Ginkgo biloba extract (EGb 761) and a platelet-activating factor antagonist protect the retina in experimental autoimmune uveoretinitis

Oxygen-free radical toxicity is an important factor of tissue necrosis in the eye, especially in the retina. Activation of synthesis and release of platelet-activating factor (PAF) by ocular inflammatory cells and resident cells initiates cascades of mediators and cytokines which contribute to tissue damage in several ocular pathologies. The authors studied the therapeutic effectiveness of Ginkgo biloba extract (EGb 761), a potent free radical scavenger with anti-PAF activity, and of BN 50730, a specific PAF antagonist, on acute experimental autoimmune uveoretinitis induced in rats by S-antigen immunization. These treatments slightly delayed disease onset but had little effect on the severity of uveal inflammation. However, they significantly reduced inflammatory cell infiltration of the retina and the damage of the outer retinal layers. These drugs should become useful adjuvants in the therapy of posterior uveitis and other disorders that might damage the retina.     

Functional protection of photoreceptors from light-induced damage by dimethylthiourea and Ginkgo biloba extract

PURPOSE: To investigate the functional protective effect of a synthetic (dimethylthiourea, DMTU) and a natural antioxidant (Ginkgo biloba extract, EGb 761) against light-induced retinal degeneration. METHODS: Wistar rats were exposed for 24 hours to 1700-lux light after treatment with DMTU or EGb 761. Electroretinograms were recorded before and on day (D)1, D3, D8, D15, D22, and D29 after light exposure. The b-wave amplitude was plotted against log L (ganzfeld luminance), providing the b-wave sensitivity curve. The Naka-Rushton function fitted to the sensitivity curve enabled derivation of the parameters Bmax (saturated amplitude) and K (luminance-inducing Bmax/2). In addition, rats from each group were killed for retinal morphometric analyses. RESULTS: In the untreated group, light exposure caused collapse of the b-wave sensitivity curves. Bmax was reduced by 51% at D1 without subsequent recovery. K increased temporarily, reverting to normal values 8 days later. The outer nuclear layer thicknesses decreased markedly in the superior retina. In the treated groups, light exposure had a weaker effect on sensitivity curves. The values of Bmax were not significantly different from those in the unexposed-untreated group, although K increased temporarily. Retinal morphometry was preserved. CONCLUSIONS: Dimethylthiourea and EGb 761 afford functional protection against light-induced retinal damage.     

Ischemia and reperfusion-induced histologic changes in the rat retina. Demonstration of a free radical-mediated mechanism

Histologic alterations of ischemia- and reperfusion-induced retinal damage are critically dependent on the duration of the period of ischemia. Male Sprague Dawley rats were anesthetized, and a suture was placed behind the globe including the central retinal artery. Because it was desirable that untreated eyes show a great histologic change due to reperfusion-induced damage (in order that maximum scope would exist for demonstration of any protective effect of a drug treatment), a preliminary series of studies established the time-induced characteristics for the retina with transient regional ischemia. Eyes (n = 6-12 in each group) were subjected to 30, 60, or 90 min of ischemia followed by 0.5, 1, 2, 4, and 24 hr of reperfusion, respectively. The 30-min ischemia followed by reperfusion did not result in any histologic changes; 60-min ischemia followed by reperfusion induced a moderate retinal edema which returned to the preischemic value after 24 hr of reperfusion. The 90-min ischemia followed by reperfusion further aggravated retinal edema and increased the migration of neutrophil leukocytes. Even after 24 hr of reperfusion, the retinal edema had not disappeared although an attenuation was observed. In this study, the rats were treated with superoxide dismutase (SOD-PEG, 15 x 10(3) U/kg) or EGB 761 (100 mg/kg) for 10 days (chronic treatment). The SOD and EGB 761 significantly reduced the development of reperfusion-induced retinal edema and significantly prevented the neutrophil leukocyte infiltration. Both also had a protective effect against reperfusion-induced injury when these agents were administered just before reperfusion ("late" administration).(ABSTRACT TRUNCATED AT 250 WORDS)     

Multiple facets in the control of acromegaly

Aims

The current article provides a brief overview of the criteria for defining disease control in acromegaly.

Methods

This was a retrospective, narrative review of previously published evidence chosen at the author’s discretion along with an illustrative case study from Latin America.

Findings and Conclusions

In the strictest sense, “cure” in acromegaly is defined as complete restoration of normal pulsatile growth hormone secretion, although this is rarely achieved. Rather than “cure”, as such, it is more appropriate to refer to disease control and remission, which is defined mainly in terms of specific biochemical targets (for growth hormone and insulin-like growth factor-1) that predict or correlate with symptoms, comorbidities and mortality. However, optimal management of acromegaly goes beyond biochemical control to include control of tumour growth (which may be independent of biochemical control) and comprehensive management of the symptoms and comorbidities typically associated with the disease, as these may not be adequately managed with acromegaly-specific therapy alone.

     

Severe Serotonin Depletion after Conditional Deletion of the Vesicular Monoamine Transporter 2 Gene in Serotonin Neurons: Neural and Behavioral Consequences

The vesicular monoamine transporter type 2 gene (VMAT2) has a crucial role in the storage and synaptic release of all monoamines, including serotonin (5-HT). To evaluate the specific role of VMAT2 in 5-HT neurons, we produced a conditional ablation of VMAT2 under control of the serotonin transporter (slc6a4) promoter. VMAT2^sert−cre mice showed a major (−95%) depletion of 5-HT levels in the brain with no major alterations in other monoamines. Raphe neurons contained no 5-HT immunoreactivity in VMAT2^sert−cre mice but developed normal innervations, as assessed by both tryptophan hydroxylase 2 and 5-HT transporter labeling. Increased 5-HT_1A autoreceptor coupling to G protein, as assessed with agonist-stimulated [³⁵S]GTP-γ-S binding, was observed in the raphe area, indicating an adaptive change to reduced 5-HT transmission. Behavioral evaluation in adult VMAT2^sert−cre mice showed an increase in escape-like reactions in response to tail suspension and anxiolytic-like response in the novelty-suppressed feeding test. In an aversive ultrasound-induced defense paradigm, VMAT2^sert−cre mice displayed a major increase in escape-like behaviors. Wild-type-like defense phenotype could be rescued by replenishing intracellular 5-HT stores with chronic pargyline (a monoamine oxidase inhibitor) treatment. Pargyline also allowed some form of 5-HT release, although in reduced amounts, in synaptosomes from VMAT2^sert−cre mouse brain. These findings are coherent with the notion that 5-HT has an important role in anxiety, and provide new insights into the role of endogenous 5-HT in defense behaviors.     

Vanilloïdes, cannabinoïdes et nociception: aspects anatomiques

Résumé  Les vanillo?des et les cannabino?des, deux substances extraites respectivement du piment du Chili et du cannabis, sont impliqués dans la douleur. Nous verrons ici comment la localisation des récepteurs cannabino?des CB1 et CB2 et des récepteurs vanillo?des VR1 peut apporter des renseignements précieux pour comprendre leu r?le. Les récepteurs VR1 sont localisés dans quatre populations cellulaires de fibres sensorielles impliquées dans la douleur aigu? et chronique. Un contr?le noradrénergique central de la nociception à partir du locus coeruleus par les vanillo?des est aussi vraisemblable. Les cannabino?des sont impliqués dans la modulation de la douleur aigu? ou chronique au niveau spinal par l’intermédiaire de récepteurs CB1 présents sur des afférences primaires, des interneurones inhibiteurs et des astrocytes. Au niveau supraspinal, les cannabino?des sont impliqués dans les contr?les monoaminergiques, sérotoninergiques ou noradrénergiques. Ils pourraient jouer un r?le également dans les régulations centrales du système autonome par la douleur et les aspects psychoaffectifs de la douleur. Les données synthétisées ici suggèrent aussi l’existence de nouveaux types ou sous-types de récepteurs aussi bien pour les cannabino?des que pour les vanillo?des. Enfin, la coexistence, au moins régionale, des récepteurs CB1 et VR1 renforce l’hypothèse récente d’une interaction entre ces deux systèmes.      

Challenges in the diagnosis and management of acromegaly: a focus on comorbidities

Introduction

Acromegaly is a rare, insidious disease resulting from the overproduction of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), and is associated with a range of comorbidities. The extent of associated complications and mortality risk is related to length of exposure to the excess GH and IGF-1, thus early diagnosis and treatment is imperative. Unfortunately, acromegaly is often diagnosed late, when patients already have a wide range of comorbidities. The presence of comorbid conditions contributes significantly to patient morbidity/mortality and impaired quality of life.

Methods

We conducted a retrospective literature review for information relating to the diagnosis of acromegaly, and its associated comorbidities using PubMed. The main aim of this review is to highlight the issues of comorbidities in acromegaly, and to reinforce the importance of early diagnosis and treatment.

Findings and conclusions

Successful management of acromegaly goes beyond treating the disease itself, since many patients are diagnosed late in disease evolution, they present with a range of comorbid conditions, such as cardiovascular disease, diabetes, hypertension, and sleep apnea. It is important that patients are screened carefully at diagnosis (and thereafter), for common associated complications, and that biochemical control does not become the only treatment goal. Mortality and morbidities in acromegaly can be reduced successfully if patients are treated using a multimodal approach with comprehensive comorbidity management.

     

Labeling of human lymphocytes with 99mTc by means of stannous pyrophosphate. Scintigraphic applications

An original ^99mTc-labeling method applied to human lymphocytes is described. This technique is based on the use of stannous pyrophosphate to reduce sodium pertechnetate. The proposed procedure has two main advantages: firstly, the labeling process takes place in a neutral and buffered medium which prevents any cellular aggregation; secondly, the labeling yield obtained is compatible with scintigraphic studies in man. The influence of each parameter on the labeling quality had been studied as well as the binding stability of the technetium fixed on cells. A systematic study of lymphocyte surface markers, before and after labeling, has led to the suggestion that the labeling process seems to affect cellular membranes, probably because of the technetium binding. Finally, scintigraphic results are presented, the study being performed on eight healthy volunteers. These results are compared with those published by other authors who used either a different radioisotope or a different labeling method.     

Antinociceptive effect of peripheral serotonin 5-HT2B receptor activation on neuropathic pain

Serotonin is critically involved in neuropathic pain. However, its role is far from being understood owing to the number of cellular targets and receptor subtypes involved. In a rat model of neuropathic pain evoked by chronic constriction injury (CCI) of the sciatic nerve, we studied the role of 5-HT(2B) receptor in dorsal root ganglia (DRG) and the sciatic nerve. We showed that 5-HT(2B) receptor activation both prevents and reduces CCI-induced allodynia. Intrathecal administration of 5-HT(2B) receptor agonist BW723C86 significantly attenuated established mechanical and cold allodynia; this effect was prevented by co-injection of RS127445, a selective 5-HT(2B) receptor antagonist. A single application of BW723C86 on the sciatic nerve concomitantly to CCI dose-dependently prevented mechanical allodynia and significantly reduced cold allodynia 17 days after CCI. This behavioral effect was accompanied with a marked decrease in macrophage infiltration into the sciatic nerve and, in the DRG, with an attenuated abnormal expression of several markers associated with local neuroinflammation and neuropathic pain. CCI resulted in a marked upregulation of 5-HT(2B) receptor expression in sciatic nerve and DRG. In the latter structure, it was biphasic, consisting of a transient early increase (23-fold), 2 days after the surgery and before the neuropathic pain emergence, followed by a steady (5-fold) increase, that remained constant until pain disappeared. In DRG and sciatic nerve, 5-HT(2B) receptors were immunolocalized on sensory neurons and infiltrating macrophages. Our data reveal a relationship between serotonin, immunocytes, and neuropathic pain development, and demonstrate a critical role of 5-HT(2B) receptors in blood-derived macrophages.