Chronic fluoxetine enhances extinction therapy for PTSD by evaluating brain glucose metabolism in rats: an [18F]FDG PET study.

BACKGROUND: Recent studies suggest that selective serotonin reuptake inhibitors (SSRIs) and exposure therapies have been used to reduced footshock-induced posttraumatic stress disorder (PTSD) symptoms. However, the therapeutic effect of the combination of SSRIs treatment with exposure therapy remains a matter of debate. This study aimed to evaluate these therapeutic effect through the behavioural and the neuroimaging changes by positron emission tomography (PET) in model rats. METHODS: Pavlovian fear conditioning paradigm to establish model rats, and serial PET imaging with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) was performed during the control, fear-conditioning, and extinction-retrieval phases. The expression of c-Fos was used to identify neural activity. RESULTS: We report that fear conditioning increased glucose metabolism in the right amygdala and left primary visual cortex but decreased glucose metabolism in the left primary somatosensory cortex. After extinction retrieval, there was increased [18F]FDG uptake in the left striatum, left cochlear nucleus and right primary visual cortex but decreased uptake in the anterior cingulate cortex in the extinction group. Fluoxetine increased [18F]FDG uptake in the left hippocampus and right primary visual cortex but decreased uptake in the bilateral primary somatosensory cortex, left primary/secondary motor cortex and cuneiform nucleus. The combined therapy increased [18F]FDG uptake in the left hippocampus, left striatum, right insular cortex, left posterior parietal cortex, and right secondary visual cortex but reduced uptake in the cerebellar lobule. c-Fos expression in the hippocampal dentate gyrus and anterior cingulate cortex in the fluoxetine and combined groups was significantly higher than that in the extinction group, with no significant difference between the two groups. CONCLUSIONS: Chronic fluoxetine enhanced the effects of extinction training in a rat model of PTSD. In vivo PET imaging may provide a promising approach for evaluation chronic fluoxetine treatment of PTSD.

Phytosterols ameliorate clinical manifestations and inflammation in experimental autoimmune encephalomyelitis.

INTRODUCTION: Using experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS), the objective of this study was to examine the effect of phytosterol (PS) administration on inflammation-based EAE development. METHODS: Female SJL mice were orally administered PS prior to disease induction and maintained throughout the experiment. EAE was induced with antigenic peptide (PLP(131-155)). Mice were clinically scored for disease and euthanized for biochemical and histological analysis of inflammation. RESULTS: PS delayed onset of EAE development by 2 days and decreased disease severity by 55%. Brain histological analysis revealed an 82% decrease in central nervous system (CNS) inflammatory infiltration and a 48% decrease in demyelination in PS-treated mice versus control. Immunohistochemistry (IHC) showed a 35% reduction in macrophages entering brains of PS-treated mice. Anti-inflammatory interleukin (IL)-10 was up-regulated by 10%, while pro-inflammatory CCL2 was inhibited by 50% with PS treatment. Additionally, PS slightly decreased other pro-inflammatory factors, such as tumor necrosis factor (TNF)-α, IL-6, and interferon (IFN)-γ. CONCLUSION: PS protects against development of EAE by reducing infiltration and inflammatory activity of immune cells into CNS of treated mice, thereby decreasing demyelination associated with EAE. These results provide evidence to support PS as a preventative agent that helps to protect against the development of inflammation-driven disease, such as MS.

Effect of carbogen on tumour oxygenation and 32P-colloid interstitial irradiation response.

BACKGROUND: Interstitial irradiation therapy using radionuclides is a slow and continual process in which the effect is exerted gradually, thus improvement of the hypoxic status of the tumor will also take a long time. It has been known that carbogen delivery of 5-15 min increases tumor oxygenation. However, the long-term effect of carbogen breathing on hypoxic cells has not yet been determined, and little is know about the effect of carbogen breathing for sensitization to interstitial irradiation therapy. MATERIAL/METHODS: 99mTc-HL91(99mTc 4,9-diaza-3,3,10,10-tetramethyldodecan-2,1-dione dioxime) hypoxic imaging was performed in 10 mice bearing sarcoma 180 (S180) before and after 2 h carbogen breathing. Radioactivity ratios of tumor to contralateral limbs (T/L) of the 2 images were calculated and compared. Mice bearing S180 were subjected to long-term carbogen breathing (2 h/day for 24 days), and were treated with or without 32P-colloid. Tumor growth rate was observed in the S180-bearing mice. RESULTS: T/L of 99mTc-HL91 uptake before and after carbogen breathing was 1.872+/-0.391 and 1.354+/-0.189, respectively (t=4.476, P<0.01). In mice in the 32P-treated air breathing group and 32P-treated carbogen breathing group, tumor growth rate did not differ on day 12 after 32P-colloid treatment, and on day 24 the tumor volume was 2.728+/-0.469 and 2.237+/-0.603 cm3 (t=2.128, P<0.05), respectively, with tumor mass being 2.437+/-0.447 and 1.965+/-0.538 g (t=2.134, P<0.05), respectively. CONCLUSIONS: Long-term carbogen breathing can increase tumor oxygenation and continual carbogen breathing is necessary for enhancing the therapeutic effect of 32P-colloid interstitial irradiation.

Evaluation of lung lesions using FDG gamma-camera PET equipped with a one-inch crystal.

The aim of this study was to evaluate the clinical value of 18-fluorodeoxyglucose (FDG) imaging with gamma-camera positron emission tomography (GCPET) equipped with a one-inch crystal for diagnosing lung lesions and determining the stage of non-small cell lung cancer (NSCLC) in regions with a high prevalence of inflammatory disease and tuberculosis. FDG-GCPET was used to examine 103 patients with suspected malignant lesions in the lung. The results of FDG-GCPET and conventional workup (CWU) including computed tomography (CT), ultrasonography and radionuclide bone scintigraphy were compared. The final diagnosis was based on the results of a histological analysis or follow-up of at least six months. The results showed 82 patients with malignant and 21 patients with benign lesions. If a lesion to background ratio > or = 2.0 was used as the threshold, then the diagnostic sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of FDG-GCPET for NSCLC were 93.9, 57.1, 86.4, 89.5 and 70.6%, respectively. In 36 patients who underwent open-chest surgery, the diagnostic positive values of FDG-GCPET and CT for lymph-node involvement were 85% (17/20) and 65% (13/20), respectively. The diagnostic sensitivity, specificity, accuracy, PPV and NPV of FDG imaging were 85, 81.3, 83.3, 85 and 81.3%, respectively compared to the CT values of 65, 75, 69.4, 76.5 and 63.2%, respectively (NS). For the evaluation of distant metastases, 31 true-positive patients were identified during the follow-up. FDG imaging correctly identified 28 patients compared to 25 by CWU. In conclusion, FDG imaging with GCPET equipped with a one-inch crystal revealed a high lesion detection capability but a low level of clinical effectiveness for differentiating between malignant and benign lesions in the lung in regions with a high prevalence of inflammatory disease and tuberculosis. For N and M staging of NSCLC, this method may provide additional data that are not available from the CWU.

Treatment with an estrogen receptor alpha ligand is neuroprotective in experimental autoimmune encephalomyelitis.

Multiple sclerosis is an inflammatory, neurodegenerative disease for which experimental autoimmune encephalomyelitis (EAE) is a model. Treatments with estrogens have been shown to decrease the severity of EAE through anti-inflammatory mechanisms. Here we investigated whether treatment with an estrogen receptor alpha (ERalpha) ligand could recapitulate the estrogen-mediated protection in clinical EAE. We then went on to examine both anti-inflammatory and neuroprotective mechanisms. EAE was induced in wild-type, ERalpha-, or ERbeta-deficient mice, and each was treated with the highly selective ERalpha agonist, propyl pyrazole triol, to determine the effect on clinical outcomes, as well as on inflammatory and neurodegenerative changes. ERalpha ligand treatment ameliorated clinical disease in both wild-type and ERbeta knock-out mice, but not in ERalpha knock-out mice, thereby demonstrating that the ERalpha ligand maintained ERalpha selectivity in vivo during disease. ERalpha ligand treatment also induced favorable changes in autoantigen-specific cytokine production in the peripheral immune system [decreased TNFalpha, interferon-gamma, and interleukin-6, with increased interleukin-5] and decreased CNS white matter inflammation and demyelination. Interestingly, decreased neuronal staining [NeuN+ (neuronal-specific nuclear protein)/beta3-tubulin+/Nissl], accompanied by increased immunolabeling of microglial/monocyte (Mac 3+) cells surrounding these abnormal neurons, was observed in gray matter of spinal cords of EAE mice at the earliest stage of clinical disease, 1-2 d after the onset of clinical signs. Treatment with either estradiol or the ERalpha ligand significantly reduced this gray matter pathology. In conclusion, treatment with an ERalpha ligand is highly selective in vivo, mediating both anti-inflammatory and neuroprotective effects in EAE.

Androgens are protective in experimental autoimmune encephalomyelitis: implications for multiple sclerosis.

A gender difference prevails in some murine strains of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Our results showed that castration of SJL males, a strain characterized by decreased susceptibility of males as compared to females, displayed increased disease severity. In contrast, castration had no effect on disease in C57BL/6 males, a strain in which no gender difference in EAE is observed. Regardless of whether endogenous androgens were protective in a given genetic background, supplemental androgen treatment was protective in gonadally intact males of both strains. These data provide a basis for the novel therapeutic use of supplemental testosterone for men with MS.

Estrogen receptor alpha mediates estrogen's immune protection in autoimmune disease.

Estrogens are known to influence a variety of autoimmune diseases, but it is not known whether their actions are mediated through classic estrogen receptor alpha (ERalpha). The presence of a functional ER was demonstrated in secondary lymphoid tissues, then ERalpha expression was shown at both the RNA and protein levels in these tissues. Use of ERalpha knockout mice revealed that both the estrogen-induced disease protection and the estrogen-induced reduction in proinflammatory cytokines were dependent upon ERalpha in the prototypic Th1-mediated autoimmune disease experimental autoimmune encephalomyelitis. These findings are central to the design of selective ER modifiers which aim to target biologic responses in specific organ systems.

Experimental autoimmune encephalomyelitis relapses are reduced in heterozygous golli MBP knockout mice.

Increased golli MBP (golli) expression has been observed in the peripheral immune system of mice in the relapsing phase of EAE, raising the possibility that golli MBP expression in the periphery may contribute to relapses. Here we describe the generation of golli MBP-deficient mice and a comparison of the clinical course of EAE between heterozygous (golli(+/-)) and wild-type (golli(+/+)) mice. There was no difference between the two groups in incidence of disease, severity of the first episode of disease, or remission after the first episode. However, there was a significant reduction in relapses in golli(+/-) mice vs. controls, suggesting a role for golli proteins in the relapses in EAE.