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PubMed2001

Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer's disease: identification of a cellular activation mechanism.

Receptor-mediated interactions with amyloid beta-peptide (Abeta) could be important in the evolution of the inflammatory processes and cellular dysfunction that are prominent in Alzheimer's disease (AD) pathology. One candidate receptor is the receptor for advanced glycation endproducts (RAGE), which can bind Abeta and transduce signals leading to cellular activation. Data are presented showing a potential mechanism for Abeta activation of microglia that could be mediated by RAGE and macrophage colony-stimulating factor (M-CSF). Using brain tissue from AD and nondemented (ND) individuals, RAGE expression was shown to be present on microglia and neurons of the hippocampus, entorhinal cortex, and superior frontal gyrus. The presence of increased numbers of RAGE-immunoreactive microglia in AD led us to further analyze RAGE-related properties of these cells cultured from AD and ND brains. Direct addition of Abeta(1-42) to the microglia increased their expression of M-CSF. This effect was significantly greater in microglia derived from AD brains compared to those from ND brains. Increased M-CSF secretion was also demonstrated using a cell culture model of plaques whereby microglia were cultured in wells containing focal deposits of immobilized Abeta(1-42). In each case, the Abeta stimulation of M-CSF secretion was significantly blocked by treatment of cultures with anti-RAGE F(ab')2. Treatment of microglia with anti-RAGE F(ab')2 also inhibited the chemotactic response of microglia toward Abeta(1-42). Finally, incubation of microglia with M-CSF and Abeta increased expression of RAGE mRNA. These microglia also expressed M-CSF receptor mRNA. These data suggest a positive feedback loop in which Abeta-RAGE-mediated microglial activation enhances expression of M-CSF and RAGE, possibly initiating an ascending spiral of cellular activation.

Aged↗
PubMed2004

Binding of receptor for advanced glycation end products (RAGE) ligands is not sufficient to induce inflammatory signals: lack of activity of endotoxin-free albumin-derived advanced glycation end products.

AIMS/HYPOTHESIS: Activation of the receptor for advanced glycation end products (RAGE) reportedly triggers cellular responses implicated in the pathogenesis of diabetes, such as increasing vascular cell adhesion molecule-1 (VCAM-1) expression on vascular endothelial cells and inducing TNF-alpha secretion by mononuclear cells. The objective of this study was to evaluate whether RAGE binding affinity of AGE-BSAs and cellular activation correlate. METHODS: To produce AGEs with varying glycation, bovine albumin AGEs were prepared with 500 mmol/l of glucose, fructose or ribose at times of incubation from 1 to 12 weeks. In addition, AGE-BSA was generated using either glyoxylic acid or glycolaldehyde. Cellular binding of the AGE-BSAs and the effect on endothelial cell VCAM-1 expression were studied in RAGE-expressing human microvascular endothelial cell line-4 cells. Induction of TNF-alpha secretion was assessed using RAGE-expressing human peripheral blood mononuclear cells (PBMCs). RESULTS: Cellular binding of the different AGE preparations correlated well with RAGE affinity. Interestingly, we found that the AGE preparations, which were essentially endotoxin free (< or =0.2 ng/mg protein), were incapable of inducing VCAM-1 or TNF-alpha secretion regardless of RAGE binding affinity, AGE concentration or incubation time. In contrast, the reported RAGE ligand S100b was confirmed to induce VCAM-1 expression on endothelial cells and TNF-alpha secretion by PBMCs after 24 h of treatment. CONCLUSIONS/INTERPRETATION: The results of this study suggest that AGE modification and high RAGE binding affinity are not sufficient to generate pro-inflammatory signalling molecules. Thus, RAGE binding affinity of AGE-BSAs does not seem to correlate with cellular activation. Our findings using AGEs with strong RAGE-binding properties indicate that AGEs may not uniformly play a role in cellular activation.

Animals↗
PubMed2005

The RAGE pathway in inflammatory myopathies and limb girdle muscular dystrophy.

Oxidative stress and nuclear factor-kappaB (NF-kappaB) activation are linked to the pathogenesis of many metabolic, degenerative, and chronic inflammatory diseases. Activation of the receptor for advanced glycation end products (RAGE) by its specific ligand N(epsilon)-carboxymethyllysine (CML) results in the activation of NF-kappaB and the production of proinflammatory cytokines. To determine whether engagement of RAGE contributes to the pathogenesis of inflammatory myopathies, we performed immunohistochemical studies on the presence of CML-modified proteins, RAGE and activated NF-kappaB in muscle biopsies of patients with polymyositis (PM, n=10), dermatomyositis (DM, n=10), limb girdle muscular dystrophy (LGMD, n=10) and in 10 controls with normal muscle biopsy results. In inflammatory myopathies CML, RAGE and NF-kappaB were detected in mononuclear cells and in regenerating muscle fibers. CML, NF-kappaB and, to a lesser extent, RAGE were also found in degenerating muscle fibers, but colocalization of CML, RAGE and NF-kappaB was only seen in infiltrating mononuclear cells and regenerating muscle fibers. Immunofluorescence double labeling demonstrated an expression of CML, RAGE and NF-kappaB in CD4-, CD8-, CD22- and CD68-positive mononuclear cells. Western blot analysis showed an increased immunoreactivity for CML-modified proteins in PM and DM. In LGMD, CML, RAGE and NF-kappaB were found in regenerating muscle fibers and less frequently in degenerating muscle fibers, and with lower staining intensities than in inflammatory myopathies. Our data suggests that the CML-RAGE-NF-kappaB pathway is an evident proinflammatory pathomechanism in mononuclear effector cells in PM and DM. RAGE-mediated NF-kappaB activation may be involved in muscle fiber regeneration in inflammatory myopathies and LGMD.

Adult↗
PubMed2004

Expression of a novel secreted splice variant of the receptor for advanced glycation end products (RAGE) in human brain astrocytes and peripheral blood mononuclear cells.

The engagement of the receptor for advanced glycation end products (RAGE) on the cell surface induces cellular dysfunction in a number of pathophysiological situations of vascular dysfunction, tumor cell invasion, inflammatory response, and T cell infiltration. The administration of truncated, soluble RAGE can modulate RAGE-mediated perturbations. Here, we report a novel splice variant (delta8-RAGE) of RAGE mRNA, which lacks exon 8 of the genomic RAGE gene and contains an early stop codon in exon 10 due to a frame shift mutation. delta8-RAGE mRNA was found in human primary astrocytes and peripheral blood mononuclear cells (PBMCs). Transient transfection experiments demonstrated that delta8-RAGE mRNA was translated into a secretory protein as deduced. Moreover, two different segments of the spliced variant were identified in PBMCs by RT-PCR. The findings of this study suggest that the diverse splicing variants of RAGE are possible in many tissues and their products may influence the RAGE-mediated pathogenesis and immune modulation.

Alternative Splicing↗
PubMed2003

Advanced glycation end-products (AGEs) induce concerted changes in the osteoblastic expression of their receptor RAGE and in the activation of extracellular signal-regulated kinases (ERK).

An increase in the interaction between advanced glycation end-products (AGEs) and their receptor RAGE is believed to contribute to the pathogenesis of chronic complications of Diabetes mellitus, which can include bone alterations such as osteopenia. We have recently found that extracellular AGEs can directly regulate the growth and development of rat osteosarcoma UMR106 cells, and of mouse calvaria-derived MC3T3E1 osteoblasts throughout their successive developmental stages (proliferation, differentiation and mineralisation), possibly by the recognition of AGEs moieties by specific osteoblastic receptors which are present in both cell lines. In the present study we examined the possible expression of RAGE by UMR106 and MC3T3E1 osteoblastic cells, by immunoblot analysis. We also investigated whether short-, medium- or long-term exposure of osteoblasts to extracellular AGEs, could modify their affinity constant and maximal binding for AGEs (by 125I-AGE-BSA binding experiments), their expression of RAGE (by immunoblot analysis) and the activation status of the osteoblastic ERK 1/2 signal transduction mechanism (by immunoblot analysis for ERK and P-ERK). Our results show that both osteoblastic cell lines express readily detectable levels of RAGE. Short-term exposure of phenotypically mature osteoblastic UMR106 cells to AGEs decrease the cellular density of AGE-binding sites while increasing the affinity of these sites for AGEs. This culture condition also dose-dependently increased the expression of RAGE and the activation of ERK. In proliferating MC3T3E1 pre-osteoblasts, 24-72 h exposure to AGEs did not modify expression of RAGE, ERK activation or the cellular density of AGE-binding sites. However, it did change the affinity of these binding sites forAGEs, with both higher- and lower-affinity sites now being apparent. Medium-term ( 1 week) incubation of differentiated MC3T3E1 osteoblasts with AGEs, induced a simultaneous increase in RAGE expression and in the relative amount of P-ERK. Mineralising MC3T3E1 cultures grown for 3 weeks in the presence of extracellular AGEs showed a decrease both in RAGE and P-ERK expression. These results indicate that, in phenotypically mature osteoblastic cells, changes in ERK activation closely follow the AGEs-induced regulation of RAGE expression. Thus, the AGEs-induced biological effects that we have observed previously in osteoblasts, could be mediated by RAGE in the later stages of development, and mediated by other AGE receptors in the earlier pre-osteoblastic stage.

3T3 Cells↗
PubMed2002

Receptor for advanced glycation end products (RAGE) signaling induces CREB-dependent chromogranin expression during neuronal differentiation.

Receptor for advanced glycation end products (RAGE) mediates neurite outgrowth and cell migration upon stimulation with its ligand, amphoterin. We show here that RAGE-dependent changes in cell morphology are associated with proliferation arrest and changes in gene expression in neuroblastoma cells. Chromogranin B, a component of secretory vesicles in endocrine cells and neurons, was found to be up-regulated by RAGE signaling during differentiation of neuroblastoma cells along with the two other members of the chromogranin family, chromogranin A and secretogranin II. Ligation of RAGE by amphoterin lead to rapid phosphorylation and nuclear localization of cyclic AMP response element-binding protein (CREB), a major regulator of chromogranin expression. Furthermore, inhibition of ERK1/2-Rsk2-dependent CREB phosphorylation efficiently inhibited up-regulation of chromogranin gene expression upon RAGE activation. To further study the effects of RAGE and amphoterin on cellular differentiation, we stimulated embryonic stem cells expressing RAGE or a signaling-deficient mutant of RAGE with amphoterin. Amphoterin was found to promote RAGE-dependent neuronal differentiation of embryonic stem cells characterized by up-regulation of neuronal markers light neurofilament protein and beta-III-tubulin, activation of CREB, and increased expression of chromogranins A and B. These data suggest that RAGE signaling is capable of driving neuronal differentiation involving CREB activation and induction of chromogranin expression.

Animals↗
PubMed2003

The receptor for advanced glycation end products (RAGE) is elevated in women with preeclampsia.

A leading theory of the pathophysiology of preeclampsia is that oxidative stress induces vascular endothelial cell dysfunction. Advanced glycation end products (AGEs) form when aldose sugars react nonenzymatically with proteins under conditions of oxidative stress. AGEs are circulating molecules and can generate reactive oxygen species and vascular dysfunction (in diabetes and atherosclerosis) through an association with cell surface receptors (RAGE). RAGE is a multiligand receptor, expressed in vascular tissue, which is upregulated by its own ligands. Insulin resistance and obesity are risk factors for developing preeclampsia, as well as being conditions that would increase RAGE levels. Thus, we hypothesized that women with preeclampsia will have elevated levels of RAGE protein compared with normal pregnant women. Biopsies of nonlaboring myometrium as well as omentum were taken from normal pregnant and preeclamptic women. Nonpregnant samples were obtained at the time of hysterectomy. Tissue sections were immunostained with anti-RAGE as well as anti-alpha-actin and anti-von Willebrand factor (to identify blood vessels and intact endothelial cells). Staining intensity was qualitatively described as well as given an intensity score, with the identity of the section concealed. Nonpregnant myometrial and omental vessels showed very low to undetectable levels of RAGE staining. Pregnancy induced a significant increase in RAGE protein levels in both myometrium and omental vasculature. Blood vessels from women with preeclampsia consistently had intense staining for RAGE in both vessel beds. Thus, our data suggest that since RAGE activation can induce similar pathophysiologic changes to those observed in women with preeclampsia (including NFkappaB activation, increased TNFalpha and endothelin), elevated RAGE protein may be contributing to the vascular dysfunction in preeclampsia.

Adult↗
PubMed2006

Suppression of RAGE as a basis of simvastatin-dependent plaque stabilization in type 2 diabetes.

OBJECTIVE: Receptor for advanced glycation end products (AGEs) (RAGE) plays a central role in the process of plaque rupture in diabetic patients. Recently, it has been reported that RAGE may be downregulated by improving glycemic control. In contrast, despite being well known that RAGE may be induced in human vessels in a glucose-independent fashion, also by myeloperoxidase (MPO)-dependent AGE generation, no data exist regarding the possibility of a pharmacological modulation of glucose-independent RAGE generation. Thus, the aim of this study was to characterize the effect of simvastatin on the expression of RAGE and RAGE-dependent plaque-destabilizing genes in human atherosclerotic plaques. METHODS AND RESULTS: Seventy type 2 diabetic patients with asymptomatic carotid artery stenosis (>70%) were randomized to American Heart Association (AHA) step 1 diet plus simvastatin (40 mg/d) or AHA step 1 diet alone for 4 months before endarterectomy. Plaque expression of MPO, AGEs, RAGE, NF-kappaB, COX-2, mPGES-1, matrix metalloproteinase (MMP)-2 and MMP-9, lipid and oxidized LDL (oxLDL) content, procollagen 1, and interstitial collagen was analyzed by immunohistochemistry and Western blot; zymography was used to detect MMP activity. Plaques from the simvastatin group had less (P<0.0001) immunoreactivity for MPO, AGEs, RAGE, p65, COX-2, mPGES-1, MMP-2, and MMP-9, lipids and oxLDL; reduced (P<0.0001) gelatinolytic activity; increased (P<0.0001) procollagen 1 and collagen content; and fewer (P<0.0001) macrophages, T-lymphocytes, and HLA-DR+ cells. Of interest, RAGE inhibition by simvastatin, observed not only in plaque sections but also in plaque-derived macrophages, was reverted by addition of AGEs in vitro. CONCLUSIONS: This study supports the hypothesis that simvastatin inhibits plaque RAGE expression by decreasing MPO-dependent AGE generation. This effect in turn might contribute to plaque stabilization by inhibiting the biosynthesis of PGE2-dependent MMPs, responsible for plaque rupture.

Aged↗
PubMed2005

The RAGE axis in early diabetic retinopathy.

PURPOSE: The receptor for advanced glycation end products (AGEs) has been implicated in the pathogenesis of diabetic complications. This study was conducted to characterize the role of the RAGE axis in a murine model of nonproliferative diabetic retinopathy (NPDR). METHODS: The retinas of hyperglycemic, hyperlipidemic (HGHL, apolipoprotein E(-/-) db/db) mice were examined for the development of early retinal vascular lesions of NPDR and compared to littermates at 6 months of age. Neural function was assessed with electroretinography. Immunohistochemistry, real-time RT-PCR, autofluorescence, and ELISA studies were used to localize and quantify the AGE/RAGE axis. Soluble RAGE, a competitor of cellular RAGE for its ligands, was administered to assess the impact of RAGE blockade. RESULTS: Early inner retinal neuronal dysfunction, manifested by prolonged latencies of the oscillatory potentials and b-wave, was detected in hyperglycemic mice. HGHL mice exhibited accelerated development of acellular capillaries and pericyte ghosts compared with littermate control animals. AGEs were localized primarily to the vitreous cavity and internal limiting membrane (ILM) of the retina, where they were intimately associated with the footplates of RAGE-expressing Müller cells. AGE accumulation measured by ELISA was increased within the retinal extracellular matrix of hyperglycemic mice. AGE fluorescence and upregulation of RAGE transcripts was highest in the retinas of HGHL mice, and attenuation of the RAGE axis with soluble RAGE ameliorated neuronal dysfunction and reduced the development of capillary lesions in these mice. CONCLUSIONS: In early diabetic retinopathy, the RAGE axis, comprising the cellular receptor and its AGE ligands, is amplified within the retina and is accentuated along the vitreoretinal interface. Antagonism of the RAGE axis in NPDR reduces neurovascular perturbations, providing an important therapeutic target for intervention.

Animals↗
PubMed2006

Renal effects of a neutralising RAGE-antibody in long-term streptozotocin-diabetic mice.

Advanced glycation endproducts (AGEs) have been implicated in the pathogenesis of diabetic kidney disease. The actions of AGEs are mediated both through a non-receptor mediated pathway and through specific receptors for AGEs (e.g. RAGE). To explore a potentially specific role for RAGE in renal changes in type 1 diabetes, we examined the renal effects of a neutralising murine RAGE-antibody (ab) in streptozotocin (STZ)-diabetic mice, a model of type 1 diabetes. One group of STZ-diabetic mice was treated for two months with the RAGE-ab, while another STZ-diabetic group was treated for the same period with an irrelevant immunoglobulin G (IgG). Two groups of non-diabetic NMRI mice were treated with either RAGE-ab or isotype-matched IgG for two months. Placebo-treated STZ-diabetic mice showed an increase in kidney weight, glomerular volume, basement membrane thickness (BMT), urinary albumin excretion (UAE) and creatinine clearance (CrCl), when compared with non-diabetic controls. In RAGE-ab-treated STZ-diabetic mice, the increase in kidney weight and UAE was reduced, while the increase in CrCl was abolished. RAGE-ab administration in NMRI mice caused a reduction in liver weight and an increase in BMT. Renal messenger RNA (mRNA) for connective tissue growth factor and collagen IValpha1 was increased in placebo-treated diabetic animals. RAGE-ab treatment had no impact on the expression of these factors. The renal effects of RAGE-ab administration in STZ-diabetic mice were seen without impact on body weight, blood glucose or food consumption. In conclusion, the present data support the hypothesis that RAGE is an important pathogenic factor in the renal changes in an animal model of type 1 diabetes.

Albuminuria↗
PubMed2001

Receptor for age (RAGE) is a gene within the major histocompatibility class III region: implications for host response mechanisms in homeostasis and chronic disease.

Receptor for AGE (RAGE), a member of the immunoglobulin superfamily, was first identified as a specific cell surface interaction site for Advanced Glycation Endproducts, or AGEs. AGEs, the products of nonenzymatic glycation/oxidation of proteins/lipids, accumulate in natural aging and disorders such as diabetes, renal failure and amyloidoses. Interaction of AGEs with RAGE has been linked to chronic inflammatory and vascular dysfunction that characterizes the chronic complications of these disorders. Recent studies have indicated that RAGE is a multiligand receptor, serving as a specific cell surface, signal transducing receptor for amphoterin, a molecule with implications for neurite outgrowth in neuronal development and in tumor cell proliferation and spread. RAGE is also a receptor for amyloid-beta peptide, whose interaction with neuronal and microglial RAGE within the CNS is linked to sustained inflammation and neuronal toxicity and cell death. RAGE also serves as a signal-transducing receptor for EN-RAGEs, and related members of the S100/calgranulin family of proinflammatory cytokines; consequences of this interaction include initiation and propagation of inflammatory responses. Consistent with an important role for ligand-RAGE interaction in these settings, blockade of RAGE suppresses chronic cellular activation and dysfunction in murine models of diabetic complications, inflammation and tumor proliferation and metastasis. Taken together, an new paradigm is emerging which links RAGE, a gene encoded within the Major Histocompatibility Complex (MHC) Class III regions, to central host response mechanisms in homeostasis and chronic disease.

Animals↗
PubMed1993

Evidence that substance P is utilized in medial amygdaloid facilitation of defensive rage behavior in the cat.

The present study was designed to test the hypothesis that a major excitatory mechanism for the expression of feline defensive rage behavior involves the medial nucleus of the amygdala which utilizes substance P as a neurotransmitter in a direct output pathway that supplies the medial hypothalamus. In phase I of the experiment, stimulating electrodes were implanted into the medial amygdala and cannula electrodes were implanted into the medial and lateral hypothalamus from which defensive rage and predatory attack behavior could be elicited by electrical stimulation, respectively. Response latencies for defensive rage were significantly lowered after dual stimulation of the medial amygdala and medial hypothalamus relative to single stimulation of the medial hypothalamus alone. In phase II, dose- and time-dependent decreases in medial amygdaloid-induced facilitation of defensive rage were observed after the i.p. administration of the NK1 antagonist, CP-96,345 (0.05, 2 and 4 mg/kg). In phase III of the study, the effects of microinjections of CP-96,345 placed directly into defensive rage sites within the medial hypothalamus (0.05, 0.5 and 2.5 nmol) upon medial amygdaloid modulation of this response were assessed. Again, intracerebral administration of this antagonist blocked the facilitatory effects of medial amygdaloid-induced facilitation of defensive rage in a manner parallel to that observed with peripheral administration of the NK1 antagonist. The results suggest that the medial amygdala facilitates defensive rage by acting through a substance P mechanism at the level of the medial hypothalamus. Other experiments revealed that peripheral administration of the NK1 antagonist: (1) had little upon the latency or threshold for elicitation of defensive rage, suggesting that the medial amygdaloid-substance P facilitatory mechanism acts in a phasic rather than tonic manner; and (2) also blocks the suppressive effects of medial amygdaloid stimulation upon predatory attack behavior elicited from the lateral hypothalamus. The latter finding suggest that similar neurochemical mechanisms regulate medial amygdaloid modulation of both forms of hypothalamically elicited aggression. The final aspect of this study utilized the combination of retrograde-tracing of amygdaloid neurons into the medial hypothalamus after microinjections of Fluoro-Gold into defensive rage sites, and the immunocytochemical analysis of substance P neurons within the amygdala. The data indicated that large numbers of retrogradely and immunocytochemically positive labeled cells were identified in the medial nucleus, including many that were double-labeled.(ABSTRACT TRUNCATED AT 400 WORDS)

Amygdala↗
PubMed2005

Is road rage increasing? Results of a repeated survey.

PROBLEM: We report on trends in road rage victimization and perpetration based on population survey data. METHOD: Based on repeated cross-sectional telephone surveys of Ontario adults between July 2001 and December 2003, logistic regression analyses examined differences between years in road rage victimization and perpetration in the previous year controlling for demographic characteristics. RESULTS: The prevalence of any road rage victimization in the previous year decreased significantly from 47.5% in 2001 to 40.6% in 2003, while prevalence of any road rage perpetration remained stable (31.0% to 33.6%). Logistic regression analyses revealed that the odds of experiencing any road rage victimization was 33% higher in 2001 and 30% higher in 2002, than in 2003. DISCUSSION: Survey data provide a valuable perspective on road rage trends, but efforts to track road rage incidents is also needed. SUMMARY: In Ontario, the proportion of adults experiencing any road rage victimization decreased from 2001 to 2003 while the proportion reporting any road rage perpetration remained stable. IMPACT ON INDUSTRY: None.

Adolescent↗
PubMed1998

Cholecystokinin B receptors in the periaqueductal gray potentiate defensive rage behavior elicited from the medial hypothalamus of the cat.

Defensive rage behavior is mediated over a descending pathway from the medial hypothalamus to the dorsolateral midbrain periaqueductal gray (PAG) where further integration of this response takes place. The present study sought to determine the roles of CCK-A and CCK-B receptor activation in the PAG in modulating defensive rage behavior. The 'hissing' component of the defensive rage response was used throughout the experiment as the measure of defensive rage behavior. The basic design of the experiment involved placement of monopolar electrodes into the medial hypothalamus from which defensive rage could be elicited and cannula electrodes into the dorsal PAG for purposes of identifying defensive rage sites in this region and for microinjections of CCK compounds into these sites at a later time. Microinjections of the selective CCK-B receptor antagonist, LY288513 (1.05, 4.2, 17.0 nmol/0.25 microliter), into the PAG suppressed the hissing response in a dose- and time-dependent manner. Microinjections of the CCK-B agonist, pentagastrin, (0.5 and 1.0 nmol/0.25 microliter) facilitated the occurrence of defensive rage behavior. Moreover, administration of LY288513 (17 nmol/0.25 microliter) 55 min prior to pentagastrin (1.0 nmol/0.25 microliter) delivery blocked the facilitatory effects of pentagastrin. Administration of the CCK-A antagonist, PD140548 (34 nmol/0.25 microliter), into the PAG failed to alter response latencies for defensive rage behavior. In contrast, microinjections of the CCK-B antagonist, LY288513 (4.2, 17.0 nmol/0.25 microliter), facilitated the occurrence of predatory attack behavior elicited from the lateral hypothalamus. This finding demonstrates the specificity of the effects of CCK-B receptor blockade upon hissing. A combination of immunocytochemical and retrograde tracing procedures using microinjections of Fluoro-Gold (8%, 6 microliters) into the PAG were employed to identify the possible loci of CCK neurons that project to the PAG. The data revealed that neurons labeled for both CCK and Fluoro-Gold were located in the dorsolateral aspect of the midbrain tegmentum, identifying this region as a source of CCK inputs to the PAG. Overall, the findings demonstrate that CCK-B receptors in the PAG potentiate defensive rage behavior and likely suppress predatory attack.

Animals↗
PubMed2003

Psychiatric distress among road rage victims and perpetrators.

OBJECTIVE: To investigate the relation between psychiatric distress and road rage, paying particular attention to the potential link between psychiatric illness and frequent involvement in serious forms of road rage. METHOD: This study reports data on road rage involvement, demographic characteristics, and mental health for a representative sample of 2610 adults in Ontario. The mental health indicator was the 12-item General Health Questionnaire. RESULTS: A cluster analysis revealed 5 distinct groups of people affected by road rage. The most serious offenders (referred to hereafter as the hard core road rage group), representing 5.5% of those affected, exhibited frequent involvement in the most severe forms of road rage and were the most likely (27.5%) to report psychiatric distress. CONCLUSIONS: Road rage, particularly experiences of victimization, is related to psychiatric distress. Evidence of psychiatric distress was highest among hard core road rage perpetrators, individuals noted for frequent involvement in serious aggressive and violent conduct. Further research is needed on violence and road rage and its link to mental health.

Adolescent↗
PubMed1998

Paroxetine treatment of episodic rages associated with Tourette's disorder.

BACKGROUND: Episodic rages have been estimated to occur in as many as 30% of patients with Tourette's syndrome (Tourette's disorder), but their treatment has never been systematically investigated. We report on the results of an open-label pilot study using paroxetine for the treatment of Tourette's disorder-associated rage episodes. METHOD: Forty-five Tourette's/rage patients (DSM-IV) were treated with paroxetine, specifically to control their rages. Other symptoms such as tics, attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) were not targeted by this study. Treatment was deemed to be therapeutic when rage symptoms were diminished by 75% or more by patient report and were diminished in frequency by at least 1 point on a 4-point scale devised by the authors. RESULTS: After 8 weeks on paroxetine treatment, 29 patients (76% of those who completed the study) reported that rages were significantly diminished or completely absent. Nine patients reported no significant change in rages. Seven patients did not complete the study (3 because of side effects and 4 whose rage frequency increased). The mean dose of paroxetine was 33 mg/day; minimum effective dose was 15 mg/day. CONCLUSION: We were unable to determine any factors that significantly altered the efficacy of paroxetine for treatment of Tourette's disorder-associated rage episodes. The great majority (87%) of the patients had both ADHD and OCD in addition to Tourette's disorder. The age, sex, and concomitant use of other medications revealed no significant differences in treatment outcome. The results suggest that paroxetine may have an important role in the clinical treatment of episodic rages in Tourette's disorder patients.

Adolescent↗
PubMed1997

Type II alveolar epithelial cells in lung express receptor for advanced glycation end products (RAGE) gene.

Messenger RNA of receptor for advanced glycation end products (RAGE) is abundantly expressed in the lung. However, cell types expressing RAGE mRNA in the lung have not been identified. In order to elucidate the function of RAGE in pulmonary tissue, we have identified a cell type expressing RAGE mRNA by in situ hybridization and compared its expression level of RAGE mRNA by RNA blot analysis of isolated cells. In situ hybridization revealed that RAGE mRNA was intensely and specifically visualized in alveolar epithelial type II (AT-II) cells, and weakly in alveolar macrophages. The expression of RAGE mRNA in the primary culture of AT-II cells was at a high level, but that in alveolar macrophages isolated from alveolar lavage was under the level of detection by RNA blot analysis. These results showed that RAGE mRNA is specifically expressed in AT-II cells, and suggested that RAGE makes a substantial contribution to the function of AT-II cells in the lung.

Animals↗
PubMed2006

RAGE, LRP-1, and amyloid-beta protein in Alzheimer's disease.

The receptor for advanced glycation end products (RAGE) is thought to be a primary transporter of beta-amyloid across the blood-brain barrier (BBB) into the brain from the systemic circulation, while the low-density lipoprotein receptor-related protein (LRP)-1 mediates transport of beta-amyloid out of the brain. To determine whether there are Alzheimer's disease (AD)-related changes in these BBB-associated beta-amyloid receptors, we studied RAGE, LRP-1, and beta-amyloid in human elderly control and AD hippocampi. In control hippocampi, there was robust RAGE immunoreactivity in neurons, whereas microvascular staining was barely detectable. LRP-1 staining, in contrast, was clearly evident within microvessels but only weakly stained neurons. In AD cases, neuronal RAGE immunoreactivity was significantly decreased. An unexpected finding was the strongly positive microvascular RAGE immunoreactivity. No evidence for colocalization of RAGE and beta-amyloid was seen within either microvessels or senile plaques. A reversed pattern was evident for LRP-1 in AD. There was very strong staining for LRP-1 in neurons, with minimal microvascular staining. Unlike RAGE, colocalization of LRP-1 and beta-amyloid was clearly present within senile plaques but not microvessels. Western blot analysis revealed a much higher concentration of RAGE protein in AD hippocampi as compared with controls. Concentration of LRP-1 was increased in AD hippocampi, likely secondary to its colocalization with senile plaques. These data confirm that AD is associated with changes in the relative distribution of RAGE and LRP-1 receptors in human hippocampus. They also suggest that the proportion of amyloid within the brains of AD patients that is derived from the systemic circulation may be significant.

Aged↗