In Vivo Non-radioactive Assessment of mGlu5 Receptor-Activated Polyphosphoinositide Hydrolysis in Response to Systemic Administration of a Positive Allosteric Modulator

Zuena, Anna Rita; Iacovelli, Luisa; Orlando, Rosamaria; Menna, Luisa Di; Casolini, Paola; Alemà, G; Cicco, Gabriele Di; Battaglia, Giuseppe; Nicoletti, Ferdinando

doi:10.3389/fphar.2018.00804

Cited by 12 publications

(12 citation statements)

References 53 publications

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“…Moreover, new studies using mGluR5‐mediated polyphosphoinositide (PI) hydrolysis functional assays in mice demonstrated that systemic administration (i.p.) of VU0360172‐stimulated PI hydrolysis at a dose of 30 mg/kg in hippocampus, striatum, and prefrontal cortex (Zuena et al, 2018). Previously we demonstrated that in addition to suppressing post‐traumatic neurotoxic neuroinflammation, VuPAM treatment also up‐regulates an anti‐inflammatory microglial phenotype in the injured cortex, whereas an mGluR5 orthosteric agonist does not (Loane et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

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

Henry

Blanchard

et al. 2020

Journal of Neurochemistry

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We have previously shown that treatment with a mGluR5 positive allosteric modulator (PAM) is neuroprotective after experimental traumatic brain injury (TBI), limiting post‐traumatic neuroinflammation by reducing pro‐inflammatory microglial activation and promoting anti‐inflammatory and neuroprotective responses. However, the specific molecular mechanisms governing this anti‐inflammatory shift in microglia remain unknown. Here we show that the mGluR5 PAM, VU0360172 (VuPAM), regulates microglial inflammatory responses through activation of Akt, resulting in the inhibition of GSK‐3β. GSK‐3β regulates the phosphorylation of CREB, thereby controlling the expression of inflammation‐related genes and microglial plasticity. The anti‐inflammatory action of VuPAM in microglia is reversed by inhibiting Akt/GSK‐3β/CREB signaling. Using a well‐characterized TBI model and CX3CR1gfp/+ mice to visualize microglia in vivo, we demonstrate that VuPAM enhances Akt/GSK‐3β/CREB signaling in the injured cortex, as well as anti‐inflammatory microglial markers. Furthermore, in situ analysis revealed that GFP + microglia in the cortex of VuPAM‐treated TBI mice co‐express pCREB and the anti‐inflammatory microglial phenotype marker YM1. Taken together, our data show that VuPAM decreases pro‐inflammatory microglial activation by modulating Akt/GSK‐3β/CREB signaling. These findings serve to clarify the potential neuroprotective mechanisms of mGluR5 PAM treatment after TBI, and suggest novel therapeutic targets for post‐traumatic neuroinflammation. Cover Image for this issue: https://doi.org/10.1111/jnc.15048.

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Section: Discussionmentioning

confidence: 99%

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

Henry

Blanchard

et al. 2020

Journal of Neurochemistry

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“…mGlu5 has a close partnership with the NMDARs in terms of regulating synaptic plasticity (Zuena et al, ).We found that, with the influence of STZ on the mGlu5 level of the model group, the expression of p‐NMDA2B presented the same downward trend, and the expression of NMDAR2B increased. Subsequently, SZL and donepezil also increased the expression of p‐NMDAR2B and decreased the NMDAR2B level in the drug treatment groups, among which the changes were most obvious in the SZL high‐dose group, while this effect was not obvious in the SZL low‐dose group (Figures and ).…”

Section: Resultsmentioning

confidence: 99%

Potential synaptic plasticity‐based Shenzhiling oral liquid for a SAD Mouse Model

Wang

Chen

et al. 2019

Brain and Behavior

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Background Synaptic plasticity is the basis of memory formation. The pathological manifestations of abnormal glucose metabolism in the nervous system of sporadic Alzheimer's disease (SAD) may affect synaptic plasticity, thus causing memory damage. As a traditional Chinese medicine compound preparation, the mechanism by which Shenzhiling (SZL) oral liquid can alleviate the cognitive impairment of SAD by improving synaptic plasticity remains unclear. Objective: This article mainly discusses whether SZL can exert a protective synaptic effect as mediated by glutamate receptors and glycogen synthesis kinase 3β (GSK3β); further, it discusses whether SZL can improve cognitive function in SAD. Methods C57BL/6 mice were used as a SAD model after injection with streptozotocin (STZ) into the bilateral lateral ventricles; mice of the same background were injected with artificial cerebrospinal fluid into bilateral ventricles and were used as a control group. After 3 months of exposure to the intervention, the step‐down test was carried out. Western blot was used to detect the levels of NMDAR2B, p‐NMDAR2B, mGlu5, GSK3β, and p‐GSK3β in the hippocampus of mice. Immunohistochemical analysis was used to observe the number of GSK3β‐positive cells in the CA1 region of mouse hippocampus. Results The memory retention ability of mice was significantly improved after 3 months of SZL treatment, and the expression levels of NMDAR2B, mGlu5, and GSK3β were significantly changed. Conclusion Shenzhiling provides a potential for the treatment for SAD with traditional Chinese medicine.

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“…in a volume of 5 mL/kg body weight. The dose used for VU0360172 (30 mg/kg) was selected on the basis of our previous data [ 31 ].…”

Section: Methodsmentioning

confidence: 99%

“…This method has a number of limitations, including the need to pool tissue from several animals, the need to perform ex vivo experiments in slices, and the lack of information on endogenous InsP levels (and, therefore, on the specific activity of 3 H-InsP). We have developed a new method for the in vivo assessment of mGlu5 receptor-mediated PI hydrolysis, based on systemic treatment with LiCl followed by the mGlu5 receptor PAM VU0360172 and determination of endogenous InsP levels by ELISA [ 31 ]. With the aid of this method, we have decided to study how mGlu5 receptor signaling is affected by spatial learning and by extinction in the dorsal and ventral hippocampus and in the prefrontal cortex.…”

Section: Introductionmentioning

confidence: 99%

Changes in mGlu5 Receptor Signaling Are Associated with Associative Learning and Memory Extinction in Mice

Teleuca

Alemà

Casolini

et al. 2022

Life

Self Cite

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Using an in vivo method for the assessment of polyphosphoinositide (PI) hydrolysis, we examine whether spatial learning and memory extinction cause changes in mGlu5 metabotropic glutamate receptor signaling in the hippocampus and prefrontal cortex. We use the following five groups of mice: (i) naive mice; (ii) control mice exposed to the same environment as learner mice; (iii) leaner mice, trained for four days in a water maze; (iv) mice in which memory extinction was induced by six trials without the platform; (v) mice that spontaneously lost memory. The mGlu5 receptor-mediated PI hydrolysis was significantly reduced in the dorsal hippocampus of learner mice as compared to naive and control mice. The mGlu5 receptor signaling was also reduced in the ventral hippocampus and prefrontal cortex of learner mice, but only with respect to naive mice. Memory extinction was associated with a large up-regulation of mGlu5 receptor-mediated PI hydrolysis in the three brain regions and with increases in mGlu5 receptor and phospholipase-Cβ protein levels in the ventral and dorsal hippocampus, respectively. These findings support a role for mGlu5 receptors in mechanisms underlying spatial learning and suggest that mGlu5 receptors are candidate drug targets for disorders in which cognitive functions are impaired or aversive memories are inappropriately retained.

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In Vivo Non-radioactive Assessment of mGlu5 Receptor-Activated Polyphosphoinositide Hydrolysis in Response to Systemic Administration of a Positive Allosteric Modulator

Cited by 12 publications

References 53 publications

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

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

Potential synaptic plasticity‐based Shenzhiling oral liquid for a SAD Mouse Model

Changes in mGlu5 Receptor Signaling Are Associated with Associative Learning and Memory Extinction in Mice

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