Neuroinflammation in neurological disorders: pharmacotherapeutic targets from bench to bedside

Mishra, Awanish; Bandopadhyay, Ritam; Singh, Prabhakar; Mishra, Pragya Shakti; Sharma, Neha; Khurana, Navneet

doi:10.1007/s11011-021-00806-4

Cited by 82 publications

(58 citation statements)

References 301 publications

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“…Neuroinflammation is a significant player in the pathogenesis and progression of multiple neurological conditions, and there is a growing interest in understanding the role of BET proteins in modulating the onset and evolution of CNS inflammation (Sofroniew, 2015;Sweeney et al, 2019;Singh and Sartor, 2020;Mishra et al, 2021;Psenicka et al, 2021).…”

Section: Contribution Of Bet Proteins To Cns Disordersmentioning

confidence: 99%

Role of BET Proteins in Inflammation and CNS Diseases

Liu

Yang

Candelario‐Jalil

2021

Front. Mol. Biosci.

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Bromodomain and extra-terminal domain (BET) proteins consist of four mammalian members (BRD2, BRD3, BRD4, and BRDT), which play a pivotal role in the transcriptional regulation of the inflammatory response. Dysregulated inflammation is a key pathological process in various CNS disorders through multiple mechanisms, including NF-κB and Nrf2 pathways, two well-known master regulators of inflammation. A better mechanistic understanding of the BET proteins’ role in regulating the inflammatory process is of great significance since it could reveal novel therapeutic targets to reduce neuroinflammation associated with many CNS diseases. In this minireview, we first outline the structural features of BET proteins and summarize genetic and pharmacological approaches for BET inhibition, including novel strategies using proteolysis-targeting chimeras (PROTACs). We emphasize in vitro and in vivo evidence of the interplay between BET proteins and NF-κB and Nrf2 signaling pathways. Finally, we summarize recent studies showing that BET proteins are essential regulators of inflammation and neuropathology in various CNS diseases.

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Section: Contribution Of Bet Proteins To Cns Disordersmentioning

confidence: 99%

Role of BET Proteins in Inflammation and CNS Diseases

Liu

Yang

Candelario‐Jalil

2021

Front. Mol. Biosci.

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“…Although inflammatory processes may not trigger such disorders alone, the immune system nonetheless can greatly influence symptom severity and progression. Scientists are actively looking for therapeutic targets that may efficiently control the exacerbated immune responses associated with neuroinflammation in such conditions ( 3 , 4 ).…”

Section: Introductionmentioning

confidence: 99%

Neurological Infection, Kynurenine Pathway, and Parasitic Infection by Neospora caninum

et al. 2022

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Neuroinflammation is one of the most frequently studied topics of neurosciences as it is a common feature in almost all neurological disorders. Although the primary function of neuroinflammation is to protect the nervous system from an insult, the complex and sequential response of activated glial cells can lead to neurological damage. Depending on the type of insults and the time post-insult, the inflammatory response can be neuroprotective, neurotoxic, or, depending on the glial cell types, both. There are multiple pathways activated and many bioactive intermediates are released during neuroinflammation. One of the most common one is the kynurenine pathway, catabolizing tryptophan, which is involved in immune regulation, neuroprotection, and neurotoxicity. Different models have been used to study the kynurenine pathway metabolites to understand their involvements in the development and maintenance of the inflammatory processes triggered by infections. Among them, the parasitic infection Neospora caninum could be used as a relevant model to study the role of the kynurenine pathway in the neuroinflammatory response and the subset of cells involved.

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“…In traditional opinions, microglial over-activation is indicated as a risk factor for the development of central nervous system disorders [ 12 – 14 ]. However, central innate immune stimulation induced by moderate activation of microglia is also neuroprotective.…”

Section: Introductionmentioning

confidence: 99%

Innate immune stimulation by monophosphoryl lipid A prevents chronic social defeat stress-induced anxiety-like behaviors in mice

Xiang

et al. 2022

J Neuroinflammation

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Background Innate immune pre-stimulation can prevent the development of depression-like behaviors in chronically stressed mice; however, whether the same stimulation prevents the development of anxiety-like behaviors in animals remains unclear. We addressed this issue using monophosphoryl lipid A (MPL), a derivative of lipopolysaccharide (LPS) that lacks undesirable properties of LPS but still keeps immune-enhancing activities. Methods The experimental mice were pre-injected intraperitoneally with MPL before stress exposure. Depression was induced through chronic social defeat stress (CSDS). Behavioral tests were conducted to identify anxiety-like behaviors. Real-time polymerase chain reaction (PCR) and biochemical assays were employed to examine the gene and protein expression levels of pro-inflammatory markers. Results A single MPL injection at the dose of 400 and 800 μg/kg 1 day before stress exposure prevented CSDS-induced anxiety-like behaviors, and a single MPL injection (400 μg/kg) five but not 10 days before stress exposure produced similar effect. The preventive effect of MPL on anxiety-like behaviors was also observed in CSDS mice who received a second MPL injection 10 days after the first MPL injection or a 4 × MPL injection 10 days before stress exposure. MPL pre-injection also prevented the production of pro-inflammatory cytokines in the hippocampus and medial prefrontal cortex in CSDS mice, and inhibiting the central immune response by minocycline pretreatment abrogated the preventive effect of MPL on CSDS-induced anxiety-like behaviors and pro-inflammatory cytokine productions in the brain. Conclusions Pre-stimulation of the innate immune system by MPL can prevent chronic stress-induced anxiety-like behaviors and neuroinflammatory responses in the brain in mice.

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Neuroinflammation in neurological disorders: pharmacotherapeutic targets from bench to bedside

Cited by 82 publications

References 301 publications

Role of BET Proteins in Inflammation and CNS Diseases

Role of BET Proteins in Inflammation and CNS Diseases

Neurological Infection, Kynurenine Pathway, and Parasitic Infection by Neospora caninum

Innate immune stimulation by monophosphoryl lipid A prevents chronic social defeat stress-induced anxiety-like behaviors in mice

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