent impairment of working memory performance was measured 2 h after scopolamine. A positive correlation between the mAChR occupancy and cognitive impairment 2 and 6 h post-scopolamine was the greatest in the brainstem (P<0.00001). Although cognitive impairment was not observed 24 h post-scopolamine, sustained mAChR occupancy (11-24%) was found with both doses in the basal forebrain and thalamus, but not in the brainstem. These results indicate that a significant degree of mAChRs occupancy is needed to produce cognitive impairment by scopolamine. Furthermore, the importance of the brainstem cholinergic system in working memory in monkey is described.


Assuntos
Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/diagnóstico por imagem , Estado de Consciência , Antagonistas Muscarínicos/toxicidade , Receptores Muscarínicos/metabolismo , Escopolamina/toxicidade , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Mapeamento Encefálico , Isótopos de Carbono , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Lisina/análogos & derivados , Lisina/efeitos dos fármacos , Macaca mulatta , Imageamento por Ressonância Magnética , Masculino , Maleimidas , Testes Neuropsicológicos , Estimulação Luminosa/métodos , Tomografia por Emissão de Pósitrons/métodos , Tempo de Reação/efeitos dos fármacos , Fatores de Tempo
16.
Neurol Res Int ; 2010: 671421, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21188225

RESUMO

Fatigue is an indispensable bioalarm to avoid exhaustive state caused by overwork or stresses. It is necessary to elucidate the neural mechanism of fatigue sensation for managing fatigue properly. We performed H(2) ( 15)O positron emission tomography scans to indicate neural activations while subjects were performing 35-min fatigue-inducing task trials twice. During the positron emission tomography experiment, subjects performed advanced trail-making tests, touching the target circles in sequence located on the display of a touch-panel screen. In order to identify the brain regions associated with fatigue sensation, correlation analysis was performed using statistical parametric mapping method. The brain region exhibiting a positive correlation in activity with subjective sensation of fatigue, measured immediately after each positron emission tomography scan, was located in medial orbitofrontal cortex (Brodmann's area 10/11). Hence, the medial orbitofrontal cortex is a brain region associated with mental fatigue sensation. Our findings provide a new perspective on the neural basis of fatigue.

17.
Prog Neuropsychopharmacol Biol Psychiatry ; 34(3): 455-8, 2010 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-20074612

RESUMO

The neurobiological basis for autism remains poorly understood. We hypothesized that adipokines, such as adiponectin, may play a role in the pathophysiology of autism. In this study, we examined whether serum levels of adiponectin are altered in subjects with autism. We measured serum levels of adiponectin in male subjects with autism (n=31) and age-matched healthy male subjects (n=31). The serum levels of adiponectin in the subjects with autism were significantly lower than that of normal control subjects. The serum adiponectin levels in the subjects with autism were negatively correlated with their domain A scores in the Autism Diagnostic Interview-Revised, which reflects their impairments in social interaction. This study suggests that decreased levels of serum adiponectin might be implicated in the pathophysiology of autism.


Assuntos
Adiponectina/sangue , Transtorno Autístico/sangue , Adolescente , Estudos de Casos e Controles , Criança , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Estatística como Assunto , Adulto Jovem
18.
PLoS One ; 3(11): e3648, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18985150

RESUMO

BACKGROUND: Obstetric complications have been regarded as a risk factor for schizophrenia later in life. One of the mechanisms underlying the association is postulated to be a hypoxic process in the brain in the offspring around the time of birth. Hippocampus is one of the brain regions implicated in the late-onset dopaminergic dysfunction associated with hypoxic obstetric complications. METHODOLOGY/PRINCIPAL FINDINGS: We used an animal model of perinatal asphyxia, in which rat pups were exposed to 15 min of intrauterine anoxia during Cesarean section birth. At 6 and 12 weeks after birth, the behavior of the pups was assessed using a methamphetamine-induced locomotion test. In addition, the histopathology of the hippocampus was examined by means of stereology. At 6 weeks, there was no change in the methamphetamine-induced locomotion. However, at 12 weeks of age, we found an elevation in methamphetamine-induced locomotor activity, which was associated with an increase of dopamine release in the nucleus accumbens. At the same age, we also found a reduction of the dentate granule cells of the hippocampus. CONCLUSIONS/SIGNIFICANCE: These results suggest that the dopaminergic dysregulation after perinatal asphyxia is associated with a reduction in hippocampal dentate granule cells, and this may partly contribute to the pathogenesis of schizophrenia.


Assuntos
Asfixia/patologia , Núcleos Cerebelares/patologia , Hipercinese/induzido quimicamente , Hipercinese/patologia , Metanfetamina , Complicações do Trabalho de Parto/patologia , Fatores Etários , Envelhecimento/fisiologia , Animais , Animais Recém-Nascidos , Asfixia/etiologia , Asfixia/fisiopatologia , Asfixia/veterinária , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Contagem de Células , Estimulantes do Sistema Nervoso Central , Cesárea/efeitos adversos , Feminino , Modelos Biológicos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Complicações do Trabalho de Parto/fisiopatologia , Complicações do Trabalho de Parto/veterinária , Gravidez , Ratos , Ratos Sprague-Dawley
19.
PLoS One ; 3(5): e2283, 2008 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-18509473

RESUMO

BACKGROUND: Epidemiological studies suggest that radiation exposure may be a potential risk factor for schizophrenia in adult humans. Here, we investigated whether adult irradiation in rats caused behavioral abnormalities relevant to schizophrenia. METHODOLOGY/PRINCIPAL FINDINGS: A total dose of 15-Gy irradiation in six fractionations during 3 weeks was exposed to the forebrain including the subventricular zone (SVZ) and subgranular zone (SGZ) with male rats in the prone position. Behavioral, immunohistochemical, and neurochemical studies were performed three months after fractionated ionizing irradiation. Three months after fractionated ionizing irradiation, the total numbers of BrdU-positive cells in both the SVZ and SGZ zones of irradiated rats were significantly lower than those of control (sham-irradiated) rats. Hyperactivity after administration of the dopaminergic agonist methamphetamine, but not the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine, was significantly enhanced in the irradiated rats although spontaneous locomotion in the irradiated rats was significantly lower than that of controls. Behavioral abnormalities including auditory sensory gating deficits, social interaction deficits, and working memory deficits were observed in the irradiated rats. CONCLUSION/SIGNIFICANCE: The present study suggests that irradiation in adulthood caused behavioral abnormalities relevant to schizophrenia, and that reduction of adult neurogenesis by irradiation may be associated with schizophrenia-like behaviors in rats.


Assuntos
Modelos Animais de Doenças , Radiação Ionizante , Esquizofrenia/etiologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Aminoácidos/metabolismo , Animais , Comportamento Animal , Dopamina/metabolismo , Imuno-Histoquímica , Masculino , Aprendizagem em Labirinto , Prosencéfalo/metabolismo , Prosencéfalo/efeitos da radiação , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto , Comportamento Social
20.
Synapse ; 61(9): 724-31, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17559093

RESUMO

Using a combination of positron emission tomography (PET) and the microdialysis technique, the effects of increased endogenous serotonin (5-hydroxytryptamine; 5-HT) on the binding of [(11)C]DASB to 5-HT transporters (5-HTT) were investigated in the conscious monkey brain. Five rhesus monkeys (Macaca mulatta) were scanned with [(11)C]DASB under the control condition and the increased endogenous 5-HT condition, in which 5-hydroxy-L-tryptophan (5-HTP) was administered (20 mg/kg, i.v.) before the PET scan. Compared with the control scan, the 5-HTP administration significantly decreased the binding potential (BP) (BP = B(max)/K(d)) of [(11)C]DASB in several brain regions. The mean % decrease of BP was biggest in the caudate and putamen. Two monkeys were scanned with [(11)C]5-HTP to assess the amino acid decarboxylase (AADC) activity in the brain, resulting in the high activity in the caudate and putamen. Microdialysis measurements showed that although 5-HTP administration (20 mg/kg, i.v.) increased the extracellular 5-HT levels in both the prefrontal cortex and caudate, the increase of the 5-HT level in the caudate was 27 times higher than that in the prefrontal cortex. These results suggest that the caudate and putamen, both of which show high AADC activity, convert 5-HTP to 5-HT at a high rate, and the increased 5-HT competes with [(11)C]DASB for the 5-HTT.


Assuntos
Benzilaminas/farmacocinética , Ligação Competitiva/efeitos dos fármacos , Encéfalo/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Serotonina/metabolismo , Vigília/fisiologia , Animais , Ligação Competitiva/fisiologia , Encéfalo/diagnóstico por imagem , Isótopos de Carbono/farmacocinética , Macaca mulatta , Masculino , Tomografia por Emissão de Pósitrons/métodos , Ligação Proteica/efeitos dos fármacos
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