Synthetic cathinone MDPV enhances reward function through purinergic P2X7 receptor-dependent pathway and increases P2X7 gene expression in nucleus accumbens

Abstract Background Purinergic P2X7 receptor plays an important role in migraine pathophysiology. Yet precise molecular mechanism underlying P2X7R signaling in migraine remains unclear. This study explores the hypothesis that P2X7 receptor transmits signaling to Src family kinases (SFKs) during cortical spreading depression (CSD) and neuroinflammation after CSD. Methods CSD was recorded using electrophysiology in rats and intrinsic optical imaging in mouse brain slices. Cortical IL-1β and TNFα mRNA levels were detected using qPCR. Glutamate release from mouse brain slices was detected using glutamate assay. Results The data showed that deactivation of SFKs by systemic injection of PP2 reduced cortical susceptibility to CSD in rats and CSD-induced IL-1β and TNF-α gene expression in rat ipsilateral cortices. Consistently, in mouse brain slices, inhibition of SFKs activity by saracatinib and P2X7 receptor by A740003 similarly reduced cortical susceptibility to CSD. When the interaction of P2X7 receptor and SFKs was disrupted by TAT-P2X7, a marked reduction of cortical susceptibility to CSD, IL-1β gene expression and glutamate release after CSD induction were observed in mouse brain slices. The reduced cortical susceptibility to CSD by TAT-P2X7 was restored by NMDA, and disrupting the Fyn-NMDA interaction using TAT-Fyn (39-57) but not disrupting Src-NMDA receptor interaction using TAT-Src (40-49) reduced cortical susceptibility to CSD. Furthermore, activation of P2X7 receptor by BzATP restored the TAT-Fyn (39-57)-reduced cortical susceptibility to CSD. Conclusion This study reveals that SFKs activity transmits P2X7 receptor signaling to facilitate CSD propagation via glutamatergic pathway and promote neuroinflammation, which is of particular relevance to migraine.

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Src Family Kinases Activity is Required for Transmitting Purinergic P2X7 Receptor Signaling in Cortical Spreading Depression and Neuroinflammation

10.21203/rs.3.rs-907798/v1 ◽

2021 ◽

Author(s):

Lingdi Nie ◽

Dongqing Ma ◽

John P Quinn ◽

Minyan Wang

Keyword(s):

Gene Expression ◽

Mouse Brain ◽

P2x7 Receptor ◽

Cortical Spreading Depression ◽

Spreading Depression ◽

Glutamate Release ◽

Brain Slices ◽

Src Family Kinases ◽

Purinergic P2x7 Receptor ◽

Precise Molecular Mechanism

Abstract Background Purinergic P2X7 receptor plays a key role in migraine pathophysiology. Yet precise molecular mechanism underlying P2X7R signaling in migraine remains unclear. This study explores the hypothesis that P2X7 receptor transmits signaling to Src family kinases (SFKs) during cortical spreading depression (CSD) and CSD-induced neuroinflammation. Methods CSD was recorded using electrophysiology in rats, and intrinsic optical imaging in mouse brain slices. Cortical IL-1β and TNFα mRNA expression were detected using qPCR. Glutamate release in mouse brain slices was detected using glutamate assay. Results The data showed that systematic deactivation of SFKs by PP2 reduced cortical susceptibility to CSD in rats and CSD-induced IL-1b and TNF-a gene expression in rat ipsilateral cortices. Consistently, in mouse brain slices, inhibition of SFKs activity by saracatinib and P2X7 receptor by A740003 similarly reduced cortical susceptibility to CSD. When the interaction of P2X7 receptor-SFKs was disrupted by TAT-P2X7, a marked reduction of cortical susceptibility to CSD, CSD-induced IL-1b gene expression and glutamate release were observed in mouse brain slices. The reduced cortical susceptibility to CSD by TAT-P2X7 was restored by NMDA and disrupting Fyn-NMDA interaction using TAT-Fyn (39-57), but not disrupting Src-NMDA receptor using TAT-Src (40-49), reduced cortical susceptibility to CSD. Furthermore, activation of P2X7 receptor by BzATP restored the TAT-Fyn (39-57)-reduced cortical susceptibility to CSD. Conclusion This study reveals that SFKs activity mediates P2X7 receptor pore formation facilitating CSD propagation, CSD-induced neuroinflammation and glutamate release, of particular relevance to migraine.

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Antisense‐induced knockdown of cAMP response element‐binding protein downregulates Per1 gene expression in the shell region of nucleus accumbens resulting in reduced alcohol consumption in mice

Alcoholism Clinical and Experimental Research ◽

10.1111/acer.14687 ◽

2021 ◽

Author(s):

Rishi Sharma ◽

Vaibhav Mishra ◽

Meet Parikh ◽

Anshul Soni ◽

Pradeep Sahota ◽

...

Keyword(s):

Gene Expression ◽

Nucleus Accumbens ◽

Alcohol Consumption ◽

Binding Protein ◽

Camp Response Element Binding ◽

Camp Response Element ◽

Response Element ◽

Element Binding Protein ◽

Shell Region

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Truncated hemoglobin 2 modulates phosphorus deficiency response by controlling of gene expression in nitric oxide-dependent pathway in Chlamydomonas reinhardtii

Planta ◽

10.1007/s00425-021-03691-4 ◽

2021 ◽

Vol 254 (2) ◽

Author(s):

Alexandra Grinko ◽

Reem Alqoubaili ◽

Tatiana Lapina ◽

Elena Ermilova

Keyword(s):

Gene Expression ◽

Nitric Oxide ◽

Chlamydomonas Reinhardtii ◽

Phosphorus Deficiency ◽

Truncated Hemoglobin ◽

Dependent Pathway

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TNF-α and serum induce SKALP/elafin gene expression in human keratinocytes by a p38 MAP kinase-dependent pathway

Archives of Dermatological Research ◽

10.1007/s004030050475 ◽

2000 ◽

Vol 292 (4) ◽

pp. 180-187 ◽

Cited By ~ 68

Author(s):

R. Pfundt ◽

M. Wingens ◽

M. Bergers ◽

M. Zweers ◽

M. Frenken ◽

...

Keyword(s):

Gene Expression ◽

Map Kinase ◽

Human Keratinocytes ◽

P38 Map Kinase ◽

Tnf Α ◽

Dependent Pathway

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Effects of Ubiquinol-10 on MicroRNA-146a Expression In Vitro and In Vivo

Mediators of Inflammation ◽

10.1155/2009/415437 ◽

2009 ◽

Vol 2009 ◽

pp. 1-7 ◽

Cited By ~ 24

Author(s):

Constance Schmelzer ◽

Mitsuaki Kitano ◽

Gerald Rimbach ◽

Petra Niklowitz ◽

Thomas Menke ◽

...

Keyword(s):

Gene Expression ◽

Reactive Oxygen Species ◽

Biological Processes ◽

Oxygen Species ◽

Moderate Reduction ◽

Suppression Of Gene Expression ◽

Fine Tune ◽

Dependent Pathway

MicroRNAs (miRs) are involved in key biological processes via suppression of gene expression at posttranscriptional levels. According to their superior functions, subtle modulation of miR expression by certain compounds or nutrients is desirable under particular conditions. Bacterial lipopolysaccharide (LPS) induces a reactive oxygen species-/NF-κB-dependent pathway which increases the expression of the anti-inflammatory miR-146a. We hypothesized that this induction could be modulated by the antioxidant ubiquinol-10. Preincubation of human monocytic THP-1 cells with ubiquinol-10 reduced the LPS-induced expression level of miR-146a to 78.9±13.22%. In liver samples of mice injected with LPS, supplementation with ubiquinol-10 leads to a reduction of LPS-induced miR-146a expression to 78.12±21.25%. From these consistent in vitro and in vivo data, we conclude that ubiquinol-10 may fine-tune the inflammatory response via moderate reduction of miR-146a expression.

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