Peripheral Pathways Research Articles

Differential of I-A b Immunopeptidome of Thymus, Splenic B cells, and Splenic DCs from C57BL/6 mice

Abstract Antigen presentation in the thymus is central to selection of CD4 and CD8 T cells. Despite postulated roles for differential central and peripheral antigen presentation pathways, comprehensive immunopeptidome analysis of the thymus has not been reported for either MHC I or MHC II. To map the immunopeptidome in the thymus of C57BL/6 mice presented by IAb, we used immunoaffinity coupled to mass spectrometry. We identified >1000 peptides using data dependent acquisition strategy. One challenge in thymic peptidome analysis is the possibility of co-eluting non-specifically bound peptides present as a result of the low abundance of MHC II antigen presenting cells (<10% of total thymic cells). We used several approaches to reduce non-specific background peptides, including analyzing elutions from isotype control antibody conjugated beads, considering only peptides present in nested sets and using predicted binding motif analysis to identify core epitopes. We compared the immunopeptidome of thymus to those of the more easily characterized splenic B cells and splenic DCs. Some of the core epitopes were unique to thymus, splenic B cells or splenic DCs, although most were shared. We observed a broader length distribution of thymic peptidome as compared to splenic B cell and DC peptidomes. To help understand these differences, we selected for detailed analysis 57 peptides representative of thymic derived, splenic B derived or shared peptidomes and studied their binding affinity to IAb. The results suggested that the pool of peptides presented by IAb in thymus has lower MHC affinity than does the pool presented by splenic B cells. Thus our data support the idea of differential antigen processing and presentation in central versus peripheral tissues.

Genetic Predictors of Knee Pain in Persons With Mild to Moderate Osteoarthritis.

The purpose of this study was to examine genetic variability and knee pain in persons with osteoarthritis (OA). Seventy-five participants with medial compartment knee OA were recruited from a large Midwestern tertiary care center. Participants exhibited a mean age of 56.3 years; females comprised 61% of the sample. Measures of pain included subjective pain intensity at rest and with movement, cutaneous mechanical sensation and pain testing, heat pain threshold, and pressure pain threshold. Seventy-four participants were genotyped for 25 genetic variants across 15 candidate genes for central or peripheral pain pathways. Analysis suggests a role for four genes (EDNRA, COMT, BDRKB1, and IL1B) in several components of pain in persons with knee OA. The results from this study will help guide the development and evaluation of tailored strategies to decrease pain, improve function, and prevent the development of new chronic pain syndromes in older adults experiencing OA. [Research in Gerontological Nursing, xx(x), xx-xx.].

Functional morphology of the primary olfactory centers in the brain of the hermit crab Coenobita clypeatus (Anomala, Coenobitidae)

Terrestrial hermit crabs of the genus Coenobita display strong behavioral responses to volatile odors and are attracted by chemical cues of various potential food sources. Several aspects of their sense of aerial olfaction have been explored in recent years including behavioral aspects and structure of their peripheral and central olfactory pathway. Here, we use classical histological methods and immunohistochemistry against the neuropeptides orcokinin and allatostatin as well as synaptic proteins and serotonin to provide insights into the functional organization of their primary olfactory centers in the brain, the paired olfactory lobes. Our results show that orcokinin is present in the axons of olfactory sensory neurons, which target the olfactory lobe. Orcokinin is also present in a population of local olfactory interneurons, which may relay lateral inhibition across the array of olfactory glomeruli within the lobes. Extensive lateral connections of the glomeruli were also visualized using the histological silver impregnation method according to Holmes-Blest. This technique also revealed the structural organization of the output pathway of the olfactory system, the olfactory projection neurons, the axons of which target the lateral protocerebrum. Within the lobes, the course of their axons seems to be reorganized in an axon-sorting zone before they exit the system. Together with previous results, we combine our findings into a model on the functional organization of the olfactory system in these animals.

Cardiac and Medullary Neuroinflammatory Pathways Trigger Androgenic Incitement of Cardiovascular Sequels of Endotoxemia in Rats

Inconsistent reports are available on the role of testosterone in end organ damage caused by endotoxemia. Here, pharmacologic, surgical, and molecular studies were employed to assess the testosterone modulation of cardiovascular and autonomic derangements caused by endotoxemia and the role of peripheral and central inflammatory pathways in this interaction. Studies were performed in conscious male rats pre‐instrumented with femoral indwelling catheters for hemodynamic monitoring and subjected to castration or pharmacologic interventions that interrupt the biosynthetic cascade of testosterone. Compared to the effects of lipopolysaccharide (LPS, 10 mg/kg i.v.) in sham operated rats, 2‐week castration significantly reduced the LPS‐evoked: (i) falls in blood pressure, (ii) decreases in time‐ and frequency domain indices of heart rate variability (HRV), (iii) shifts in cardiac sympathovagal balance towards parasympathetic dominance as evidenced by decreases in low‐frequency to high‐frequency ratio of spectral powers, and (iii) increases in protein expressions of toll‐like receptor 4 and monocyte chemoattractant protein‐1 in the heart as well as in medullary neurons of the nucleus tractus solitarius and rostral ventrolateral medulla. The favorable influences of castration on inflammatory and cardiovascular abnormalities of endotoxemia were replicated in intact rats pretreated with degarelix (gonadotropin‐releasing hormone receptor blocker) or finasteride (5α‐reductase inhibitor), but not formestane (aromatase inhibitor). The data signifies the importance of testosterone and its biosynthetic enzymes in cardiovascular and autonomic insults induced by the endotoxic inflammatory response. Clinically, the interruption of testosterone biosynthesis could offer a potential therapeutic strategy for endotoxemia.Support or Funding InformationSupported by the Science and Technology Development Fund, Egypt (STDF Grants No. 14895)

Back to the Drawing Paper : Active Learning Approaches That Are Not All Boring

The most traditional approach for delivering gross anatomical information today is the traditional lecture and/or laboratory cadaver dissection or prosection. The anatomy laboratory provides the most active learning approach to learning body structure and function. Some anatomical concepts, however, cannot be visualized in a dissection or prosection, one of which is the concept of the somatic and visceral nervous systems peripheral structure and pathways. The objective of this study was to evaluate the use of drawing and labeling to gain appreciation of basic nervous systems concepts. Before the scheduled learning session, students were assigned a section to read in their textbook regarding the nervous system. At the beginning of the scheduled session, students were provided a sheet of paper with 4 boxes. In box 1 they were to copy a list of neuroanatomical terms that were shown on a Power Point slide. Next, they were shown on a Power Point slide an unlabeled drawing of the spinal cord and peripheral nerves. Using the terms listed in box 1, the various parts of the drawing were identified by the instructor for the students. The students were then asked to draw/sketch the drawing in box 2. In box 3, the students were asked to again copy the terms in box 1. In box 4, the students were asked to re‐draw/sketch the drawing in box 2 and label the drawing. When drawing and labeling in box 4, students were encouraged to check their neighbors’ drawing and labeling. Following this exercise, a shortened lecture was presented regarding the gross and cellular aspects of the neuroanatomical structures. This was followed by a Turning Point quiz using pictures from the textbook and lecture, and students were asked to check their answer with neighboring peers before submitting their answer. At the end of the neuroanatomical learning sessions, a survey with three questions using a five‐point scale was given to the students for them to evaluate the value for their learning of each segment (the list and drawing, lecture, and Turning Point quiz) of this learning session. Suggestions and comments were asked for. On a scale of 1–5, the value for each learning segment was as follows: list and drawing 4.3, lecture 3.8, Turning Point quiz 4.6. The survey results, and suggestions and comments, indicate that these various approaches to learning facilitate the learning process, and they serve as an active learning and peer teaching approach that is not boring.

Increased plasma bradykinin level is associated with cognitive impairment in Alzheimer's patients

Alzheimer's disease (AD) is characterized by the presence of proteinaceous brain deposits, brain atrophy, vascular dysfunction, and chronic inflammation. Along with cerebral inflammation, peripheral inflammation is also evident in many AD patients. Bradykinin, a proinflammatory plasma peptide, is also linked to AD pathology. For example, bradykinin infusion into the hippocampus causes learning and memory deficits in rats, and blockade of the bradykinin receptor lessens cognitive impairment in AD mouse models. Even though it has been hypothesized that plasma bradykinin could contribute to inflammation in AD, the level of plasma bradykinin and its association with beta-amyloid (Aβ) pathology in AD patients had not been explored. Here, we assessed plasma bradykinin levels in AD patients and age-matched non-demented (ND) control individuals. We found significantly elevated plasma bradykinin levels in AD patients compared to ND subjects. Additionally, changes in plasma bradykinin levels were more profound in many AD patients with severe cognitive impairment, suggesting that peripheral bradykinin could play a role in dementia most likely via inflammation. Bradykinin levels in the cerebrospinal fluid (CSF) were reduced in AD patients and exhibited an inverse correlation with the CSF Aβ40/Aβ42 ratio. We also report that bradykinin interacts with the fibrillar form of Aβ and co-localizes with Aβ plaques in the post-mortem human AD brain. These findings connect the peripheral inflammatory pathway to cerebral abnormalities and identify a novel mechanism of inflammatory pathology in AD.

Ocular movement and nystagmus: basics and clinical diagnosis

Eye movements are one of the most complex motor functions of the central nervous system (CNS). Eye movement disorders including nystagmus occur in diseases of the CNS and the vestibular system. Asystematic clinical examination often allows atopodiagnostic classification of the lesion. The basics of eye movements, the role of the cerebellum, the clinical examination of the oculomotor system, and the most important forms of nystagmus and their diagnostic implications are described. A literature analysis assessing eye movements, cerebellar control of eye movements, clinical examination of eye movement, and nystagmus was performed. In disorders of eye movement, diseases of the oculomotor cranial nerves and the central nervous structures are to be distinguished from diseases of the orbit, eye muscles, and motor end plates. The former result in cranial nerve-related paralysis of extraocular muscles, disturbances of saccadic and smooth pursuit eye movements, vertical or horizontal gaze palsy, internuclear ophthalmoplegia, or impaired gaze holding. Nystagmus in combination with other disturbances of ocular movement is highly related to alesion within the CNS. Intense nystagmus with arotatory component that decreases during fixation usually has aperipheral vestibular cause. Clinical examination of eye movements and nystagmus enables the diagnosis of typical eye movement disorders with astrong relation to distinct lesions of the CNS or the peripheral vestibular pathway.

Effect of Preoperative Pregabalin on Stress Response during Laryngoscopy, Intubation and Postoperative Analgesia in Normotensive Normoglycemic Patients Undergoing Abdominal Hysterectomy

Abstract Introduction abdominal hyterectomy is common operation and have many indications. Laryngoscopy and intubation induce marked sympathetic hemodynamic effect resulting in cardiac response which may be fatal in some patients. Postoperative pain in the form of hyperalgesia caused by surgical trauma can lead to chronic postoperative pain. Preemptive analgesia is a concept in managing postoperative pain. Preemptive analgesia prevents sensitization of peripheral and central pain pathways caused by tissue damage. Pregbalin is thought to supress the hemodynamic effect of intubation and to have analgesic effect. Aim The aim of this work is to evaluate the effects of different doses of pregabalin as a premedication to attenuate cardiovascular response during laryngoscopy and intubation. Intubation-induced hyperglycemia will be also assessed, in addition to the effect of the drug on postoperative analgesia in normotensive normoglycemic patients undergoing abdominal hysterectomy. Subjects and Methods The current study was performed as a randomized, prospective, placebo-controlled, and double blind study on 120 female patients ASA I, scheduled for elective abdominal hysterectomy under general anesthesia and meeting the inclusion criteria, were allocated into four groups. Group A (n = 30) were given placebo 2 hrs preoperatively, Group B, C and D were given oral pregablin in the following doses 75 mg, 150 mg and 300 mg recpectively. preoperative vital data (systolic blood pressure, diastolic blood pressure, mean blood pressure and heart rate were measured before intubation and after intubation by 2, 4 and 6 minutes. Capillary blood glucose was measured before and after intubation. Intraoperative and postoperative analgesic consumption were recorded. Anesthetic and surgical techniques were standardized. Results The increase in hemodynamic parameters were minimized by pregablinin 150 and 300 mg when compared to the control group and patients received 75 mg. The intraoperative and postoperative consumption of analgesia were decreased in the groups receiving 150 and 300 mg. Conclusion Oral pregablin in 150 and 300 mg in the present study attenuates hemodynamic responses tolaryngoscopy and intubation. Oral pregablin in 150 and 300 mg decreases the consumption of analgesics intraoperatively and postoperatively.

Chronic migraine and Botulinum Toxin Type A: Where do paths cross?

Migraine is a highly prevalent and disabling disorder accounted among the primary headaches. It is the expression of a complex, and not yet fully understood, pathophysiology involving the sensitization of peripheral and central nociceptive pathways. In this review we succinctly illustrate the molecular, anatomical, and functional abnormalities underlying the migraine attack that are relevant for understanding in more depth the neurobiology behind the therapeutic effect of Botulinum Toxin Type A (BoNT-A). BoNT-A has proved effective in several neurological conditions and, more recently, also in chronic migraine. Its antimigraine mechanism of action was initially thought to be limited to the periphery and interpreted as an inhibitory activity on the processes associated to the local release of neuropeptides, with subsequent induction of peripheral sensitization. Increasing experimental evidence has become available to suggest that additional mechanisms are possibly involved, including the direct/indirect inhibition of sensitization processes in central nociceptive pathways.

Enhanced post-traumatic headache-like behaviors and diminished contribution of peripheral CGRP in female rats following a mild closed head injury.

Females are thought to have increased risk of developing post-traumatic headache following a traumatic head injury or concussion. However, the processes underlying this susceptibility remain unclear. We previously demonstrated the development of post-traumatic headache-like pain behaviors in a male rat model of mild closed head injury, along with the ability of sumatriptan and an anti-calcitonin-gene-related peptide monoclonal antibody to ameliorate these behaviors. Here, we conducted a follow-up study to explore the development of post-traumatic headache-like behaviors and the effectiveness of these headache therapies in females subjected to the same head trauma protocol. Adult female Sprague Dawley rats were subjected to a mild closed head injury using a weight-drop device (n = 126), or to a sham procedure (n = 28). Characterization of headache and pain related behaviors included assessment of changes in cutaneous cephalic and extracephalic tactile pain sensitivity, using von Frey monofilaments. Sensitivity to headache/migraine triggers was tested by examining the effect of intraperitoneal administration of a low dose of glyceryl trinitrate (100 µg/kg). Treatments included acute systemic administration of sumatriptan (1 mg/kg) and repeated systemic administration of a mouse anti-calcitonin gene-related peptide monoclonal antibody (30 mg/kg). Serum levels of calcitonin gene-related peptide were measured at baseline and at various time points post head injury in new cohorts of females (n = 38) and males (n = 36). Female rats subjected to a mild closed head injury developed cutaneous mechanical hyperalgesia, which was limited to the cephalic region and was resolved 4 weeks later. Cephalic pain hypersensitivity was ameliorated by treatment with sumatriptan but was resistant to an early and prolonged treatment with the anti-calcitonin gene-related peptide monoclonal antibody. Following the resolution of the head injury-evoked cephalic hypersensitivity, administration of glyceryl trinitrate produced a renewed and pronounced cephalic and extracephalic pain hypersensitivity that was inhibited by sumatriptan, but only partially by the anti-calcitonin gene-related peptide treatment. Calcitonin gene-related peptide serum levels were elevated in females but not in males at 7 days post head injury. Development of post-traumatic headache-like pain behaviors following a mild closed head injury, and responsiveness to treatment in rats is sexually dimorphic. When compared to the data obtained from male rats in the previous study, female rats display a prolonged state of cephalic hyperalgesia, increased responsiveness to a headache trigger, and a poorer effectiveness of an early and prolonged anti-calcitonin gene-related peptide treatment. The increased risk of females to develop post-traumatic headache may be linked to enhanced responsiveness of peripheral and/or central pain pathways and a mechanism independent of peripheral calcitonin gene-related peptide signaling.

Physiology and Pathophysiology of the Autonomic Nervous System

This article reviews the anatomic, functional, and neurochemical organization of the sympathetic and parasympathetic outputs; the effects on target organs; the central mechanisms controlling autonomic function; and the pathophysiologic basis for core symptoms of autonomic failure. Functional neuroimaging studies have elucidated the areas involved in central control of autonomic function in humans. Optogenetic and other novel approaches in animal experiments have provided new insights into the role of these areas in autonomic control across behavioral states, including stress and the sleep-wake cycle. Control of the function of the sympathetic, parasympathetic, and enteric nervous system functions depends on complex interactions at all levels of the neuraxis. Peripheral sympathetic outputs are critical for maintenance of blood pressure, thermoregulation, and response to stress. Parasympathetic reflexes control lacrimation, salivation, pupil response to light, beat-to-beat control of the heart rate, gastrointestinal motility, micturition, and erectile function. The insular cortex, anterior and midcingulate cortex, and amygdala generate autonomic responses to behaviorally relevant stimuli. Several nuclei of the hypothalamus generate coordinated patterns of autonomic responses to internal or social stressors. Several brainstem nuclei participate in integrated control of autonomic function in relationship to respiration and the sleep-wake cycle. Disorders affecting the central or peripheral autonomic pathways, or both, manifest with autonomic failure (including orthostatic hypotension, anhidrosis, gastrointestinal dysmotility, and neurogenic bladder or erectile dysfunction) or autonomic hyperactivity, primary hypertension, tachycardia, and hyperhidrosis.

One Month Weight Loss Predicts the Efficacy of Liraglutide in Obese Patients: Data from A Single Center

Objective: Liraglutide is a glucagon-like peptide 1 receptor agonist which acts through peripheral and central receptor pathways affecting food intake. Preliminary identification of responder patients represents a crucial point to reduce an inappropriate exposure to the drug and the health expenditure. The primary endpoint of our study was to identify predictors of liraglutide efficacy in the short term follow-up. The secondary endpoint was to evaluate the treatment efficacy stratified by the underlying psychiatric disorder. Methods: We evaluated a cohort of 100 patients (77 females, 23 males, mean body mass index 38.6 ± 3.2 kg/m2) who were evaluated at baseline, and after 1, 3, and 6 months of treatment. Liraglutide efficacy was defined by a weight loss ≥5% of initial weight. Sociodemographic/metabolic parameters, food intake, smoking habit, and physical activity were correlated with liraglutide efficacy. Results: There was a significant weight loss after 1 month of therapy, as well as after 3 and 6 months when compared to the baseline (P<.0001; 27%, 45%, and 57% of patients showed a weight loss ≥5%, respectively). No difference was found in weight loss between the 3 groups of patients (with binge eating, with/without psychiatric disorders). The weight loss at 1 month was the only predictor of a positive response to the treatment. Conclusion: Our results confirm the efficacy of liraglutide even at a lower dose than conventional. The early response to the drug seems to be a good predictor of long-term efficacy and it might be useful in clinical practice to identify patients in whom liraglutide may induce a significant weight loss. Abbreviations: BMI = body mass index; EMA = European Medicine Agency; FDA = Food and Drug Administration; GLP-1 RA = glucagon-like peptide 1 receptor agonist.

Fractions of Selaginella convoluta (Arn.) Spring (Selaginellaceae) attenuate the nociceptive behavior events in mice.

Selaginella convoluta (Arn.) Spring is a species popularly known as "jericó", and used in folk medicine as analgesic and anti-inflammatory. This study aimed to investigate in mice the antinociceptive and anti-inflammatory activities of the hexane (Sc-Hex) and chloroform (Sc-CHCl3) fractions (100, 200 and 400 mg/kg) obtained by partition of crude ethanol extract from S. convoluta. The preliminary phytochemical analysis of the fractions was performed. Antinociceptive activity was evaluated by writhing, formalin and hot-plate tests. Anti-inflammatory activity was evaluated using carrageenan-induced pleurisy. The rota-rod test was used to evaluate motor coordination. Preliminary phytochemical screening showed that the Sc-Hex and the Sc-CHCl3 were positive for the presence of flavonoids, anthracene derivatives, quinones, triterpenes and steroids. Inhibition of writhing was observed for fractions tested. The Sc-Hex at all doses tested was effective in reducing the nociceptive behavior produced by formalin only in the second phase. However, the Sc-CHCl3 decreased the paw licking time in the first and second phases. In the hot plate no significant effect was observed for any fraction. In the rota-rod test, treated mice did not demonstrate any significant motor performance changes. In the carrageenan-induced pleurisy, Sc-CHCl3 (200 mg/kg) reduced cell migration to the pleural cavity. These results reveal the antinociceptive properties of S. convoluta , which support, in part, its traditional use, since the fractions did not presented significant activity in the inflammatory response profile. We further verify that this antinociceptive effect could be by activation of nociceptive peripheral pathway.

Wnt Pathway Gene Expression Is Associated With Arterial Stiffness.

BackgroundAnimal and in vitro experiments implicate the Wnt pathway in cardiac development, fibrosis, vascular calcification, and atherosclerosis, but research in humans is lacking. We examined peripheral blood Wnt pathway gene expression and arterial stiffness in 369 healthy African ancestry men (mean age, 64 years).Methods and ResultsGene expression was assessed using a custom Nanostring nCounter gene expression panel (N=43 genes) and normalized to housekeeping genes and background signal. Arterial stiffness was assessed via brachial‐ankle pulse‐wave velocity. Fourteen Wnt genes showed detectable expression and were tested individually as predictors of pulse‐wave velocity using linear regression, adjusting for age, height, weight, blood pressure, medication use, resting heart rate, current smoking, alcohol intake, and sedentary lifestyle. Adenomatous polyposis coli regulator of Wnt signaling pathway (APC), glycogen synthase kinase 3β (GSK3B), and transcription factor 4 (TCF4) were significantly associated with arterial stiffness (P<0.05 for all). When entered into a single model, APC and TCF4 expression remained independently associated with arterial stiffness (P=0.04 and 0.003, respectively), and each explained ≈3% of the variance in pulse‐wave velocity.ConclusionsThe current study establishes a novel association between in vivo expression of the Wnt pathway genes, APC and TCF4, with arterial stiffness in African ancestry men, a population at high risk of hypertensive vascular disease.

Motility of the Labial Palps in Feeding Behavior and its Innervation in the Marine Mussel, Mytilus galloprovincialis.

The labial palps of bivalves are thought to be involved in suspension feeding. However, the function of their muscular movements and neural regulation are still unclear. In semi-intact preparations of Mytilus, in which one valve was removed, suspended particles were removed from the labial palps following two kinds of compound movements: torsional and rotational. Both of these compound movements are therefore thought to function in rejection during feeding. These movements were observed in reduced preparations of isolated labial palps with intact cerebral ganglia, and were maintained even after removal of the cerebral ganglia, suggesting that they are generated by the peripheral neural network. Stimulation of the anterior pallial nerve elicited tetanic contraction of the labial palp, followed by secondary responses, including torsional movement. Secondary responses were dramatically reduced by a high concentration of divalent cations, in which polysynaptic pathways were inhibited. Hence, the cerebral ganglia may play an excitatory role within the peripheral neural network and the labial palp musculature via the anterior pallial nerve. Administration of serotonin induced repetitive muscular movements, whereas dopamine did not induce muscular movements. Serotonin-induced muscular movements were not elicited under a high concentration of divalent cation condition. In histochemical experiments, both the serotonergic and dopaminergic neural processes and cell body-like structures were widely observed inside the labial palp, the anterior pallial nerve, and the cerebral ganglia. Serotonin may thus contribute to activation of polysynaptic peripheral pathways, which are involved in regulating compound movements.

Immune and Neuroendocrine Trait and State Markers in Psychotic Illness: Decreased Kynurenines Marking Psychotic Exacerbations.

Objective: Different patterns of immune system upregulation are present in the acute vs. post-treatment states of psychotic illness. We explored the existence of state and trait markers in the peripheral immune system and two immune-associated neuroendocrine pathways (IDO and GTP-CH1 pathway) in a longitudinal sample of psychosis patients. We also evaluated the association of these markers with neuropsychiatric symptomatology.Method: Plasma concentrations of peripheral blood markers were measured in a transdiagnostic group of 49 inpatients with acute psychosis and 52 matched healthy control subjects. Samples were obtained in patients within 48 h after hospital admission for an acute psychotic episode (before initiation of antipsychotics), after 1–2 weeks and again after 8 weeks of treatment. Kynurenine, kynurenic acid (KA), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), phenylalanine, tyrosine, nitrite, and neopterin were measured using HPLC and LC-MS/MS analysis. Concentrations of CRP, CCL2 (MCP1) and cytokines were determined with multiplex immunoassay. PANSS interviews and cognitive tests were performed at baseline and follow-up. Mixed model analyses were used to identify trait and state markers.Results: Patients had significantly higher plasma concentrations of CRP, CCL2, IL1RA, and lower concentrations of KA and KA/Kyn at all time points (F7.5–17.5, all p < 0.001). Increased concentrations of IL6, IL8, IL1RA, TNFα, and CCL2 and decreased QA and 3-HK (F8.7–21.0, all p < 0.005) were found in the acute psychotic state and normalized after treatment. Low nitrite concentrations at admission rose sharply after initiation of antipsychotic medication (F42.4, p < 0.001). PANSS positive scale scores during the acute episode correlated with pro-inflammatory immune markers (r ≥ |0.5|), while negative scale scores correlated inversely with IDO pathway markers (r ≥ |0.4|). Normalization of KA and 3-HK levels between admission and follow-up corresponded to a larger improvement of negative symptoms (r = 0.5, p < 0.030) A reverse association was found between relative improvement of SDST scores and decreasing KA levels (r = 0.5, p < 0.010).Conclusion: The acute psychotic state is marked by state-specific increases of immune markers and decreases in peripheral IDO pathway markers. Increased CRP, CCL2, and IL1RA, and decreased KA and KA/Kyn are trait markers of psychotic illness.

Associations among peripheral and central kynurenine pathway metabolites and inflammation in depression.

Kynurenine pathway (KP) metabolites are believed to be a link between inflammation and depression through effects on brain glutamate receptors. However, neither the relationship between plasma and cerebrospinal fluid (CSF) KP metabolites nor their association with inflammatory mediators is well-established in depression. Moreover, the clinical profile associated with combined activation of plasma inflammatory and kynurenine pathways is unknown. Accordingly, plasma and CSF-KP metabolites and inflammatory markers along with depressive symptoms and antidepressant treatment response were measured in 72 unmedicated depressed patients. Following bivariate analyses, component factors representing immune and kynurenine variables in the plasma and CSF were extracted and were used to examine directionality of associations in a path model. In addition, patients were clustered using individual markers that most accounted for the association between plasma immune and KP systems. Path analysis revealed a directional association extending from plasma inflammatory markers to plasma kynurenines, to CSF kynurenines. Among immune markers, plasma tumor necrosis factor (TNF) was robustly associated with plasma kynurenine (KYN) and KYN/tryptophan (TRP), which was in turn significantly associated with CSF KYN, kynurenic acid, and quinolinic acid. Clustering of patients based on plasma TNF and KYN/TRP yielded subgroups of high (N = 17) and low (N = 55) TNF-KYN/TRP groups. High TNF-KYN/TRP subjects exhibited greater depression severity, anhedonia, and treatment nonresponse. In conclusion, plasma-KP metabolites may mediate an inflammation-associated depressive symptom profile via CNS KP metabolites that can serve as a target for intervention at the level of inflammation, peripheral KYN metabolism, KYN transport to the brain, or effects of KP metabolites on glutamate receptors.

Neuroprotective and Neuromodulatory Effects Induced by Cannabidiol and Cannabigerol in Rat Hypo-E22 cells and Isolated Hypothalamus.

Background: Cannabidiol (CBD) and cannabigerol (CBG) are non-psychotropic terpenophenols isolated from Cannabis sativa, which, besides their anti-inflammatory/antioxidant effects, are able to inhibit, the first, and to stimulate, the second, the appetite although there are no studies elucidating their role in the hypothalamic appetite-regulating network. Consequently, the aim of the present research is to investigate the role of CBD and CBG in regulating hypothalamic neuromodulators. Comparative evaluations between oxidative stress and food intake-modulating mediators were also performed. Methods: Rat hypothalamic Hypo-E22 cells and isolated tissues were exposed to either CBD or CBG, and the gene expressions of neuropeptide (NP)Y, pro-opiomelanocortin (POMC) and fatty acid amide hydrolase were assessed. In parallel, the influence of CBD on the synthesis and release of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) was evaluated. The 3-hydroxykinurenine/kinurenic acid (3-HK/KA) ratio was also determined. Results: Both CBD and CBG inhibited NPY and POMC gene expression and decreased the 3-HK/KA ratio in the hypothalamus. The same compounds also reduced hypothalamic NE synthesis and DA release, whereas the sole CBD inhibited 5-HT synthesis. Conclusion: The CBD modulates hypothalamic neuromodulators consistently with its anorexigenic role, whereas the CBG effect on the same mediators suggests alternative mechanisms, possibly involving peripheral pathways.

Longitudinal Basal Forebrain Degeneration Interacts with TREM2/C3 Biomarkers of Inflammation in Presymptomatic Alzheimer's Disease.

Cholinergic inputs originating from the peripheral nervous system regulate the inflammatory immune responses of macrophages during clearance of blood-based pathogens. Because microglia are involved in clearing amyloid and tau pathology from the central nervous system, we hypothesized that cholinergic input originating from the basal forebrain might similarly regulate inflammatory immune responses to these pathologies in the aging brain. To explore this hypothesis, we leveraged the Alzheimer's Disease Neuroimaging Initiative dataset. Cognitively normal older male and female human adults were differentiated according to the relative concentration of phosphorylated tau and amyloid in their cerebrospinal fluid, yielding neurotypical and preclinical, cognitively healthy, subgroups. We then tracked these two groups longitudinally with structural MRI and biomarkers of inflammation, including soluble sTREM2 levels in the CSF and complement C3 expression in the blood transcriptome. Longitudinal loss of basal forebrain volume was larger in the preclinical compared with the neurotypical subgroup. Across preclinical adults, loss of basal forebrain volume was associated with greater longitudinal accumulation of sTREM2 and higher peripheral blood C3 expression. None of these relationships were attributable to degeneration in the whole-brain gray matter volume. Preclinical APOE e4 carriers exhibited the largest loss of basal forebrain volume and highest C3 expression. Consistent with the known anti-inflammatory influence of the peripheral cholinergic pathways on macrophages, our findings indicate that a loss of central cholinergic input originating from the basal forebrain might remove a key check on microglial inflammation induced by amyloid and tau accumulation.SIGNIFICANCE STATEMENT In the peripheral nervous system, cholinergic modulation holds the reactivity of macrophages to blood-based pathogens in check, promoting clearance while preventing runaway inflammation and immune-triggered cell death. Microglia are the brain's resident macrophages and play an important role in clearing accumulated amyloid and tau from neurons. Here, we demonstrate that a loss of cholinergic integrity in the CNS, indexed by longitudinal decreases of basal forebrain volume, interacts with multiple biomarkers of inflammation in cognitively normal older adults with abnormal amyloid and tau pathology. These interactions were not detected in cognitively normal older adults with "neurotypical" levels of amyloid and tau. An age-related loss of cholinergic neuromodulation may remove key checks on microglial reactivity to amyloid and tau.

The Effect of Tryptophan 2,3-Dioxygenase Inhibition on Kynurenine Metabolism and Cognitive Function in the APP23 Mouse Model of Alzheimer's Disease.

Alzheimer’s disease (AD) is associated with progressive endogenous neurotoxicity and hampered inflammatory regulation. The kynurenine (Kyn) pathway, which is controlled by tryptophan 2,3-dioxygenase (TDO), produces neuroactive and anti-inflammatory metabolites. Age-related Kyn pathway activation might contribute to AD pathology in humans, and inhibition of TDO was found to reduce AD-related cellular toxicity and behavioral deficits in animal models. To further explore the effect of aging on the Kyn pathway in the context of AD, we analyzed Kyn metabolite profiles in serum and brain tissue of the APP23 amyloidosis mouse model. We found that aging had genotype-independent effects on Kyn metabolite profiles in serum, cortex, hippocampus and cerebellum, whereas serum concentrations of many Kyn metabolites were reduced in APP23 mice. Next, to further establish the role of TDO in AD-related behavioral deficits, we investigated the effect of long-term pharmacological TDO inhibition on cognitive performance in APP23 mice. Our results indicated that TDO inhibition reversed recognition memory deficits without producing measurable changes in cerebral Kyn metabolites. TDO inhibition did not affect spatial learning and memory or anxiety-related behavior. These data indicate that age-related Kyn pathway activation is not specific for humans and could represent a cross-species phenotype of aging. These data warrant further investigation on the role of peripheral Kyn pathway disturbances and cerebral TDO activity in AD pathophysiology.