Dataset Information

Oxiracetam Offers Neuroprotection by Reducing Amyloid ?-Induced Microglial Activation and Inflammation in Alzheimer's Disease.

ABSTRACT: Background: Alzheimer's disease (AD) is characterized by amyloid beta (A?) accumulation in the brain, which triggers the activation of microglia; in turn, microglia release neuroinflammatory factors capable of damaging neurons. Thus, a therapeutic approach targeting this sustained microglia-induced inflammatory response deserves investigation. Here, we examined whether oxiracetam (ORC), a nootropic of the racetam family, can indirectly prevent A?-induced neurotoxicity by attenuating microglial activation. Methods: A?42 oligomers were used to stimulate BV2 microglial cells, and the morphological changes and phagocytic capacity of BV2 cells were evaluated using fluorescence microscopy. We used quantitative reverse transcription polymerase chain reaction to assess the inhibitory effects of ORC on A?-induced mRNA levels of interleukin-1? (IL-1?), IL-6, and tumor necrosis factor-? (TNF-?); enzyme-linked immunosorbent assay was used to examine the productions of these cytokines. We also assessed the mRNA level of inducible nitric oxide synthase and the production of nitric oxide (NO). The conditioned medium from BV2 cells was used to culture hippocampal HT22 cells to assess indirect toxicity using the MTT assay. Results: ORC prevented the A?-induced activation of BV2 cells, as reflected by reduced morphological changes and phagocytic ability. In addition, ORC downregulated the expression of A?-induced cytokines (IL-1?, IL-6, and TNF-?) and the production of NO in BV2 cells. Furthermore, ORC protected HT22 cells from indirect damage evoked by A?-treated BV2 cell-conditioned medium, but not from direct A?-induced toxicity. Conclusions: ORC suppressed the activation of BV2 cells, decreased the production of A?-induced inflammatory molecules and NO in BV2 cells, and protected HT22 cells against indirect toxicity mediated by A?-treated BV2 cell-conditioned medium. Thus, ORC may exert a protective role in AD through attenuating the damage caused by inflammation and oxidative stress.

SUBMITTER: Zhang H

PROVIDER: S-EPMC7380077 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Oxiracetam Offers Neuroprotection by Reducing Amyloid β-Induced Microglial Activation and Inflammation in Alzheimer's Disease.

Zhang Heng H Jia Longfei L Jia Jianping J

Frontiers in neurology 20200717

<b>Background:</b> Alzheimer's disease (AD) is characterized by amyloid beta (Aβ) accumulation in the brain, which triggers the activation of microglia; in turn, microglia release neuroinflammatory factors capable of damaging neurons. Thus, a therapeutic approach targeting this sustained microglia-induced inflammatory response deserves investigation. Here, we examined whether oxiracetam (ORC), a nootropic of the racetam family, can indirectly prevent Aβ-induced neurotoxicity by attenuating micro ...[more]

PMID: 32765394

Similar Datasets

Project description:BackgroundReactive microglia are associated with ?-amyloid (A?) deposit and clearance in Alzhiemer's Disease (AD). Paradoxically, entocranial resident microglia fail to trigger an effective phagocytic response to clear A? deposits although they mainly exist in an "activated" state. Oligomeric A? (oA?), a recent target in the pathogenesis of AD, can induce more potent neurotoxicity when compared with fibrillar A? (fA?). However, the role of the different A? forms in microglial phagocytosis, induction of inflammation and oxidation, and subsequent regulation of phagocytic receptor system, remain unclear.ResultsWe demonstrated that A?(1-42) fibrils, not A?(1-42) oligomers, increased the microglial phagocytosis. Intriguingly, the pretreatment of microglia with oA?(1-42) not only attenuated fA?(1-42)-triggered classical phagocytic response to fluorescent microspheres but also significantly inhibited phagocytosis of fluorescent labeled fA?(1-42). Compared with the fA?(1-42) treatment, the oA?(1-42) treatment resulted in a rapid and transient increase in interleukin 1? (IL-1?) level and produced higher levels of tumor necrosis factor-? (TNF-?), nitric oxide (NO), prostaglandin E2 (PGE2) and intracellular superoxide anion (SOA). The further results demonstrated that microglial phagocytosis was negatively correlated with inflammatory mediators in this process and that the capacity of phagocytosis in fA?(1-42)-induced microglia was decreased by IL-1?, lippolysaccharide (LPS) and tert-butyl hydroperoxide (t-BHP). The decreased phagocytosis could be relieved by pyrrolidone dithiocarbamate (PDTC), a nuclear factor-?B (NF-?B) inhibitor, and N-acetyl-L-cysteine (NAC), a free radical scavenger. These results suggest that the oA?-impaired phagocytosis is mediated through inflammation and oxidative stress-mediated mechanism in microglial cells. Furthermore, oA?(1-42) stimulation reduced the mRNA expression of CD36, integrin ?1 (Itgb1), and Ig receptor Fc?RIII, and significantly increased that of formyl peptide receptor 2 (FPR2) and scavenger receptor class B1 (SRB1), compared with the basal level. Interestingly, the pre-stimulation with oA?(1-42) or the inflammatory and oxidative milieu (IL-1?, LPS or t-BHP) significantly downregulated the fA?(1-42)-induced mRNA over-expression of CD36, CD47 and Itgb1 receptors in microglial cells.ConclusionThese results imply that A? oligomers induce a potent inflammatory response and subsequently disturb microglial phagocytosis and clearance of A? fibrils, thereby contributing to an initial neurodegenerative characteristic of AD. Antiinflammatory and antioxidative therapies may indeed prove beneficial to delay the progression of AD.

Project description:PurposeMicroglia and Müller cells are prominent participants in retinal responses to injury and disease that shape eventual tissue adaptation or damage. This investigation examined how microglia and Müller cells interact with each other following initial microglial activation.MethodsMouse Müller cells were cultured alone, or co-cultured with activated or unactivated retinal microglia, and their morphological, molecular, and functional responses were evaluated. Müller cell-feedback signaling to microglia was studied using Müller cell-conditioned media. Corroborative in vivo analyses of retinal microglia-Müller cell interactions in the mouse retina were also performed.ResultsOur results demonstrate that Müller cells exposed to activated microglia, relative to those cultured alone or with unactivated microglia, exhibit marked alterations in cell morphology and gene expression that differed from those seen in chronic gliosis. These Müller cells demonstrated in vitro (1) an upregulation of growth factors such as GDNF and LIF, and provide neuroprotection to photoreceptor cells, (2) increased pro-inflammatory factor production, which in turn increased microglial activation in a positive feedback loop, and (3) upregulated chemokine and adhesion protein expression, which allowed Müller cells to attract and adhere to microglia. In vivo activation of microglia by intravitreal injection of lipopolysaccharide (LPS) also induced increased Müller cell-microglia adhesion, indicating that activated microglia may translocate intraretinally in a radial direction using Müller cell processes as an adhesive scaffold.ConclusionOur findings demonstrate that activated microglia are able to influence Müller cells directly, and initiate a program of bidirectional microglia-Müller cell signaling that can mediate adaptive responses within the retina following injury. In the acute aftermath following initial microglia activation, Müller cell responses may serve to augment initial inflammatory responses across retinal lamina and to guide the intraretinal mobilization of migratory microglia using chemotactic cues and adhesive cell contacts. Understanding adaptive microglia-Müller cell interactions in injury responses can help discover therapeutic cellular targets for intervention in retinal disease.

Dataset Information

Oxiracetam Offers Neuroprotection by Reducing Amyloid ?-Induced Microglial Activation and Inflammation in Alzheimer's Disease.

Publications

Oxiracetam Offers Neuroprotection by Reducing Amyloid β-Induced Microglial Activation and Inflammation in Alzheimer's Disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets