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Disturbances in the one-carbon metabolism are often indicated by altered levels of the endogenous amino acid homocysteine (HCys), which is additionally discussed to causally contribute to diverse pathologies. In the first part of the present review, we profoundly and critically discuss the metabolic role and pathomechanisms of HCys, as well as its potential impact on different human disorders. The use of adequate animal models can aid in unravelling the complex pathological processes underlying the role of hyperhomocysteinemia (HHCys). Therefore, in the second part, we systematically searched PubMed/Medline for animal studies regarding HHCys and focused on the potential impact on cognitive performance and decline. The majority of reviewed studies reported a significant effect of HHCys on the investigated behavioral outcomes. Despite of persistent controversial discussions about equivocal findings, especially in clinical studies, the present evaluation of preclinical evidence indicates a causal link between HHCys and cognition-related- especially dementia-like disorders, and points out the further urge for large-scale, well-designed clinical studies in order to elucidate the normalization of HCys levels as a potential preventative or therapeutic approach in human pathologies.

Hyperhomocysteinemia has been suggested potentially to contribute to a variety of pathologies, such as Alzheimer&rsquo, s disease (AD). While the impact of hyperhomocysteinemia on AD has been investigated extensively, there are scarce data on the effect of AD on hyperhomocysteinemia. The aim of this in vivo study was to investigate the kinetics of homocysteine (HCys) and homocysteic acid (HCA) and effects of AD-like pathology on the endogenous levels. The mice received a B-vitamin deficient diet for eight weeks, followed by the return to a balanced control diet for another eight weeks. Serum, urine, and brain tissues of AppNL-G-F knock-in and C57BL/6J wild type mice were analyzed for HCys and HCA using LC-MS/MS methods. Hyperhomocysteinemic levels were found in wild type and knock-in mice due to the consumption of the deficient diet for eight weeks, followed by a rapid normalization of the levels after the return to control chow. Hyperhomocysteinemic AppNL-G-F mice had significantly higher HCys in all matrices, but not HCA, compared to wild type control. Higher serum concentrations were associated with elevated levels in both the brain and in urine. Our findings confirm a significant impact of AD-like pathology on hyperhomocysteinemia in the AppNL-G-F mouse model. The immediate normalization of HCys and HCA after the supply of B-vitamins strengthens the idea of a B-vitamin intervention as a potentially preventive treatment option for HCys-related disorders such as AD.

Background: Hyperhomocysteinemia is considered a possible contributor to the complex pathology of Alzheimer&rsquo, s disease (AD). For years, researchers in this field have discussed the apparent detrimental effects of the endogenous amino acid homocysteine in the brain. In this study, the roles of hyperhomocysteinemia driven by vitamin B deficiency, as well as potentially beneficial dietary interventions, were investigated in the novel AppNL-G-F knock-in mouse model for AD, simulating an early stage of the disease. Methods: Urine and serum samples were analyzed using a validated LC-MS/MS method and the impact of different experimental diets on cognitive performance was studied in a comprehensive behavioral test battery. Finally, we analyzed brain samples immunohistochemically in order to assess amyloid-&beta, (A&beta, ) plaque deposition. Results: Behavioral testing data indicated subtle cognitive deficits in AppNL-G-F compared to C57BL/6J wild type mice. Elevation of homocysteine and homocysteic acid, as well as counteracting dietary interventions, mostly did not result in significant effects on learning and memory performance, nor in a modified A&beta, plaque deposition in 35-week-old AppNL-G-F mice. Conclusion: Despite prominent A&beta, plaque deposition, the AppNL-G-F model merely displays a very mild AD-like phenotype at the investigated age. Older AppNL-G-F mice should be tested in order to further investigate potential effects of hyperhomocysteinemia and dietary interventions.

IL-38 is an IL-1 family receptor antagonist that restricts IL-17–driven inflammation by limiting cytokine production from macrophages and T cells. In the current study, we aimed to explore its role in experimental autoimmune encephalomyelitis in mice, which is, among others, driven by IL-17. Unexpectedly, IL-38–deficient mice showed strongly reduced clinical scores and histological markers of experimental autoimmune encephalomyelitis. This was accompanied by reduced inflammatory cell infiltrates, including macrophages and T cells, as well as reduced expression of inflammatory markers in the spinal cord. IL-38 was highly expressed by infiltrating macrophages in the spinal cord, and in vitro activated IL-38–deficient bone marrow–derived macrophages showed reduced expression of inflammatory markers, accompanied by altered cellular metabolism. These data suggest an alternative cell-intrinsic role of IL-38 to promote inflammation in the CNS.

Summary: Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. However, its main cellular targets and receptors remain obscure. IL-38 is highly expressed in the skin and downregulated in psoriasis patients. We report an investigation in cellular targets of IL-38 during the progression of imiquimod-induced psoriasis. In this model, IL-38 knockout (IL-38 KO) mice show delayed disease resolution with exacerbated IL-17-mediated inflammation, which is reversed by the administration of mature IL-38 or γδ T cell-receptor-blocking antibodies. Mechanistically, X-linked IL-1 receptor accessory protein-like 1 (IL1RAPL1) is upregulated upon γδ T cell activation to feedforward-amplify IL-17 production and is required for IL-38 to suppress γδ T cell IL-17 production. Accordingly, psoriatic IL1RAPL1 KO mice show reduced inflammation and IL-17 production by γδ T cells. Our findings indicate a role for IL-38 in the regulation of γδ T cell activation through IL1RAPL1, with consequences for auto-inflammatory disease. : Han et al. report that genetic depletion of IL-38 in mice delays the resolution of imiquimod-induced psoriasis by increasing the production of the inflammatory cytokine IL-17A by skin-infiltrating T cells. Depleting these T cells or the receptor that is targeted by IL-38 reduces psoriatic skin inflammation. Keywords: IL-38, IL1RAPL1, IL-17, γδ T cells, psoriasis, inflammation

Background Myeloperoxidase is used as a marker and diagnostic tool for inflammatory processes. Hypochlorous acid produced by myeloperoxidase oxidizes luminol to produce light. By injecting luminol into experimental animals, inflammatory processes can be tracked in real-time by bioluminescence imaging (BLI). Objective We aimed to establish BLI as a standardized assessment measure in three mouse models of dermal inflammation. Methods Oxazolone-induced delayed-type-hypersensitivity (DTH) (acute), a model for dermatitis, imiquimod (IMQ) (sub-chronic) model for psoriasis and the (chronic) bleomycin model for scleroderma were used. In the first two models, dexamethasone and clobetasol, respectively, were used as reference compounds. In all cases, classical readouts such as dermal swelling, severity scores and histological analyses were compared with in- vivo bioluminescence. Results In DTH, bioluminescence peaked earlier than ear swelling, reflecting early cell infiltration. Dexamethasone blocked both ear swelling and bioluminescence. In the IMQ model, bioluminescence closely reflected the psoriasis scores and histology and revealed a relapse-remitting course of the disease. Clobetasol partially decreased the disease severity. After stopping IMQ and clobetasol treatment, BLI adopted a rhythmic pattern during resolution. Bleomycin induced an increase in bioluminescence and in collagen thickness. BLI revealed a time-course of the effects of bleomycin that was not reflected by histology alone. Conclusion For drug discovery and translational purposes, it is important that disease processes be tracked in vivo and possibly over a long period. We conclude that BLI is a valuable and reliable method for in-vivo measurement of dermal inflammation and potentially for inflammation resolution.

Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. However, its main cellular targets and receptor(s) remain obscure. IL-38 is highly expressed in the skin and downregulated in psoriasis patients. Therefore, we investigated cellular targets of IL-38 during the progression of imiquimod-induced psoriasis. In this model, IL-38-knockout (IL-38 KO) mice showed delayed disease resolution due to exacerbated IL-17-mediated inflammation, which was reversed by administration of mature IL-38. Mechanistically, IL-38 antagonized X-linked interleukin-1 receptor accessory protein-like 1 (IL1RAPL1), which was upregulated upon γδ T cell activation to feed-forward amplify IL-17 production. Heightened activation of tumor-infiltrating γδ T cells was also observed in IL-38 KO oncogene-driven mammary carcinoma, accompanied by attenuated tumor growth. Our findings, which are supported by clinical data, highlight the connection between auto-inflammation and anti-tumor immunity and indicate IL-38 as a potential therapeutic target under these conditions.

Contains fulltext : 166569.pdf (Publisher’s version ) (Open Access) Cannabinoid CB1 antagonists have been investigated for possible treatment of e.g. obesity-related disorders. However, clinical application was halted due to their symptoms of anxiety and depression. In addition to these adverse effects, we have shown earlier that chronic treatment with the CB1 antagonist rimonabant may induce EEG-confirmed convulsive seizures. In a regulatory repeat-dose toxicity study violent episodes of "muscle spasms" were observed in Wistar rats, daily dosed with the CB1 receptor antagonist SLV326 during 5 months. The aim of the present follow-up study was to investigate whether these violent movements were of an epileptic origin. In selected SLV326-treated and control animals, EEG and behavior were monitored for 24 hours. 25% of SLV326 treated animals showed 1 to 21 EEG-confirmed generalized convulsive seizures, whereas controls were seizure-free. The behavioral seizures were typical for a limbic origin. Moreover, interictal spikes were found in 38% of treated animals. The frequency spectrum of the interictal EEG of the treated rats showed a lower theta peak frequency, as well as lower gamma power compared to the controls. These frequency changes were state-dependent: they were only found during high locomotor activity. It is concluded that long term blockade of the endogenous cannabinoid system can provoke limbic seizures in otherwise healthy rats. Additionally, SLV326 alters the frequency spectrum of the EEG when rats are highly active, suggesting effects on complex behavior and cognition. 16 p.

Multiple sclerosis is presumed to be an inflammatory autoimmune disease, which is characterized by lesion formation in the central nervous system (CNS) resulting in cognitive and motor impairment. Experimental autoimmune encephalomyelitis (EAE) is a useful animal model of MS, because it is also characterized by lesion formation in the CNS, motor impairment and is also driven by autoimmune and inflammatory reactions. One of the EAE models is induced with a peptide derived from the myelin oligodendrocyte protein (MOG)35-55 in mice. The EAE mice develop a progressive disease course. This course is divided into three phases: the preclinical phase (day 0 - 9), the disease onset (day 10 - 11) and the acute phase (day 12 - 14). MS and EAE are induced by autoreactive T cells that infiltrate the CNS. These T cells secrete chemokines and cytokines which lead to the recruitment of further immune cells. Therefore, the immune cell distribution in the spinal cord during the three disease phases was investigated. To highlight the time point of the disease at which the activation/proliferation/accumulation of T cells, B cells and monocytes starts, the immune cell distribution in lymph nodes, spleen and blood was also assessed. Furthermore, the levels of several cytokines (IL-1β, IL-6, IL-23, TNFα, IFNγ) in the three disease phases were determined, to gain insight into the inflammatory processes of the disease. In conclusion, the data provide an overview of the functional profile of immune cells during EAE pathology.

Contains fulltext : 57569.pdf (Publisher’s version ) (Closed access) BACKGROUND: There is now ample evidence that schizophrenia is due to an interaction between genetic and (early) environmental factors which disturbs normal development of the central nervous system and ultimately leads to the development of clinical symptoms. Recently, we showed that a single 24-hour period of maternal deprivation of rat pups at postnatal day 9 leads to a disturbance in prepulse inhibition, similar to what is seen in schizophrenia. The present set of experiments was designed to further characterize the information processing deficits of maternally deprived Wistar rats. METHODS: Wistar rats were deprived from their mother for 24 hours on postnatal day 9. At adult age, rats were tested in the acoustic startle paradigm for prepulse inhibition and startle habituation. Rats were also tested in the evoked potentials paradigm for auditory sensory gating. RESULTS: The results show that maternal deprivation led to a reduction in acoustic startle habituation and auditory sensory gating in adult rats. Moreover, maternal deprivation disrupted prepulse inhibition but only when the prepulses were given shortly (50-100 milliseconds) before the startle stimulus. At longer intervals (250-1000 milliseconds), no effect was seen. CONCLUSIONS: The implications for the model and the development of disturbances in information processes are discussed.

R‐flurbiprofen is the non‐cyclooxygenase inhibiting R‐enantiomer of the non‐steroidal anti‐inflammatory drug flurbiprofen, which was assessed as a remedy for Alzheimer9s disease. Because of its anti‐inflammatory, endocannabinoid‐modulating and antioxidative properties, combined with low toxicity, the present study assessed R‐flurbiprofen in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis in mice. Oral R‐flurbiprofen prevented and attenuated primary progressive EAE in C57BL6/J mice and relapsing‐remitting EAE in SJL mice, even if the treatment was initiated on or after the first flare of the disease. R‐flurbiprofen reduced immune cell infiltration and microglia activation and inflammation in the spinal cord, brain and optic nerve and attenuated myelin destruction and EAE‐evoked hyperalgesia. R‐flurbiprofen treatment increased CD4 + CD25 + FoxP3 + regulatory T cells, CTLA4 + inhibitory T cells and interleukin‐10, whereas the EAE‐evoked upregulation of pro‐inflammatory genes in the spinal cord was strongly reduced. The effects were associated with an increase of plasma and cortical endocannabinoids but decreased spinal prostaglandins, the latter likely due to R to S inversion. The promising results suggest potential efficacy of R‐flurbiprofen in human MS, and its low toxicity may justify a clinical trial.