Development Of Brain Inflammation Research Articles

Nicotinamide Prevents Diabetic Brain Inflammation via NAD+-Dependent Deacetylation Mechanisms.

This study investigated the effect of nicotinamide (NAM) supplementation on the development of brain inflammation and microglial activation in a mouse model of type 1 diabetes mellitus. C57BL/6J male mice, which were made diabetic with five consecutive, low-dose (55 mg/kg i.p.) streptozotocin (STZ) injections. Diabetic mice were randomly distributed in different experimental groups and challenged to different doses of NAM (untreated, NAM low-dose, LD, 0.1%; NAM high-dose, HD, 0.25%) for 25 days. A control, non-diabetic group of mice was used as a reference. The NAD+ content was increased in the brains of NAM-treated mice compared with untreated diabetic mice (NAM LD: 3-fold; NAM HD: 3-fold, p-value < 0.05). Immunohistochemical staining revealed that markers of inflammation (TNFα: NAM LD: -35%; NAM HD: -46%; p-value < 0.05) and microglial activation (IBA-1: NAM LD: -29%; NAM HD: -50%; p-value < 0.05; BDKRB1: NAM LD: -36%; NAM HD: -37%; p-value < 0.05) in brains from NAM-treated diabetic mice were significantly decreased compared with non-treated T1D mice. This finding was accompanied by a concomitant alleviation of nuclear NFκB (p65) signaling in treated diabetic mice (NFκB (p65): NAM LD: -38%; NAM HD: -53%, p-value < 0.05). Notably, the acetylated form of the nuclear NFκB (p65) was significantly decreased in the brains of NAM-treated, diabetic mice (NAM LD: -48%; NAM HD: -63%, p-value < 0.05) and inversely correlated with NAD+ content (r = -0.50, p-value = 0.03), suggesting increased activity of NAD+-dependent deacetylases in the brains of treated mice. Thus, dietary NAM supplementation in diabetic T1D mice prevented brain inflammation via NAD+-dependent deacetylation mechanisms, suggesting an increased action of sirtuin signaling.

Transabdominal ultrasound alleviates LPS-induced neuroinflammation by modulation of TLR4/NF-κB signaling and tight junction protein expression

AimInflammatory bowel disease (IBD) may be a risk factor in the development of brain inflammation. It has been demonstrated noninvasive neuromodulation through sub-organ ultrasound stimulation. The purpose of this study was to investigate whether abdominal low-intensity pulsed ultrasound (LIPUS) alleviates lipopolysaccharide (LPS)-induced cortical inflammation via inhibition of colonic inflammation. Materials and methodsColonic and cortical inflammation was induced in mice by LPS (0.75 mg/kg, i.p. injection) for 7 days, followed by application of LIPUS (0.5 and 1.0 W/cm2) to the abdominal area for 6 days. Biological samples were collected for Western blot analysis, gelatin zymography, colon length measurement, and histological evaluation. Key findingsLIPUS treatment significantly attenuated LPS-induced increases in IL-6, IL-1β, COX-2, and cleaved caspase-3 expression in the colon and cortex of mice. Moreover, LIPUS significantly increased the levels of tight junction proteins in the epithelial barrier in the mouse colon and cortex with LPS-induced inflammation. Compared to the group treated only with LPS, the LIPUS-treated groups showed decreased muscle thickness and increased crypt length and colon length. Furthermore, LIPUS treatment reduced inflammation by inhibiting the LPS-induced activation of TLR4/NF-κB inflammatory signaling in the brain. SignificanceWe found that LIPUS alleviated LPS-induced colonic and cortical inflammation through abdominal stimulation of mice. These results suggest that abdominal LIPUS stimulation may be a novel therapeutic strategy against neuroinflammation via enhancement of tight junction protein levels and inhibition of inflammatory responses in the colon.

The impact of the histone deacetylase inhibitor sodium butyrate on microglial polarization after oxygen and glucose deprivation.

Microglia play a major role in the development of brain inflammation after central nervous system injury. On the other hand, microglia also participate in the repair process. The dualistic role of these cells results from the fact that various states of their activation are associated with specific phenotypes. The M1 phenotype is responsible for the production of proinflammatory mediators, whereas the M2 microglia release anti-inflammatory and trophic factors and take part in immunosuppressive and neuroprotective processes. The histone deacetylase inhibitor sodium butyrate (SB) shows anti-inflammatory and neuroprotective effects in some animal models of brain injury. The aim of this study was to examine the effects of sodium butyrate on the proliferation and M1/M2 polarization of primary microglial cells after oxygen and glucose deprivation (OGD) in vitro. Primary microglial cultures were prepared from 1-day-old rats, subjected to the OGD procedure and treated with SB (0.1mM, 1mM and 10mM). The effect of OGD and SB on microglial proliferation was assessed by double immunofluorescence, and microglial phenotypes were evaluated by qPCR. The OGD procedure stimulated the proliferation of microglia after 24h of culturing, and SB treatment reduced the division of these cells. This effect was inversely proportional to the SB concentration. The OGD procedure increased proinflammatory CD86 and IL1β gene expression and reduced the expression of the anti-inflammatory M2 markers arginase and CD200 in microglia. SB can change the polarization of microglia after OGD from an unfavourable M1 to a beneficial M2 phenotype. Our results show that SB is a potential immunosuppressive agent that can modulate microglial activation stimulated by ischaemic-like conditions.

Inhibition of NF-κB activity by aminoguanidine alleviates neuroinflammation induced by hyperglycemia.

Neuroinflammation is a key feature of cerebral complication which is associated with diabetes mellitus (DM). Inducible nitric oxide synthase (iNOS) is implicated in the pathogenesis of neuroinflammation. However, how iNOS facilitates the development of inflammation in brain is still unidentified. The aim of the present study was to investigate the association of iNOS and neuroinflammation in diabetic mice, and elucidate the potential mechanisms underlying aminoguanidine (AG), the selective inhibitor of iNOS, protected neurons against inflammation in diabetic mice. In present experiment, diabetic mice model were established by a single intraperitoneal injection of streptozotocin (STZ). AG was administered to diabetic mice for ten weeks after this disease induction. Then we measured iNOS activity in the serum and brain, detected the glial fibrillary acidic protein (GFAP) and ionised calcium binding adaptor molecule-1 (Iba-1) expressions in the brain. Moreover, nuclear factor-kappa B (NF-κB) in cytoplasm and nucleus were tested by IP and WB. Results revealed that high expression of iNOS in serum and brain could be reversed by AG treatment. Furthermore, AG could also inhibit GFAP and Iba-1 expressions, and NF-κB nuclear translocation by inhibiting it from binding to iNOS in cytoplasm. Our findings indicated that iNOS can combine with NF-κB in cytoplasm and promote its nuclear transfer in diabetic mice. Furthermore, AG decreased neuroinflammation through inhibiting iNOS activity and reducing NF-κB nuclear translocation by promoting its dissociation with iNOS in cytoplasm.

Complement drives neurodegeneration in Gaucher disease

Abstract GBA1 mutations result in excess storage of glucosylceramide (GC) and the induction of Gaucher disease (GD). GD is frequently associated with elevated levels of pro-inflammatory cytokines and the development of brain inflammation. The mechanisms underlying GC-driven brain inflammation in GD are ill-defined. Recently, we described immune complexes of GC-specific IgG autoantibodies in experimental and clinical GD, which induced massive complement activation and C5a generation. Further, we found that C5a-mediated activation of its cognate C5a receptor 1 (C5aR1) tips the balance between GC formation and degradation, thereby fueling excess GC accumulation and inflammation in visceral tissues in experimental and clinical GD. Previously, the C5a/C5aR1 axis was found to regulate the blood brain barrier integrity in systemic lupus and promote neurodegeneration in Alzheimer’s disease. Here, we determined the production of C5a in the brain of Gba1 D409V/knockout (9V/null) GD-prone mice. C5a production in the brain of 9V/null mice was markedly elevated, when compared to WT control mice. Also, 9V/null mice suffered from massive accumulation of GC in the brain and loss of neurons. To assess the relevance of C5a/C5aR1 axis activation for brain inflammation in GD, we targeted glucocerebrosidase (GCase) with conduritol B epoxide (CBE) in WT and C5aR1−/− mice. Strikingly, CBE-injected WT mice died within 30 days. In contrast, all C5aR1−/− mice survived the 60 days observation window, were protected from CBE-induced accumulation of GC in the brain, showed a marked reduction of microglial cell activation and only a minor loss of neurons. Our data suggest that the C5a/C5aR1 axis is a critical driver of neurodegeneration in experimental GD.

Current diagnosis of mixed herpesvirus infection in children with viral encephalitis

Sixty-five children aged 1 month to 15 years with a diagnosis of viral encephalitis, who had been admitted to the Clinic of the Pediatric Research and Clinical Center for Infectious Diseases, Federal Biomedical Agency, in 2013-2016 were examined. Objective: to establish the frequency of mixed herpesvirus infection in children with viral encephalitis, by using the current diagnostic methods to determine the role of reactivation of herpesvirus infection on the development of viral encephalitis. The investigators identified anti-herpesvirus antibodies and their avidity using an enzyme immunoassay and anti-cytomegalovirus antibodies specific for antigens by immunoblotting applying the kits. Herpesvirus DNA was detected in the biological material (blood, cerebrospinal fluid) by real-time polymerase chain reaction (PCR) and by electrophoresis using the PCR kits (Central Research Institute of Epidemiology, Russian Federal Service for Supervision of Consumer Rights Protection and Human Welfare (Moscow). Young children were shown to develop the disease as a result of primary infection more commonly as monoinfection in the old age groups during the persistence of one or two herpesviruses in the body. In encephalitis caused by herpes simplex virus type 1 and type 2, reactivation of cytomegalovirus that could be a cofactor in the development of brain inflammation was proven by the current diagnostic technique immunoblotting. The comprehensive laboratory approach to the etiological diagnosis of viral encephalitis, which encompassesthe determination of antibody classes, avidity, and antibodiesto individual protein determinants of viral particles, makes it possible to specify the activity of different herpesviruses in mixed infection and to determine the stage of the infectious process, which is important for the choice of therapeutic policy.

Osteopontin expression in the brain triggers localized inflammation and cell death when immune cells are activated by pertussis toxin.

Upregulation of osteopontin (OPN) is a characteristic of central nervous system pathologies. However, the role of OPN in inflammation is still controversial, since it can both prevent cell death and induce the migration of potentially damaging inflammatory cells. To understand the role of OPN in inflammation and cell survival, we expressed OPN, utilizing an adenoviral vector, in the caudoputamen of mice deficient in OPN, using beta-galactosidase- (β-gal-) expressing vector as control. The tissue pathology and the expression of proinflammatory genes were compared in both treatments. Interestingly, inflammatory infiltrate was only found when the OPN-vector was combined with a peripheral treatment with pertussis toxin (Ptx), which activated peripheral cells to express the OPN receptor CD44v6. Relative to β-gal, OPN increased the levels of inflammatory markers, including IL13Rα1, CXCR3, and CD40L. In Ptx-treated OPN KOs, apoptotic TUNEL+ cells surrounding the OPN expression site increased, compared to β-gal. Together, these results show that local OPN expression combined with a peripheral inflammatory stimulus, such as Ptx, may be implicated in the development of brain inflammation and induction of cell death, by driving a molecular pattern characteristic of cytotoxicity. These are characteristics of inflammatory pathologies of the CNS in which OPN upregulation is a hallmark.

Blood–brain barrier dysfunction and epilepsy: Pathophysiologic role and therapeutic approaches

The blood-brain barrier (BBB) is located within a unique anatomic interface and has functional ramifications to most of the brain and blood cells. In the past, the BBB was considered a pharmacokinetic impediment to antiepileptic drug penetration into the brain; nowadays it is becoming increasingly evident that targeting of the damaged or dysfunctional BBB may represent a therapeutic approach to reduce seizure burden. Several studies have investigated the mechanisms linking the onset and sustainment of seizures to BBB dysfunction. These studies have shown that the BBB is at the crossroad of a multifactorial pathophysiologic process that involves changes in brain milieu, altered neuroglial physiology, development of brain inflammation, leukocyte-endothelial interactions, faulty angiogenesis, and hemodynamic changes leading to energy mismatch. A number of knowledge gaps, conflicting points of view, and discordance between clinical and experimental data currently characterize this field of neuroscience. As more pieces are added to this puzzle, it is apparent that each mechanism needs to be validated in an appropriate clinical context. We now offer a BBB-centric view of seizure disorders, linking several aspects of seizures and epilepsy physiopathology to BBB dysfunction. We have reviewed the therapeutic, antiseizure effect of drugs that promote BBB repair. We also present BBB neuroimaging as a tool to correlate BBB restoration to seizure mitigation. Add-on cerebrovascular drug could be of efficacy in reducing seizure burden when used in association with neuronal antiepileptic drugs.

Induction of immunoreactive interleukin-1β and tumor necrosis factor-α in the brains of rabies virus infected rats

Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα) are important cytokines in the development of brain inflammation during pathological process. During rabies virus infection, the level of these proinflammatory cytokines are enhanced in the brain. In the present study we determined the cellular localization of these two cytokines by immunocytochemistry in brains of rats infected with rabies virus, at different time-intervals of the disease (day 1, 3, 4, 5 and at final stage day 6 post-infection (p.i.)). Cellular identification of IL-1β (irIL-1β) and TNFα (irTNFα) immunopositive cells was studied using a polyclonal antibody against these cytokines and against glial fibrillary acidic protein (GFAP) to detect astrocytes and GSA-I-B4 isolectin to detect microglial cells and/or infiltrating macrophages. In brains of control and early infected rats, irIL-1β was only detected in fibers located in the hypothalamus, supraoptic and tractus optic nuclei and infundibular nucleus. From day 4 onwards until day 6 p.i., enhanced irIL-1β was found and identified either in activated ameboid and/or infiltrated macrophages (amygdala, thalamus, internal capsula, subtantia nigra, septal nuclei and around blood vessels), or in activated ramified cells (hypothalamus and periventricular nucleus, piriformis and cingulate cortex, hippocampus). IrTNFα was observed in the brains of rats at a final stage of disease (day 5 and 6 p.i.): in the hypothalamus, the amygdala, the internal capsula, the thalamus, the septal nuclei, the hippocampus, the habenular nuclei and around the blood vessels. Ir-TNFα was detected in round cells identified as ameboid microglia and/or infiltrated macrophages. A marked activation of microglial and astroglial cells was observed mainly in the hypothalamus, the thalamus and hippocampus and around the blood vessels, at day 4 p.i. and later, revealing a high central inflammatory reaction in brains of rabies virus infected rats. These results showed that IL-1β and TNFα are produced in the brain both by local microglial cells and infiltrating macrophages during rabies infection. Thus, these cytokines may play an important role in coordinating the dramatic inflammatory response associated with the rabies-encephalopathy as well as in the neural modification and alteration of brain functions.