Enhanced Akt/GSK‐3β/CREB signaling mediates the anti‐inflammatory actions of mGluR5 positive allosteric modulators in microglia and following traumatic brain injury in male mice

Bhat, Shahnawaz Ali; Henry, Rebecca J.; Blanchard, Alexa C.; Stoica, Bogdan A.; Loane, David J.; Faden, Alan I.

doi:10.1111/jnc.14954

Cited by 30 publications

(16 citation statements)

References 70 publications

(126 reference statements)

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“…The neuroprotective mechanism for the anti-inflammatory effects of activated Akt/GSK-3 β on LPS-induced PD model can be partly attributed to the gene expression inhibition of proinflammatory mediators [ 29 ]. Similar to our findings, it has been reported that the downregulation of Akt/GSK-3 β /CREB signaling would weaken the anti-inflammatory action related to mGluR5 in microglia [ 42 ].…”

Section: Discussionsupporting

confidence: 92%

The Anti-Inflammatory Effect of Preventive Intervention with Ketogenic Diet Mediated by the Histone Acetylation of mGluR5 Promotor Region in Rat Parkinson’s Disease Model: A Dual-Tracer PET Study

Zhu

Tang

Cheng

et al. 2022

Parkinson's Disease

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Background and Objectives. The exact pathological mechanism of Parkinson’s disease (PD) remains elusive, and the existing therapies fail to reverse the disease progression. This study intended to explore the epigenetic anti-inflammatory mechanism of ketogenic diet (KD). Materials and Methods. The neuroprotective effect of ketosis state prior to the onset of PD (preventive KD, KDp) was compared with that receiving KD after the onset (therapeutic KD, KDt) in the lipopolysaccharide- (LPS-) induced rat PD model. A total of 100 rats were randomly assigned to the following 4 groups: sham, LPS, LPS + KDp, and LPS + KDt groups. Results. Significant dopamine deficient behaviors (rotational behavior and contralateral forelimb akinesia), upregulation of proinflammatory mediators (TNF-α, IL-1β, and IL-6), loss of dopaminergic neurons, reduction of mGluR5+ microglia cells, increase of TSPO+ microglia cells, reduction of H3K9 acetylation in the mGluR5 promoter region and mGluR5 mRNA expression, and decline in the phosphorylation levels of Akt/GSK-3β/CREB pathway were observed after the intervention of LPS ( P < 0.01 ). TSPO and DAT PET imaging revealed the increased uptake of 18F-DPA-714 in substantia nigra and decreased uptake of 18F-FP-CIT in substantia nigra and striatum in LPS-treated rats ( P < 0.001 ). These impairments were alleviated by the dietary intervention of KD, especially with the strategy of KDp ( P < 0.05 ). Conclusions. The anti-inflammatory effect of KD on PD was supposed to be related to the modulation of Akt/GSK-3β/CREB signaling pathway mediated by the histone acetylation of mGluR5 promotor region. The KD intervention should be initiated prior to the PD onset in high-risk population to achieve a more favorable outcome.

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Section: Discussionsupporting

confidence: 92%

The Anti-Inflammatory Effect of Preventive Intervention with Ketogenic Diet Mediated by the Histone Acetylation of mGluR5 Promotor Region in Rat Parkinson’s Disease Model: A Dual-Tracer PET Study

Zhu

Tang

Cheng

et al. 2022

Parkinson's Disease

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“…Microglia, astrocytes, and peripheral immune cells express mGlu5, which promotes anti-inflammatory responses (Fazio et al, 2018). Interestingly, a recent study showed that neuroinflammation induced by traumatic brain injury in mice is reduced by mGlu5 PAM treatment and that the mechanism of action involves Akt/GSK-3β/CREB signaling (Bhat et al, 2021). This corroborates previous evidence showing that stimulation of mGlu5 reduces LPS-induced microglial activation and proinflammatory signaling (Byrnes et al, 2009).…”

Section: Posttraumatic Stress Disordersupporting

confidence: 84%

Neuroimmune Mechanisms as Novel Treatment Targets for Substance Use Disorders and Associated Comorbidities

et al. 2021

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Recent studies examining the neurobiology of substance abuse have revealed a significant role of neuroimmune signaling as a mechanism through which drugs of abuse induce aberrant changes in synaptic plasticity and contribute to substance abuse-related behaviors. Immune signaling within the brain and the periphery critically regulates homeostasis of the nervous system. Perturbations in immune signaling can induce neuroinflammation or immunosuppression, which dysregulate nervous system function including neural processes associated with substance use disorders (SUDs). In this review, we discuss the literature that demonstrates a role of neuroimmune signaling in regulating learning, memory, and synaptic plasticity, emphasizing specific cytokine signaling within the central nervous system. We then highlight recent preclinical studies, within the last 5 years when possible, that have identified immune mechanisms within the brain and the periphery associated with addiction-related behaviors. Findings thus far underscore the need for future investigations into the clinical potential of immunopharmacology as a novel approach toward treating SUDs. Considering the high prevalence rate of comorbidities among those with SUDs, we also discuss neuroimmune mechanisms of common comorbidities associated with SUDs and highlight potentially novel treatment targets for these comorbid conditions. We argue that immunopharmacology represents a novel frontier in the development of new pharmacotherapies that promote long-term abstinence from drug use and minimize the detrimental impact of SUD comorbidities on patient health and treatment outcomes.

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“…Targeting the PI3K/Akt pathway could promote Akt phosphorylation, inhibit the expression of the apoptosis-related factor BCl2, and reduce neuronal apoptosis 29 . Another study by Bhat and colleagues found that use of an anti-inflammatory modulator that promoted Akt activity in an experimental traumatic brain injury model resulted in decreased pro-inflammatory microglial activation and favorable outcomes in rodents 30 . These results suggest that PI3K/Akt signaling may promote an anti-inflammatory response in microglia.…”

Section: Discussionmentioning

confidence: 99%

High-mobility Group Box 1 Contributes to Hypoxic-Ischemic Brain Damage by Facilitating Imbalance of Microglial Polarization through RAGE-PI3K/Akt Pathway in Neonatal Rats

Sun

Zhu

et al. 2022

Int. J. Med. Sci.

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High mobility group box 1 (HMGB1) is a damage-associated molecular pattern integral for hypoxicischemic brain damage (HIBD) in neonatal rats since it regulates the phenotypic polarization of microglia, as depicted in our previous studies. Since this mechanism is not clear, this study establishes an oxygen-glucose deprivation (OGD) model of highly aggressively proliferating immortalized microglia while modulating the expression of HMGB1 by plasmid transfection. The M1/M2 microglial phenotype and receptor for advanced glycation end products-phosphoinositide 3-kinase/Akt (RAGE-PI3K/Akt) activation were evaluated, showing that HMGB1 promoted the polarization of microglia to the M1 phenotype under OGD conditions. Meanwhile, RAGE, which is the main receptor of HMGB1, was activated, and phosphorylation of PI3K/Akt was upregulated. However, knockdown or inhibition of HMGB1 can weaken the activation of RAGE and phosphorylation of PI3K/Akt. The inhibition of HMGB1 or RAGE-PI3K/Akt attenuated microglial polarization to the M1 phenotype and promoted M2 microglial polarization instead, reducing the release of pro-inflammatory factors. In the neonatal HIBD rat model, the RAGE-PI3K/Akt pathway was activated seven days after hypoxic-ischemic (HI) exposure, and the activation was partly inhibited after pretreatment with the HMGB1 inhibitor. Concurrently, inhibition of the HMGB1-RAGE-PI3K/Akt pathway alleviated neuronal damage in the hippocampus. These findings verified that HMGB1 could lead to an imbalance in M1/M2 microglial polarization through activation of the RAGE-PI3K/Akt signaling pathway under OGD conditions. Obstructing this pathway may attenuate the imbalanced polarization of microglia, enabling its utilization as a therapeutic strategy against brain injury in HIBD.

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Enhanced Akt/GSK‐3β/CREB signaling mediates the anti‐inflammatory actions of mGluR5 positive allosteric modulators in microglia and following traumatic brain injury in male mice

Cited by 30 publications

References 70 publications

The Anti-Inflammatory Effect of Preventive Intervention with Ketogenic Diet Mediated by the Histone Acetylation of mGluR5 Promotor Region in Rat Parkinson’s Disease Model: A Dual-Tracer PET Study

The Anti-Inflammatory Effect of Preventive Intervention with Ketogenic Diet Mediated by the Histone Acetylation of mGluR5 Promotor Region in Rat Parkinson’s Disease Model: A Dual-Tracer PET Study

Neuroimmune Mechanisms as Novel Treatment Targets for Substance Use Disorders and Associated Comorbidities

High-mobility Group Box 1 Contributes to Hypoxic-Ischemic Brain Damage by Facilitating Imbalance of Microglial Polarization through RAGE-PI3K/Akt Pathway in Neonatal Rats

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