Peripheral Administration Of Lipopolysaccharide Research Articles

Evaluation of Ketamine after subacute low dosage Lipopolysaccharide-activated Microglia produced depressive-like phenotype in mice

Depression is a common mental illness, with an estimated 3.8% of global population affected. Peripheral administration of lipopolysaccharide (LPS) culminate in a distinct depressive-like behavioral syndrome, measured by increased duration of immobility in the forced swim test (FST) and anhedonia in sucrose preference tests (SPT). After 6 days of LPS stimulation, we established a depression model in C57BL/6 mice, where animals started to recover from the B/W loss brought on by the LPS and the significant immunological response that resulted in microglial activation in the brain. There was a modulation in the relative weight of the thymus and spleen observed under these experimental conditions. Ketamine having a quick onset of action reduces the emergence of depressive-like behaviour by modifying the intensity of Iba-1 in stressed mice by reducing swimming behaviour and boosting desire for sucrose. However, it did not result in an improvement in the number of microglia or CD11b cells activation in the hippocampus of C57BL/6 mice or in the relative weights of the spleen and thymus. In summary, these data emphasizes that Ketamine treatment improves depressive-like behavior and Iba-1 immunoreactivity, but the hyperactive in terms of number of microglia and CD11b expression were not modulated in the mouse hippocampus.

Dexpramipexole ameliorates cognitive deficits in sepsis-associated encephalopathy through suppressing mitochondria-mediated pyroptosis and apoptosis.

This study was aimed at evaluating the effects of dexpramipexole (DPX) - a mitochondrial protectant that sustains mitochondrial function and energy production - on cognitive function in a mouse model of sepsis-associated encephalopathy (SAE) induced by peripheral administration of lipopolysaccharide (LPS) and examining the potential mechanisms. C57BL/6 male mice were randomized into one of four treatment protocols: Con+Sal, Con+DPX, LPS+Sal or LPS+DPX. The mice were intraperitoneally (i.p.) injected with LPS or equivalent volumes of normal saline once daily for 3 consecutive days. To evaluate the protective effects of DPX, we administered DPX or normal saline i.p. to the mice once daily for 6 consecutive days. Six mice in each group were decapitated on day 7, and each brain was rapidly removed and separated into two halves for biochemical and histochemical analysis. The remaining surviving mice in each group were subjected to behavioral tests from days 7 to 10. Peripheral administration of LPS to mice led to learning and memory deficits in behavioral tests, which were associated with mitochondrial impairment and ATP depletion in the hippocampus. Repeated DPX treatment protected the mitochondria against LPS-induced morphological and functional impairment; inhibited the activation of the Nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome-caspase-1-dependent pyroptosis pathway and cytochrome c (Cyt-c)-caspase-3-dependent apoptosis pathway; and attenuated LPS-induced neuroinflammation and cell death in the hippocampus in SAE mice. Mitochondria-mediated pyroptosis and apoptosis are involved in the pathogenesis of cognitive deficits in a mouse model of SAE and DPX protects mitochondria and suppresses the mitochondria-medicated pyroptosis and apoptosis pathways, and ameliorates LPS-induced neuroinflammation and cognitive deficits. This study provides theoretical evidence supporting DPX for the treatment of SAE.

Effects of peripheral administration of lipopolysaccharide on chronic sickness responses in TRPM8-deficient mice

Transient receptor potential melastatin 8 (TRPM8) is a cold-sensing thermoreceptor cation channel; however, its functional role in endotoxin-induced neuroinflammation remains unclear. In the present study, we investigated chronic sickness responses in TRPM8 knockout (KO) mice during lipopolysaccharide (LPS)-induced sepsis. The intraperitoneal administration of 5 mg/kg LPS generated longer-lasting hypothermia in TRPM8 KO mice than in wild-type (WT) mice. TRPM8 KO mice also exhibited longer-lasting declines in locomotor activity, body weight, and food and water intakes than WT mice upon LPS administration. In addition, LPS-induced decreases in the numbers of leucocytes and lymphocytes that persisted for a longer time in TRPM8 KO mice than in WT mice. The present results indicate TRPM8 attenuated chronic sickness responses in endotoxin-induced sepsis.

Investigation of the optimal dose for experimental lipopolysaccharide-induced recognition memory impairment: behavioral and histological studies.

Lipopolysaccharide (LPS) administration is one of the most commonly used methods for inducing inflammation in animal models. Several animal studies have investigated the effects of acute and chronic peripheral administration of LPS on cognitive impairment. However, no previous study has compared the effects of different doses of chronically administered LPS on recognition memory performance. Here, we aimed to investigate the optimal dose of chronically administered LPS for the induction of recognition memory impairment in mice. LPS at different doses (0.25, 0.50 and 0.75 mg/kg) was administered to SWR/J mice daily for 7 days. On day 9, the open field, novel object recognition and novel arm discrimination behavioral tests were performed. Additionally, prefrontal cortical histological examination was conducted. Compared with the control group, mice injected with 0.75 mg/kg LPS notably showed no object preference (familiar vs. novel), a reduction in the discrimination index, and spatial recognition impairment. Administration of the 0.25 and 0.50 mg/kg doses of LPS showed a preference for the novel object compared with the familiar object, had no significant impact on the discrimination index, and caused spatial recognition impairment. These behavioral results are in line with the histological examination of the prefrontal cortex, which revealed that the 0.75 mg/kg dose produced the most histological damage. Our findings suggest that for chronic peripheral administration of LPS, 0.75 mg/kg is the optimal dose for inducing neuroinflammation-associated recognition memory deficits.

Microglial proliferation attenuates sickness responses in adult mice during endotoxin-induced inflammation

We previously reported that the single peripheral administration of lipopolysaccharide (LPS) induced robust and transient microglial proliferation or increased the microglial population in the circumventricular organs (CVOs) and other regions, including the hypothalamus, medulla oblongata, and limbic system. However, the functional significance of an increased microglial population during endotoxin-induced inflammation remains unclear. The present study showed microglial proliferation in the mouse brain during inflammation induced by 50 mg/kg zymosan, 160 nmol/kg prostaglandin E2, and 5 mg/kg LPS. The inhibition of LPS-induced microglial proliferation with a continuous i.c.v. infusion of mitotic inhibitor cytosine arabinoside (AraC) caused persistent decreases in body weight and food and water intakes. The continuous infusion of AraC also prolonged LPS-induced sickness responses, such as lower locomotor activity and core body temperature. Collectively, the present results indicate that a transient increase in the microglial population is beneficial during endotoxin-induced inflammation in the mouse brain because it attenuates sickness responses.

Neuroprotective and Anti-Microglial Activation Effects of Tocotrienols in Brains of Lipopolysaccharide-Induced Inflammatory Model Mice

Inflammation is the cause and/or result of many diseases in peripheral tissues and the central nervous system. Recent findings suggested that inflammation in peripheral tissue induces an inflammatory response in the brain that activates glial cells, which, in turn, induce neuronal cell dysfunction. Therefore, anti-inflammatory compounds are important for the suppression of chronic inflammation and prevention of disease. The present study revealed microglial activation in the hippocampus of the brain two days after the peripheral administration of lipopolysaccharide (LPS). Furthermore, the expression of the synaptic vesicle membrane protein, synaptophysin, in the CA3 stratum lucidum of the hippocampus was down-regulated 7 days after the LPS injection. The administration of tocotrienols, a type of vitamin E, significantly attenuated these changes in the hippocampus. Collectively, the present results demonstrated the spread of peripheral inflammatory responses to the brain, in which glial activation and neuronal dysfunction were induced, while tocotrienols exerted anti-inflammatory effects and protected neurons from damage.

Effect of tetrahedral DNA nanostructures on LPS‐induced neuroinflammation in mice

Neuroinflammation plays a significant role in inducing depression-like behavior. Tetrahedral DNA nanostructures (TDNs) are molecules that exhibit anti-inflammatory properties and can effectively penetrate the blood-brain barrier. Thus, researchers have hypothesized that TDNs regulate the secretion of proinflammatory cytokines and consequently alleviate depression-like behavior. To test this hypothesis, we investigated the effect of TDNs on the depression-like behavior of C57 mice induced by lipopolysaccharide (LPS). We performed open-field, tail suspension, and sucrose preference tests on LPS- and LPS/TDN-treated mice. The results indicated that the injection of TDNs into LPS-treated mice resulted in increased velocity, center zone duration, frequency to the center zone, and sucrose preference, and decreased immobility time. Immunofluorescence results indicated that peripheral administration of LPS in the mice activated inflammation, which culminated in distinct depression-like behavior. However, TDNs effectively alleviated the inflammation and depression-like behavior through the reduction of the expression levels of proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α in the brain. Additionally, TDNs normalized the expression level of microglia cell activation markers, such as ionized calcium binding adaptor molecule 1, in the hippocampus of mice. These results indicated that TDNs attenuated the LPS-induced secretion of inflammatory factors and consequently alleviated depression-like behavior.

Intravenous administration of LPS activates the kynurenine pathway in healthy male human subjects: a prospective placebo-controlled cross-over trial

BackgroundAdministration of lipopolysaccharide (LPS) from Gram-negative bacteria, also known as the human endotoxemia model, is a standardized and safe model of human inflammation. Experimental studies have revealed that peripheral administration of LPS leads to induction of the kynurenine pathway followed by depressive-like behavior and cognitive dysfunction in animals. The aim of the present study is to investigate how acute intravenous LPS administration affects the kynurenine pathway in healthy male human subjects.MethodsThe present study is a prospective, single-blinded, randomized, placebo-controlled cross-over study to investigate the effects of intravenously administered LPS (Escherichia coli O113, 2 ng/kg) on tryptophan and kynurenine metabolites over 48 h and their association with interleukin-6 (IL-6) and C-reactive protein (CRP). The study included 10 healthy, non-smoking men (18–40 years) free from medication. Statistical differences in tryptophan and kynurenine metabolites as well as associations with IL-6 and CRP in LPS and placebo treated subjects were assessed with linear mixed-effects models.ResultsSystemic injection of LPS was associated with significantly lower concentrations of plasma tryptophan and kynurenine after 4 h, as well as higher concentrations of quinolinic acid (QUIN) after 48 h compared to the placebo injection. No differences were found in kynurenic acid (KYNA) or picolinic acid plasma concentrations between LPS or placebo treatment. The KYNA/kynurenine ratio peaked at 6 h post LPS injection while QUIN/kynurenine maintained significantly higher from 3 h post LPS injection until 24 h. The kynurenine/tryptophan ratio was higher at 24 h and 48 h post LPS treatment. Finally, we report an association between the kynurenine/tryptophan ratio and CRP.ConclusionsOur findings strongly support the concept that an inflammatory challenge with LPS induces the kynurenine pathway in humans, activating both the neurotoxic (QUIN) and neuroprotective (KYNA) branch of the kynurenine pathway.Trial registrationThis study is based on a study registered at ClinicalTrials.gov, NCT03392701. Registered 21 December 2017.

Central Activation of Alpha7 Nicotinic Signaling Attenuates LPS-Induced Neuroinflammation and Sickness Behavior in Adult but Not in Aged Animals.

We previously reported that lipopolysaccharide (LPS) challenge caused microglial-mediated neuroinflammation and sickness behavior that was amplified in aged mice. As α7 nAChRs are implicated in the “Cholinergic anti-inflammatory pathway”, we aimed to determine how α7 nAChR stimulation modulates microglial phenotype in an LPS-induced neuroinflammation model in adult and aged mice. For this, BALB/c mice were injected intraperitoneally with LPS (0.33 mg/kg) and treated with the α7 nAChR agonist PNU282987, using different administration protocols. LPS challenge reduced body weight and induced lethargy and social withdrawal in adult mice. Peripheral (intraperitoneal) co-administration of the α7 nAChR agonist PNU282987 with LPS, attenuated body weight loss and sickness behavior associated with LPS challenge in adult mice, and reduced microglial activation with suppression of IL-1β and TNFα mRNA levels. Furthermore, central (intracerebroventricular) administration of the α7 nAChR agonist, even 2 h after LPS injection, attenuated the decrease in social exploratory behavior and microglial activation induced by peripheral administration of LPS, although this recovery was not achieved if activation of α7 nAChRs was performed peripherally. Finally, we observed that the positive results of central activation of α7 nAChRs were lost in aged mice. In conclusion, we provide evidence that stimulation of α7 nAChR signaling reduces microglial activation in an in vivo LPS-based model, but this cholinergic-dependent regulation seems to be dysfunctional in microglia of aged mice.

Microglial Ultrastructure in the Hippocampus of a Lipopolysaccharide-Induced Sickness Mouse Model.

Sickness behavior is a set of behavioral changes induced by infections and mediated by pro-inflammatory cytokines. It is characterized by fatigue, decreased appetite and weight loss, changes in sleep patterns, cognitive functions, and lost interest in social activity. It can expedite recovery by conserving energy to mount an immune response involving innate immunity. To provide insights into microglial implication in sickness behavior with special focus on cognitive and social impairment, we investigated changes in their ultrastructure and interactions with synapses using a toxemia mouse model. Adult mice were injected with 1 mg/kg lipopolysaccharide (LPS) or saline, and assayed for signs of sickness behavior. LPS treated mice displayed reduced activity in open-field tests 24 h post-injection, while social avoidance and weight gain/loss were not significantly different between treatment groups. Microglia were investigated using electron microscopy to describe changes in their structure and function at nanoscale resolution. Microglial cell bodies and processes were investigated in the hippocampus CA1, a region responsible for learning and memory that is often impacted after peripheral LPS administration. Microglia in LPS treated animals displayed larger cell bodies as well as less complex processes at the time point examined. Strikingly, microglial processes in LPS injected animals were also more likely to contact excitatory synapses and contained more phagocytic material compared with saline injected controls. We have identified at the ultrastructural level significant changes in microglia-synapse interactions shortly after LPS administration, which draws attention to studying the roles of microglia in synaptic rewiring after inflammatory stimuli.

Interactive effects of peripheral and central administration of LPS with inhibition of CRF receptors on food intake in neonatal chicks

Anorexia is a part of the acute phase response (APR). Lipopolysaccharide (LPS) is frequently used to mimic APR and induces anorexia. The mechanism underlying anorexia associated with APR in chicks is not well understood. In the present study, the possible involvement of corticotrophin-releasing factor (CRF) on anorexic effects of LPS in neonatal chicks was investigated. For this aim, different doses of LPS were administrated via both intracerebroventricular (ICV) and intraperitoneal (IP) routes in order to assess its effects on chick’s food intake. Subsequently, the effect of ICV injection of astressin, a CRF receptor antagonist, on anorexia induced by ICV and IP administration of LPS was investigated. Food intake was significantly decreased following either central or systemic administration of LPS. ICV co -injection of astressin and LPS significantly diminished anorexic effects of central LPS. However, anorexia induced by peripheral LPS was not attenuated by central injection of astressin. These data indicated that the brain CRF receptors are involved in central LPS-induced anorexia in chicks.

The differential impact of acute microglia activation on the excitability of cholinergic neurons in the mouse medial septum.

The medial septal nucleus is one of the basal forebrain nuclei that projects cholinergic input to the hippocampus and cortex. Two of the hallmarks of Alzheimer's disease (AD) are a significant loss of cholinergic transmission and neuroinflammation, and it has been suggested that these two hallmarks are causally linked to the medial septum. Therefore, we have investigated the age-related susceptibility of medial septal cholinergic neurons to glial activation, mediated via peripheral administration of lipopolysaccharide (500μg/kg) into ChAT(BAC)-eGFP mice at different ages (3-22months). Our results show that during normal aging, cholinergic neurons experience a bi-phasic excitability profile, in which increased excitability at adulthood (ages ranging between 9 and 12months) decreases in aged animals (> 18months). Moreover, activation of glia had a differential impact on mice from different age groups, affecting K+ conductances in young and adult animals, without affecting aged mice. These findings provide a potential explanation for the increased vulnerability of cholinergic neurons to neuroinflammation with aging as reported previously, thus providing a link to the impact of acute neuroinflammation in AD.

Lipopolysaccharide Increases Cortical Kynurenic Acid and Deficits in Reference Memory in Mice.

Kynurenic acid (KYNA), a glial-derived metabolite of tryptophan metabolism, is an antagonist of the alpha 7 nicotinic acetylcholine receptor and the glycine-binding site of N-methyl-d-aspartate (NMDA) receptors. Kynurenic acid levels are increased in both the brain and cerebrospinal fluid of several psychiatric disorders including bipolar disorder, schizophrenia, and Alzheimer disease. In addition, pro-inflammatory cytokines have been found to be elevated in the blood of schizophrenic patients suggesting inflammation may play a role in psychiatric illness. As both pro-inflammatory cytokines and KYNA can be elevated in the brain by peripheral lipopolysaccharide (LPS) injection, we therefore sought to characterize the role of neuroinflammation on learning and memory using a well-described dual-LPS injection model. Mice were injected with an initial injection (0.25 mg/kg LPS, 0.50 mg/kg, or saline) of LPS and then administrated a second injection 16 hours later. Our results indicate both 0.25 and 0.50 mg/kg dual-LPS treatment increased l-kynurenine and KYNA levels in the medial pre-frontal cortex (mPFC). Mice exhibited impaired acquisition of CS+ (conditioned stimulus) Pavlovian conditioning. Notably, mice showed impairment in reference memory while working memory was normal in an 8-arm maze. Taken together, our findings suggest that neuroinflammation induced by peripheral LPS administration contributes to cognitive dysfunction.

Dietary n-3 long chain PUFA supplementation promotes a pro-resolving oxylipin profile in the brain

The brain is highly enriched in long chain polyunsaturated fatty acids (LC-PUFAs) that display immunomodulatory properties in the brain. At the periphery, the modulation of inflammation by LC-PUFAs occurs through lipid mediators called oxylipins which have anti-inflammatory and pro-resolving activities when derived from n-3 LC-PUFAs and pro-inflammatory activities when derived from n-6 LC-PUFAs. However, whether a diet rich in LC-PUFAs modulates oxylipins and neuroinflammation in the brain has been poorly investigated. In this study, the effect of a dietary n-3 LC-PUFA supplementation on oxylipin profile and neuroinflammation in the brain was analyzed. Mice were given diets deficient or supplemented in n-3 LC-PUFAs for a 2-month period starting at post-natal day 21, followed by a peripheral administration of lipopolysaccharide (LPS) at adulthood. We first showed that dietary n-3 LC-PUFA supplementation induced n-3 LC-PUFA enrichment in the hippocampus and subsequently an increase in n-3 PUFA-derived oxylipins and a decrease in n-6 PUFA-derived oxylipins. In response to LPS, n-3 LC-PUFA deficient mice presented a pro-inflammatory oxylipin profile whereas n-3 LC-PUFA supplemented mice displayed an anti-inflammatory oxylipin profile in the hippocampus. Accordingly, the expression of cyclooxygenase-2 and 5-lipoxygenase, the enzymes implicated in pro- and anti-inflammatory oxylipin synthesis, was induced by LPS in both diets. In addition, LPS-induced pro-inflammatory cytokine increase was reduced by dietary n-3 LC-PUFA supplementation. These results indicate that brain n-3 LC-PUFAs increase by dietary means and promote the synthesis of anti-inflammatory derived bioactive oxylipins. As neuroinflammation plays a key role in all brain injuries and many neurodegenerative disorders, the present data suggest that dietary habits may be an important regulator of brain cytokine production in these contexts.

Implications of Systemic Inflammation and Periodontitis for Major Depression.

Increasing evidence suggests that infection and persistent low-grade inflammation in peripheral tissues are important pathogenic factors in major depression. Major depression is frequently comorbid with systemic inflammatory diseases/conditions such as rheumatoid arthritis, allergies of different types, multiple sclerosis, cardiovascular disease, inflammatory bowel disease, chronic liver disease, diabetes, and cancer, in which pro-inflammatory cytokines are overexpressed. A number of animal studies demonstrate that systemic inflammation induced by peripheral administration of lipopolysaccharide increases the expression of pro-inflammatory cytokines in both the periphery and brain and causes abnormal behavior similar to major depression. Systemic inflammation can cause an increase in CNS levels of pro-inflammatory cytokines associated with glial activation, namely, neuroinflammation, through several postulated pathways. Such neuroinflammation can in turn induce depressive moods and behavioral changes by affecting brain functions relevant to major depression, especially neurotransmitter metabolism. Although various clinical studies imply a causal relationship between periodontitis, which is one of the most common chronic inflammatory disorders in adults, and major depression, the notion that periodontitis is a risk factor for major depression is still unproven. Additional population-based cohort studies or prospective clinical studies on the relationship between periodontitis and major depression are needed to substantiate the causal link of periodontitis to major depression. If such a link is established, periodontitis may be a modifiable risk factor for major depression by simple preventive oral treatment.

Fish oil ameliorates sickness behavior induced by lipopolysaccharide in aged mice through the modulation of kynurenine pathway

Sickness behavior is an expression of a central motivational state triggered by activation of the immune system, being considered a strategy of the organism to fight infection. Sickness behavior is induced by peripheral administration of lipopolysaccharide (LPS). LPS can increase the levels of proinflammatory cytokines, which induce the activation of the kynurenine pathway (KP) and behavioral alterations. Previous studies have shown that omega-3 (n-3) polyunsaturated fatty acid (PUFA) has anti-inflammatory properties. Because of this, the purpose of the present study was to evaluate the protective effect of fish oil (FO) supplementation against LPS-induced sickness behavior in aged mice with respect to anhedonia, locomotor activity and body weight. Moreover, we evaluated the ability of FO treatment on the regulation of neuroinflammation (levels of interleukin-1β, interleukin-6, tumor factor necrosis-α and interferon-γ), KP biomarkers (levels of tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine and quinolinic acid and activities of indoleamine-2,3-dioxygenase, kynurenine monooxygenase and kynurenine aminotransferase) and serotonergic system (levels of serotonin and 5-hydroxyindoleactic acid) in the hippocampus, striatum and prefrontal cortex of LPS-treated mice. We found that FO prevented the LPS-mediated body weight loss, anhedonic behavior, reduction of locomotor activity, up-regulation of the proinflammatory cytokines and serotoninergic alterations. We also found that FO was effective in modulating the KP biomarkers, inhibiting or attenuating KP dysregulation induced by LPS. Together, our results indicated that FO may have beneficial effects on LPS induced sickness-behavior in aged mice either by modulating central inflammation, KP and serotonergic signaling (indirectly effect) or by fatty acids incorporation into neuronal membranes (direct effect).

Inhibition of Phosphodiesterase 4 by FCPR03 Alleviates Lipopolysaccharide-Induced Depressive-Like Behaviors in Mice: Involvement of p38 and JNK Signaling Pathways.

Inflammatory responses induced by peripheral administration of lipopolysaccharide (LPS) triggers depressive-like behavioral syndrome in rodents. Inhibition of phosphodiesterase 4 (PDE4) produces a robust anti-inflammatory effect in inflammatory cells. Unfortunately, archetypal PDE4 inhibitors cause intolerable gastrointestinal side-effects, such as vomiting and nausea. N-isopropyl-3-(cyclopropylmethoxy)-4-difluoromethoxy benzamide (FCPR03) is a novel, selective PDE4 inhibitor with little, or no, emetic potency. Our previous studies show that FCPR03 is effective in attenuating neuroinflammation in mice treated with LPS. However, whether FCPR03 could exert antidepressant-like effect induced by LPS is largely unknown. In the present study, mice injected intraperitoneally (i.p.) with LPS was established as an in vivo animal model of depression. The antidepressant-like activities of FCPR03 were evaluated using a tail suspension test, forced swimming test, and sucrose preference test. We demonstrated that administration of FCPR03 (1 mg/kg) produced antidepressant-like effects in mice challenged by LPS, as evidenced by decreases in the duration of immobility in the forced swim and tail suspension tests, while no significant changes in locomotor activity were observed. FCPR03 also increased sucrose preference in mice treated with LPS. In addition, treatment with FCPR03 abolished the downregulation of brain-derived neurotrophic factor induced by LPS and decreased the level of corticosterone in plasma. Meanwhile, periphery immune challenge by LPS induced enhanced phosphorylation of p38-mitogen activated protein kinase (p38) and c-Jun N-terminal kinase (JNK) in both the cerebral cortex and hippocampus in mice. Interestingly, treatment with FCPR03 significantly blocked the role of LPS and reduced the levels of phosphorylated p38 and JNK. Collectively, these results indicate that FCPR03 shows antidepressant-like effects in mice challenged by LPS, and the p38/JNK signaling pathway is possibly involved in this process. Our findings suggest that FCPR03 is a potential compound for the prevention or treatment of depression.

The Dopamine Receptor D3 Regulates Lipopolysaccharide-Induced Depressive-Like Behavior in Mice.

BackgroundThe altered expression and function of dopamine receptor D3 (D3R) in patients and animal models have been correlated with depression disease severity. However, the morphological alterations and biological effects of D3R in the brain after inflammation-induced depressive-like behavior remain elusive.MethodsIn the present study, we ascertained the changes of D3R expression in the brain regions after depressive-like behavior induced by peripheral administration of lipopolysaccharide (LPS). Protein levels of proinflammatory cytokines, brain-derived neurotrophic factor (BDNF), and extracellular signal-regulated kinase (ERK1/2)-cAMP-response element-binding protein (CREB) signaling pathway after activation or inhibition of D3R in the brain of depressive mice were also investigated.ResultsLPS caused a significant reduction of D3R in the ventral tegmental area (VTA), medial prefrontal cortex (mPFC), and nucleus accumbens (NAc), which are areas related to the mesolimbic dopaminergic system. Pretreatment with pramipexole (PPX), a preferential D3R agonist, showed antidepressant effects on LPS-induced depression-like behavior through preventing changes in LPS-induced proinflammatory cytokines (tumour necrosis factor-α, interleukin-1β, and interleukin-6), BDNF, and ERK1/2-CREB signaling pathway in the VTA and NAc. In opposition, treatment with a D3R selective antagonist NGB 2904 alone made mice susceptible to depression-like effects and caused changes in accordance with the LPS-induced alterations in proinflammatory cytokines, BDNF, and the ERK1/2-CREB signaling pathway in the mPFC and NAc.ConclusionsThese findings provide a relevant mechanism for D3R in LPS-induced depressive-like behavior via its mediation of proinflammatory cytokines and potential cross-effects between BDNF and the ERK1/2-CREB signaling pathway.

Transmission of \u03b1-synuclein-containing erythrocyte-derived extracellular vesicles across the blood-brain barrier via adsorptive mediated transcytosis: another mechanism for initiation and progression of Parkinson\u2019s disease?

Parkinson’s disease (PD) pathophysiology develops in part from the formation, transmission, and aggregation of toxic species of the protein α-synuclein (α-syn). Recent evidence suggests that extracellular vesicles (EVs) may play a vital role in the transport of toxic α-syn between brain regions. Moreover, increasing evidence has highlighted the participation of peripheral molecules, particularly inflammatory species, which may influence or exacerbate the development of PD-related changes to the central nervous system (CNS), although detailed characterization of these species remains to be completed. Despite these findings, little attention has been devoted to erythrocytes, which contain α-syn concentrations ~1000-fold higher than the cerebrospinal fluid, as a source of potentially pathogenic α-syn. Here, we demonstrate that erythrocytes produce α-syn-rich EVs, which can cross the BBB, particularly under inflammatory conditions provoked by peripheral administration of lipopolysaccharide. This transport likely occurs via adsorptive-mediated transcytosis, with EVs that transit the BBB co-localizing with brain microglia. Examination of microglial reactivity upon exposure to α-syn-containing erythrocyte EVs in vitro and in vivo revealed that uptake provoked an increase in microglial inflammatory responses. EVs derived from the erythrocytes of PD patients elicited stronger responses than did those of control subjects, suggesting that inherent characteristics of EVs arising in the periphery might contribute to, or even initiate, CNS α-syn-related pathology. These results provide new insight into the mechanisms by which the brain and periphery communicate throughout the process of synucleinopathy pathogenesis.

Monocytes, microglia, and CD200-CD200R1 signaling are essential in the transmission of inflammation from the periphery to the central nervous system.

Peripheral inflammation is known to trigger neuroinflammation and neurodegenerative disease. However, the key components during the propagation of inflammation from the periphery to the central nervous system (CNS) remain unclear. Lipopolysaccharide (LPS) was administered to Sprague-Dawley rats to induce peripheral inflammation. An intravenous injection and an intranigral injection of clodronate liposomes were given to deplete monocytes and microglia, respectively. Recombinant CD200 fusion protein (CD200Fc) or an anti-CD200R1 antibody was injected into the substantia nigra to manipulate the involvement of CD200 and CD200R1. Immunohistochemistry and immunofluorescence staining were used to measure microglial activation and dopaminergic neuronal loss. The expression of brain pro-inflammatory cytokines (i.e., tumor necrosis factor alpha, IL-1β) and CD200-CD200R1 signaling were measured by quantitative RT-PCR. Our data showed that the peripheral LPS injection activated the microglia and induced an increase in the levels of pro-inflammatory cytokines (i.e., tumor necrosis factor alpha, IL-1β). The depletion of either monocytes or microglia suppressed these inflammatory effects that were induced by peripheral LPS administration. The peripheral LPS injection increased the expression of CD200 and CD200R1 in the substantia nigra. Dopaminergic neuronal loss induced by the peripheral LPS injection was accelerated by the blockade of CD200-CD200R1 signaling with an anti-CD200R1 antibody and attenuated by intensifying the signaling with CD200Fc. These results highlight the importance of monocytes, microglia, and CD200-CD200R1 signaling in the transmission of inflammation from the periphery to the CNS.