Peripheral Inflammatory Diseases Research Articles

Nalmefene, an opioid receptor modulator, aggravates atherosclerotic plaque formation in apolipoprotein E knockout mice by enhancing oxidized low-density lipoprotein uptake in macrophages

Nalmefene, an antagonist of mu- and delta-opioid receptors and a partial agonist of kappa-opioid receptors, has shown promise in reducing alcohol consumption among patients with alcohol dependence. Opioid receptors play pivotal roles in various physiological processes, including those related to peripheral inflammatory diseases such as colitis and arthritis, as well as functions in the immune system and phagocytosis. Atherosclerosis, a chronic inflammatory disease, progresses through the phagocytosis and uptake of oxidized low-density lipoprotein (oxLDL) by macrophages in atherosclerotic plaques. Despite this knowledge, it remains unclear whether nalmefene influences the formation of atherosclerotic plaques and increases the risk of serious cardiovascular events. This study aims to elucidate the impact of nalmefene on atherosclerosis in apolipoprotein E knockout (ApoE KO) mice and peritoneal macrophages in vitro.In this experiment, 8-week-old male ApoE KO mice were fed a high-fat diet intraperitoneally administered either vehicle (saline) or nalmefene (1 mg and 3 mg kg−1 day−1) for 21 days. Oil red O-staining and immunohistochemistry with an anti-MOMA2 (monocyte/macrophage) antibody showed that a dose-dependent increase in atherosclerotic plaque formation and augmentation of macrophage-rich plaque formation in ApoE-KO mice. Further investigations focused on the effects of nalmefene on the expression of scavenger receptor CD36 in RAW264.7 cells, conducted through western blotting analysis. Nalmefene demonstrated a significant increase in CD36 protein expression in RAW264.7 cells. To explore the impact on oxidized LDL uptake in peritoneal macrophages, cells were treated with nalmefene (300 μg/mL) for 24 h, followed by the addition of DiI-labeled oxLDL (DiI-oxLDL) for 4 h. Nalmefene significantly enhanced DiI-oxLDL uptake in macrophages. Additionally, treatment with nalmefene (300 μg/mL) for 24 h decreased the mRNA expression of mu-, delta-, and kappa-opioid receptors in RAW264.7 cells.In conclusion, nalmefene may augment oxLDL uptake by macrophages through increased CD36 expression and decreased opioid receptor, thereby contributing to atherosclerotic plaque formation and vulnerability. Consequently, the use of nalmefene may be associated with an elevated risk of cardiovascular events.

Long-term neurological dysfunction associated with COVID-19: Lessons from influenza and inflammatory diseases?

As the COVID-19 pandemic persists, SARS-CoV-2 infection is increasingly associated with long-term neurological side effects including cognitive impairment, fatigue, depression, and anxiety, colloquially known as "long-COVID." While the full extent of long-COVID neuropathology across years or even decades is not yet known, we can perhaps take direction from long-standing research into other respiratory diseases, such as influenza, that can present with similar long-term neurological consequences. In this review, we highlight commonalities in the neurological impacts of influenza and COVID-19. We first focus on the common potential mechanisms underlying neurological sequelae of long-COVID and influenza, namely (1) viral neurotropism and (2) dysregulated peripheral inflammation. The latter, namely heightened peripheral inflammation leading to central nervous system dysfunction, is emerging as a shared mechanism in various peripheral inflammatory or inflammation-associated diseases and conditions. We then discuss historical and modern examples of influenza- and COVID-19-associated cognitive impairment, depression, anxiety, and fatigue, revealing key similarities in their neurological sequelae. Although we are learning that the effects of influenza and COVID differ somewhat in terms of their influence on the brain, as the impacts of long-COVID grow, such comparisons will likely prove valuable in guiding ongoing research into long-COVID, and perhaps foreshadow what could be in store for individuals with COVID-19 and their brain health.

Evaluation of [18F]RoSMA-18-d6 as a CB2 PET Radioligand in Nonhuman Primates.

The cannabinoid type 2 receptor (CB2) has been implicated in a variety of central and peripheral inflammatory diseases, prompting significant interest in the development of CB2-targeted diagnostic and therapeutic agents. A validated positron emission tomography (PET) radioligand for imaging CB2 in the living human brain as well as in peripheral tissues is currently lacking. As part of our research program, we have recently identified the trisubstituted pyridine, [18F]RoSMA-18-d6, which proved to be highly suitable for in vitro and in vivo mapping of CB2 in rodents. The aim of this study was to assess the performance characteristics of [18F]RoSMA-18-d6 in nonhuman primates (NHPs) to pave the way for clinical translation. [18F]RoSMA-18-d6 was synthesized from the respective tosylate precursor according to previously reported procedures. In vitro autoradiograms with NHP spleen tissue sections revealed a high binding of [18F]RoSMA-18-d6 to the CB2-rich NHP spleen, which was significantly blocked by coincubation with the commercially available CB2 ligand, GW405833 (10 μM). In contrast, no specific binding was observed by in vitro autoradiography with NHP brain sections, which was in agreement with the notion of a CB2-deficient healthy mammalian brain. In vitro findings were corroborated by PET imaging experiments in NHPs, where [18F]RoSMA-18-d6 uptake in the spleen was dose-dependently attenuated with 1 and 5 mg/kg GW405833, while no specific brain signal was observed. Remarkably, we observed tracer uptake and retention in the NHP spinal cord, which was reduced by GW405833 blockade, pointing toward a potential utility of [18F]RoSMA-18-d6 in probing CB2-expressing cells in the bone marrow. If these observations are substantiated in NHP models of enhanced leukocyte proliferation in the bone marrow, [18F]RoSMA-18-d6 may serve as a valuable marker for hematopoietic activity in various pathologies. In conclusion, [18F]RoSMA-18-d6 proved to be a suitable PET radioligand for imaging CB2 in NHPs, supporting its translation to humans.

Cognitive Functions, Neurotransmitter Alterations, and Hippocampal Microstructural Changes in Mice Caused by Feeding on Western Diet.

Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) is the most common chronic liver disease in Western countries. It is becoming increasingly evident that peripheral organ-centered inflammatory diseases, including liver diseases, are linked with brain dysfunctions. Therefore, this study aims to unravel the effect of MASLD on brain histology, cognitive functions, and neurotransmitters. For this purpose, mice fed for 48 weeks on standard (SD) or Western diet (WD) were evaluated by behavioral tests, followed by sacrifice and analysis of the liver-brain axis including histopathology, immunohistochemistry, and biochemical analyses. Histological analysis of the liver showed features of Metabolic Dysfunction-Associated Steatohepatitis (MASH) in the WD-fed mice including lipid droplet accumulation, inflammation, and fibrosis. This was accompanied by an elevation of transaminase and alkaline phosphatase activities, increase in inflammatory cytokine and bile acid concentrations, as well as altered amino acid concentrations in the blood. Interestingly, compromised blood capillary morphology coupled with astrogliosis and microgliosis were observed in brain hippocampus of the WD mice, indicating neuroinflammation or a disrupted neurovascular unit. Moreover, attention was impaired in WD-fed mice along with the observations of impaired motor activity and balance, enhanced anxiety, and stereotyped head-twitch response (HTR) behaviors. Analysis of neurotransmitters and modulators including dopamine, serotonin, GABA, glutamate, and acetylcholine showed region-specific dysregulation in the brain of the WD-fed mice. In conclusion, the induction of MASH in mice is accompanied by the alteration of cellular morphology and neurotransmitter expression in the brain, associated with compromised cognitive functions.

Associations of attention-deficit/hyperactivity disorder with inflammatory diseases. Results from the nationwide German Health Interview and Examination Survey for Children and Adolescents (KiGGS).

Despite conflicting data, some studies have suggested apathophysiological relationship between inflammation and attention-deficit/hyperactivity disorder (ADHD). Using data from the nationwide and representative German Health Interview and Examination Survey for Children and Adolescents (KiGGS; n = 6922 study participants aged 11-17years), this posthoc analysis assessed the associations between ADHD and three common inflammatory diseases. Results showed univariate associations between ADHD and lifetime inflammatory diseases including atopic dermatitis (p = 0.002), otitis media (p = 0.001), and herpes simplex infection (p = 0.032). In logistic regression models adjusted for clinically relevant confounders, we found that ADHD remained asignificant predictor of all three inflammatory diseases (atopic dermatitis, Exp(β) = 1.672, 95% confidence interval [CI] 1.239-2.257, p = 0.001; otitis media, Exp(β) = 1.571, 95% CI 1.209-2.040, p = 0.001; herpes simplex, Exp(β) = 1.483, 95% CI 1.137-1.933, p = 0.004). Our findings demonstrate apositive link between ADHD and peripheral inflammatory diseases, including atopic dermatitis, otitis media, and herpes simplex infection. Further studies are needed to understand the exact pathophysiological mechanisms underlying these associations.

Leukocyte invasion of the brain after peripheral trauma in zebrafish (Danio rerio)

Despite well-known systemic immune reactions in peripheral trauma, little is known about their roles in posttraumatic neurological disorders, such as anxiety, sickness, and cognitive impairment. Leukocyte invasion of the brain, a common denominator of systemic inflammation, is involved in neurological disorders that occur in peripheral inflammatory diseases, whereas the influences of peripheral leukocytes on the brain after peripheral trauma remain largely unclear. In this study, we found that leukocytes, largely macrophages, transiently invaded the brain of zebrafish larvae after peripheral trauma through vasculature-independent migration, which was a part of the systemic inflammation and was mediated by interleukin-1b (il1b). Notably, myeloid cells in the brain that consist of microglia and invading macrophages were implicated in posttraumatic anxiety-like behaviors, such as hyperactivity (restlessness) and thigmotaxis (avoidance), while a reduction in systemic inflammation or myeloid cells can rescue these behaviors. In addition, invading leukocytes together with microglia were found to be responsible for the clearance of apoptotic cells in the brain; however, they also removed the nonapoptotic cells, which suggested that phagocytes have dual roles in the brain after peripheral trauma. More importantly, a category of conserved proteins between zebrafish and humans or rodents that has been featured in systemic inflammation and neurological disorders was determined in the zebrafish brain after peripheral trauma, which supported that zebrafish is a translational model of posttraumatic neurological disorders. These findings depicted leukocyte invasion of the brain during systemic inflammation after peripheral trauma and its influences on the brain through il1b-dependent mechanisms.

MGMT-Methylation in Non-Neoplastic Diseases of the Central Nervous System.

Quantifying O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation plays an essential role in assessing the potential efficacy of alkylating agents in the chemotherapy of malignant gliomas. MGMT promoter methylation is considered to be a characteristic of subgroups of certain malignancies but has also been described in various peripheral inflammatory diseases. However, MGMT promoter methylation levels have not yet been investigated in non-neoplastic brain diseases. This study demonstrates for the first time that one can indeed detect slightly enhanced MGMT promoter methylation in individual cases of inflammatory demyelinating CNS diseases such as multiple sclerosis and progressive multifocal leucencephalopathy (PML), as well as in other demyelinating diseases such as central pontine and exptrapontine myelinolysis, and diseases with myelin damage such as Wallerian degeneration. In this context, we identified a reduction in the expression of the demethylase TET1 as a possible cause for the enhanced MGMT promoter methylation. Hence, we show for the first time that MGMT hypermethylation occurs in chronic diseases that are not strictly associated to distinct pathogens, oncogenic viruses or neoplasms but that lead to damage of the myelin sheath in various ways. While this gives new insights into epigenetic and pathophysiological processes involved in de- and remyelination, which might offer new therapeutic opportunities for demyelinating diseases in the future, it also reduces the specificity of MGMT hypermethylation as a tumor biomarker.

Mapping of Translocator Protein (18 kDa) in Peripheral Sterile Inflammatory Disease and Cancer through PET Imaging.

Positron emission tomography (PET) imaging of the translocator 18 kDa protein (TSPO) with radioligands has become an effective means of research in peripheral inflammatory conditions that occur in many diseases and cancers. The peripheral sterile inflammatory diseases (PSIDs) are associated with a diverse group of disorders that comprises numerous enduring insults including the cardiovascular, respiratory, gastrointestinal, or musculoskeletal system. TSPO has recently been introduced as a potential biomarker for peripheral sterile inflammatory diseases (PSIDs). The major critical issue related to PSIDs is its timely characterization and localization of inflammatory foci for proper therapy of patients. As an alternative to metabolic imaging, protein imaging expressed on immune cells after activation is of great importance. The five transmembrane domain translocator protein-18 kDa (TSPO) is upregulated on the mitochondrial cell surface of macrophages during inflammation, serving as a potential ligand for PET tracers. Additionally, the overexpressed TSPO protein has been positively correlated with various tumor malignancies. In view of the association of escalated TSPO expression in both disease conditions, it is an immensely important biomarker for PET imaging in oncology and PSIDs. In this review, we summarize the most outstanding advances on TSPO-targeted PSIDs and cancer in the development of TSPO ligands as a potential diagnostic tool, specifically discussing the last five years.

Peripheral inflammation and blood-brain barrier disruption: effects and mechanisms.

The blood–brain barrier (BBB) is an important physiological barrier that separates the central nervous system (CNS) from the peripheral circulation, which contains inflammatory mediators and immune cells. The BBB regulates cellular and molecular exchange between the blood vessels and brain parenchyma. Normal functioning of the BBB is crucial for the homeostasis and proper function of the brain. It has been demonstrated that peripheral inflammation can disrupt the BBB by various pathways, resulting in different CNS diseases. Recently, clinical research also showed CNS complications following SARS‐CoV‐2 infection and chimeric antigen receptor (CAR)‐T cell therapy, which both lead to a cytokine storm in the circulation. Therefore, elucidation of the mechanisms underlying the BBB disruption induced by peripheral inflammation will provide an important basis for protecting the CNS in the context of exacerbated peripheral inflammatory diseases. In the present review, we first summarize the physiological properties of the BBB that makes the CNS an immune‐privileged organ. We then discuss the relevance of peripheral inflammation‐induced BBB disruption to various CNS diseases. Finally, we elaborate various factors and mechanisms of peripheral inflammation that disrupt the BBB.

Cellular processes involved in RAW 264.7 macrophages exposed to NPFF: A transcriptional study

Neuropeptide FF (NPFF) is a neuropeptide that modulates various physiological processes. The regulatory role of NPFF in the immune and inflammatory response is currently being revealed. However, the effect of NPFF at the transcriptome level in macrophages has not been fully elucidated. Here, the impact of NPFF on gene expression at the transcriptome level of RAW 264.7 cells was investigated by RNA-seq. RAW 264.7 macrophages were treated with NPFF (1 nM) for 18 h, followed by RNA-seq examination. Differentially expressed genes (DEGs) were acquired, followed by GO, KEGG, and PPI analysis. A total of eight qPCR-verified DEGs were obtained. Next, three-dimensional models of the eight hub proteins were constructed by using homology modeling with Modeller (9v23). Finally, molecular dynamics simulation (300 ns) was performed with GROMACS 2018.2 to investigate the structural characteristics of these hub proteins. NPFF had no detectable effect on the morphology of RAW264.7 cells. A total of 211 DEGs were acquired, and an enrichment study demonstrated that the immune response-related pathway was significantly inhibited by NPFF. Moreover, the molecular dynamics optimized-protein models of the hub proteins were obtained. Collectively, NPFF inhibited the expression of immune-related genes in RAW 264.7 cells at the transcriptome level, which suggested a negative relationship between NPFF and this set of immune-related genes in RAW 264.7 macrophages. Therefore, our data may provide direct evidence of the role of NPFF in peripheral or central inflammatory diseases.

The Role of Periodontitis and Periodontal Bacteria in the Onset and Progression of Alzheimer's Disease: A Systematic Review.

The evidence of a connection between the peripheral inflammatory processes and neurodegenerative diseases of the central nervous system is becoming more apparent. This review of the related literature highlights the most recent clinical, epidemiological, and in vitro studies trying to investigate possible connections between periodontal bacteria and the onset and progression of Alzheimer’s disease. This review was conducted by searching databases such as PubMed and Scopus using keywords or combinations such as Alzheimer’s Disease AND periodontal or dementia AND periodontitis OR periodontal. After eliminating overlaps and screening the articles not related to these issues, we identified 1088 records and proceeded to the selection of articles for an evaluation of the associative assumptions. The hypothesis suggested by the authors and confirmed by the literature is that the bacterial load and the inflammatory process linked to periodontal disease can intensify inflammation at the level of the central nervous system, favoring the occurrence of the disease. The analysis of the literature highlights how periodontal disease can directly contribute to the peripheral inflammatory environment by the introduction of periodontal or indirect pathogenic bacteria and proinflammatory cytokines locally produced at the periodontal level following bacterial colonization of periodontal defects.

Effect of Naoxintong Capsule on Inflammation in Peripheral Ischemic Tissue and Its Mechanism

To study the mechanism of naoxintong capsule (NXT) -inhibiting peripheral ischemic inflammation. Mice were randomly double-blindly divided into 3 groups: sham-operation group, model group and NXT group. Both model and NXT groups underwent the hind limb ischemia (HLI) surgery followed by oral gavage with saline or NXT, respectively, one hour after operation. Three days after operation, the percentages of neutrophils and macrophages in the gastrocnemius muscle were examined by flow cytomety and immunohistochemical method. The changes in gene and protein expressions induced by NXT were examined by real-time PCR and protein chip, respectively. The changes of signaling pathways were analyzed. Compared with sham oparation and model groups, NXT could decrease the ratios of neutrophils and macrophages in gastrocnemius inflammation site (P＜0.01), and downregulate the mRNA expression of gene EMR1 (P＜0.01). NXT reduced the expression of TNF-α and IL-1β at both mRNA (P＜0.001) and protein levels (P＜0.05). The proteomic analysis showed that the use of NXT resulted in the expression changes of 13 proteins. The expression of 6 cytokines was increased, and the secretion of 7 proteins was upregulated. Besides, most of identified 13 proteins were involved in the function regulation of other immune cells. NXT can significantly alleviate ischemia-induced peripheral inflammation by reducing the ratio of immune cells and altering the expression patterns of mRNA and protein. The expression changes provide theoretical guidance and the potential targets for the clinical use of NXT in the treatment of ischemia-induced peripheral inflammatory diseases.

Blocking Thrombin Significantly Ameliorates Experimental Autoimmune Neuritis.

Thrombin and its protease-activated receptor 1 (PAR1) are potentially important in peripheral nerve inflammatory diseases. We studied the role of thrombin and PAR1 in rat experimental autoimmune neuritis (EAN), a model of the human Guillain-Barré syndrome (GBS). EAN was induced by bovine peripheral myelin with complete Freund's adjuvant (CFA). Thrombin activity in the sciatic nerves, clinical scores and rotarod performance were measured. Thrombin activity in the sciatic nerve was elevated in EAN compared to CFA control rats (sham rats) (p ≤ 0.004). The effect of blocking the thrombin-PAR1 pathway was studied using the non-selective thrombin inhibitor N-Tosyl-Lys-chloromethylketone (TLCK), and the highly specific thrombin inhibitor N-alpha 2 naphtalenesulfonylglycyl 4 amidino-phenylalaninepiperidide (NAPAP). In-vitro TLCK and NAPAP significantly inhibited specific thrombin activity in EAN rats sciatics (p<0.0001 for both inhibitors). Treatment with TLCK 4.4 mg/kg and NAPAP 69.8 mg/kg significantly improved clinical and rotarod scores starting at day 12 and 13 post immunization (DPI12, DPI13) respectively (p < 0.0001) compared to the untreated EAN rats. In nerve conduction studies, distal amplitude was significantly lower in EAN compared to sham rats (0.76 ± 0.34 vs. 9.8 ± 1.2, mV, p < 0.0001). Nerve conduction velocity was impaired in EAN rats (23.6 ± 2.6 vs. sham 43 ± 4.5, m/s p = 0.01) and was normalized by TLCK (41.2 ± 7.6 m/s, p < 0.05). PAR1 histology of the sciatic node of Ranvier indicated significant structural damage in the EAN rats which was prevented by TLCK treatment. These results suggest the thrombin-PAR1 pathway as a possible target for future intervention in GBS.

Peripherally Restricted, Highly Potent, Selective, Aqueous-Soluble EP2 Antagonist with Anti-Inflammatory Properties.

The prostaglandin E2 receptor, EP2, plays an important role in physiology and in a variety of pathological conditions. Studies indicate that EP2 is pro-inflammatory in chronic peripheral and central nervous system disease and cancer models. Thus, targeting the EP2 receptor with small molecules could be a therapeutic strategy for treating inflammatory diseases and cancer. We recently reported a novel class of competitive antagonists of the EP2 receptor. However, earlier leads displayed low selectivity against the DP1 prostanoid receptor, moderate plasma half-life, and low aqueous solubility, which renders them suboptimal for testing in animal models of disease. We now report a novel compound TG8-69, which has suitable drug-like properties. We present synthesis, lead-optimization studies, pharmacological characterization, and anti-inflammatory properties of this compound that support its use in chronic peripheral inflammatory diseases, including rheumatoid arthritis, endometriosis, and cancer, in which EP2 appears to play a pathogenic role.

A Reversible Region-Specific Innate Immune Fingerprint in the Brain Induced by Chronic Peripheral Inflammation

Rheumatoid arthritis (RA) is linked to depression and dementia in later life by inflammatory involvement of the central nervous system (CNS). Regional heterogeneity of brain immunophenotypes was described under homeostasis, but a topographical resolution of CNS immune responses in chronic peripheral inflammatory diseases like RA is missing. We demonstrate regional heterogeneity of CNS susceptibility to chronic peripheral inflammation in the human tumor necrosis factor α transgenic (TNFtg) mouse model of RA. TNFtg mice showed myeloid cell infiltration, microglial activation, and a mutual transcriptomic fingerprint of neuroinflammation in the cortex, striatum, and thalamus. Immune responses were minimal in the hippocampus and cerebellum. Treatment with the anti-TNF-α antibody infliximab reversed regional inflammatory CNS response. We demonstrate regional CNS immune responses to chronic peripheral inflammation, sparing the hippocampus and cerebellum and reversible by peripheral anti-inflammatory treatment. Targeting microenvironmental susceptibility or resilience of brain regions will help to prevent and treat RA-related neuropsychiatric comorbidity.

Development of Novel Monoamine Oxidase-B (MAO-B) Inhibitors with Reduced Blood-Brain Barrier Permeability for the Potential Management of Noncentral Nervous System (CNS) Diseases.

Studies indicate that MAO-B is induced in peripheral inflammatory diseases. To target peripheral tissues using MAO-B inhibitors that do not permeate the blood-brain barrier (BBB) the MAO-B-selective inhibitor deprenyl was remodeled by replacing the terminal acetylene with a CO2H function, and incorporating a para-OCH2Ar motif (compounds 10a-s). Further, in compound 32 the C-2 side chain corresponded to CH2CN. In vitro, 10c, 10j, 10k, and 32 were identified as potent reversible MAO-B inhibitors, and all four compounds were more stable than deprenyl in plasma, liver microsomal, and hepatocyte stability assays. In vivo, they demonstrated greater plasma bioavailability. Assessment of in vitro BBB permeability showed that compound 10k is a P-glycoprotein (P-gp) substrate and 10j displayed mild interaction. Importantly, compounds 10c, 10j, 10k, and 32 displayed significantly reduced BBB permeability after intravenous, subcutaneous, and oral administration. These polar MAO-B inhibitors are pertinent leads for evaluation of efficacy in noncentral nervous system (CNS) inflammatory disease models.

Discovery of Novel 1-Cyclopentenyl-3-phenylureas as Selective, Brain Penetrant, and Orally Bioavailable CXCR2 Antagonists.

CXCR2 has emerged as a therapeutic target for not only peripheral inflammatory diseases but also neurological abnormalities in the central nervous system (CNS). Herein, we describe the discovery of a novel 1-cyclopentenyl-3-phenylurea series as potent and CNS penetrant CXCR2 antagonists. Extensive SAR studies, wherein molecules' property forecast index (PFI) was carefully optimized for overall balanced developability profiles, led to the discovery of the advanced lead compound 68 with a desirable PFI. Compound 68 demonstrated good in vitro pharmacology with excellent selectivity over CXCR1 and other chemokine receptors. Rat and dog pharmacokinetics (PK) revealed good oral bioavailability, high oral exposure, and desirable elimination half-life of the compound in both species. In addition, the compound demonstrated dose-dependent efficacy in the in vivo pharmacology neutrophil infiltration "air pouch" model in rodents after oral administration. Further, compound 68 is a CNS penetrant molecule with high unbound fraction in brain tissue.

TSPO PET Imaging: From Microglial Activation to Peripheral Sterile Inflammatory Diseases?

Peripheral sterile inflammatory diseases (PSIDs) are a heterogeneous group of disorders that gathers several chronic insults involving the cardiovascular, respiratory, gastrointestinal, or musculoskeletal system and wherein inflammation is the cornerstone of the pathophysiology. In PSID, timely characterization and localization of inflammatory foci are crucial for an adequate care for patients. In brain diseases, in vivo positron emission tomography (PET) exploration of inflammation has matured over the last 20 years, through the development of radiopharmaceuticals targeting the translocator protein-18 kDa (TSPO) as molecular biomarkers of activated microglia. Recently, TSPO has been introduced as a possible molecular target for PSIDs PET imaging, making this protein a potential biomarker to address disease heterogeneity, to assist in patient stratification, and to contribute to predicting treatment response. In this review, we summarized the major research advances recently made in the field of TSPO PET imaging in PSIDs. Promising preliminary results have been reported in bowel, cardiovascular, and rheumatic inflammatory diseases, consolidated by preclinical studies. Limitations of TSPO PET imaging in PSIDs, regarding both its large expression in healthy peripheral tissues, unlike in central nervous system, and the production of peripheral radiolabeled metabolites, are also discussed, regarding their possible consequences on TSPO PET signal's quantification.

Collateral Damage: Contribution of Peripheral Inflammation to Neurodegenerative Diseases.

Neurodegenerative diseases are characterized by a progressive deterioration of brain function, with a consequent significant decline in the quality of life of patients and their families. Due to the concurrent increase in life expectancy, the incidence of these diseases has been increasing over the last years and thus there is a growing interest in finding potential risk factors. This review focuses on the correlation between peripheral inflammatory diseases and neurodegeneration, in particular on the relationship between gastrointestinal disorders and Parkinson&#39;s disease, especially through the so called gut-brain axis.

Microglia-dependent alteration of glutamatergic synaptic transmission and plasticity in the hippocampus during peripheral inflammation.

Peripheral inflammatory diseases are often associated with behavioral comorbidities including anxiety, depression, and cognitive dysfunction, but the mechanism for these is not well understood. Changes in the neuronal and synaptic functions associated with neuroinflammation may underlie these behavioral abnormalities. We have used a model of colonic inflammation induced by 2,4,6-trinitrobenzenesulfonic acid in Sprague Dawley rats to identify inflammation-induced changes in hippocampal synaptic transmission. Hippocampal slices obtained 4 d after the induction of inflammation revealed enhanced Schaffer collateral-induced excitatory field potentials in CA1 stratum radiatum. This was associated with larger-amplitude mEPSCs, but unchanged mEPSC frequencies and paired-pulse ratios, suggesting altered postsynaptic effects. Both AMPA- and NMDA-mediated synaptic currents were enhanced, and analysis of AMPA-mediated currents revealed increased contributions of GluR2-lacking receptors. In keeping with this, both transcripts and protein levels of the GluR2 subunit were reduced in hippocampus. Both long-term potentiation (LTP) and depression (LTD) were significantly reduced in hippocampal slices taken from inflamed animals. Chronic administration of the microglial/macrophage activation inhibitor minocycline to the inflamed animals both lowered the level of the cytokine tumor necrosis factor α in the hippocampus and completely abolished the effect of peripheral inflammation on the field potentials and synaptic plasticity (LTP and LTD). Our results reveal profound synaptic changes caused by a mirror microglia-mediated inflammatory response in hippocampus during peripheral organ inflammation. These synaptic changes may underlie the behavioral comorbidities seen in patients.