Investigation Into the Effects of Tenilsetam on Markers of Neuroinflammation in GFAP-IL6 Mice

Gyengési, Erika; Liang, Huazheng; Millington, Christopher L.; Sonego, Sandra; Sirijovski, Daniel; Gunawardena, Dhanushka; Dhananjayan, Karthik; Venigalla, Madhuri; Niedermayer, Garry; Münch, Gerald

doi:10.1007/s11095-017-2326-9

Cited by 10 publications

(12 citation statements)

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“…Our study has reported that LC has the potential to downregulate the TSPO + microglia in chronic neuroinflammation. A recent study performed in the same mouse model found that the number of TSPO + cells increased in GFAP-IL6 mice and it increased even more in Tenilsetam treated mice 30 . The present study has revealed that the TSPO + microglia is significantly increased in both regions (hippocampus and cerebellum) of the brain in GFAP-IL6 normal-fed mice compared to the wild type normal-fed mice.…”

Section: Discussionmentioning

confidence: 83%

“…The weight of the GFAP-IL6 animals was not significantly affected by diet. increased in response to injury and inflammation 30 . In order to investigate the genotype difference between the wild type and GFAP-IL6 normal food-fed mice, and to test the effect of LC on TSPO + microglia in both wild type and GFAP-IL6 mice, immunohistochemistry and stereological counting of the TSPO positive microglia/ macrophages was performed.…”

Section: Resultsmentioning

confidence: 99%

“…Stereological counting. The estimated number of glial cells in both the cerebellum and the hippocampus was counted on Iba1, TSPO and GFAP stained sections using the Zeiss AxioImager M2 microscope equipped with MBF Biosciences StereoInvestigator 30 . The contour of the cerebellum and the hippocampus was first drawn under the 2.5× objective.…”

Section: Cohortsmentioning

confidence: 99%

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Effects of a solid lipid curcumin particle formulation on chronic activation of microglia and astroglia in the GFAP-IL6 mouse model

Ullah

Asgarov

Venigalla

et al. 2020

Sci Rep

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Chronic glial activation is characterized by increased numbers of activated glial cells, secreting free radicals and cytotoxic cytokines, subsequently causing neuronal damage. In order to investigate the anti-inflammatory activity of Longvida ® Optimised Curcumin (LC), we fed 500 ppm of LC to 2-monthold wild type and GFAP-IL6 mice for 6 months. LC feeding led to a significant reduction in the number of Iba-1 + microglia by 26% in the hippocampus and by 48% in the cerebellum, GFAP + astrocytes by 30%, and TSPO + cells by 24% in the hippocampus and by 31% in the cerebellum of the GFAP-IL6 mice. The morphology of the cells was assessed and LC significantly decreased the dendritic length of microglia and the convex area, convex perimeter, dendritic length, nodes and number of processes of astrocytes in the hippocampus while decreasing the soma area and perimeter in the cerebellum, in LC-fed GFAP-IL6 mice. In addition, LC feeding increased pre-and postsynaptic protein levels and improved balance measured by Rotarod. Together, these data suggest that LC is able to attenuate the inflammatory pathology and ameliorate neurodegeneration and motor deficits in GFAP-IL6 mice. For patients with neuro-inflammatory disorders, LC might potentially reverse the detrimental effects of chronic glial activation.In a healthy brain, microglia and astrocytes play a key role in the normal function of the central nervous system (CNS). The inflammatory response is mediated by the activated microglia, which is considered as the hallmark of neuroinflammation. The chronic activation of microglia leads to neuronal damage through the release of various cytotoxic molecules such as cytokines, reactive oxygen intermediates, and proteinases 1 . Microglia are involved in neural development including through phagocytosis of apoptotic cells. They also influence the function of neurons and their progenitor cells 2 . Astrocytes regulate synaptic transmission, for example through re-uptake of neurontransmitters such as glutamate, and support neurons with metabolic substrates such as gluthathione and lactate 3 .Chronic microglial activation, or neuroinflammation, has been described in many neurodegenerative diseases including chronic traumatic encephalopathy, amyotrophic lateral sclerosis, Parkinson's (PD) and Alzheimer's disease (AD) 4 . For sporadic AD, surmounting histological evidence points to chronic microglial activation as a part of the disease process 1,5 . Chronic microglial activation describes long lasting, CNS-specific, aberrant glial responses that do not reproduce the classic characteristics of inflammation although they do contribute to neurodegeneration 6 . To further support the role of neuroinflammation in AD, genome-wide association studies have identified a variety of inflammation-relevant genes that are associated with AD including clusterin (CLU), complement receptor 1 (CR1) and triggering receptor expressed on myeloid cells 2 (TREM2) 7 . The role of the microglial receptor TREM2 is to activate phagocytosis or microglial survival, an...

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Section: Discussionmentioning

confidence: 83%

Section: Resultsmentioning

confidence: 99%

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Effects of a solid lipid curcumin particle formulation on chronic activation of microglia and astroglia in the GFAP-IL6 mouse model

Ullah

Asgarov

Venigalla

et al. 2020

Sci Rep

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“…Interestingly, however, the microglia phenotype of GFAP‐IL6 and GFAP‐IFN mice does differ, indicating that the cellular characteristics of microglia in these transgenic mice are defined by the specific transgene driven local environment (Figure ). In the CNS of GFAP‐IL6 mice, the number of microglia is increased (Gyengesi et al, ) and these cells show characteristic changes in their morphology similar to those observed in patients with NMOSD, such as decreased ramification and retracted processes (Figure ; Campbell et al, ; Quintana et al, ; Vallieres, Campbell, Gage, & Sawchenko, ). Microglia from GFAP‐IL6 mice have activated STAT3 in their nucleus (Campbell et al, ; Campbell et al, ; Sanz, Hofer, Unzeta, & Campbell, ), consistent with these cells mounting a direct response to IL‐6.…”

Section: The Response Of Microglia In Il‐6‐ and Ifn‐i‐mediated Neuroimentioning

confidence: 90%

Microglia responses to interleukin‐6 and type I interferons in neuroinflammatory disease

West

Viengkhou

Campbell

et al. 2019

Glia

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Microglia are the resident macrophages of the central nervous system (CNS). They are a heterogenous, exquisitely responsive, and highly plastic cell population, which enables them to perform diverse roles. They sense and respond to the local production of many different signals, including an assorted range of cytokines. Microglia respond strongly to interleukin‐6 (IL‐6) and members of the type I interferon (IFN‐I) family, IFN‐alpha (IFN‐α), and IFN‐beta (IFN‐β). Although these cytokines are essential in maintaining homeostasis and for activating and regulating immune responses, their chronic production has been linked to the development of distinct human neurological diseases, termed “cerebral cytokinopathies.” IL‐6 and IFN‐α have been identified as key mediators in the pathogenesis of neuroinflammatory disorders including neuromyelitis optica and Aicardi‐Goutières syndrome, respectively, whereas IFN‐β has an emerging role as a causal factor in age‐associated cognitive decline. One of the key features that unites these diseases is the presence of highly reactive microglia. The current understanding is that microglia contribute to the development of cerebral cytokinopathies and represent an important therapeutic target. However, it remains to be resolved whether microglia have beneficial or detrimental effects. Here we review and discuss what is currently known about the microglial response to IL‐6 and IFN‐I, based on both animal models and clinical studies. Foundational knowledge regarding the microglial response to IL‐6 and IFN‐I is now being used to devise therapeutic strategies to ameliorate neuroinflammation and promote repair: either through targeting microglia, or by targeting the reduction of CNS levels or downstream biological pathways of IL‐6 or IFN‐I.

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“…In the GFAP-IL6 mouse model, the murine IL-6 gene is expressed by astrocytes under the transcriptional control of the glial fibrillary acidic protein (GFAP) promoter, resulting in brain-specific overexpression of IL6 and chronic low-grade neuroinflammation, characterized by microglia and astrocyte activation throughout the lifespan (Gyengesi et al, 2019). This has been demonstrated via a significant increase in Iba-1 + and TSPO + microglia and macrophages, GFAP + astroglia and neurodegeneration predominantly in the cerebellum (Campbell et al, 1993), leading to the activation of microglia (microgliosis) and astrocytes (astrocytosis) (Gyengesi et al, 2018) and a range of structural and functional neurological impairments that typify various neurodegenerative diseases (Campbell et al, 1993). Previous studies have reported that GFAP-IL6 transgenic mice display a high level of IL6 expression in the cerebellum compared with other brain regions (Campbell et al, 1993;Quintana et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Phytosomal Curcumin as an Anti-inflammatory Agent for Chronic Glial Activation in the GFAP-IL6 Mouse Model

et al. 2020

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Chronic glial activation is characterized by an increased number of activated microglia and astroglia; these secrete free radicals and cytotoxic cytokines, subsequently causing neuronal damage. This study investigated the hypothesis that a soy-lecithin based phytosomal curcumin formulation can decrease glial activation in the brains of GFAP-IL6 mice, a model of chronic glial activation, which exhibits gliosis in various regions of the brain. Three doses of Meriva curcumin (MC) (874, 436, and 218 PPM) were fed to 3-month-old GFAP-IL6 and wild-type (WT) mice for 4 weeks. As markers of glial activation, the total numbers of Iba-1 + and TSPO + microglia and macrophages, and GFAP + astrocytes, were determined in the cerebellum and hippocampus by immunohistochemistry and unbiased stereology. Furthermore, the morphology of the glial cells was assessed by confocal microscopy and Sholl analysis. Administration of phytosomal curcumin led to a dose-dependent reduction in neuroinflammatory markers. Phytosomal curcumin (874 PPM) decreased the number of microglia by 26.2% in the hippocampus and by 48% in the cerebellum of the GFAP-IL6 mice compared with the GFAP-IL6 mice on normal food. Additionally, GFAP + astrocyte numbers in the hippocampus of the GFAP-IL6 mice were decreased by 42%. The GFAP-IL6 mice exhibited a different microglial morphology to the WT mice, showing an increased soma size and perimeter. This difference was significantly reduced by the 874 PPM phytosomal curcumin dose. Our findings demonstrate that phytosomal curcumin is able to attenuate the inflammatory pathology, and potentially reverse the detrimental effects of chronic glial activation.

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Investigation Into the Effects of Tenilsetam on Markers of Neuroinflammation in GFAP-IL6 Mice

Abstract: Tenilsetam has anti-inflammatory effects evidenced by the decreased number of microglia in both the cerebellum and hippocampus, and decreased TNF-α levels in the GFAP-IL6 Tenilsetam fed animals.

Cited by 10 publications

References 57 publications

Effects of a solid lipid curcumin particle formulation on chronic activation of microglia and astroglia in the GFAP-IL6 mouse model

Effects of a solid lipid curcumin particle formulation on chronic activation of microglia and astroglia in the GFAP-IL6 mouse model

Microglia responses to interleukin‐6 and type I interferons in neuroinflammatory disease

Evaluation of Phytosomal Curcumin as an Anti-inflammatory Agent for Chronic Glial Activation in the GFAP-IL6 Mouse Model

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