Giamal Luheshi

McGill University | McGill · Douglas Mental Health University Institute

Translation of mRNA into protein has a fundamental role in neurodevelopment, plasticity, and memory formation; however, its contribution in the pathophysiology of depressive disorders is not fully understood. We investigated the involvement of MNK1/2 (MAPK-interacting serine/threonine-protein kinase 1 and 2) and their target, eIF4E (eukaryotic init...

Epidemiological studies revealed that environmental factors comprising prenatal infection are strongly linked to risk for later development of neuropsychiatric disorders such as schizophrenia. Considering strong sex differences in schizophrenia and its increased prevalence in males, we designed a methodological approach to investigate possible sex...

Environmental challenges to the maternal immune system during pregnancy have been associated with an increase in the frequency of neurodevelopmental disorders such as Autism Spectrum Disorders (ASD) appearing in the offspring. Microglia, the brain’s resident immune-cells, are now known to be critically involved in normal brain development, shaping...

Obesity is associated with a high prevalence of mood disorders and cognitive dysfunctions in addition to being a significant risk factor for important health complications such as cardiovascular diseases and type 2 diabetes. Identifying the pathophysiological mechanisms underlying these health issues is a major public health challenge. Based on rec...

Obesity is associated with a high prevalence of mood disorders and cognitive dysfunctions in addition to being a significant risk factor for important health complications such as cardiovascular diseases and type 2 diabetes. Identifying the pathophysiological mechanisms underlying these health issues is a major public health challenge. Based on rec...

Over the past decades, obesity rates have continued to increase at alarming rates globally, fostering the rise in serious comorbidities, particularly cardiovascular diseases and type 2 diabetes, collectively known as metabolic syndrome (MetS). Obesity is also linked with brain disease and is often associated with a high prevalence of mood and cogni...

Leptin is an important modulator of both inflammation and energy homeostasis, making it a key interface between the inflammatory response to pathogenic stimuli and the energy status of the host. In previous studies we demonstrated that sickness responses to systemic immune challenge, including fever, are significantly exacerbated in diet induced ob...

The blood-nerve barrier (BNB) is a selectively permeable barrier that creates an immunologically and biochemically privileged space for peripheral axons and supporting cells. The breakdown of the BNB allows access of blood-borne (hematogenous) cells and molecules to the endoneurium to engage in the local inflammatory cascade. This process was exami...

Obesity contributes to a state of subclinical peripheral and central inflammation and is often associated with aging. Here we investigated the source and contribution of adipose tissue derived cytokines and the cytokine-like hormone leptin to age-related changes in lipopolysaccharide (LPS)-induced brain-controlled sickness-responses. Old (24 months...

Abstract The intra-uterine environment provides the first regulatory connection for the developing fetus and shapes its physiological responses in preparation for postnatal life. Psychological stress acts as a programming determinant by setting functional parameters to abnormal levels, thus inducing postnatal maladaptation. The effects of prenatal...

Peripheral inflammation induces transmigration of interleukin (IL)-1β-expressing neutrophils to the brain. We investigated the possibility that this presents a new route of immune-to-brain communication by assessing their role in sickness behaviors relevant for mood disorders. Mice treated with lipopolysaccharide (LPS) developed despair-like behavi...

Recent evidence has demonstrated that consumption of high fat diets can trigger brain inflammation and subsequent injury in the absence of any peripheral inflammatory signaling. Here we sought to investigate whether a link exists between the concentration of highly saturated fats in the diet and the development of inflammation in the brain of rats...

Sickness behaviors and fever during infection constitute an adaptive and tightly regulated mechanism designed to efficiently clear the invading pathogen from the body. Recent literature has demonstrated that changes in energy status can profoundly affect the fever response to an acute immune challenge. The purpose of the present study was to invest...

Aging leads to subclinical peripheral and central inflammation and obesity. Obesity is known to be accompanied by enhanced fat-derived cytokine production and elevated circulating leptin, an adipocyte-derived hormone implicated in the regulation of food intake and in the proinflammatory immune response. Here, we aimed to investigate the contributio...

Many aspects of the immune system, including circulating cytokine levels as well as counts and function of various immune cell types, present circadian rhythms. Notably, the mortality rate of animals subjected to high doses of lipopolysaccharide is dependent on the time of treatment. In addition, the severity of symptoms of various inflammatory con...

Primer sequences used in the SYBR Green quantitative PCR assays. (PDF)

Time-dependent effect of TURP injection on cytokine levels. Animals were treated with either TURP or saline at ZT14, ZT20, ZT2, or ZT8 (time of injection, TOI) and sacrificed 10 h later at ZT0, ZT6, ZT12 and ZT18 (time of sacrifice, TOS), respectively. (A) IL-1Ra and (B) TNFα levels in serum at sacrifice were measured by ELISA. Closed boxes represe...

Controls genes selected by GeNorm for each in vivo experiment. (PDF)

IL-Ra induction after TURP treatment with or without hrIL-1Ra co-treatment. All animals were treated with either saline or TURP at ZT2 and sacrificed at either ZT12 or ZT16 time of sacrifice (TOS) with additional IL-1Ra treatment at 0, 4, and 8 h (ZT12 TOS) and 0, 4, 8 and 12 h (ZT16 TOS) after the initial treatment. One-way ANOVA for the four grou...

Cytokine induction over time after TURP treatment at ZT2. Animals were treated with either saline or TURP at ZT2 (0 hours) and sacrificed at 6 different time points ZT4, ZT8, ZT12, ZT16, ZT20, and ZT0 (time after sacrifice, TOS) corresponding to 2, 6, 10, 14, 18, and 22 h after injection (HAI), respectively. (A) IL-1Ra and (B) TNFα levels in serum...

Background Whereas the role played by interleukin (IL)-10 in modulating fever and sickness behavior has been linked to it targeting the production of pro-inflammatory cytokines in the circulation, liver and spleen, it is not known whether it could directly target the local production of pro-inflammatory cytokines within the sensory circumventricula...

Non-pregnant female rats have a lower inflammatory response to lipopolysaccharide (LPS) than males, and at late stages of gestation, the fever response to this immunogen is almost completely suppressed. We have shown in males that obesity exacerbates sickness responses to pathogenic stimuli, thus here we investigated whether obesity would have a si...

Aging is associated with altered immune responses to stimuli such as lipopolysaccharide (LPS) and a mitochondrial decline is proposed to be a main underlying factor in age-related diseases. Recently, rosiglitazone (RZG), a peroxisome proliferator-activated receptor (PPAR) gamma agonist was shown to exert anti-inflammatory properties and to induce a...

Maternal inflammation during critical stages of gestation is thought to underlie the link between prenatal infection and several neurodevelopmental psychiatric disorders in the offspring, including schizophrenia. Increased activity of mesolimbic dopamine (DA) neurons, a hallmark of psychosis, is found in offspring of rodents exposed to a prenatal i...

Interleukin-(IL)6 is the most prominent circulating cytokine induced by systemic infection and inflammation, and the main humoral mediator to the brain in fever. We have previously demonstrated that the PG-pathway, the ultimate step in fever generation, is activated by circulating IL-6 by triggering the expression of the rate limiting enzyme cycloo...

Glucocorticoids (GCs) are released in response to immune activation by the bacterial endotoxin, lipopolysaccharide (LPS). However, GC secretion in response to immune activation and other stressors is attenuated at term of pregnancy. GCs are important modulators of the immune response, and both pro- and anti-inflammatory effects are described. Here,...

Rats injected with lipopolysaccharide (LPS) show brain-controlled sickness symptoms, including fever. In these animals, early genomic activation of brain cells was previously monitored by immunohistochemical detection of transcription factors such as nuclear factor (NF)-κB or signal transducer and activator of transcription (STAT)3 and was linked t...

Maternal infection during human pregnancy has been associated with the development of schizophrenia in the adult offspring. The stage of development and the maternal inflammatory response to infection, which undergoes quantitative and qualitative changes throughout gestation, are thought to determine critical windows of vulnerability for the develo...

A decrease in leptin levels with the onset of starvation triggers a myriad of physiological responses including immunosuppression and hypometabolism/hypothermia, both of which can counteract the fever response to pathogens. Here we examined the role of leptin in LPS-induced fever in rats that were fasted for 48 h prior to inflammation with or witho...

Nuclear factor interleukin 6 is a new delayed ealy cell activation marker in the rat brain during the time course of LPS-induced systemic inflammation Rats, injected with lipopolysaccharide (LPS), show brain-controlled sickness type responses such as fever, linked to early genomic brain-cell activation. This was previously monitored by immunohistoc...

Inflammatory response remained intact in iron supplemented mothers. (A) Febrile response followed the same kinetics in vehicle and iron supplemented mothers, peaking at 10 h after TURP injection and returning to baseline 24 h later. Basal temperature was not affected by iron supplementation. (B and C) Serum IL-6 and IL-1ra levels followed the same...

Maternal infection during pregnancy has been associated with increased incidence of schizophrenia in the adult offspring. Mechanistically, this has been partially attributed to neurodevelopmental disruption of the dopamine neurons, as a consequence of exacerbated maternal immunity. In the present study we sought to target hypoferremia, a cytokine-i...

The appetite suppressing hormone, leptin is now established as an important component of the immune response to pathogens partly via the induction of brain IL-1beta. We have previously demonstrated that this hormone acts on microglia to induce the release of IL-1beta through actions on its functional receptors. In the present study, we extended the...

The appetite suppressing hormone leptin has emerged as an important modulator of immune function and is now considered to be a critical link between energy balance and host defense responses to pathogens. These 'adaptive' responses can, in situations of severe and sustained systemic inflammation, lead to adverse effects including brain damage that...

Recent evidence suggests that inflammation may be a common underlying cause of many obesity-associated conditions. To test whether obesity changes the response to inflammation, we investigated its effects on the acute phase of the inflammatory response to an endogenous pathogen, lipopolysaccharide (LPS). Diet-induced obese male Wistar rats exhibite...

Studies investigating the association between low cholesterol and suicidality have generated a range of ideas about how cholesterol might play a role in influencing suicide risk, extending studies to other aspects of lipid metabolism, as well as immune response, in relation to suicide. We performed large-scale microarray gene expression analysis us...

Maternal infection during pregnancy has been associated with an increased risk for the development of schizophrenia, a disorder characterized by abnormalities in hippocampal morphology and function. Neurogenesis occurs in the hippocampus throughout development into adulthood and is believed to modulate hippocampal function. This study used a rat mo...

Although receptors for the pro-inflammatory cytokine interleukin-1 have long been known to be expressed in the brain, their role in fever and behavioural depression observed during the acute phase response (APR) to tissue infection remains unclear. This may in part be due to the fact that interleukin-1 in the brain is bioactive only several hours a...

This study aimed to address the relative contributions of the proinflammatory cytokine interleukin-6 (IL-6) and the cytokine-like hormone leptin to the genomic activation of brain cells during lipopolysaccharide (LPS)-induced systemic inflammation. Wildtype and IL-6KO mice were injected with LPS (50 microg/kg, intraperitoneally) and the brains anal...

The main cause of hypoxic/ischemic brain damage in term human neonates is intrauterine asphyxia, in which the whole body is subjected to hypoxia. Inflammatory cytokines are thought to play an important role in modulating hypoxic/ischemic damage in immature brain. Evidence for this from animal models is based mainly on studies that used a model of c...

Prenatal exposure to infection is known to affect brain development and has been linked to increased risk for schizophrenia. The goal of this study was to investigate whether maternal infection and associated fever near term disrupts synaptic transmission in the hippocampus of the offspring. We used LPS to mimic bacterial infection and trigger the...

Acute starvation attenuates the fever response to pathogens in several mammalian species. The underlying mechanisms responsible for this effect are not fully understood but may involve a compromised immune and/or thermoregulatory function, both of which are prerequisites for fever generation. In the present study, we addressed whether the impaired...

An attenuated fever response to pathogens during late pregnancy is a phenomenon that has been described in several mammalian species, and although mechanisms are not completely understood, decreased prostaglandin E2 (PGE2) synthesis has been implicated. Upstream of PGE2, there is evidence to suggest that anti-inflammatory cytokines such as interleu...

Maternal infection during pregnancy is a risk factor for some psychiatric illnesses of neurodevelopmental origin such as schizophrenia and autism. In experimental animals, behavioral and neuropathological outcomes relevant to schizophrenia have been observed in offspring of infected dams. However, the type of infectious agent used and gestational a...

Leptin regulates energy balance by suppressing appetite and increasing energy expenditure through actions in the hypothalamus. Recently we demonstrated that the effects of leptin are, at least in part, mediated by the release of interleukin (IL)-1beta in the brain. Microglia constitute the major source of IL-1beta in the brain but it is not known w...

Leptin, the product of the obese (ob) gene, is mainly known for its regulatory role of energy balance by direct activation of hypothalamic receptors. Recently, its function in the acute control of food intake was additionally attributed to activation of the vagus nerve to regulate meal termination. Whether vagal afferent neurones are involved in lo...

Febrile responses to bacterial pathogens are attenuated near term of pregnancy in several mammalian species. It is unknown, however, whether this reflects a fundamental physiological adaptation of female rats or whether it is specific to pregnancy. The aims of this study therefore were 1) to determine whether febrile responses to the bacterial endo...

An association between low levels of serum cholesterol and violent or suicidal behaviour has frequently been reported, but it remains unclear how cholesterol in the peripheral system might be related to the brain functions involved in mediating suicidal behaviour. To our knowledge, there have been no previous studies aimed at answering the importan...

Interleukin (IL)-6 is an important humoral mediator of fever following infection and inflammation and satisfies a number of criteria for a circulating pyrogen. However, evidence supporting such a role is diminished by the moderate or even absent ability of the recombinant protein to induce fever and activate the cyclooxygenase-2 (COX-2) pathway in...

In addition to its central effects on appetite regulation, leptin has been implicated in immune function and inflammation. Previous data suggested that leptin acts as an inflammatory signal within the brain, as exogenously administered leptin induced fever, a typical brain-regulated inflammatory response. The present study aimed to delineate the in...

Maternal infections with bacterial or viral agents during pregnancy are associated with an increased incidence of schizophrenia in the offspring at adulthood although little is known about the mechanism by which maternal infection might affect fetal neurodevelopment. Exposure of pregnant rodents to the bacterial endotoxin, lipopolysaccharide (LPS),...

Chronic inflammation has been reported to be a significant factor in the induction and progression of a number of chronic neurological disorders including Alzheimer's disease and Down syndrome. It is believed that inflammation may promote synaptic dysfunction, an effect that is mediated in part by pro-inflammatory cytokines such as interleukin-1bet...

Anorexia and fever are important features of the host's response to inflammation that can be triggered by the bacterial endotoxin lipopolysaccharide (LPS) and the appetite suppressant leptin. Previous studies have demonstrated that LPS induces leptin synthesis and secretion in the periphery, and that the action of leptin on appetite suppression and...

Polyinosinic:polycytidylic acid (poly I:C) is a synthetic double-stranded RNA that is used experimentally to model viral infections in vivo. Previous studies investigating the inflammatory properties of this agent in rodents demonstrated that it is a potent pyrogen. However, the mechanisms underlying this response have not been fully elucidated. In...

An increased incidence of schizophrenia has been associated with several perinatal insults, most notably maternal infection during pregnancy and perinatal hypoxia. This study used a rat model to directly test if maternal exposure to bacterial endotoxin (lipopolysaccharide, LPS) during pregnancy alters behaviors relevant to schizophrenia, in offspri...

Interleukin (IL)-18, a member of the IL-1 family, is a key mediator of peripheral inflammation and host defense responses, and has been implicated in inflammatory and neurodegenerative diseases in the brain. IL-18 acts via a receptor complex that closely resembles that of IL-1, consisting of a ligand binding protein, IL-18Ralpha, and an accessory p...

Increased incidence of schizophrenia has been observed following maternal infections with either viral or bacterial pathogens during pregnancy. This suggests that infection during pregnancy might contribute to the pathophysiology of schizophrenia through adverse effects on brain development. Animal models in which live viruses, bacterial endotoxin...

Interleukin (IL)-18, a member of the IL-1 family, is a key mediator of peripheral inflammation and host defense responses, and has been implicated in inflammatory and neurodegenerative diseases in the brain. IL-18 acts via a receptor complex that closely resembles that of IL-1, consisting of a ligand binding protein, IL-18Rα, and an accessory prote...

Interleukin (IL)-18, a member of the IL-1 cytokine family, is an important mediator of peripheral inflammation and host defence responses. IL-1 is a key proinflammatory cytokine in the brain, but the role of IL-18 in the CNS is not yet clear. The objective of this study was to investigate the actions of IL-18 on mouse glial cells. IL-18 induced int...

There is now extensive evidence to show that the cytokine interleukin-1 (IL-1) contributes directly to reversible and permanent ischemic brain damage in rodents. Because interleukin-18 (IL-18) shares many structural and functional similarities with IL-1, the authors tested the hypothesis that IL-18 contributes directly to ischemic brain damage in m...

Interleukin (IL)-18 is a pro-inflammatory cytokine that plays a critical role in inflammation leading to liver damage, through promotion of Fas-mediated apoptosis. Inhibition of IL-18 activity protects against LPS-induced lethality in mice and against liver damage induced by LPS after sensitisation of mice with Proprionibacterium acnes. A specific,...

Interleukin (IL)-1 is an important mediator of acute brain injury and inflammation, and has been implicated in chronic neurodegeneration. The main source of IL-1 in the CNS is microglial cells, which have also been suggested as targets for its action. However, no data exist demonstrating expression of IL-1 receptors [IL-1 type-I receptor (IL-1RI),...

Interleukin-1 (IL-1) has been implicated in neurodegeneration and in central nervous system (CNS)-mediated host defence responses to inflammation. All actions of IL-1 identified to date appear to be mediated through its only known functional type I receptor (IL-1RI). However, our recent evidence suggests that some actions of IL-1 in the brain may b...

The cytokine interleukin-1beta (IL-1beta) contributes to ischemic, excitotoxic, and traumatic brain injury. IL-1beta actions depend on interaction with a single receptor (IL-1RI), which associates with an accessory protein (IL-1RAcP), and is blocked by IL-1 receptor antagonist (IL-1ra). Here we show that in normal mice [wild-type (WT)], intracerebr...

The cytokine interleukin-1

1. Interleukin (IL)-1 is a mediator of host defence responses to inflammation and injury, including fever, but its sites of synthesis and action have not been fully elucidated. The actions of IL-1 are antagonised by IL-1 receptor antagonist (IL-1ra). The present study tested the hypothesis that IL-1 and IL-1ra are produced locally at sites of perip...

The cytokine interleukin 1 (IL-1) has diverse actions in the brain. In normal brain the IL-1 system is expressed at low levels and is upregulated rapidly in response to local or peripheral insults. IL-1 mediates host defence responses to local and systemic disease and injury (e.g. fever, slow-wave sleep, appetite suppression and neuroendocrine resp...

A novel pre-formed pyrogenic factor (PFPF), released by LPS-stimulated macrophages, has been identified, that induces an indomethacin-resistant fever. Its activity has to date not been found to match that of any described cytokine. In this study we observed that PFPF induced the release of large amounts of IL-6 from rat peritoneal macrophages. A co...

Cytokines act on the brain to induce fever and behavioural depression after infection. Although several mechanisms of cytokine-to-brain communication have been proposed, their physiological significance is unclear. We propose that behavioural depression is mediated by the vagus nerve activating limbic structures, while fever would primarily be due...

Vagal afferent signals, have been implicated in cytokine mediated interactions between the periphery and the central nervous system. Studies in experimental animals have shown that cytokine induced activation of brain mediated responses to infection such as fever, sickness behaviour and pituitary-adrenal activation, are inhibited by subdiaphragmati...