Role Of Peripheral Inflammation Research Articles

Role of peripheral inflammation in minimal hepatic encephalopathy.

Many patients with liver cirrhosis show minimal hepatic encephalopathy (MHE) with mild cognitive impairment (MCI) and motor alterations that reduce their quality of life. Some patients with steatotic liver disease also suffer MCI. To design treatments to improve MHE/MCI it is necessary to understand the mechanisms by which liver disease induce them. This review summarizes studies showing that appearance of MHE/MCI is associated with a shift in the immunophenotype leading to an "autoimmune-like" form with increased pro-inflammatory monocytes, enhanced CD4 T and B lymphocytes activation and increased plasma levels of pro-inflammatory cytokines, including IL-17, IL-21, TNFα, IL-15 and CCL20. The contribution of peripheral inflammation to trigger MHE is supported by studies in animal models and by the fact that rifaximin treatment reverses MHE in around 60% of patients in parallel with reversal of the changes in peripheral inflammation. MHE does not improve in patients in which peripheral inflammation is not improved by rifaximin. The process by which peripheral inflammation induces MHE involves induction of neuroinflammation in brain, with activation of microglia and astrocytes and increased pro-inflammatory TNFα and IL-1β, which is observed in patients who died with steatotic liver disease (SLD) or liver cirrhosis and in animal models of MHE. Neuroinflammation alters glutamatergic and GABAergic neurotransmission, leading to cognitive and motor impairment. Transmission of peripheral alterations into the brain is mediated by infiltration in brain of extracellular vesicles from plasma and of cells from the peripheral immune system. Acting on any step of the process peripheral inflammation - neuroinflammation - altered neurotransmission may improve MHE.

Sex Differences in Hepatic Inflammation, Lipid Metabolism, and Mitochondrial Function Following Early Lipopolysaccharide Exposure in Epileptic WAG/Rij Rats.

Among the non-communicable neurological diseases, epilepsy is characterized by abnormal brain activity with several peripheral implications. The role of peripheral inflammation in the relationship between seizure development and nonalcoholic fatty liver disease based on sex difference remains still overlooked. Severe early-life infections lead to increased inflammation that can aggravate epilepsy and hepatic damage progression, both related to increased odds of hospitalization for epileptic patients with liver diseases. Here, we induced a post-natal-day 3 (PND3) infection by LPS (1 mg/kg, i.p.) to determine the hepatic damage in a genetic model of young epileptic WAG/Rij rats (PND45). We evaluated intra- and inter-gender differences in systemic and liver inflammation, hepatic lipid dysmetabolism, and oxidative damage related to mitochondrial functional impairment. First, epileptic rats exposed to LPS, regardless of gender, displayed increased serum hepatic enzymes and altered lipid profile. Endotoxin challenge triggered a more severe inflammatory and immune response in male epileptic rats, compared to females in both serum and liver, increasing pro-inflammatory cytokines and hepatic immune cell recruitment. Conversely, LPS-treated female rats showed significant alterations in systemic and hepatic lipid profiles and reduced mitochondrial fatty acid oxidation. The two different sex-dependent mechanisms of LPS-induced liver injury converge in increased ROS production and related mitochondrial oxidative damage in both sexes. Notably, a compensatory increase in antioxidant defense was evidenced only in female rats. Our study with a translational potential demonstrates, for the first time, that early post-natal infections in epileptic rats induced or worsened hepatic disorders in a sex-dependent manner, amplifying inflammation, lipid dysmetabolism, and mitochondrial impairment.

A Fast-Binding, Functionally Reversible, COX-2 Radiotracer for CNS PET Imaging.

Cyclooxygenase-2 (COX-2) is an enzyme that plays a pivotal role in peripheral inflammation and pain via the prostaglandin pathway. In the central nervous system (CNS), COX-2 is implicated in neurodegenerative and psychiatric disorders as a potential therapeutic target and biomarker. However, clinical studies with COX-2 have yielded inconsistent results, partly due to limited mechanistic understanding of how COX-2 activity relates to CNS pathology. Therefore, developing COX-2 positron emission tomography (PET) radiotracers for human neuroimaging is of interest. This study introduces [11C]BRD1158, which is a potent and uniquely fast-binding, selective COX-2 PET radiotracer. [11C]BRD1158 was developed by prioritizing potency at COX-2, isoform selectivity over COX-1, fast binding kinetics, and free fraction in the brain. Evaluated through in vivo PET neuroimaging in rodent models with human COX-2 overexpression, [11C]BRD1158 demonstrated high brain uptake, fast target-engagement, functional reversibility, and excellent specific binding, which is advantageous for human imaging applications. Lastly, post-mortem samples from Huntington's disease (HD) patients and preclinical HD mouse models showed that COX-2 levels were elevated specifically in disease-affected brain regions, primarily from increased expression in microglia. These findings indicate that COX-2 holds promise as a novel clinical marker of HD onset and progression, one of many potential applications of [11C]BRD1158 human PET.

Peripheral immune profile in drug-naïve dementia with Lewy bodies.

Accumulating evidence suggests that peripheral inflammation is associated with the pathogenesis of Parkinson's disease (PD). We examined peripheral immune profiles and their association with clinical characteristics in patients with DLB and compared these with values in patients with PD. We analyzed peripheral blood from 93 participants (drug-naïve DLB, 31; drug-naïve PD, 31; controls, 31). Absolute leukocyte counts, absolute counts of leukocyte subpopulations, and peripheral blood inflammatory indices such as neutrophil-to-lymphocyte ratio were examined. Associations with clinical characteristics, cardiac sympathetic denervation, and striatal 123I-2-carbomethoxy-3-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) binding were also examined. Patients with DLB had lower absolute lymphocyte and basophil counts than did age-matched controls (both; p < 0.005). Higher basophil counts were marginally associated with higher global cognition (p = 0.054) and were significantly associated with milder motor severity (p = 0.020) and higher striatal 123I-FP-CIT binding (p = 0.038). By contrast, higher basophil counts were associated with more advanced PD characterized by decreased global cognition and severe cardiac sympathetic denervation. Although lower lymphocyte counts had relevance to more advanced PD, they had little relevance to clinical characteristics in patients with DLB. Higher peripheral blood inflammatory indices were associated with lower body mass index in both DLB and PD. As in patients with PD, the peripheral immune profile is altered in patients with DLB. Some peripheral immune cell counts and inflammatory indices reflect the degree of disease progression. These findings may deepen our knowledge on the role of peripheral inflammation in the pathogenesis of DLB.

The associations between common neuroimaging parameters of Progressive Supranuclear Palsy in magnetic resonance imaging and non-specific inflammatory factors - pilot study.

Progressive Supranuclear Palsy is an atypical parkinsonism based on tauopathic pathology. Growing interest is associated with the pathomechanism of this disease. Among theories analyzing this issue can be mentioned the one highlighting the significance of inflammation. In this study authors examined 14 patients with PSP-Richardson syndrome (PSP-RS) and 13 healthy volunteers using laboratory testing based on the analysis of interleukins 1 and 6 (IL-1 and IL-6), tau in the cerebrospinal fluid (CSF) and non-specific parameters of peripheral inflammation in the serum (IL-1, IL-6, neutrophils, lymphocytes, monocytes, platelets and the ratios based on the factors). All of the patients underwent neuroimaging using magnetic resonance imaging using 3 Tesla. The serum levels of IL-1 were positively correlated with the area of the mesencephalon, suggesting that higher levels of IL-1 are not linked with atrophic changes in this region, whereas serum levels IL-6 was positively correlated with frontal horn width and negatively correlated with superior cerebellar area. Additionally IL-6 in the serum was found to be correlated with neutrophil-to-high density lipoprotein ratio. The observations were not confirmed in the analysis of the levels of interleukins in the CSF. To the best of our knowledge this work is one of the first analyzing this issue. The outcome of the work shows that the role of interleukins associated with microglial activation may possibly differ in the context of neurodegenerative changes, moreover the role of peripheral inflammation in PSP requires further analysis.

Role of peripheral inflammation in driving central nervous system inflammatory signature in pathogenesis of Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) impacts an estimated 6.5 million people in the United States, however, it cannot yet be prevented, slowed or cured. Although the sporadic AD form comprises around 95% of cases, animal models of familial AD are the ones used for basic and translational research. Most of these models are based on human mutations that cause amyloid‐β (Aβ) pathological accumulation. However, the failure of the majority of Aβ‐related clinical trials, has begged the necessity of an alternative approach to address AD. Interestingly, most of the genetic and non‐genetic risk factors for developing sporadic AD are associated with inflammation. Thus, it has been suggested that microglia, the immune cells in the central nervous system, play a key role in the pathogenesis of AD, and that people with systemic inflammatory diseases have a higher incidence of developing AD. In this context, we hypothesize that a specific subset of cells in peripheral blood contributes to AD development through its communication with microglial cells in the brain parenchyma.MethodTo address this hypothesis, we analyzed peripheral blood mononuclear cells (PBMCs) from sex‐ and age‐matched healthy and AD subjects using mass cytometry (CyTOF) and cellular indexing of transcriptomes and epitopes by sequencing (CITE‐seq) technologies. Moreover, we used in vitro and histological approaches to study interactions between PBMCs and human microglial cells.ResultOur preliminary data show a different proportion of peripheral blood immune cell types between healthy controls and AD patients. Remarkably, a specific inflammatory subset of immune cells characterized by the upregulation of pro‐inflammatory signaling pathways and cytokines was detected in blood of AD patients. In addition, T cells in contact with microglia were detected in the parenchyma of AD brains by histological analysis, suggesting adrive of microglial cells towards an inflammatory phenotype that could contribute to AD pathology. We corroborated the pathogenic component of AD blood as healthy PBMCs developed an inflammatory phenotype after stimulation with AD plasma.ConclusionTogether, our data demonstrate the importance of peripheral immune cells in AD disease and reinforce that studying AD as a multifactorial disease could be key to its prevention and treatment.

Peripheral inflammation is a potential etiological factor in Alzheimer's disease.

Peripheral inflammation could constitute a risk factor for AD. This review summarizes the research related to peripheral inflammation that appears to have a relationship with Alzheimer's disease. We find there are significant associations between AD and peripheral infection induced by various pathogens, including herpes simplex virus type 1, cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus, severe acute respiratory syndrome coronavirus 2, Porphyromonas gingivalis, Helicobacter pylori, and Toxoplasma gondii. Chronic inflammatory diseases are also reported to contribute to the pathophysiology of AD. The mechanisms by which peripheral inflammation affects the pathophysiology of AD are complex. Pathogen-derived neurotoxic molecule composition, disrupted BBB, and dysfunctional neurogenesis may all play a role in peripheral inflammation, promoting the development of AD. Anti-pathogenic medications and anti-inflammatory treatments are reported to decrease the risk of AD. Studies that could improve understanding the associations between AD and peripheral inflammation are needed. If our assumption is correct, early intervention against inflammation may be a potential method of preventing and treating AD.

Investigating the Prognostic Role of Peripheral Inflammatory Markers in Mild Cognitive Impairment

Growing evidence suggests that neuroinflammation plays a critical role in the pathogenesis of neurodegenerative diseases. Peripheral markers of inflammation, including blood cell counts and their ratios, such as the neutrophil-to-lymphocyte ratio (NLR), have been reported as an easily accessible and reliable proxy of central nervous system inflammation. However, the role of peripheral inflammation in dementia and Mild Cognitive Impairment (MCI) still needs to be clarified. In the current study, we aimed to assess the prognostic role of the NLR and other peripheral markers of inflammation in a sample of 130 amnestic MCI, followed up for two to five years. The Mini-Mental state examination (MMSE) score at baseline and follow-up visits was used to assess global cognitive status at each visit and the degree of cognitive decline over time. Baseline peripheral markers of inflammation included blood cell counts and ratios, specifically the NLR, the platelet-to-lymphocyte ratio (PLR), the monocyte-to-lymphocyte ratio (MLR), and the systemic immune inflammation index (SII). After classifying subjects into CONVERTERS and non-CONVERTERS (respectively, patients converting to dementia and subjects showing stability at the last available follow-up), we compared peripheral markers of inflammation among groups ed correlated them with cognitive measures, testing the ability of significant factors to predict conversion to dementia. In our cohort, CONVERTERS showed lower baseline MMSE scores (p-value = 0.004) than non-CONVERTERS. In addition, CONVERTERS had statistically elevated NLR (p-value = 0.005), PLR (p-value = 0.002), and SII levels (p-value = 0.015), besides a lower number of lymphocytes (p-value = 0.004) compared with non-CONVERTERS. In a logistic regression analysis, baseline MMSE scores and NLR predicted conversion to dementia. Tertiles analysis showed that MCI with the highest NLR values had a higher conversion risk. Our study supports the hypothesis that a dysregulation of peripheral inflammation involving both lymphocytes and neutrophils may play a role in the pathogenesis of dementia, even at the early stages of neurodegeneration, as in the MCI condition.

Role of Peripheral Inflammation in Risk of Suicide

Role of Peripheral Inflammation in Risk of Suicide

Peripheral Inflammation Links with the Severity of Clinical Phenotype in Spinocerebellar Ataxia 2.

The role of peripheral inflammation in spinocerebellar ataxia type 2 (SCA2) is unknown. The objective of this study was to identify peripheral inflammation biomarkers and their relationship with the clinical and molecular features. Blood cell count-derived inflammatory indices were measured in 39 SCA2 subjects and their matched controls. Clinical scores of ataxia, nonataxia, and cognitive dysfunction were assessed. The neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), the Systemic Inflammation Index (SII), and the Aggregate Index of Systemic Inflammation (AISI) were significantly increased in SCA2 subjects compared with controls. The increases in PLR, SII, and AISI were even observed in preclinical carriers. NLR, PLR, and SII were correlated with the Scale for the Assessment and Rating of Ataxia speech item score rather than with the total score. The NLR and SII were correlated with the nonataxia and the cognitive scores. Peripheral inflammatory indices are biomarkers in SCA2, which may help to design future immunomodulatory trials and advance our understanding of the disease. © 2023 International Parkinson and Movement Disorder Society.

The interleukin-6/interleukin-23/T helper 17-axis as a driver of neuro-immune toxicity in the major neurocognitive psychosis or deficit schizophrenia: A precision nomothetic psychiatry analysis.

BackgroundSchizophrenia and especially deficit schizophrenia (DSCZ) are characterized by increased activity of neuroimmunotoxic pathways and a generalized cognitive decline (G-CoDe). There is no data on whether the interleukin (IL)-6/IL-23/T helper 17 (IL-6/IL-23/Th17)-axis is more associated with DSCZ than with non-deficit schizophrenia (NDSCZ) and whether changes in this axis are associated with the G-CoDe and the phenome (a factor extracted from all symptom domains) of schizophrenia.MethodsThis study included 45 DSCZ and 45 NDSCZ patients and 40 controls and delineated whether the IL-6/IL-23/Th17 axis, trace elements (copper, zinc) and ions (magnesium, calcium) are associated with DSCZ, the G-CoDe and the schizophrenia phenome.ResultsIncreased plasma IL-23 and IL-6 levels were associated with Th17 upregulation, assessed as a latent vector (LV) extracted from IL-17, IL-21, IL-22, and TNF-α. The IL-6/IL-23/Th17-axis score, as assessed by an LV extracted from IL-23, IL-6, and the Th17 LV, was significantly higher in DSCZ than in NDSCZ and controls. We discovered that 70.7% of the variance in the phenome was explained by the IL-6/IL-23/Th17-axis (positively) and the G-CoDe and IL-10 (both inversely); and that 54.6% of the variance in the G-CoDe was explained by the IL-6/IL-23/Th17 scores (inversely) and magnesium, copper, calcium, and zinc (all positively).ConclusionThe pathogenic IL-6/IL-23/Th17-axis contributes to the generalized neurocognitive deficit and the phenome of schizophrenia, especially that of DSCZ, due to its key role in peripheral inflammation and neuroinflammation and its consequent immunotoxic effects on neuronal circuits. These clinical impairments are more prominent in subjects with lowered IL-10, magnesium, calcium, and zinc.

11.18 The Role of Peripheral Inflammation and Striatal Glutathione (GSH) As Predictors for Depression in Adolescents

11.18 The Role of Peripheral Inflammation and Striatal Glutathione (GSH) As Predictors for Depression in Adolescents

Peripheral inflammation induces neuroinflammation that alters neurotransmission and cognitive and motor function in hepatic encephalopathy: Underlying mechanisms and therapeutic implications.

Several million patients with liver cirrhosis suffer minimal hepatic encephalopathy (MHE), with mild cognitive and coordination impairments that reduce their quality of life and life span. Hyperammonaemia and peripheral inflammation act synergistically to induce these neurological alterations. We propose that MHE appearance is because of the changes in peripheral immune system, which are transmitted to brain, leading to neuroinflammation that alters neurotransmission leading to cognitive and motor alterations. We summarize studies showing that MHE in cirrhotic patients is associated with alterations in the immune system and that patients died with HE show neuroinflammation in cerebellum, with microglial and astrocytic activation and Purkinje cell loss. We also summarize studies in animal models of MHE on the role of peripheral inflammation in neuroinflammation induction, how neuroinflammation alters neurotransmission and how this leads to cognitive and motor alterations. These studies identify therapeutic targets and treatments that improve cognitive and motor function. Rats with MHE show neuroinflammation in hippocampus and altered NMDA and AMPA receptor membrane expression, which impairs spatial learning and memory. Neuroinflammation in cerebellum is associated with altered GABA transporters and extracellular GABA, which impair motor coordination and learning in a Y maze. These alterations are reversed by treatments that reduce peripheral inflammation (anti-TNFα, ibuprofen), neuroinflammation (sulphoraphane, p38 inhibitors), GABAergic tone (bicuculline, pregnenolone sulphate) or increase extracellular cGMP (sildenafil or cGMP). The mechanisms identified would also occur in other chronic diseases associated with inflammation, aging and some mental and neurodegenerative diseases. Treatments that improve MHE may also be beneficial to treat these pathologies.

Abstract TMP117: Relationship of Cerebral White Matter Hyperintensity Progression and Leukocyte Activation

Background: Cerebral white matter hyperintensities (WMH) are an important contributor to injury in the aging brain. Progression in WMH volume is associated with cognitive decline and gait impairment. Understanding the factors associated with WMH progression may provide insight to pathogenesis and identify novel treatment targets to improve cognitive health. Methods: In 60 patients assessed for a cognitive complaint, an MRI brain was obtained at baseline and then repeated at a median of 5.9 years (IQR 3.5-8.2 years) from start of study. WMH was measured by semi-automated segmentation protocol and rate of progression per year determined. A blood sample was acquired at baseline in a PAXgene tube and used to measure whole genome RNA expression by RNA sequencing. The relationship between rate of WMH progression over time and leukocyte RNA expression was analyzed. Results: The mean age was 76.1 (SD 8.3) years and 61% of participants were female. The median rate of WMH progression over 5.8 years was 1.3 mm 3 /year (IQR 0.27-3.3mm 3 /year). The median WMH volume was 5.5 mL (IQR 2.2-14.2). Patients in the quartile with the highest rate of WMH progression had increased leukocyte expression of genes involved in pattern recognition receptors (INFK, NLRP3, OAS1, TGFB1), interferon signaling (IFI6, IFIT1, IFITM3), and leukocyte extravasation (CLDN5, ICAM1, ITGB3, NCF1, TIMP2). A gene model could predict patients likely to experience a high rate of WMH progression over time with &gt;80% accuracy. This remained significant when adjusted for factors associated with WMH progression. Conclusions: Progression of WMH over time is associated with increased expression of genes involved in leukocyte extravasation, pattern recognition receptor activation and interferon signaling. Patients at risk for WMH progression may be identified by leukocyte RNA expression. Further studies are needed to evaluate the role of peripheral inflammation in relation to rate of WMH progression and contribution to cognitive decline.

The exogenous administration of CB2 specific agonist, GW405833, inhibits inflammation by reducing cytokine production and oxidative stress.

The present study aimed to investigate the role of cannabinoid 2 (CB2) receptors in a rat model of acute inflammation. Therefore, the potential of anti-inflammatory effects of CB2 receptor agonist (GW405833), CB2 receptor antagonist (AM630), and diclofenac, were investigated in carrageenan induced paw oedema in rats: as were assessed by measuring paw oedema; myeloperoxidase (MPO) activity in paw tissue; malondialdehyde (MDA) concentration; glutathione (GSH) level in paw tissue for oxidant/antioxidant balance; cytokine (interleukin-1β, IL-1β; tumour necrosis factor-α, TNF-α) levels in serum; histopathology of paw tissue for inflammatory cell accumulations. The results showed that GW405833 or diclofenac significantly reduced carrageenan-induced paw oedema. GW405833 also inhibited the increase of MPO activity, the recruitment of total leukocytes and neutrophils, and MDA concentration during carrageenan-induced acute inflammation, along with reversed nearly to the normal levels the increased of TNF-α, and IL-1β in serum. AM630 did not affect inflammation alone however clearly reversed the effects of agonist when co-administered. The mechanism of GW405833's suppression of inflammation is supported by these results, which are achieved by the inhibition of neutrophil migration, which regulates the reduction of oxidative stress, TNF-α and IL-1β levels. Finally, the activation of CB2 receptor, by selective agonist, has a major role in peripheral inflammation, and in the near future, targeting the peripheral cannabinoid system as a promising alternative to treat inflammation diseases may be considered a novel pharmacologic approach.

Role of peripheral inflammation in central cytokine signaling, depression, and fear

Activation of the innate immune system by chronic illness or injury is correlated with depression, anxiety and PTSD. In patients of heart attack (myocardial infarction, MI), rates of major depression and PTSD diagnoses are two‐ and three‐fold higher, respectively, than the population at large. Consistent with other patients, post‐MI incidence of PTSD and depression are correlated with increased levels of circulating pro‐ inflammatory cytokines. How circulating cytokines affect the brain remains unknown.We used a surgical model of myocardial infarction in mice to investigate the role of sustained peripheral inflammation on alterations in (1) fear conditioning and depression‐like behaviors (2) cytokine signaling in the brain and (3) sex differences in post‐ MI behavioral and inflammatory changes.Male, but not female mice exhibited enhanced fear conditioning soon after MI. Both males and females showed impaired memory and depression‐like behavior at later time points. 舲Within the hippocampus and prefrontal cortex, cytokine signaling and JAK/STAT3 were upregulated after MI in both female and male mice. The role of the cytokines and their downstream signaling in behavioral and emotional alterations are currently under investigation.These findings suggest cytokine‐dependent signaling as a candidate mechanism for susceptibility to, or development of depression and PTSD.

Is there a Role for Immunological Mechanisms in Etiopathogenesis of Obsessive Compulsive Disorder?

Byline: Naren. Rao, M. Reddy, Janardhan. Reddy Obsessive compulsive disorder (OCD) is a common and debilitating neuropsychiatric disorder with a prevalence of approximately 2%. Though selective serotonin reuptake inhibitors (SSRI) are the mainstay of treatment, it is increasingly being recognized that serotonin abnormality may be the final common pathway and other mechanisms may also play important roles in the etiopathogenesis of OCD. Growing evidence from different lines of research in the last few years suggest possible role of immunologicalabnormalities in the pathogenesis of OCD. [sup][1] Influential studies from National Institute of Mental Health suggested higher prevalence of OCD and tics in patients with Sydenham's chorea and group A Streptococcal infection, implicating immunological mechanisms in a subtype of childhood OCD such as pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). [sup][2] Following this, studies examined other markers of immune abnormality and reported higher concentration of anti-basal ganglia antibodies [sup][3] and increased prevalence of B lymphocyte marker D8/17 [sup][4] in OCD patients than in healthy controls. Neuroimaging studies supported immune hypothesis in PANDAS, reporting decreased basal ganglia volume in children with streptococcus-associated OCD [sup][5] as well as correlation between basal ganglia volume and anti-basal ganglia antibody titers. [sup][5],[6] While these results suggest a role of immunological mechanisms in the pathogenesis of OCD, one needs to be careful before drawing final conclusion because these results are preliminary and not unequivocal. [sup][7] Recent research advances in psychoneuroimmunology have implicated cytokines as mediators between brain and immune system. In addition to their role in peripheral inflammation, cytokines affect central nervous system functioning by altering the neurotransmitter systems, importantly serotonin and glutamate. Pro- and anti-inflammatory cytokines have stimulatory and inhibitory effects, respectively, on the activity of enzyme indoleamine 2,3 dioxygenase (IDO). Stimulation of IDO converts tryprophan to kynurenine, decreasing tryptophan availability for serotonin production. Kynurenine is further converted to quinolinic acid, which is a glutamate (NMDA) receptor agonist. [sup][8] Hence, cytokines are proposed to play an important role in the pathogenesis of different neuropsychiatric disorders such as depression, post-traumatic stress disorder, schizophrenia, and dementia. In the last decade, studies have examined plasma cytokines in the pathogenesis of OCD, but have reported inconclusive results. On the other hand, few studies have reported elevated cytokine levels in OCD, with majority studies reporting absence of difference between patients and controls, as also corroborated by a recent meta-analysis. [sup][9] In summary, the existing data is inconsistent regarding the role of immunological mechanisms in the pathogenesis of OCD. The evidence does not conclusively suggest a role of immunological mechanisms in the pathogenesis for OCD in general, and, at the same time, does not rule out its possible role in a subgroup of OCD. Few possible reasons for the inconsistency are methodological. First, OCD is a heterogeneous disorder with varying age at onset, and pediatric OCD may be distinctly different from adult OCD. While pediatric OCD studies have implicated possible role for immunological mechanisms, results of studies in adult OCD are equivocal. In one study, age at onset had negative correlation with tumor necrosis factor-a levels, [sup][10] further supporting this view. Second confounding factor is the presence of comorbid diagnosis, importantly depression. Only few studies have examined OCD patients without comorbid diagnosis, and because immunological mechanisms are implicated in pathogenesis of other psychiatric disorders as well, it is difficult to delineate the effects specific to OCD. …

Histamine H 3 receptor activation potentiates peripheral opioid-mediated antinociception: Substance P role in peripheral inflammation in mice

Opioids provide effective analgesia in adult patients with painful inflammatory diseases. The proposed mechanism of action is the activation of peripheral opioid receptors, which may be up-regulated in such conditions. Here, by using a chronic inflammation model, namely subplantar injection of Complete Freund's adjuvant, we show a peripheral synergistic interaction between the histamine H 3 receptor agonist R-(α)-methylhistamine and fentanyl on the inhibition of thermal hyperalgesia and of peripheral substance P accumulation. Firstly, dose-related effects obtained for the subplantar antinociceptive effect of fentanyl (0.05–1 µg) in the presence of a fixed dose of R-(α)-methylhistamine (12.5 µg) showed a shift to the left when compared to that obtained with fentanyl alone. In a similar way, the subcutaneous administration of fentanyl (0.005–0.1 mg/kg) plus a fixed dose of R-(α)-methylhistamine (0.5 mg/kg) induced a supra additive effect on the inhibition of substance P accumulation in the hind-paw skin of inflamed mice. Interestingly, when a neurokinin-1 receptor antagonist was co-administered, the antinociceptive effects of the combined treatment were potentiated. The peripheral adjuvant effect of R-(α)-methylhistamine on fentanyl antinociception and inhibition of substance P accumulation was also demonstrated by means of opioid and histamine H 3 receptors selective antagonists: first, naloxone blockade of fentanyl-mediated effects were partially reversed by co-administration of R-(α)-methylhistamine, and second, thioperamide partially antagonised the combined R-(α)-methylhistamine/fentanyl effects. Overall, our results clearly show that R-(α)-methylhistamine enhances fentanyl effects at peripheral sites, and that the control of substance P levels might be one of the mechanisms responsible of such interaction.

Contributions of peripheral inflammation to seizure susceptibility: Cytokines and brain excitability

Inflammation is an important factor in the pathophysiology of seizure generation and epileptogenesis. While the role of CNS inflammation is well acknowledged as an important factor in seizure pathophysiology, less is known about the role of peripheral inflammation. Systemic inflammation induces a mirror inflammatory response in the brain that might have transient or long-term effects on seizure susceptibility. The focus of our laboratory research is the study of the interaction of systemic inflammatory events with neuronal excitability and seizure susceptibility. In this paper we provide a review of our findings and discuss possible mechanisms.

5-lipoxygenase (5LOX)-deficient mice express reduced anxiety-like behavior

{\it Purpose:} 5-Lipoxygenase (5LOX) is an enzyme critical for leukotriene synthesis from arachidonic acid. In addition to its role in peripheral inflammation, this enzyme is also expressed in the brain but its functional role in the central nervous system is poorly understood. An upregulated expression of brain 5LOX, for example during aging and in multiple sclerosis, has been associated with increased vulnerability to neurodegeneration. Moreover, the 5LOX pathway has been associated with the neurotoxicity of the prion peptide. 5LOX-deficient mice [5LOX(-); B6129S$^{Alox5tm1Fun}$] and their controls (B6129SF2/J) have not been behaviorally characterized. {\it Methods:} The following behavioral tests were used for behavioral characterization of 5LOX(-) mice: elevated plus-maze, marble burying, locomotor activity, rota-road, and the spontaneous alternations in T-maze. {\it Results:} We found that in an elevated plus-maze, 5LOX(-) mice spent a shorter time in the "safe" closed arms, a longer time in the "anxiogenic" open arms, and entered the open arms more frequently. They also covered fewer marbles in the marble-burying anxiety test. No difference was observed between 5LOX(-) and 5LOX(+) mice in other tests. {\it Conclusion:} These results indicate that 5LOX(-) mice are less prone to anxiety and point to a possible role for 5LOX in affective behaviors. We propose that creating congenic 5LOX(-) mice by backcrossing into inbred strains would provide additional tools to further elucidate this putative role.