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ABSTRACT: Central sleep apnea (CSA) is common in patients with heart failure. Recent studies link ticagrelor use with CSA. We aimed to evaluate CSA prevalence in patients with coronary heart disease (CHD) and whether ticagrelor use is associated with CSA. We reviewed consecutive patients with CHD who underwent a polysomnography (PSG) test over a 5-year period from 3 sleep centers. We sampled patients who were on ticagrelor or clopidogrel during a PSG test at a 1:4 ticagrelor:clopidogrel ratio. Patients with an active opioid prescription during PSG test were excluded. Age, left ventricle (LV) dysfunction, and P2Y12 inhibitor use were included in a multivariate logistic regression. A total of 135 patients were included with 26 on ticagrelor and 109 on clopidogrel (age 64.1 ± 11.4, 32% male). High CSA burden (12%) and strict CSA (4.4%) were more common in patients on ticagrelor than in those on clopidogrel (27% vs. 8.3% and 10.0% vs. 1.8%). Ticagrelor use (vs. clopidogrel) was associated with high CSA burden (OR 3.53, 95% CI 1.04-12.9, P = 0.039) and trended toward significance for strict CSA (OR 6.32, 95% CI 1.03-51.4, P = 0.052) when adjusting for age and LV dysfunction. In an additional analysis also adjusting for history of atrial fibrillation, ticagrelor use and strict CSA became significantly associated (OR 10.0, 95% CI 1.32-117, P = 0.035). CSA was uncommon in patients with CHD undergoing sleep studies. Ticagrelor use (vs. clopidogrel) was associated with high CSA burden and trended toward significance for strict CSA.
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Enfermedad Coronaria , Apnea Central del Sueño , Humanos , Masculino , Persona de Mediana Edad , Anciano , Femenino , Apnea Central del Sueño/inducido químicamente , Apnea Central del Sueño/diagnóstico , Apnea Central del Sueño/epidemiología , Clopidogrel , Ticagrelor/efectos adversos , Analgésicos Opioides , Enfermedad Coronaria/diagnóstico , Enfermedad Coronaria/tratamiento farmacológico , Enfermedad Coronaria/epidemiologíaRESUMEN
For >30 years, positron emission tomography (PET) has proven to be a powerful approach for measuring aspects of dopaminergic transmission in the living human brain; this technique has revealed important relationships between dopamine D2-like receptors and dimensions of normal behavior, such as human impulsivity, and psychopathology, particularly behavioral addictions. Nevertheless, PET is an indirect estimate that lacks cellular and functional resolution and, in some cases, is not entirely pharmacologically specific. To identify the relationships between PET estimates of D2-like receptor availability and direct in vitro measures of receptor number, affinity, and function, we conducted neuroimaging and behavioral and molecular pharmacological assessments in a group of adult male vervet monkeys. Data gathered from these studies indicate that variation in D2-like receptor PET measurements is related to reversal-learning performance and sensitivity to positive feedback and is associated with in vitro estimates of the density of functional dopamine D2-like receptors. Furthermore, we report that a simple behavioral measure, eyeblink rate, reveals novel and crucial links between neuroimaging assessments and in vitro measures of dopamine D2 receptors.
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Parpadeo/fisiología , Cuerpo Estriado/fisiología , Aprendizaje Discriminativo/fisiología , Retroalimentación Fisiológica/fisiología , Receptores de Dopamina D2/fisiología , Animales , Chlorocebus aethiops , Masculino , Estimulación Luminosa/métodos , Factores de TiempoRESUMEN
Schizophrenia is characterized by affective, cognitive, neuromorphological, and molecular abnormalities that may have a neurodevelopmental origin. MicroRNAs (miRNAs) are small noncoding RNA sequences critical to neurodevelopment and adult neuronal processes by coordinating the activity of multiple genes within biological networks. We examined the expression of 854 miRNAs in prefrontal cortical tissue from 100 control, schizophrenic, and bipolar subjects. The cyclic AMP-responsive element binding- and NMDA-regulated microRNA miR-132 was significantly down-regulated in both the schizophrenic discovery cohort and a second, independent set of schizophrenic subjects. Analysis of miR-132 target gene expression in schizophrenia gene-expression microarrays identified 26 genes up-regulated in schizophrenia subjects. Consistent with NMDA-mediated hypofunction observed in schizophrenic subjects, administration of an NMDA antagonist to adult mice results in miR-132 down-regulation in the prefrontal cortex. Furthermore, miR-132 expression in the murine prefrontal cortex exhibits significant developmental regulation and overlaps with critical neurodevelopmental processes during adolescence. Adult prefrontal expression of miR-132 can be down-regulated by pharmacologic inhibition of NMDA receptor signaling during a brief postnatal period. Several key genes, including DNMT3A, GATA2, and DPYSL3, are regulated by miR-132 and exhibited altered expression either during normal neurodevelopment or in tissue from adult schizophrenic subjects. Our data suggest miR-132 dysregulation and subsequent abnormal expression of miR-132 target genes contribute to the neurodevelopmental and neuromorphological pathologies present in schizophrenia.
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Encéfalo/crecimiento & desarrollo , Encéfalo/fisiopatología , Regulación de la Expresión Génica , MicroARNs/genética , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Adulto , Animales , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/genética , Trastorno Bipolar/fisiopatología , Encéfalo/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN Metiltransferasa 3A , Bases de Datos Genéticas , Demografía , Modelos Animales de Enfermedad , Factor de Transcripción GATA2/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Ratones , MicroARNs/metabolismo , Proteínas Musculares/metabolismo , N-Metilaspartato/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Sistemas de Lectura Abierta/genética , Reacción en Cadena de la Polimerasa , Ratas , Receptores de N-Metil-D-Aspartato/metabolismo , Reproducibilidad de los Resultados , Esquizofrenia/tratamiento farmacológico , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Cognitive deficits are a core symptom of schizophrenia, yet they remain particularly resistant to treatment. The model provided by repeatedly exposing adult nonhuman primates to phencyclidine has generated important insights into the neurobiology of these deficits, but it remains possible that administration of this psychotomimetic agent during the pre-adult period, when the dorsolateral prefrontal cortex in human and nonhuman primates is still undergoing significant maturation, may provide a greater understanding of schizophrenia-related cognitive deficits. METHODS: The effects of repeated phencyclidine treatment on spine synapse number, dopamine turnover and BDNF expression in dorsolateral prefrontal cortex, and working memory accuracy were examined in pre-adult monkeys. RESULTS: One week following phencyclidine treatment, juvenile and adolescent male monkeys demonstrated a greater loss of spine synapses in dorsolateral prefrontal cortex than adult male monkeys. Further studies indicated that in juvenile males, a cognitive deficit existed at 4 weeks following phencyclidine treatment, and this impairment was associated with decreased dopamine turnover, decreased brain derived neurotrophic factor messenger RNA, and a loss of dendritic spine synapses in dorsolateral prefrontal cortex. In contrast, female juvenile monkeys displayed no cognitive deficit at 4 weeks after phencyclidine treatment and no alteration in dopamine turnover or brain derived neurotrophic factor messenger RNA or spine synapse number in dorsolateral prefrontal cortex. In the combined group of male and female juvenile monkeys, significant linear correlations were detected between dopamine turnover, spine synapse number, and cognitive performance. CONCLUSIONS: As the incidence of schizophrenia is greater in males than females, these findings support the validity of the juvenile primate phencyclidine model and highlight its potential usefulness in understanding the deficits in dorsolateral prefrontal cortex in schizophrenia and developing novel treatments for the cognitive deficits associated with schizophrenia.
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Conducta Animal , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cognición , Dopamina/metabolismo , Fenciclidina , Corteza Prefrontal/metabolismo , Esquizofrenia/metabolismo , Psicología del Esquizofrénico , Médula Espinal/metabolismo , Sinapsis/metabolismo , Factores de Edad , Animales , Chlorocebus aethiops , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Femenino , Masculino , Memoria a Corto Plazo , Corteza Prefrontal/fisiopatología , Esquizofrenia/inducido químicamente , Esquizofrenia/patología , Esquizofrenia/fisiopatología , Factores Sexuales , Médula Espinal/fisiopatología , Médula Espinal/ultraestructura , Sinapsis/ultraestructura , Factores de TiempoRESUMEN
We combined viral vector delivery of human glial-derived neurotrophic factor (GDNF) with the grafting of dopamine (DA) precursor cells from fetal ventral mesencephalon (VM) to determine whether these strategies would improve the anti-Parkinson's effects in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, an animal model for Parkinson's disease (PD). Both strategies have been reported as individually beneficial in animal models of PD, leading to clinical studies. GDNF delivery has also been reported to augment VM tissue implants, but no combined studies have been done in monkeys. Monkeys were treated with MPTP and placed into four balanced treatment groups receiving only recombinant adeno-associated virus serotype 5 (rAAV5)/hu-GDNF, only fetal DA precursor cells, both together, or a buffered saline solution (control). The combination of fetal precursors with rAAV5/hu-GDNF showed significantly higher striatal DA concentrations compared with the other treatments, but did not lead to greater functional improvement in this study. For the first time under identical conditions in primates, we show that all three treatments lead to improvement compared with control animals.
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Dependovirus/genética , Dopamina/metabolismo , Trasplante de Tejido Fetal , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Intoxicación por MPTP/terapia , Mesencéfalo/trasplante , Enfermedad de Parkinson/terapia , Animales , Conducta Animal , Trasplante de Tejido Encefálico , Chlorocebus aethiops , Terapia Combinada , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiopatología , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/citología , Neuronas Dopaminérgicas/metabolismo , Terapia Genética , Vectores Genéticos , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Humanos , Virus de la Anemia Infecciosa Equina/genética , Intoxicación por MPTP/fisiopatología , Intoxicación por MPTP/psicología , Masculino , Mesencéfalo/citología , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/psicologíaRESUMEN
Parkinson's disease is usually characterized as a movement disorder; however, cognitive abilities that are dependent on the prefrontal cortex decline at an early stage of the disease in most patients. The changes that underlie cognitive deficits in Parkinson's disease are not well understood. We hypothesize that reduced dopamine signalling in the prefrontal cortex in Parkinson's disease is a harbinger of detrimental synaptic changes in pyramidal neurons in the prefrontal cortex, whose function is necessary for normal cognition. Our previous data showed that monkeys exposed to the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), but not exhibiting overt motor deficits (motor-asymptomatic), displayed cognitive deficits in prefrontal cortex-dependent tasks. The present results demonstrate that motor-asymptomatic MPTP-treated monkeys have a reduced dopamine concentration and a substantially lower number (50%) of asymmetric (excitatory) spine synapses in layer II/III, but not layer V, of the dorsolateral prefrontal cortex, compared to controls. In contrast, neither dopamine concentration nor asymmetric synapse number was altered in the entorhinal cortex of MPTP-treated monkeys. Together, these findings suggest that the number of asymmetric spine synapses on dendrites in the prefrontal cortex is dopamine-dependent and that the loss of synapses may be a morphological substrate of the cognitive deficits induced by a reduction in dopamine neurotransmission in this region.
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Trastornos del Conocimiento/metabolismo , Espinas Dendríticas/metabolismo , Dopamina/metabolismo , Trastornos Parkinsonianos/metabolismo , Corteza Prefrontal/metabolismo , Sinapsis/metabolismo , Animales , Chlorocebus aethiops , Trastornos del Conocimiento/patología , Espinas Dendríticas/patología , Masculino , Trastornos Parkinsonianos/patología , Corteza Prefrontal/patología , Sinapsis/patologíaRESUMEN
Several addictive or neurotoxic drugs are dependent on the dopamine transporter (DAT) and/or vesicular monoamine transporter (VMAT2) to exert their detrimental effects on dopamine neurons. For example, methamphetamine and MPTP are substrates for both DAT and VMAT2, with the ratio of DAT to VMAT2 in striatum being a determinant of the degree of toxicity inflicted by these drugs on dopamine neurons. Thus, the susceptibility of dopamine neurons to agents whose pharmacology involves DAT and VMAT2 may vary during development if the ontogeny of DAT and VMAT2 differs, and this is relevant as exposure of dopamine neurons to toxic agents during development is hypothesized to underlie some neurological or psychiatric disorders. However, the relative expression of DAT and VMAT2 has not been studied in either primate or nonprimate fetal brain, and this was addressed in the present study by measuring the binding of specific radioligands of DAT and VMAT2 to striatal membranes from nonhuman primates at mid-gestation, late-gestation, and the postnatal and adult periods. Dopamine concentration was also determined in striatal tissue from the same brains. These data indicate that in striatum of primates, unlike rodents, there is a sharp increase in DAT and VMAT2 expression after mid-gestation, with adult levels being attained at the time of birth. In addition, this study demonstrated that there is a coordinated expression of DAT and VMAT2 from the time of mid-gestation to adulthood.
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Cuerpo Estriado/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Regulación del Desarrollo de la Expresión Génica , Proteínas de Transporte Vesicular de Monoaminas/metabolismo , Animales , Chlorocebus aethiops , Cuerpo Estriado/embriología , Cuerpo Estriado/crecimiento & desarrollo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Ensayo de Unión Radioligante , Proteínas de Transporte Vesicular de Monoaminas/genéticaRESUMEN
Current NCCN guidelines for second-line therapy in recurrent or metastatic esophago-gastric cancers recommend the use of VEGF inhibitors such as ramucirumab. VEGF inhibitors have been shown to be associated with gastrointestinal perforation in clinical trials and late colorectal anastomotic leaks in a few case reports. Here, we present a case of late esophageal anastomotic leak in a patient receiving ramucirumab. Case information was obtained from our institution's electronic medical records. The patient was found to have T4N1M0, poorly differentiated invasive adenocarcinoma and subsequently received neoadjuvant chemoradiation followed by hybrid Ivor-Lewis esophagectomy 6 weeks later. He recovered well with no leak or perioperative complications. The patient had disease progression 9 months postoperatively on CT and PET imaging. Sixteen months after surgery he began paclitaxel and ramucirumab and 16 weeks after ramucirumab initiation, he was found to have an esophago-pulmonary fistula in the region of the anastomosis. Biopsies were negative for recurrence at the anastomosis. He died one week later from progressive pneumonia despite stenting. In conclusion, this is the only known report of delayed esophageal anastomotic complication associated with ramucirumab. VEGF inhibitor therapies such as bevacizumab have been associated with late (greater than 3 months postoperative) colorectal anastomotic complications including fistulas and leaks. Risk factors that have been associated are perioperative radiotherapy and history of early postoperative leak. These findings raise concern whether VEGF inhibitor therapy should be used in post-esophagectomy patients with recurrence if these rare but catastrophic events are likely to be terminal.
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Guanidinopropionic acid (GPA) increases AMPK activity, mitochondrial function and biogenesis in muscle and improves physiological function, for example during aging. Mitochondrial dysfunction is a major contributor to the pathogenesis of Parkinson's disease. Here we tested whether GPA prevents neurodegeneration of the nigrostriatal dopamine system in MPTP-treated mice. Mice were fed a diet of 1% GPA or normal chow for 4 weeks and then treated with either MPTP or saline. Indices of nigrostriatal function were examined by HPLC, immunohistochemistry, stereology, electron microscopy and mitochondrial respiration. MPTP intoxication decreased TH neurons in the SNpc of normal chow-fed mice; however GPA-fed mice remarkably exhibited no loss of TH neurons in the SNpc. MPTP caused a decrease in striatal dopamine of both normal chow- and GPA-fed mice, although this effect was significantly attenuated in GPA-fed mice. GPA-fed mice showed increased AMPK activity, mitochondrial respiration and mitochondrial number in nigrostriatal TH neurons, suggesting that the neuroprotective effects of GPA involved AMPK-dependent increases in mitochondrial function and biogenesis. MPTP treatment produced a decrease in mitochondrial number and volume in normal chow-fed mice but not GPA-fed mice. Our results show the neuroprotective properties of GPA in a mouse model of Parkinson's disease are partially mediated by AMPK and mitochondrial function. Mitochondrial dysfunction is a common problem in neurodegeneration and thus GPA may slow disease progression in other models of neurodegeneration.
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Cuerpo Estriado/fisiología , Dopamina/metabolismo , Guanidinas/farmacología , Mitocondrias/fisiología , Fármacos Neuroprotectores/administración & dosificación , Trastornos Parkinsonianos/tratamiento farmacológico , Propionatos/farmacología , Sustancia Negra/fisiología , Regulación hacia Arriba/fisiología , Administración Oral , Animales , Cuerpo Estriado/efectos de los fármacos , Dopamina/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Schizophrenia patients, long-term abusers of phencyclidine (PCP), and monkeys treated with PCP all exhibit enduring cognitive deficits. Evidence indicates that loss of prefrontal cortex spine synapses results in cognitive dysfunction, suggesting the presence of synaptic pathology in the monkey PCP model; however, there is no direct evidence of such changes. In this study we use the monkey PCP model of schizophrenia to investigate at the ultrastructural level whether remodelling of dorsolateral prefrontal cortex (DLPFC) asymmetric spine synapses occurs following PCP. Subchronic PCP treatment resulted in a decrease in the number of asymmetric spine synapses, which was greater in layer II/III than layer V of DLPFC, compared to vehicle-treated controls. This decrease may contribute to PCP-induced cognitive dysfunction in the non-human primate model and perhaps in schizophrenia. Thus, the synapse loss in the PCP model provides a novel target for the development of potential treatments of cognitive dysfunction in this model and in schizophrenia.
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Trastornos del Conocimiento/patología , Cognición , Espinas Dendríticas/patología , Fenciclidina , Corteza Prefrontal/patología , Esquizofrenia/patología , Sinapsis/patología , Animales , Chlorocebus aethiops , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/psicología , Espinas Dendríticas/ultraestructura , Modelos Animales de Enfermedad , Masculino , Microscopía Electrónica de Transmisión , Corteza Prefrontal/ultraestructura , Esquizofrenia/inducido químicamente , Psicología del Esquizofrénico , Sinapsis/ultraestructuraRESUMEN
Vectors derived from adeno-associated virus (AAV) are promising candidates for neural cell transduction in vivo because they are nonpathogenic and achieve long-term transduction in the central nervous system. AAV serotype 2 (AAV2) is the most widely used AAV vector in clinical trials based largely on its ability to transduce neural cells in the rodent and primate brain. Prior work in rodents suggests that other serotypes might be more efficient; however, a systematic evaluation of vector transduction efficiency has not yet been performed in the primate brain. In this study, AAV viral vectors of serotypes 1-6 with an enhanced green-fluorescent protein (GFP) reporter gene were generated at comparable titers, and injected in equal amounts into the brains of Chlorocebus sabaeus. Vector injections were placed in the substantia nigra (SN) and the caudate nucleus (CD). One month after injection, immunohistochemistry for GFP was performed and the total number of GFP+ cells was calculated using unbiased stereology. AAV5 was the most efficient vector, not only transducing significantly more cells than any other serotype, but also transducing both NeuN+ and glial-fibrillary-acidic protein positive (GFAP+) cells. These results suggest that AAV5 is a more effective vector than AAV2 at delivering potentially therapeutic transgenes to the nigrostriatal system of the primate brain.
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Cuerpo Estriado/metabolismo , Dependovirus/metabolismo , Sustancia Negra/metabolismo , Animales , Encéfalo/metabolismo , Línea Celular , Técnicas de Transferencia de Gen , Vectores Genéticos , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Inmunohistoquímica/métodos , Microscopía Confocal , Neuronas/metabolismo , PrimatesRESUMEN
STUDY OBJECTIVES: Sleep quality in patients studied with laboratory-based polysomnography may differ from sleep quality in patients studied at home but remains clinically relevant and important to describe. We assessed objective sleep quality and explored factors associated with poor sleep in patients undergoing laboratory-based polysomnography. METHODS: We reviewed diagnostic polysomnography studies from a 10-year period at a single sleep center. Total sleep time (TST) and sleep efficiency (SE) were assessed as markers of sleep quality. Poor sleep was defined as TST ≤ 4 hours or SE ≤ 50%. Multivariable analysis was performed to determine associations between objective sleep quality as an outcome and multiple candidate predictors including age, sex, race, body mass index, comorbidities, severity of obstructive sleep apnea, and central nervous system medications. RESULTS: Among 4957 patients (age 53 ± 15 years), average TST and median SE were 5.8 hours and 79%, respectively. There were 556 (11%) and 406 (8%) patients who had poor sleep based on TST and SE, respectively. In multivariable analysis, those who were older (per 10 years: 1.48 [1.34, 1.63]), male (1.38 [1.14,1.68]), and had severe obstructive sleep apnea (1.76 [1.28, 2.43]) were more likely to have short sleep. Antidepressant use was associated with lower odds of short sleep (0.77 [0.59,1.00]). Older age (per 10 years: 1.48 [1.34, 1.62]), male sex (1.34 [1.07,1.68]), and severe obstructive sleep apnea (2.16 [1.47, 3.21]) were associated with higher odds of poor SE. CONCLUSIONS: We describe TST and SE from a single sleep center cohort. Multiple demographic characteristics were associated with poor objective sleep in patients during laboratory-based polysomnography. CITATION: Harrison EI, Roth RH, Lobo JM, et al. Sleep time and efficiency in patients undergoing laboratory-based polysomnography. J Clin Sleep Med. 2021;17(8):1591-1598.
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Laboratorios , Apnea Obstructiva del Sueño , Adulto , Anciano , Humanos , Masculino , Persona de Mediana Edad , Polisomnografía , Sueño , Apnea Obstructiva del Sueño/diagnóstico , Calidad del SueñoRESUMEN
Ghrelin targets the hypothalamus to regulate food intake and adiposity. Endogenous ghrelin receptors [growth hormone secretagogue receptor (GHSR)] are also present in extrahypothalamic sites where they promote circuit activity associated with learning and memory, and reward seeking behavior. Here, we show that the substantia nigra pars compacta (SNpc), a brain region where dopamine (DA) cell degeneration leads to Parkinson's disease (PD), expresses GHSR. Ghrelin binds to SNpc cells, electrically activates SNpc DA neurons, increases tyrosine hydroxylase mRNA and increases DA concentration in the dorsal striatum. Exogenous ghrelin administration decreased SNpc DA cell loss and restricted striatal dopamine loss after 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP) treatment. Genetic ablation of ghrelin or the ghrelin receptor (GHSR) increased SNpc DA cell loss and lowered striatal dopamine levels after MPTP treatment, an effect that was reversed by selective reactivation of GHSR in catecholaminergic neurons. Ghrelin-induced neuroprotection was dependent on the mitochondrial redox state via uncoupling protein 2 (UCP2)-dependent alterations in mitochondrial respiration, reactive oxygen species production, and biogenesis. Together, our data reveal that peripheral ghrelin plays an important role in the maintenance and protection of normal nigrostriatal dopamine function by activating UCP2-dependent mitochondrial mechanisms. These studies support ghrelin as a novel therapeutic strategy to combat neurodegeneration, loss of appetite and body weight associated with PD. Finally, we discuss the potential implications of these studies on the link between obesity and neurodegeneration.
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Cuerpo Estriado/fisiología , Dopamina/metabolismo , Ghrelina/metabolismo , Canales Iónicos/metabolismo , Mitocondrias/fisiología , Proteínas Mitocondriales/metabolismo , Sustancia Negra/fisiología , Acilcoenzima A/metabolismo , Animales , Muerte Celular/fisiología , Cuerpo Estriado/efectos de los fármacos , Ghrelina/genética , Canales Iónicos/genética , Intoxicación por MPTP , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Mitocondrias/efectos de los fármacos , Proteínas Mitocondriales/genética , ARN Mensajero/metabolismo , Receptores de Ghrelina/genética , Receptores de Ghrelina/metabolismo , Sustancia Negra/efectos de los fármacos , Tirosina 3-Monooxigenasa/metabolismo , Proteína Desacopladora 2RESUMEN
Paraoxonase-2 regulates reactive oxygen species production in mitochondria. Stimulating its expression has therapeutic potential for diseases where oxidative stress plays a significant role in the pathology. Evidence suggests that the anti-diabetic drug pioglitazone may provide neuroprotection in Parkinson's disease, Alzheimer's disease, brain trauma and ischemia, but the biochemical pathway(s) responsible has not been fully elucidated. Here we report that pioglitazone (10 mg/kg/day) for 5 days significantly increased paraoxonase-2 expression in mouse striatum. Thus, this result highlights paraoxonase-2 as a target for neuroprotective strategies and identifies pioglitazone as a tool to study the role of paraoxonase-2 in brain.
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Arildialquilfosfatasa/metabolismo , Encéfalo/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Pioglitazona/farmacología , Animales , Encéfalo/metabolismo , Masculino , Ratones , Especies Reactivas de Oxígeno/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
The gut hormone ghrelin targets the brain to promote food intake and adiposity. The ghrelin receptor growth hormone secretagogue 1 receptor (GHSR) is present in hypothalamic centers controlling energy metabolism as well as in the ventral tegmental area (VTA), a region important for motivational aspects of multiple behaviors, including feeding. Here we show that in mice and rats, ghrelin bound to neurons of the VTA, where it triggered increased dopamine neuronal activity, synapse formation, and dopamine turnover in the nucleus accumbens in a GHSR-dependent manner. Direct VTA administration of ghrelin also triggered feeding, while intra-VTA delivery of a selective GHSR antagonist blocked the orexigenic effect of circulating ghrelin and blunted rebound feeding following fasting. In addition, ghrelin- and GHSR-deficient mice showed attenuated feeding responses to restricted feeding schedules. Taken together, these data suggest that the mesolimbic reward circuitry is targeted by peripheral ghrelin to influence physiological mechanisms related to feeding.
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Apetito/efectos de los fármacos , Dopamina/metabolismo , Neuronas/metabolismo , Hormonas Peptídicas/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Técnica del Anticuerpo Fluorescente/métodos , Ghrelina , Masculino , Mesencéfalo/citología , Mesencéfalo/efectos de los fármacos , Mesencéfalo/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/efectos de los fármacos , Neuronas/fisiología , Núcleo Accumbens/citología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Técnicas de Placa-Clamp , Hormonas Peptídicas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Ghrelina , Factores de Tiempo , Área Tegmental Ventral/citología , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/metabolismoRESUMEN
The mechanism responsible for the therapeutic effects of the prototypical atypical antipsychotic drug, clozapine, is still not understood; however, there is persuasive evidence from in vivo studies in normal rodents and primates that the ability to elevate dopamine neurotransmission preferentially in the prefrontal cortex is a key component to the beneficial effects of clozapine in schizophrenia. Theoretically, such an effect of clozapine would counteract the deficient dopaminergic innervation of the prefrontal cortex that appears to be part of the pathophysiology of schizophrenia. We have previously shown that following repeated, intermittent administrations of phencyclidine to monkeys there is lowered prefrontal cortical dopamine transmission and impairment of cognitive performance that is dependent on the prefrontal cortex; these biochemical and behavioral changes therefore model certain aspects of schizophrenia. We now investigate the effects of clozapine on the dopamine projections to prefrontal cortex, nucleus accumbens, and striatum in control monkeys and in those withdrawn from repeated phencyclidine treatment, using a dose regimen of clozapine that ameliorates the cognitive deficits described in the primate phencyclidine (PCP) model. In normal monkeys, clozapine elevated dopamine turnover in all prefrontal cortical, but not subcortical, regions analyzed. In the primate PCP model, clozapine normalized dopamine (DA) turnover in the dorsolateral prefrontal cortex, prelimbic cortex, and cingulate cortex. Thus, the present data support the hypothesis that the therapeutic effects of clozapine in this primate model and perhaps in schizophrenia may be related at least in part to the restoration of DA tone in the prefrontal cortex.
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Antipsicóticos/farmacología , Clozapina/farmacología , Dopamina/fisiología , Alucinógenos/toxicidad , Fenciclidina/toxicidad , Corteza Prefrontal/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Animales , Química Encefálica/efectos de los fármacos , Chlorocebus aethiops , Dopamina/metabolismo , Femenino , Masculino , Memoria/efectos de los fármacos , Corteza Prefrontal/metabolismo , Desempeño Psicomotor/efectos de los fármacosRESUMEN
RATIONALE: Repeated exposure to the N-methyl-D-aspartate antagonist, phencyclidine, has been shown to result in biochemical and cognitive changes similar to aspects of schizophrenia. Recently, emerging evidence indicated that the symptoms of schizophrenia might result at least in part from dysfunction of local circuit neurons containing parvalbumin, including a loss of their axo-axonic projections to pyramidal neurons. OBJECTIVES: In this report, we test if repeated exposure to phencyclidine in the primate shares this change to parvalbumin-containing cells and their axo-axonic structures. MATERIALS AND METHODS: Eight adult male African green monkeys were treated with saline or phencyclidine (0.3 mg/kg BID x 14 days) and, after 8 days drug-free, perfused and fixed, and the principal sulcus was collected (Walker's area 46) for immunohistochemical analysis. RESULTS: Prior treatment with phencyclidine resulted in a 40% reduction in the density of parvalbumin-containing axo-axonic structures. There was no apparent change in the lengths or laminar location of the axo-axonic projections. Additionally, there was no change in the total density or laminar location of parvalbumin-containing or calretinin-containing cell bodies in area 46. CONCLUSIONS: These results indicate that repeated treatment with phencyclidine results in plastic changes in parvalbumin-containing local circuit neurons in the prefrontal cortex similar to that reported in schizophrenia and that these changes may contribute to the common cognitive disruption seen in both schizophrenic patients and the phencyclidine monkey model.
Asunto(s)
Axones/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Plasticidad Neuronal/efectos de los fármacos , Parvalbúminas/efectos de los fármacos , Fenciclidina/farmacología , Análisis de Varianza , Animales , Axones/metabolismo , Axones/ultraestructura , Calbindina 2 , Chlorocebus aethiops , Modelos Animales de Enfermedad , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Inmunohistoquímica , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Parvalbúminas/metabolismo , Fenciclidina/administración & dosificación , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Células Piramidales/efectos de los fármacos , Células Piramidales/ultraestructura , Proteína G de Unión al Calcio S100/efectos de los fármacos , Proteína G de Unión al Calcio S100/metabolismo , Esquizofrenia/fisiopatologíaRESUMEN
Potential long term effects on brain development are a concern when drugs are used to treat depression and anxiety in childhood. In this study, male juvenile rhesus monkeys (three-four years of age) were dosed with fluoxetine or vehicle (N=16/group) for two years. Histomorphometric examination of cortical dendritic spines conducted after euthanasia at one year postdosing (N=8/group) suggested a trend toward greater dendritic spine synapse density in prefrontal cortex of the fluoxetine-treated monkeys. During dosing, subjects were trained for automated cognitive testing, and evaluated with a test of sustained attention. After dosing was discontinued, sustained attention, recognition memory and cognitive flexibility were evaluated. Sustained attention was affected by fluoxetine, both during and after dosing, as indexed by omission errors. Response accuracy was not affected by fluoxetine in post-dosing recognition memory and cognitive flexibility tests, but formerly fluoxetine-treated monkeys compared to vehicle controls had more missed trial initiations and choices during testing. Drug treatment also interacted with genetic and environmental variables: MAOA genotype (high- and low transcription rate polymorphisms) and testing location (upper or lower tier of cages). Altered development of top-down cortical regulation of effortful attention may be relevant to this pattern of cognitive test performance after juvenile fluoxetine treatment.
Asunto(s)
Cognición/efectos de los fármacos , Fluoxetina/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Animales , Fluoxetina/administración & dosificación , Fluoxetina/farmacología , Macaca mulatta , Masculino , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
Mitochondrial uncoupling proteins dissociate ATP synthesis from oxygen consumption in mitochondria and suppress free-radical production. We show that genetic manipulation of uncoupling protein-2 (UCP2) directly affects substantia nigra dopamine cell function. Overexpression of UCP2 increases mitochondrial uncoupling, whereas deletion of UCP2 reduces uncoupling in the substantia nigra-ventral tegmental area. Overexpression of UCP2 decreased reactive oxygen species (ROS) production, which was measured using dihydroethidium because it is specifically oxidized to fluorescent ethidium by the superoxide anion, whereas mice lacking UCP2 exhibited increased ROS relative to wild-type controls. Unbiased electron microscopic analysis revealed that the elevation of in situ mitochondrial ROS production in UCP2 knock-out mice was inversely correlated with mitochondria number in dopamine neurons. Lack of UCP2 increased the sensitivity of dopamine neurons to 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP), whereas UCP2 overexpression decreased MPTP-induced nigral dopamine cell loss. The present results expose the critical importance of UCP2 in normal nigral dopamine cell metabolism and offer a novel therapeutic target, UCP2, for the prevention/treatment of Parkinson's disease.
Asunto(s)
Dopamina/fisiología , Proteínas de Transporte de Membrana/fisiología , Proteínas Mitocondriales/fisiología , Trastornos Parkinsonianos/metabolismo , Sustancia Negra/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , 1-Metil-4-fenilpiridinio/metabolismo , Animales , Supervivencia Celular/fisiología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Dopamina/metabolismo , Humanos , Inmunohistoquímica , Canales Iónicos , Masculino , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Mitocondrias/patología , Mitocondrias/fisiología , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Consumo de Oxígeno/fisiología , Trastornos Parkinsonianos/patología , Especies Reactivas de Oxígeno/metabolismo , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patología , Proteína Desacopladora 2RESUMEN
BACKGROUND: A growing body of evidence suggests the existence of synaptic pathology in schizophrenia. Here we used the phencyclidine schizophrenia model to directly investigate at the electron microscopic level whether structural synaptic alterations are present in these animals. METHODS: Adult male rats were treated according to our subchronic phencyclidine paradigm (5 mg/kg twice daily for 7 days, intraperitoneally). Following a one-week withdrawal period, the number of prefrontal cortical spine synapses was calculated using an unbiased electron microscopic stereological approach. The number of astroglia cells and the density of their processes was also analyzed following glial-fibrillary acidic protein immunohistochemistry. RESULTS: Subchronic phencyclidine treatment resulted in a 41.2% decrease in the number of prefrontal spine synapses when compared to controls. This was accompanied by a 58.8% increase in astroglia process density, without significant change in the number of astroglia cells. CONCLUSIONS: Our results demonstrate a severe reduction in the number of prefrontal spine synapses in an animal model of schizophrenia. This phenomenon may contribute to phencyclidine-induced cognitive dysfunction and decreased prefrontal cellular activity observed in this model.