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BACKGROUND: Myocardial infarction (MI) coinciding with depression worsens prognosis. Although Tumor Necrosis Factor alpha (TNF) is recognized to play a role in both conditions, the therapeutic potential of TNF inhibition is disappointing. TNF activates two receptors, TNFR1 and TNFR2, associated with opposite effects. Therefore, anti-inflammatory treatment with specific TNF receptor interference was compared to non-specific TNF inhibition regarding effects on heart, (neuro)inflammation, brain and behavior in mice with MI.METHODS: Male C57BL/6 mice were subjected to MI or sham surgery. One hour later, MI mice were randomized to either non-specific TNF inhibition by Enbrel, specific TNFR1 antagonist-, or specific TNFR2 agonist treatment until the end of the protocol. Control sham and MI mice received saline. Behavioral evaluation was obtained day 10-14 after surgery. Eighteen days post-surgery, cardiac function was measured and mice were sacrificed. Blood and tissue samples were collected for analyses of (neuro)inflammation.RESULTS: MI mice displayed left ventricular dysfunction, without heart failure, (neuro) inflammation or depressive-like behavior. Both receptor-specific interventions, but not Enbrel, doubled early post-MI mortality. TNFR2 agonist treatment improved left ventricular function and caused hyper-ramification of microglia, with no effect on depressive-like behavior. In contrast, TNFR1 antagonist treatment was associated with enhanced (neuro)inflammation: more plasma eosinophils and monocytes; increased plasma Lcn2 and hippocampal microglia and astrocyte activation. Moreover, increased baseline heart rate, with reduced beta-adrenergic responsiveness indicated sympathetic activation, and coincided with reduced exploratory behavior in the open field. Enbrel did not affect neuroinflammation nor behavior.CONCLUSION: Early receptor interventions, but not non-specific TNF inhibition, increased mortality. Apart from this undesired effect, the general beneficial profile after TNFR2 stimulation, rather than the unfavourable effects of TNFR1 inhibition, would render TNFR2 stimulation preferable over non-specific TNF inhibition in MI with comorbid depression. However, follow-up studies regarding optimal timing and dosing are needed.

CNS inflammation is a major driver of MS pathology. Differential immune responses, including the adaptive and the innate immune system, are observed at various stages of MS and drive disease development and progression. Next to these immune-mediated mechanisms, other mediators contribute to MS pathology. These include immune-independent cell death of oligodendrocytes and neurons as well as oxidative stress-induced tissue damage. In particular, the complex influence of oxidative stress on inflammation and vice versa makes therapeutic interference complex. All approved MS therapeutics work by modulating the autoimmune response. However, despite substantial developments in the treatment of the relapsing-remitting form of MS, approved therapies for the progressive forms of MS as well as for MS-associated concomitants are limited and much needed. Here, we summarize the contribution of inflammation and oxidative stress to MS pathology and discuss consequences for MS therapy development.

Tumour necrosis factor (TNF) signalling is mediated via two receptors, TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2), which work antithetically to balance CNS immune responses involved in autoimmune diseases such as multiple sclerosis. To determine the therapeutic potential of selectively inhibiting TNFR1 in mice with experimental autoimmune encephalomyelitis, we used chimeric human/mouse TNFR1 knock-in mice allowing the evaluation of antagonistic anti-human TNFR1 antibody efficacy. Treatment of mice after onset of disease with ATROSAB resulted in a robust amelioration of disease severity, correlating with reduced central nervous system immune cell infiltration. Long-term efficacy of treatment was achieved by treatment with the parental mouse anti-human TNFR1 antibody, H398, and extended by subsequent re-treatment of mice following relapse. Our data support the hypothesis that anti-TNFR1 therapy restricts immune cell infiltration across the blood-brain barrier through the down-regulation of TNF-induced adhesion molecules, rather than altering immune cell composition or activity. Collectively, we demonstrate the potential for anti-human TNFR1 therapies to effectively modulate immune responses in autoimmune disease.

Tumor necrosis factor receptor 2 (TNFR2) is a transmembrane receptor that promotes immune modulation and tissue regeneration and is recognized as a potential therapeutic target for multiple sclerosis (MS). However, TNFR2 also contributes to T effector cell function and macrophage-TNFR2 recently was shown to promote disease development in the experimental autoimmune encephalomyelitis (EAE) model of MS. We here demonstrate that systemic administration of a TNFR2 agonist alleviates peripheral and central inflammation, and reduces demyelination and neurodegeneration, indicating that protective signals induced by TNFR2 exceed potential pathogenic TNFR2-dependent responses. Our behavioral data show that systemic treatment of female EAE mice with a TNFR2 agonist is therapeutic on motor symptoms and promotes long-term recovery from neuropathic pain. Mechanistically, our data indicate that TNFR2 agonist treatment follows a dual mode of action and promotes both suppression of CNS autoimmunity and remyelination. Strategies based on the concept of exogenous activation of TNFR2 therefore hold great promise as a new therapeutic approach to treat motor and sensory disease in MS as well as other inflammatory diseases or neuropathic pain conditions.

Background: Soluble oligomeric (misfolded) species of amyloid-beta (A beta) are the main mediators of toxicity in Alzheimer's disease (AD). These oligomers subsequently form aggregates of insoluble fibrils that precipitate as extracellular and perivascular plaques in the brain. Active immunization against A beta is a promising disease modifying strategy. However, eliciting an immune response against A beta in general may interfere with its biological function and was shown to cause unwanted side-effects. Therefore, we have developed a novel experimental vaccine based on conformational neo-epitopes that are exposed in the misfolded oligomeric A beta, inducing a specific antibody response.Objective: Here we investigate the protective effects of the experimental vaccine against oligomeric A beta(1-42)-induced neuronal fiber loss in vivo.Methods: C57BL/6 mice were immunized or mock-immunized. Antibody responses were measured by enzyme-linked immunosorbent assay. Next, mice received a stereotactic injection of oligomeric A beta(1-42) into the nucleus basalis of Meynert (NBM) on one side of the brain (lesion side), and scrambled A beta(1-42) peptide in the contralateral NBM (control side). The densities of choline acetyltransferase-stained cholinergic fibers origination from the NBM were measured in the parietal neocortex postmortem. The percentage of fiber loss in the lesion side was determined relative to the control side of the brain.Results: Immunized responders (79%) showed 23% less cholinergic fiber loss (p = 0.01) relative to mock-immunized mice. Moreover, fiber loss in immunized responders correlated negatively with the measured antibody responses (R-2 = 0.29, p = 0.02).Conclusion: These results may provide a lead towards a (prophylactic) vaccine to prevent or at least attenuate (early onset) AD symptoms.

Background Lipocalin 2 (Lcn2) is an acute-phase protein implicated in multiple neurodegenerative conditions. Interestingly, both neuroprotective and neurodegenerative effects have been described for Lcn2. Increased Lcn2 levels were found in human post-mortem Alzheimer (AD) brain tissue, and in vitro studies indicated that Lcn2 aggravates amyloid-β-induced toxicity. However, the role of Lcn2 has not been studied in an in vivo AD model. Therefore, in the current study, the effects of Lcn2 were studied in the J20 mouse model of AD. Methods J20 mice and Lcn2-deficient J20 (J20xLcn2 KO) mice were compared at the behavioral and neuropathological level. Results J20xLcn2 KO and J20 mice presented equally strong AD-like behavioral changes, cognitive impairment, plaque load, and glial activation. Interestingly, hippocampal iron accumulation was significantly decreased in J20xLcn2 KO mice as compared to J20 mice. Conclusions Lcn2 contributes to AD-like brain iron dysregulation, and future research should further explore the importance of Lcn2 in AD. Electronic supplementary material The online version of this article (10.1186/s12974-018-1372-5) contains supplementary material, which is available to authorized users.

Autoimmunity develops when self-tolerance mechanisms are failing to protect healthy tissue. A sustained reaction to self is generated, which includes the generation of effector cells and molecules that destroy tissues. A way to restore this intrinsic tolerance is through immune modulation that aims at refurbishing this immunologically naive or unresponsive state, thereby decreasing the aberrant immune reaction taking place. One major cytokine has been shown to play a pivotal role in several autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS): tumor necrosis factor alpha (TNF alpha) modulates the induction and maintenance of an inflammatory process and it comes in two variants, soluble TNF (solTNF) and transmembrane bound TNF (tmTNF). tmTNF signals via TNFR1 and TNFR2, whereas solTNF signals mainly via TNFR1. TNFR1 is widely expressed and promotes mainly inflammation and apoptosis. Conversely, TNFR2 is restricted mainly to immune and endothelial cells and it is known to activate the pro-survival PI3K-Akt/PKB signaling pathway and to sustain regulatory T cells function. Anti-TNF alpha therapies are successfully used to treat diseases such as RA, colitis, and psoriasis. However, clinical studies with a non-selective inhibitor of TNFa in MS patients had to be halted due to exacerbation of clinical symptoms. One possible explanation for this failure is the non-selectivity of the treatment, which avoids TNFR2 stimulation and its immune and tissue protective properties. Thus, a receptor-selective modulation of TNFa signal pathways provides a novel therapeutic concept that might lead to new insights in MS pathology with major implications for its effective treatment.

BackgroundIn patients with heart failure (HF) depressive symptoms have been associated with mortality, as well as biological risk factors, including inflammation, nitric oxide (NO) regulation, and oxidative stress. We investigated the joint predictive value of depressive symptoms, inflammation and NO regulation on all-cause mortality in patients with HF, adjusted for covariates.MethodsSerum levels of inflammation (TNFα, sTNFr1, sTNFr2, IL-6, hsCRP, NGAL), NO regulation (l-arginine, ADMA, and SDMA), and oxidative stress (isoprostane 8-Epi Prostaglandin F2 Alpha) were measured in 104 patients with HF (mean age 65.7 ± SD 8.4 years, 28% women). Depressive symptoms (Beck Depression Inventory, BDI) were measured as continuous total, cognitive, and somatic symptoms, as well as categorized presence of mild/moderate depression (cut-off BDI ⩾10). In Cox proportional hazard models we adjusted for age, sex, poor exercise tolerance and comorbidity.ResultsAfter on average 6.1 years follow-up (SD = 2.9, range 0.4–9.2), 49 patients died. Total and somatic depressive symptoms, mild/moderate depression, higher NGAL, sTNFr2, IL-6, hsCRP and SDMA serum levels were significantly associated with a higher all-cause mortality rate, adjusted for covariates. The findings were most consistent for CRP level and somatic depressive symptoms. When combined, both depressive symptoms and markers of inflammation and NO regulation remained significantly associated with all-cause mortality. These associations were not confounded by age, sex, poor exercise tolerance and comorbidity.ConclusionDepressive symptoms and markers of inflammation and NO regulation are codominant risk factors for all-cause mortality in heart failure.KeywordsHeart failureDepressive symptomsInflammationCRPAll-cause mortalityNGALNO regulationMethylargininesPrognosis

Depression is more common in patients with cardiovascular disease than in the general population. Conversely, depression is a risk factor for developing cardiovascular disease. Comorbidity of these two pathologies worsens prognosis. Several mechanisms have been indicated in the link between cardiovascular disease and depression, including inflammation. Systemic inflammation can have long-lasting effects on the central nervous system, which could be associated with depression. NGAL is an inflammatory marker and elevated plasma levels are associated with both cardiovascular disease and depression. While patients with depression show elevated NGAL levels, in patients with comorbid heart failure, NGAL levels are significantly higher and associated with depression scores. Systemic inflammation evokes NGAL expression in the brain. This is considered a proinflammatory effect as it is involved in microglia activation and reactive astrocytosis. Animal studies support a direct link between NGAL and depression/anxiety associated behavior. In this review we focus on the role of NGAL in linking depression and cardiovascular disease.

Depression adversely affects prognosis in heart failure (HF) patients. Inflammation is indicated as potential biological pathway in this co-morbidity. Since increased levels of the cytokine Neutrophil Gelatinase-Associated Lipocalin (NGAL) are predictive for HF prognosis, and recently indicated in patients with major depression, this study examined the association of serum NGAL levels with symptoms of depression in patients with HF. Serum NGAL levels were measured in 104 patients with HF (left ventricular ejection fraction, LVEF ⩽ 40). Depression, evaluated using the Beck Depression Inventory (BDI; total score, somatic and cognitive component), and the Hamilton Depression Rating scale (HAMD), at baseline and 12 months follow-up, was associated with NGAL levels using mixed model analysis. Analyses were adjusted for demographics measures, disease severity indicators, inflammation, comorbidity and medication. Increased serum NGAL levels were significantly associated with depression measured by HAMD (baseline: r = 0.25, p < .05) and BDI (baseline: r = 0.22, p < .05; 12 months: r = 0.37, p < .01). This association remained significant after adjustment for covariates; age, sex, time, LVEF, and creatinine (HAMD, t = 2.01, p = .047; BDI, t = 2.28, p = .024). NGAL was significantly associated with somatic- (p = 0.004), but not cognitive depressive symptoms (p = 0.32). NGAL levels were associated with the experienced HF-related functional limitations (6 min walk test), rather than the severity of cardiac dysfunction (LVEF). This study indicates that depression in patients with chronic HF is associated with elevated NGAL levels, independent of clinical severity of the underlying disease. Keywords: Lipocalin 2, Depression, Cognitive and somatic depressive symptoms, Inflammation, Heart failure, Follow-up

Alzheimer's disease (AD) is associated with an altered immune response, resulting in chronic increased inflammatory cytokine production with a prominent role of TNF-alpha. TNF-alpha signals are mediated by two receptors: TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Signaling through TNFR2 is associated with neuroprotection, whereas signaling through TNFR1 is generally proinflammatory and proapoptotic. Here, we have identified a TNF-alpha-induced proinflammatory agent, lipocalin 2 (Lcn2) via gene array in murine primary cortical neurons. Further investigation showed that Lcn2 protein production and secretion were activated solely upon TNFR1 stimulation when primary murine neurons, astrocytes, and microglia were treated with TNFR1 and TNFR2 agonistic antibodies. Lcn2 was found to be significantly decreased in CSF of human patients with mild cognitive impairment and AD and increased in brain regions associated with AD pathology in human postmortem brain tissue. Mechanistic studies in cultures of primary cortical neurons showed that Lcn2 sensitizes nerve cells to beta-amyloid toxicity. Moreover, Lcn2 silences a TNFR2-mediated protective neuronal signaling cascade in neurons, pivotal for TNF-alpha-mediated neuroprotection. The present study introduces Lcn2 as a molecular actor in neuroinflammation in early clinical stages of AD.-Naud, P.J.W., Nyakas, C., Eiden, L. E., Ait-Ali, D., van der Heide, R., Engelborghs, S., Luiten, P. G. M., De Deyn, P. P., den Boer, J.A., Eisel, U. L. M. Lipocalin 2: Novel component of proinflammatory signaling in Alzheimer's disease. FASEB J. 26, 2811-2823 (2012). www.fasebj.org

Indoleamine 2,3-dioxygenase (IDO), an enzyme which is activated by pro-inflammatory cytokines, has been suggested as a potential link between neuroinflammatory processes in neurodegenerative diseases (like Alzheimer's disease) and depression. The present study aimed to determine whether neuroinflammation-induced increased IDO levels in the mammalian brain will lead to depressive-like behavior. Neuroinflammation was initiated in mice by a single intracerebroventricular injection of lipopolysaccharide (LPS). Cerebral inflammation was monitored 1, 2, 3 and 4 days after the injection with small-animal positron emission tomography (PET) using the inflammatory marker [C-11]-PK11195. In the presence or absence of systemically applied 1-methyl-tryptophan (1-MT), a competitive IDO-inhibitor, we assessed the development of depressive-like behavioral symptoms in parallel with IDO expression and activity. The PK11195 PET signal reached a highly significant peak 3 days after LPS injection, while these animals displayed a significant increase of depressive-like behavior in the forced swim test compared to vehicle-injected animals. These findings were paralleled by a significant increase of IDO in the brainstem, and an increased kynurenine/tryptophan ratio in the serum. Moreover, we report here for the first time, that inhibition of IDO by 1-MT in centrally induced neuroinflammation under experimental conditions can prevent the development of depressive-like behavior.

Chronic inflammatory conditions during peritoneal dialysis (PD)-treatment lead to the impairment of peritoneal tissue integrity. The resulting structural and functional reorganization of the peritoneal membrane diminishes ultrafiltration rate and thereby enhances mortality by limiting dialysis effectiveness over time. Tumour necrosis factor (TNF) and its receptors TNFR1 and TNFR2 are key players during inflammatory processes. To date, the role of TNFR1 in peritoneal tissue damage during PD-treatment is completely undefined. In this study, we used an acute PD-mouse model to investigate the role of TNFR1 on structural and morphological changes of the peritoneal membrane. TNFR1-mediated TNF signalling in transgenic mice expressing human TNFR1 was specifically blocked by applying a monoclonal antibody (H398) highly selective for human TNFR1 prior to PD-treatment. Cancer antigen-125 (CA125) plasma concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Western blot analyses were applied to determine TNFR2 protein concentrations. Histological staining of peritoneal tissue sections was performed to assess granulocytes within the peritoneal membrane as well as the content of hyaluronic acid and collagen. We show for the first time that the number of granulocytes within the peritoneal membrane is significantly reduced in mice pre-treated with H398. Moreover, we demonstrate that blocking of TNFR1 not only influences CA125 values but also hyaluronic acid and collagen contents of the peritoneal tissue in these mice. These results strongly suggest that TNFR1 inhibition attenuates peritoneal damage caused by peritoneal dialysis fluid (PDF) and therefore may represent a new therapeutic approach in the treatment of PD-related side effects.

Background Long-term neuroimmune activation is a common finding in major depressive disorder (MDD). Literature suggests a dual effect of electroconvulsive therapy (ECT), a highly effective treatment strategy for MDD, on neuroimmune parameters: while ECT acutely increases inflammatory parameters, such as serum levels of pro-inflammatory cytokines, there is evidence to suggest that repeated ECT sessions eventually result in downregulation of the inflammatory response. We hypothesized that this might be due to ECT-induced attenuation of microglial activity upon inflammatory stimuli in the brain. Methods Adult male C57Bl/6J mice received a series of ten electroconvulsive seizures (ECS) or sham shocks, followed by an intracerebroventricular (i.c.v.) lipopolysaccharide (LPS) or phosphate-buffered saline (PBS) injection. Brains were extracted and immunohistochemically stained for the microglial marker ionized calcium-binding adaptor molecule 1 (Iba1). In addition, a sucrose preference test and an open-field test were performed to quantify behavioral alterations. Results LPS induced a short-term reduction in sucrose preference, which normalized within 3 days. In addition, LPS reduced the distance walked in the open field and induced alterations in grooming and rearing behavior. ECS did not affect any of these parameters. Phenotypical analysis of microglia demonstrated an LPS-induced increase in microglial activity ranging from 84 to 213 % in different hippocampal regions (CA3 213 %; CA1 84 %; dentate gyrus 131 %; and hilus 123 %). ECS-induced alterations in microglial activity were insignificant, ranging from −2.6 to 14.3 % in PBS-injected mice and from −20.2 to 6.6 % in LPS-injected mice. Conclusions We were unable to demonstrate an effect of ECS on LPS-induced microglial activity or behavioral alterations. Electronic supplementary material The online version of this article (doi:10.1186/s12974-015-0454-x) contains supplementary material, which is available to authorized users.

Objectives. Neutrophil gelatinase-associated lipocalin (NGAL) is an inflammatory marker associated with the pathophysiology of heart failure (HF), the psychopathology of depression and the co-existing symptoms of depression in HF patients. The aim of this study is to determine whether the association of serum NGAL levels with depressive symptoms dimensions in HF is independent of well-known inflammatory markers. Methods. Serum NGAL, high sensitive C-reactive protein (hsCRP), tumour necrosis factor-α (TNF-α), its two soluble receptors; sTNFR1, sTNFR2, Interleukin-6 (IL-6) and leukocytes were measured in 104 patients with HF at baseline and 12 months. Depressive symptoms were evaluated using the Beck Depression Inventory (BDI) at both timepoints. Correlations between NGAL and inflammatory markers and depressive symptoms dimensions were determined. The effect of hsCRP, IL-6, TNF-α, sTNFR1, sTNFR2 and leukocytes on the association of NGAL with depressive symptoms was determined and adjusted for time, demographics, cardiac disease severity, and kidney function. Results. NGAL levels were significantly correlated with hsCRP, TNF-α, sTNFR1, sTNFR2 and leukocytes. NGAL was significantly associated with somatic depressive symptoms, independent of abovementioned markers. Conclusions. Serum NGAL is an independent inflammatory marker for somatic depressive symptoms in HF and may function as an immunopathogen linking somatic symptoms of depression to HF.Keywords:: Lipocalin 2, cognitive and somatic depressive symptoms, tumor necrosis factor alpha, interleukin-6, C reactive protein

Inflammatory processes are of particular importance in Alzheimer's disease (AD). We identified Lipocalin 2 as a neuroinflammatory component that is increased during early stages of the disease and ...

Numerous studies have revealed the pleiotropic functions of tumor necrosis factor alpha (TNF-), and have linked it with several neurodegenerative disorders. This review describes the signaling pathways induced by TNF- via its two receptors (TNFR1 and TNFR2), and their functions in neurodegenerative processes as in Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and ischemic stroke. It has become clear that TNF- may exert divergent actions in neurodegenerative disorders, including neurodegenerative and neuroprotective effects, which appear to depend on its signaling via either TNFR1 or TNFR2. Specific targeting of these receptors is a promising therapeutic strategy for many disorders.

The TetR gene immediately upstream from the tetanus toxin (TeTx) gene was characterized. It encodes a 21,562-Da protein which is related (50 to 65% identity) to the equivalent genes ( botR ) in Clostridium botulinum . TetR has the feature of a DNA binding protein with a basic pI (9.53). It contains a helix-turn-helix motif and shows 29% identity with other putative regulatory genes in Clostridium , i.e., uviA from C. perfringens and txeR from C. difficile . We report for the first time the transformation of C. tetani by electroporation, which permitted us to investigate the function of tetR . Overexpression of tetR in C. tetani induced an increase in TeTx production and in the level of the corresponding mRNA. This indicates that TetR is a transcriptional activator of the TeTx gene. Overexpression of botR/A (60% identity with TetR at the amino acid level) in C. tetani induced an increase in TeTx production comparable to that for overexpression of tetR . However, botR/C (50% identity with TetR at the amino acid level) was less efficient. This supports that TetR positively regulates the TeTx gene in C. tetani and that a conserved mechanism of regulation of the neurotoxin genes is involved in C. tetani and C. botulinum .

It is now recognized that myocardial infarction (MI) leads to changes in the brain, which may be linked to mental problems. Myocardial infarction (MI) evokes TNF-alpha expression and microglia activation in the paraventricular nucleus of the hypothalamus (PVN), reflecting neuroinflammation. Here we studied the effect of TNF-alpha interference on microglia activity after MI. Male 12-week old c57bl/6 mice underwent coronary artery ligation or sham surgery. MI mice were treated with either saline, Etanercept, a TNF-R1 antagonist or a TNF-R2 agonist. Sham mice received saline injections. Mice were sacrificed 18 days later and the PVN and hippocampus were stained for microglia. Microglia activity score was based on morphology, as we calculated the ratio of cell body/total cell size. In the PVN, we found a significant decrease in the number of microglia in the MI + TNF-R2 agonist group compared to sham ( p p

Proinflammatory state of the brain increases the risk for seizure development. Neonatal Borna disease virus (BDV)-infection of mice with neuronal overexpression of tumor necrosis factor-alpha (TNF) was used to investigate the complex relationship between enhanced cytokine levels, neurotropic virus infection and reaction pattern of brain cells focusing on its role for seizure induction. Viral antigen and glial markers were visualized by immunohistochemistry. Different levels of TNF in the CNS were provided by the use of heterozygous and homozygous TNF overexpressing mice. Transgenic TNF, total TNF (native and transgenic), TNF-receptor (TNFR1, TNFR2), IL-1 and N-methyl-D-aspartate (NMDA)-receptor subunit 2B (NR2B) mRNA values were measured by real time RT-PCR. BDV-infection of TNF-transgenic mice resulted in non-purulent meningoencephalitis accompanied by epileptic seizures with a higher frequency in homozygous animals. This correlated with lower weight gain, stronger degree and progression of encephalitis and early, strong microglia activation in the TNF-transgenic mice, most obviously in homozygous animals. Activation of astroglia could be more intense and associated with an unusual hypertrophy in the transgenic mice. BDV-antigen distribution and infectivity in the CNS was comparable in TNF-transgenic and wild-type animals. Transgenic TNF mRNA-expression was restricted to forebrain regions as the transgene construct comprised the promoter of NMDA-receptor subunit2B and induced up-regulation of native TNF mRNA. Total TNF mRNA levels did not increase significantly after BDV-infection in the brain of transgenic mice but TNFR1, TNFR2 and IL-1 mRNA values, mainly in the TNF overexpressing brain areas. NR2B mRNA levels were not influenced by transgene expression or BDV-infection. Neuronal TNF-overexpression combined with BDV-infection leads to cytokine up-regulation, CNS inflammation and glial cell activation and confirmed the presensitizing effect of elevated cytokine levels for the development of spontaneous epileptic seizures when exposed to additional infectious noxi.

Tumor necrosis factor (TNF)-alpha, a pro-inflammatory cytokine, has been implicated in both neuronal death and survival in Parkinson's disease (PD). The substantia nigra (SN), a CNS region affected in PD, is particularly susceptible to inflammatory insults and possesses the highest density of microglial cells, but the effects of inflammation and in particular TNF-alpha on neuronal survival in this region remains controversial. Using adenoviral vectors, the CRE/loxP system and hypomorphic mice, we achieved chronic expression of two levels of TNF-alpha in the SN of adult mice. Chronic low expression of TNF-alpha levels reduced the nigrostriatal neurodegeneration mediated by intrastriatal 6-hydroxydopamine administration. Protective effects of low TNF-alpha level could be mediated by TNF-R1, GDNF, and IGF-1 in the SN and SOD activity in the striatum (ST). On the contrary, chronic expression of high levels of TNF-alpha induced progressive neuronal loss (63% at 20 days and 75% at 100 days). This effect was accompanied by gliosis and an inflammatory infiltrate composed almost exclusively by monocytes/macrophages. The finding that chronic high TNF-alpha had a slow and progressive neurodegenerative effect in the SN provides an animal model of PD mediated by the chronic expression of a single cytokine. In addition, it supports the view that cytokines are not detrimental or beneficial by themselves, i.e., their level and time of expression among other factors can determine its final effect on CNS damage or protection. These data support the view that new anti-parkinsonian treatments based on anti-inflammatory therapies should consider these dual effects of cytokines on their design. (C) 2010 Elsevier Inc. All rights reserved.

Inflammatory processes are a hallmark of many chronic diseases including Alzheimer's disease and diabetes mellitus. Fairly recent statistical evidence indicating that type 2 diabetes increases the risk of developing Alzheimer's disease has led to investigations of the potential common processes that could explain this relation. Here, we review the literature on how inflammation and the inducible nuclear factor NF-kappa B might be involved in both diabetes mellitus and Alzheimer's disease and whether these factors can link both diseases.

Clinical trials report that the class of drugs known as statins may be neuroprotective in Alzheimer's and Parkinson's disease, and further trials are currently underway to test whether these drugs are also beneficial in multiple sclerosis and acute stroke treatment. Since statins are well tolerated and have relatively few side effects, they may be considered as viable drugs to ameliorate neurodegenerative diseases. However, the mechanism of their neuroprotective effects is only partly understood. In this article, we review the current data on the neuroprotective effects of statins and their underlying mechanisms. In the first section, we detail the mechanisms by which statins affect cellular signalling. The primary action of statins is to inhibit cellular cholesterol synthesis. However, the cholesterol synthesis pathway also has several by-products, the non-sterol isoprenoids that are also important in cellular functioning. Furthermore, reduced cholesterol levels may deplete the cholesterol-rich membrane domains known as lipid rafts, which in turn could affect cellular signalling. In the second section, we summarize how the effects on signalling translate into general neuroprotective effects through peripheral systems. Statins improve blood-flow, reduce coagulation, modulate the immune system and reduce oxidative damage. The final section deals with the effects of statins on the central nervous system, particularly during Alzheimer's and Parkinson's disease, stroke and multiple sclerosis. (C) 2009 Elsevier Ltd. All rights reserved.

Based on recent research neuro inflammation is more than Just a pathological mechanism in neurodegenerative diseases. As representatives for the cytokine family we will review the functions of Interleukin-6 and Tumor Necorosis Factor with respect to their role in neuroprotection and neurodegeneration. Both cytokines have been found to be strongly upregulated during diseases such as Alzheimer's disease, stroke or Parkinson's syndrome. By comparing signaling function of these cytokines during health and disease it becomes clear that the role of cytokine mediated tissue modulation depends very much on the molecular and cellular state of nerve cells e.g. physiological vs. pathological. Finally, we will discuss the possibilities of using cytokine activated pathways as a potential targets for therapeutic avenues.

Tumor necrosis factor (TNF) is an important factor in various acute and chronic neurodegenerative disorders. In retinal ischemia, we show early, transient upregulation of TNF, TNF receptor 1 (TNF-R1), and TNF-R2 6 hr after reperfusion preceding neuronal cell loss. To assess the specific role of TNF and its receptors, we compared ischemia-reperfusion- induced retinal damage in mice deficient for TNF-R1, TNF-R2, or TNF by quantifying neuronal cell loss 8 d after the insult. Surprisingly, TNF deficiency did not affect overall cell loss, yet absence of TNF-R1 led to a strong reduction of neurodegeneration and lack of TNF-R2 led to an enhancement of neurodegeneration, indicative of TNF-independent and TNF-dependent processes in the retina, with TNF-R1 augmenting neuronal death and TNF-R2 promoting neuroprotection. Western blot analyses of retinas revealed that reduction of neuronal cell loss in TNFR1 -/- animals correlated with the presence of activated Akt/ protein kinase B (PKB). Inhibition of the phosphatidylinositol 3-kinase signaling pathway reverted neuroprotection in TNFR1-deficient mice, indicating an instrumental role of Akt/ PKB in neuroprotection and TNF-R2 dependence of this pathway. Selective inhibition of TNF-R1 function may represent a new approach to reduce ischemia-induced neuronal damage, being potentially superior to strategies aimed at suppression of TNF activity in general.

Neurodegeneration occurs not only in brain injury, i.e. after trauma or ischemia. It is also part of the typical pathology in various disorders such as Alzheimer’s disease, Huntington’s chorea, Parkinson’s syndrome, AIDS dementia, Creuzfeldt-Jakob disease and other prion derived pathologies, the autoimmune disease multiple sclerosis, and during viral or bacterial infections.

Endothelial activation is an important feature of many inflammatory diseases and has been implicated as the cause of vascular complications in disorders such as diabetes, atherosclerosis, and transplant rejection. One of the most potent activators of the endothelium is TNF, which can also be expressed by endothelial cells, causing a permanent, autocrine stimulatory signal. To establish a model of continuous endothelial activation and to elucidate the role of endothelial derived TNF in vivo, we generated transgenic mice expressing a noncleavable transmembrane form of TNF under the control of the endothelial-specific tie2 promoter. Adult tie2-transmembrane TNF-transgenic mice developed chronic inflammatory pathology in kidney and liver, characterized by perivascular infiltration of mononuclear cells into these organs. Along with the infiltrate, an up-regulation of the adhesion molecules ICAM-1 and VCAM-1, but not E-selectin, in the endothelium was observed. Despite predisposition to chronic inflammation these mice were protected from immune-mediated liver injury in a model of Con A-induced acute hepatitis. Although the blood levels of soluble TNF and IFN-γ were increased in transgenic animals after challenge with Con A, no damage of hepatocytes could be detected, as assessed by the lack of increase in plasma transaminase activities and the absence of TUNEL staining in the liver. We conclude that expression of transmembrane TNF in the endothelium causes continuous endothelial activation, leading to both proinflammatory and protective events.

To define epitopes of tetanus toxin, we compared four different in vitro systems in terms of their ability to produce tetanus toxin-specific subfragments from cloned DNA. A transcription-translation system developed from a nontoxigenic strain of Clostridium tetani was found to yield predominantly full-sized peptides. Such peptides were used to map six different epitopes for eight monoclonal antibodies. The toxin-neutralizing properties of the antibodies were determined in an in vitro assay, based on the toxin-mediated inhibition of norepinephrine release from rat brain particles. Two monoclonal antibodies recognizing epitopes within the regions Ser-744 to Ser-864 and Ile-1224 to Asp-1315 could neutralize the toxin. A third nonneutralizing antibody was shown to recognize the synthetic peptide Phe-947 to Glu-967 derived from the tetanus toxin sequence. This peptide contains a human T-cell epitope.