Sterile Neuroinflammation and Strategies for Therapeutic Intervention

Banjara, Manoj; Ghosh, Chaitali

doi:10.1155/2017/8385961

Cited by 71 publications

(73 citation statements)

References 200 publications

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“…We demonstrated increased uptake of the PET ligand at the neuroinflammatory site. These findings show promise for [ 18 F]JNJ-64413739 as a PET ligand to study P2X7 receptors in a variety of brain disorders involving neuroinflammation [3,4]. We acknowledge that local LPSinduced changes in neuroinflammation, as described in our paper, are extreme and most likely do not represent neuroinflammatory changes in chronic CNS diseases; detailed discussion is provided in the ESM.…”

Section: Discussionmentioning

confidence: 74%

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PET Imaging of the P2X7 Ion Channel with a Novel Tracer [18F]JNJ-64413739 in a Rat Model of Neuroinflammation

et al. 2019

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Purpose: The P2X7 receptor, an adenosine triphosphate (ATP)-gated purinoreceptor, has emerged as one of the key players in neuroinflammatory processes. Therefore, developing a positron emission tomography (PET) tracer for imaging of P2X7 receptors in vivo presents a promising approach to diagnose, monitor, and study neuroinflammation in a variety of brain disorders. To fulfill the goal of developing a P2X7 PET ligand as a biomarker of neuroinflammation, [ 18 F]JNJ-64413739 has been recently disclosed. Procedures: We evaluated [ 18 F]JNJ-64413739 in a rat model of neuroinflammation induced by an intracerebral injection of lipopolysaccharide (LPS). In vivo brain uptake was determined by PET imaging. Upregulation of neuroinflammatory biomarkers was determined by quantitative polymerase chain reaction (qPCR). Distribution of the tracer in the brain was determined by ex vivo autoradiography (ARG). The specificity of [ 18 F]JNJ-64413739 was confirmed by performing blocking experiments with the P2X7 antagonist JNJ-54175446. Results: Brain regions of rats injected with LPS had a significantly increased uptake (34 % ± 3 % s.e.m., p = 0.036, t test, standardized uptake value measured over the entire scanning period) of [ 18 F]JNJ-64413739 relative to the corresponding brain regions of control animals injected with phosphate-buffered saline (PBS). The uptake in the contralateral regions and cerebellum was not significantly different between the groups of animals. The increase in uptake of [ 18 F]JNJ-64413739 at the LPS-injected site observed by PET imaging was concordant with ex vivo ARG, upregulation of neuroinflammatory biomarkers, and elevated P2X7 expression levels. Conclusions: While further work is needed to study [ 18 F]JNJ-64413739 in other types of neuroinflammation, the current results favorably characterize [ 18 F]JNJ-64413739 as a potential PET tracer of central neuroinflammation.

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Section: Discussionmentioning

confidence: 74%

“…Neuroinflammation is thought to play a role in many neuropsychiatric and neurological conditions [1][2][3][4]; however, its exact contribution remains poorly understood [5][6][7]. This is partially due to limited diagnostic tools to measure inflammation in the central nervous system (CNS) [8].…”

Section: Introductionmentioning

confidence: 99%

PET Imaging of the P2X7 Ion Channel with a Novel Tracer [18F]JNJ-64413739 in a Rat Model of Neuroinflammation

et al. 2019

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Section: Discussionmentioning

confidence: 99%

“…The presence of HMGB1 is considered to be a risk factor for memory impairment, chronic neurodegeneration and advanced progression of neuroinflammation [6,9,13,16,19]. Additionally, the DAMP molecule for TLR4 is known to induce sterile neuroinflammation [6,16]. Nevertheless, no study has been done to investigate the astroglial inflammatory mechanisms resulting from the ligation of HMGB1 to TLR4 and TLR2 via mediating signalling pathways, such as the NF-ҡβ [27].…”

Section: Discussionmentioning

confidence: 99%

High-Mobility Group Box 1 (HMGB1), an Endogenous Ligand of Toll-Like Receptors 2 and 4, Induces Astroglial Inflammation via NF-ҡβ Pathway

Al-ofi

Alghamdi

2015

Folia Morphol

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Neuroinflammation has a definitive role in neurodegenerative diseases, such as Parkinson's and Alzheimer's disease. In addition to its pathogenic ligands, toll-like receptors (TLRs) can be activated by damaged endogenous molecules that induce inflammatory signalling pathways such as high-mobility group box 1 protein (HMGB1). Using an ex-vivo rat optic nerve (RON) model, we sought to determine the effects of lipopolysaccharides (LPS; TLR4 agonist), zymosan (TLR2 agonist) or HMGB1-with or without TLR2/4 antagonists, on the expression of glial fibrillary acidic protein (GFAP) and nuclear factor kappa B (NF-ҡβ) for signalling pathway and astrocyte reactivity, using double immunohistochemistry; as well as on the modulation of the neurotoxicity. HMGB1-treated RON had significant higher expression and co-localisation of GFAP and NF‑ҡβ as compared to the untreated control, which was a similar result to those treated with LPS and zymosan. Moreover, the HMGB1-induced inflammation was blocked by TLR2/4 antagonists (P=0.05). However, the HMGB1-induced cell death was unblocked by TLR antagonists. Overall, HMGB1 endogenously mediates the signalling mechanisms of neuroinflammation through TLR2/4. Whereas, the neuronal death mechanism resulting from HMGB1 could be caused by a different signalling pathway. Gaining an understanding of these mechanisms may help researchers discover new therapeutic targets for neurodegenerative diseases.

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“…Microglia are the assigned immune cells aimed at protecting brain cells from any damage [1,2,7]. Microglia reside within the normal brain as a ubiquitously distributed quiescent cell population which respond to changes within the system's micro-environment, in order to interact swiftly with diseases [1,8,9].…”

Section: Introductionmentioning

confidence: 99%

Dynamic Modelling of Interactions between Microglia and Endogenous Neural Stem Cells in the Brain during a Stroke

2020

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In this paper, we study the interactions between microglia and neural stem cells and the impact of these interactions on the brain cells during a stroke. Microglia cells, neural stem cells, the damage on brain cells from the stroke and the impacts these interactions have on living brain cells are considered in the design of mathematical models. The models consist of ordinary differential equations describing the effects of microglia on brain cells and the interactions between microglia and neural stem cells in the case of a stroke. Variables considered include: resident microglia, classically activated microglia, alternatively activated microglia, neural stem cells, tissue damage on cells in the brain, and the impacts these interactions have on living brain cells. The first model describes what happens in the brain at the stroke onset during the first three days without the generation of any neural stem cells. The second model studies the dynamic effect of microglia and neural stem cells on the brain cells following the generation of neural stem cells and potential recovery after this stage. We look at the stability and the instability of the models which are both studied analytically. The results show that the immune cells can help the brain by cleaning dead cells and stimulating the generation of neural stem cells; however, excessive activation may cause damage and affect the injured region. Microglia have beneficial and harmful functions after ischemic stroke. The microglia stimulate neural stem cells to generate new cells that substitute dead cells during the recovery stage but sometimes the endogenous neural stem cells are highly sensitive to inflammatory in the brain.

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Sterile Neuroinflammation and Strategies for Therapeutic Intervention

Cited by 71 publications

References 200 publications

PET Imaging of the P2X7 Ion Channel with a Novel Tracer [18F]JNJ-64413739 in a Rat Model of Neuroinflammation

PET Imaging of the P2X7 Ion Channel with a Novel Tracer [18F]JNJ-64413739 in a Rat Model of Neuroinflammation

High-Mobility Group Box 1 (HMGB1), an Endogenous Ligand of Toll-Like Receptors 2 and 4, Induces Astroglial Inflammation via NF-ҡβ Pathway

Dynamic Modelling of Interactions between Microglia and Endogenous Neural Stem Cells in the Brain during a Stroke

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