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Developmental complex trauma is strongly associated with various psychiatric disorders in adulthood. Multiple lines of evidence have demonstrated that the amygdala-mPFC circuit regulates emotion and plays an important role in stress reactions. However, most studies on developmental trauma have mainly focused on neurological aspects in biological, behavioral, and structural changes with regard to a single stressor. In the present study, after applying complex stressors to the developmental phase, we would like to elucidate the functional changes in amygdala-mPFC circuit in the dopaminergic and serotonergic systems in the adult brain. Here, maternal separation and restraint stress were used to generate the trauma. The results showed that the body weights and corticosterone levels of animals exposed to developmental trauma decreased when compared to controls. In the neuroendocrine aspect, trauma leads to changes in proinflammatory cytokines, resulting in a decrease in IL-ß and an increase in TNF-α. In the neuroPET studies, the developmental trauma group displayed a reduction in serotonergic and dopaminergic PET uptake in the amygdala and mPFC. Collectively, our results indicate that developmental trauma weakens the serotonergic and dopaminergic systems in the amygdala-mPFC circuit.
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Amígdala del Cerebelo , Privación Materna , Adulto , Amígdala del Cerebelo/diagnóstico por imagen , Animales , Encéfalo , Corticosterona , Dopamina , Emociones , Humanos , Corteza PrefrontalRESUMEN
Global aging has led to growing health concerns posed by Alzheimer's disease (AD), the most common type of dementia. Aripiprazole is an atypical FDA-approved anti-psychotic drug with potential against AD. To investigate its therapeutic effects on AD pathology, we administered aripiprazole to 5xFAD AD model mice and examined beta-amyloid (ßA)-induced AD-like phenotypes, including ßA production, neuroinflammation, and cerebral glucose metabolism. Aripiprazole administration significantly decreased ßA accumulation in the brains of 5xFAD AD mice. Aripiprazole significantly modified amyloid precursor protein processing, including carboxyl-terminal fragment ß and ßA, a disintegrin and metalloproteinase domain-containing protein 10, and beta-site APP cleaving enzyme 1, as determined by Western blotting. Neuroinflammation, as evidenced by ionized calcium binding adapter molecule 1 and glial fibrillary acidic protein upregulation was dramatically inhibited, and the neuron cell layer of the hippocampal CA1 region was preserved following aripiprazole administration. In 18F-fluorodeoxyglucose positron emission tomography, after receiving aripiprazole, 5xFAD mice showed a significant increase in glucose uptake in the striatum, thalamus, and hippocampus compared to vehicle-treated AD mice. Thus, aripiprazole effectively alleviated ßA lesions and prevented the decline of cerebral glucose metabolism in 5xFAD AD mice, suggesting its potential for ßA metabolic modification and highlighting its therapeutic effect over AD progression.
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Enfermedad de Alzheimer/tratamiento farmacológico , Aripiprazol/farmacología , Encéfalo/efectos de los fármacos , Enfermedad de Alzheimer/etiología , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Femenino , Glucosa/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/patología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/etiología , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
Early life stress (ELS) is strongly associated with psychiatric disorders such as anxiety, depression, and schizophrenia in adulthood. To date, biological, behavioral, and structural aspects of ELS have been studied extensively, but their functional effects remain unclear. Here, we examined NeuroPET studies of dopaminergic, glutamatergic, and serotonergic systems in ELS animal models. Maternal separation and restraint stress were used to generate single or complex developmental trauma. Body weights of animals exposed to single trauma were similar to those of control animals; however, animals exposed to complex trauma exhibited loss of body weight when compared to controls. In behavioral tests, the complex developmental trauma group exhibited a decrease in time spent in the open arm of the elevated plus-maze and an increase in immobility time in the forced swim test when compared to control animals. In NeuroPET studies, the complex trauma group displayed a reduction in brain uptake values when compared to single trauma and control groups. Of neurotransmitter systems analyzed, the rate of decrease in brain uptake was the highest in the serotonergic group. Collectively, our results indicate that developmental trauma events induce behavioral deficits, including anxiety- and depressive-like phenotypes and dysfunction in neurotransmitter systems.
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Encéfalo/metabolismo , Encéfalo/fisiología , Neurotransmisores/metabolismo , Heridas y Lesiones/metabolismo , Heridas y Lesiones/fisiopatología , Animales , Animales Recién Nacidos/metabolismo , Animales Recién Nacidos/fisiología , Ansiedad/metabolismo , Ansiedad/fisiopatología , Trastornos de Ansiedad/metabolismo , Trastornos de Ansiedad/fisiopatología , Conducta Animal/fisiología , Depresión/metabolismo , Depresión/fisiopatología , Modelos Animales de Enfermedad , Conducta Exploratoria/fisiología , Femenino , Masculino , Privación Materna , Aprendizaje por Laberinto/fisiología , Imagen Molecular/métodos , Ratas , Ratas Sprague-Dawley , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología , Natación/fisiologíaRESUMEN
Alzheimer's disease (AD) is a progressive neurodegenerative disease. In this study, to investigate the effect of microglial elimination on AD progression, we administered PLX3397, a selective colony-stimulating factor 1 receptor inhibitor, to the mouse model of AD (5xFAD mice). Amyloid-beta (Aß) deposition and amyloid precursor protein (APP), carboxyl-terminal fragment ß, ionized calcium-binding adaptor molecule 1, synaptophysin, and postsynaptic density (PSD)-95 levels were evaluated in the cortex and hippocampus. In addition, the receptor density changes in dopamine D2 receptor (D2R) and metabotropic glutamate receptor 5 were evaluated using positron emission tomography (PET). D2R, tyrosine hydroxylase (TH), and dopamine transporter (DAT) levels were analyzed in the brains of Tg (5xFAD) mice using immunohistochemistry. PLX3397 administration significantly decreased Aß deposition following microglial depletion in the cortex and hippocampus of Tg mice. In the neuro-PET studies, the binding values for D2R in the Tg mice were lower than those in the wild type mice; however, after PLX3397 treatment, the binding dramatically increased. PLX3397 administration also reversed the changes in synaptophysin and PSD-95 expression in the brain. Furthermore, the D2R and TH expression in the brains of Tg mice was significantly lower than that in the wild type; however, after PLX3397 administration, the D2R and TH levels were significantly higher than those in untreated Tg mice. Thus, our findings show that administering PLX3397 to aged 5xFAD mice could prevent amyloid pathology, concomitant with the rescue of dopaminergic signaling, suggesting that targeting microglia may serve as a useful therapeutic option for neurodegenerative diseases, including AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Aminopiridinas/farmacología , Péptidos beta-Amiloides/genética , Factor Estimulante de Colonias de Macrófagos/genética , Pirroles/farmacología , Receptores del Factor Estimulante de Colonias/genética , Envejecimiento/efectos de los fármacos , Envejecimiento/patología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Amiloide/genética , Amiloide/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Animales , Encéfalo/efectos de los fármacos , Encéfalo/patología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Hipocampo/efectos de los fármacos , Hipocampo/patología , Humanos , Ratones , Ratones Transgénicos , Transducción de Señal/efectos de los fármacosRESUMEN
The purpose of this study was to determine whether the brain uptake of [18 F]FPEB is influenced by P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) as efflux transporters in rodents. To assess this possible modulation, positron emission tomography studies were performed in animal models of pharmacological or genetic ablation of these transporters. Compared with the control conditions, when P-gp was blocked with tariquidar, there was an 8%-12% increase in the brain uptake of [18 F]FPEB. In P-gp knockout mice, such as Mdr1a/b(-/-) and Mdr1a/b(-/-) Bcrp1(-/-) , genetic ablation models, there was an increment of 8%-53% in [18 F]FPEB uptake compared with that in the wild-type mice. In contrast, Bcrp knockout mice showed a decrement of 5%-12% uptake and P-gp/Bcrp knockout group displayed an increment of 5%-17% compared with wild type. These results indicate that [18 F]FPEB is possibly a weak substrate for P-gp.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Animales , Transporte Biológico , Barrera Hematoencefálica/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Ratones , Ratones Noqueados , Tomografía de Emisión de PositronesRESUMEN
INTRODUCTION: In this study, we retrospectively reviewed the patients' outcomes after cardiac arrest based on age in one center, to determine whether geriatric patients had worse outcomes. METHODS: This was a single-center, retrospective cohort study. The patients admitted to the intensive care unit on successful resuscitation after OHCA were retrospectively identified and evaluated. RESULTS: This was a retrospective cohort study of patients over 18years of-age with return of spontaneous circulation (ROSC) (>24h) after cardiac arrest who were admitted to the emergency intensive care unit (EICU) and received post-cardiac arrest care between March 2007 and December 2013. Finally, a total of 295 patients were enrolled during the study period; of these, 79 patients (36.6%) had a good cerebral performance category (CPC). In stepwise multivariate analysis, young age (per 10years) (odds ratio [OR] 1.42, 95% CI 1.00-1.99, p=0.044), high hemoglobin level (per 1g/dL) (OR 1.31, 95% CI 1.07-1.60, p=0.008), non-diabetic patients (OR 15.21, 95% CI 1.85-125.3, p=0.01), cardiogenic cardiac arrest (OR 8.68, 95% CI 3.72-20.30, p<0.001), pre-hospital cardiopulmonary resuscitation (CPR) by bystander (OR 3.61, 95% CI 1.23-10.57, p=0.019), short time from collapsed to ACLS (per 1min) (OR 1.12, 95% CI 1.06-1.18, p<0.001) had good CPC at 6-month post-admission. CONCLUSION: Elderly patients with OHCA had a poor neurological outcome; but several other factors were also related with the outcome. In decision-making for resuscitation, physicians should consider the patients' physiologic factors as well as age.
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Hipotermia Inducida/estadística & datos numéricos , Enfermedades del Sistema Nervioso/etiología , Paro Cardíaco Extrahospitalario/terapia , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Reanimación Cardiopulmonar , Servicios Médicos de Urgencia , Femenino , Humanos , Hipotermia Inducida/mortalidad , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/mortalidad , Paro Cardíaco Extrahospitalario/mortalidad , República de Corea , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
To evaluate the efficacy of 18F-FC119S as a positron emission tomography (PET) radiopharmaceutical for the imaging of Alzheimer's disease (AD), we studied the drug absorption characteristics and distribution of 18F-FC119S in normal mice. In addition, we evaluated the specificity of 18F-FC119S for ß-amyloid (Aß) in the AD group of an APP/PS1 mouse model and compared it with that in the wild-type (WT) group. The behavior of 18F-FC119S in the normal mice was characteristic of rapid brain uptake and washout patterns. In most organs, including the brain, 18F-FC119S reached its maximum concentration within 1 min and was excreted via the intestine. Brain PET imaging of 18F-FC119S showed highly specific binding of the molecule to Aß in the cortex and hippocampus. The brain uptake and binding values for the AD group were higher than those for the WT group. These results indicated that 18F-FC119S would be a candidate PET imaging agent for targeting Aß plaque.
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Enfermedad de Alzheimer/diagnóstico por imagen , Radioisótopos de Flúor/análisis , Tomografía de Emisión de Positrones/métodos , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Placa Amiloide/diagnóstico por imagen , Placa Amiloide/metabolismoRESUMEN
This study aimed to determine the optimal injection dose for non-human primate positron emission tomography (PET). We first used a monkey brain phantom with a volume of 80,000 mm3 containing 250 MBq of [18F]FDG. Next, we compared the radioactivity difference between the PET images and the actual radioactivity from the dose calibrator to determine the low-error range. We then evaluated the image quality using the NEMA-NU phantom. Finally, [18F]FP-CIT PET images were obtained from two monkeys with middle and high doses. As a result, PET images with a middle injected dose generated reasonable image quality and showed a high signal-to-noise ratio in monkey brain PET with [18F]FP-CIT. These results are expected to be actively applied in PET research using non-human primates.
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Encéfalo , Fluorodesoxiglucosa F18 , Fantasmas de Imagen , Tomografía de Emisión de Positrones , Radiofármacos , Animales , Tomografía de Emisión de Positrones/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Fluorodesoxiglucosa F18/administración & dosificación , Radiofármacos/administración & dosificación , Macaca mulatta , Relación Señal-RuidoRESUMEN
PURPOSE: Many patients with Alzheimer's disease (AD) also have psychosis, and it has been reported that these patients have more severely impaired cognitive functions than patients without psychosis. The glutamatergic system in the brain is known to play an important role in memory and learning in the neural circuits. However, there has been limited research on how antipsychotic drugs affect the glutamatergic system of AD. Therefore, we aimed to investigate the effects of aripiprazole on the glutamatergic system in an animal model of AD using functional molecular imaging. PROCEDURES: In this study, 5xFAD mice were used as the animal model. At the age of 5 months, the mice were divided into wild-type, vehicle control, and aripiprazole-treated groups (n = 6 per group). The aripiprazole-treated group was administered aripiprazole for 2 months at a dose of 1 mg·kg-1·day-1. At 7 months of age, the animals underwent behavioral tests and glutamate positron emission tomography (PET) scans. RESULTS: The aripiprazole-treated group exhibited alleviated memory impairment in a novel object recognition test. Moreover, this group displayed 7-8% higher binding in the glutamate PET scan than the vehicle-treated 5xFAD group. Postmortem examination confirmed the recovery of glutamatergic damage. CONCLUSIONS: The administration of aripiprazole alleviated memory impairment and restored the damaged glutamatergic system in 5xFAD mice. Although the use of aripiprazole in AD patients may be a constraint in terms of safety, we confirmed the possibility that the administration of antipsychotic drugs can be effective in AD.
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The effective dose represents the overall internal radiation exposure to the whole body when exposed to radiation sources. This study aims to compare conventional and software-aided methods to derive the effective dose. In the present study, 8F-T807 and 18F-Mefway, specific radiotracers for the paired helical tau and serotonin 1A receptor, were administered to healthy subjects (n = 6, each radiotracer), following which whole-body positron emission tomography (PET) images were obtained for 2 h. Subsequently, time-activity curves for major organs were obtained, and the residence times were calculated using the "conventional" and "Residence Times model" tools in PMOD software. The residence times from each method was input into OLINDA/EXM software, and the effective dose was estimated. The differences in the average residence times of the brain, heart, lung, and liver were 18.4, 20.8, 10.4, and 13.3% for 18F-T807, and 17.5, 16.4, 18.1, and 17.5% for 18F-Mefway, respectively. For the mean effective dose, the error rates between the methods were 3.8 and 1.9% for 18F-T807 and 18F-Mefway, respectively. The organs that showed the greatest difference in the absorbed dose were the urinary bladder for 18F-T807 (40.4%) and the liver for 18F-Mefway (14.1%). This method of obtaining the residence time using PMOD can be easily used to derive the effective dose, and is applicable in evaluating the safety of radiotracers for clinical trials.
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Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Humanos , Hígado , Imagen Corporal , RadiometríaRESUMEN
Introduction: Traumatic events in early life have a deleterious effect on the development of normal brain developments, which may be a cause of various psychiatric disorders in adulthood. Most prior studies focused on molecular biological aspects, and research on functional changes in neural circuits is still limited. We aimed to elucidate the effect of early life stress on in vivo excitation-inhibition and serotonergic neurotransmission in the adulthood using non-invasive functional molecular imaging (positron emission tomography, PET). Methods: To compare the effect of stress intensity, early life stress animal models were divided into single trauma (MS) and double trauma groups (MRS). MS was derived from maternal separation, whereas MRS was derived from maternal separation and restraint stress after birth. And to evaluate the stress vulnerability on the sex, we used male and female rats. Results: The MRS group showed greater weight loss and more severe depressive/anxiety-like behaviors than the MS and control groups. Corticosterone levels in MRS showed a greater extent of decline than in the MS group; however, there was no significant difference in the change of T3 and T4 between MS and MRS. In the PET, the stress exposure groups showed lower brain uptake for GABAergic, glutamatergic, and serotonergic systems compared with the control group. The excitatory/inhibitory balance, which was derived by dividing glutamate brain uptake into GABAergic uptake, increased as stress intensity increased. Neuronal degeneration in the stress exposure groups was confirmed by immunohistochemistry. In the sex comparison, female showed the greater changes of body weight, corticosterone level, depressive/anxiety-like behavior, and neurotransmission systems than those in male. Conclusion: Taken together, we demonstrated that developmental stress induces dysfunction of neurotransmission in vivo, and that females are more vulnerable to stress than males.
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PURPOSE: Although escitalopram is known to be an effective drug for adult depression, its disease-modifying efficacy on adolescents remains controversial. The present study aimed to evaluate the therapeutic effect of escitalopram on behavioral aspects as well as functional neural circuits by means of positron emission tomography. PROCEDURES: To generate the animal models of depression, restraint stress was used during the peri-adolescent period (RS group). Thereafter, escitalopram was administered after the end of stress exposure (Tx group). We performed NeuroPET studies of glutamate, glutamate, GABA, and serotonin systems. RESULTS: The Tx group showed no body weight change compared to the RS group. In the behavioral tests, the Tx group also displayed the similar time spent in open arms and immobility time to those for RS. In the PET studies, brain uptake values for the Tx group revealed no significant differences in terms of glucose, GABAA, and 5-HT1A receptor densities, but lower mGluR5 PET uptake compared to the RS group. In the immunohistochemistry, the Tx group showed the significant loss of neuronal cells in the hippocampus compared to the RS group. CONCLUSION: The administration of escitalopram had no therapeutic effect on the adolescent depression.
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Citalopram , Escitalopram , Animales , Citalopram/farmacología , Citalopram/uso terapéutico , Depresión/tratamiento farmacológico , Modelos Animales de Enfermedad , Glutamatos , Ácido gamma-AminobutíricoRESUMEN
[This corrects the article DOI: 10.3389/fnins.2022.930613.].
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This study aimed to investigate how amyloid pathology affects the functional aspects of neurotransmitter systems in Alzheimer's disease. APPswe/PS2 mice (21 months of age) and wild-type (WT) mice underwent positron emission tomography (PET) and magnetic resonance spectroscopy (MRS). First, we obtained 18F-FDG and 18F-florbetaben PET scans to evaluate neuronal integrity and amyloid pathology. Second, 18F-FPEB and 18F-FMZ PET data were acquired to assess the excitatory-inhibitory neurotransmission. Third, to monitor the dopamine system, 18F-fallypride PET was performed. Amyloid PET imaging revealed that radioactivity was higher in the AD group than that in the WT group, which was validated by immunohistochemistry. In the cortical and limbic areas, the AD group showed a 25-27% decrease and 14-35% increase in the glutamatergic and GABAergic systems, respectively. The dopaminergic system in the AD group exhibited a 29% decrease in brain uptake compared with that in the WT group. A reduction in glutamate, N-acetylaspartate, and taurine levels was observed in the AD group using MRS. Our results suggest that dysfunction of the neurotransmitter system is associated with AD pathology. Among the systems, the GABAergic system was prominent, implying that the inhibitory neurotransmission system may be the most vulnerable to AD pathology.
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Meteorological disasters caused by climate change like heat, cold waves, and unusually long rainy seasons affect the milk productivity of cows. Studies have been conducted on how milk productivity and milk compositions change due to heat stress (HS). However, the estimation of losses in milk production due to HS and hereby environmental impacts of greenhouse gas (GHG) emissions are yet to be evaluated in Korean dairy farms. Dairy milk production and milk compositions data from March to October 2018, provided by the Korea Dairy Committee (KDC), were used to compare regional milk production with the temperature-humidity index (THI). Raw data for the daily temperature and relative humidity in 2018 were obtained from the Korea Meteorological Administration (KMA). This data was used to calculate the THI and the difference between the maximum and minimum temperature changing rate, as the average daily temperature range, to show the extent to which the temperature gap can affect milk productivity. The amount of milk was calculated based on the price of 926 won/kg from KDC. The results showed that the average milk production rate was the highest within the THI range 60-73 in three regions in May: Chulwon (northern region), Hwasung (central region), and Gunwi (southern region). The average milk production decreased by 4.96 ± 1.48% in northern region, 7.12 ± 2.36% in central region, and 7.94 ± 2.57% in southern region from June to August, which had a THI range of 73 or more, when compared to May. Based on the results, the level of THI should be maintained like May. If so, the farmers can earn a profit of 9,128,730 won/farm in northern region, 9,967,880 won/farm in central region, and 12,245,300 won/farm in southern region. Additionally, the average number of cows raised can be reduced by 2.41 ± 0.35 heads/farm, thereby reducing GHG emissions by 29.61 ± 4.36 kg CO2eq/day on average. Overall, the conclusion suggests that maintaining environmental conditions in the summer that are similar to those in May is necessary. This knowledge can be used for basic research to persuade farmers to change farm facilities to increase the economic benefits and improve animal welfare.
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Background: Micro-positron emission tomography (micro-PET), a small-animal dedicated PET system, is used in biomedical studies and has the quantitative imaging capabilities of radiotracers. A single-bed system, commonly used in micro-PET, is laborious to use in large-scale studies. Here, we evaluated the image qualities of a multi-bed system. Methods: Phantom imaging studies were performed to assess the recovery coefficients (RCs), uniformity, and spill-over ratios (SORs) in water- and air-filled chambers. 18F-FDG and 18F-FPEB PET images of xenograft and normal mice from the multi-bed and single-bed systems were compared. Results: For small diameters (< 3 mm), the RC values between the two systems differed significantly. However, for large diameters (> 4 mm), there were no differences in RC values between the two systems. Uniformity and SORs of both systems were within the tolerance limit of 15%. In the oncological study, the estimation of 18F-FDG uptake in the tumor was significantly lower in the multi-bed system than that in the single-bed system. However, 18F-FDG PET in xenograft mice with tumor size > 4 mm revealed the variation between subjects within the multi-bed system group to be less than 12%. In the neurological study, SUV for the multi-bed group was 25-26% lower than that for the single-bed group; however, inter-object variations within the multi-bed system were below 7%. Conclusions: Although the multi-bed system showed lower estimation of radiotracer uptake than that of the single-bed system, the inter-subject variations were within acceptable limits. Our results indicate that the multi-bed system can be used in oncological and neurological studies.
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We monitored a physiological response in a neutron-exposed normal mouse brain using two imaging tools, [18F]fluro-deoxy-D-glucose positron emission tomography ([18F]FDG-PET) and diffusion weighted-magnetic resonance imaging (DW-MRI), as an imaging biomarker. We measured the apparent diffusion coefficient (ADC) of DW-MRI and standardized uptake value (SUV) of [18F]FDG-PET, which indicated changes in the cellular environment for neutron irradiation. This approach was sensitive enough to detect cell changes that were not confirmed in hematoxylin and eosin (H&E) results. Glucose transporters (GLUT) 1 and 3, indicators of the GLUT capacity of the brain, were significantly decreased after neutron irradiation, demonstrating that the change in blood-brain-barrier (BBB) permeability affects the GLUT, with changes in both SUV and ADC values. These results demonstrate that combined imaging of the same object can be used as a quantitative indicator for in vivo pathological changes. In particular, the radiation exposure assessment of combined imaging, with specific integrated functions of [18F]FDG-PET and MRI, can be employed repeatedly for noninvasive analysis performed in clinical practice. Additionally, this study demonstrated a novel approach to assess the extent of damage to normal tissues as well as therapeutic effects on tumors.
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Encéfalo/fisiología , Encéfalo/efectos de la radiación , Imagen de Difusión por Resonancia Magnética , Fluorodesoxiglucosa F18 , Neutrones/efectos adversos , Tomografía de Emisión de Positrones , Exposición a la Radiación/efectos adversos , Animales , Encéfalo/diagnóstico por imagen , Femenino , Ratones Endogámicos BALB C , Imagen Multimodal , Exposición Profesional/efectos adversosRESUMEN
Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the leading cause of dementia, but therapeutic treatment options are limited. Taurine has been reported to have neuroprotective properties against dementia, including AD. The present study aimed to investigate the treatment effect of taurine in AD mice by functional molecular imaging. To elucidate glutamate alterations by taurine, taurine was administered to 5xFAD transgenic mice from 2 months of age, known to apear amyloid deposition. Then, we performed glutamate positron emission tomography (PET) imaging studies for three groups (wild-type, AD, and taurine-treated AD, n = 5 in each group). As a result, brain uptake in the taurine-treated AD group was 31-40% higher than that in the AD group (cortex: 40%, p < 0.05; striatum: 32%, p < 0.01; hippocampus: 36%, p < 0.01; thalamus: 31%, p > 0.05) and 3-14% lower than that in the WT group (cortex: 10%, p > 0.05; striatum: 15%, p > 0.05; hippocampus: 14%, p > 0.05; thalamus: 3%, p > 0.05). However, we did not observe differences in Aß pathology between the taurine-treated AD and AD groups in immunohistochemistry experiments. Our results reveal that although taurine treatment did not completely recover the glutamate system, it significantly increased metabolic glutamate receptor type 5 brain uptake. Therefore, taurine has therapeutic potential against AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/genética , Fármacos Neuroprotectores/farmacología , Taurina/farmacología , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Hipocampo/diagnóstico por imagen , Hipocampo/efectos de los fármacos , Humanos , Imagen por Resonancia Magnética , Ratones , Ratones Transgénicos , Tomografía de Emisión de Positrones , Taurina/genéticaRESUMEN
PURPOSE: Neuroinflammation in Parkinson's disease (PD) is known to play a pivotal role in progression to neuronal degeneration. It has been reported that colony-stimulation factor 1 receptor (CSF-1R) inhibition can effectively deplete microglia. However, its therapeutic efficacy in PD is unclear still now. PROCEDURES: To elucidate this issue, we examined the contribution of microglial depletion to PD by behavioral testing, positron emission tomography (PET) imaging, and immunoassays in sham, PD, and microglial depletion PD model (PLX3397 was administered to PD groups, with n = 6 in each group). RESULTS: The microglial depletion in PD model showed improved sensory motor function and depressive-like behavior. NeuroPET revealed that PLX3397 treatment resulted in partial recovery of striatal neuro-inflammatory functions (binding values of [18F]DPA-174 for PD, 1.47 ± 0.12, p < 0.01 vs. for PLX3397 in PD: 1.33 ± 0.26) and the dopaminergic (binding values of 18F-FP-CIT for PD, 1.32 ± 0.07 vs. for PLX3397 in PD: 1.54 ± 0.10, p < 0.01) and glutamatergic systems (binding values of [18F]FPEB for PD: 9.22 ± 0.54 vs. for PLX3397 Tx in PD: 9.83 ± 0.96, p > 0.05). Western blotting for microglia showed similar changes. CONCLUSION: Microglial depletion has inflammation-related therapeutic effects, which have beneficial effects on motor and nonmotor symptoms of PD.
Asunto(s)
Microglía/metabolismo , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/patología , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Animales , Conducta Animal , Modelos Animales de Enfermedad , Dopamina/metabolismo , Ácido Glutámico/metabolismo , Masculino , Microglía/efectos de los fármacos , Enfermedad de Parkinson/diagnóstico por imagen , Tomografía de Emisión de Positrones , Pirazoles/química , Pirimidinas/química , Ratas Sprague-Dawley , Receptor de Factor Estimulante de Colonias de Macrófagos/metabolismo , Natación , Tropanos/químicaRESUMEN
Colorectal cancer (CRC) is a major cause of mortality that can be treated effectively with chemotherapy and radiotherapy, although resistance to these therapeutic modalities often occurs. Tumor-treating fields (TTFields) can block tumor growth by selectively impairing tumor cell division. In this study, we investigated the mechanism by which 5-fluorouracil (5-FU) sensitizes tumor cells to TTFields. Human HCT116 and SW480 CRC cells were treated with 5-FU and/or TTFields, and characterized in vitro in terms of cell viability, apoptosis through reactive oxygen species production, autophagy, and metastatic potentials. The biological effects of 5-FU and/or TTFields were studied via positron emission tomography and computed tomography on xenograft tumor growth and were confirmed with organoid models of patients. Our results revealed that combination treatment with 5-FU and TTFields increased the efficiency of TTFields therapy in colon cancer cells by downregulating signaling pathways associated with cell proliferation, survival, cell invasion, and migration while upregulating pathways mediating apoptosis and autophagic cell death. The novel mechanistic insights gleaned in this study suggest that combination therapy with TTFields and 5-FU may be effective in treating CRC, although safety and efficacy testing in patients with CRC will need to be performed before this strategy can be implemented clinically for TTF-sensitization.