Dock4 contributes to neuropathic pain by regulating spinal synaptic plasticity in mice DOI Creative Commons
Qiaochu Fu, Hongyi Li,

Zhuanxu Zhu

et al.

Frontiers in Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 17

Published: Aug. 30, 2024

Neuropathic pain (NP) conditions arising from injuries to the nervous system due trauma, disease, or neurotoxins are chronic, severe, debilitating, and exceedingly difficult treat. However, mechanisms of NP not yet clear. Here we explored role Dock4, an atypical Rac1 GEF, in development NP.

Language: Английский

Increased TSPO alleviates neuropathic pain by preventing pyroptosis via the AMPK-PGC-1α pathway DOI Creative Commons
Bao‐Long Li, Kai Yu,

Xiongyao Zhou

et al.

The Journal of Headache and Pain, Journal Year: 2025, Volume and Issue: 26(1)

Published: Jan. 27, 2025

Neuropathic pain poses a significant clinical challenge, largely due to the incomplete understanding of its molecular mechanisms, particularly role mitochondrial dysfunction. Bioinformatics analysis revealed that pyroptosis and inflammatory responses induced by spared nerve injury (SNI) in spinal dorsal horn play critical initiation persistence neuropathic pain. Among factors involved, TSPO (translocator protein) emerged as key regulator. Our experimental findings showed expression was upregulated during pain, accompanied dysfunction, specifically manifested impaired biogenesis, disrupted dynamics (including insufficient biogenesis fusion-related proteins, well significantly increased fission-related proteins), activation pyroptosis. Pharmacological upregulation TSPO, but not downregulation, effectively alleviated SNI-induced hypersensitivity, improving function reducing Immunofluorescence staining confirmed primarily localized astrocytes, mirrored protective effects on health prevention. PCR array suggested strong association between regulation pathway AMPK-PGC-1α. Notably, inhibition AMPK-PGC-1α abolished balance suppression. Furthermore, Mendelian randomization GWAS data indicated linked relief. Through drug screening, docking, behavioral assays, we identified zopiclone promising TSPO-targeting for treatment. In summary, this study enhances our interplay health, highlighting potential therapeutic target management.

Language: Английский

Citations

2
Excitation–transcription coupling, neuronal gene expression and synaptic plasticity DOI
Huan Ma, Houda G. Khaled, Xiaohan Wang

et al.

Nature reviews. Neuroscience, Journal Year: 2023, Volume and Issue: 24(11), P. 672 - 692

Published: Sept. 29, 2023

Language: Английский

Citations

35
Microglial STING activation alleviates nerve injury-induced neuropathic pain in male but not female mice DOI Creative Commons
Arthur Silveira Prudente, Sang Hoon Lee,

Jueun Roh

et al.

Brain Behavior and Immunity, Journal Year: 2024, Volume and Issue: 117, P. 51 - 65

Published: Jan. 6, 2024

Microglia, resident immune cells in the central nervous system, play a role neuroinflammation and development of neuropathic pain. We found that stimulator interferon genes (STING) is predominantly expressed spinal microglia upregulated after peripheral nerve injury. However, mechanical allodynia, as marker pain following injury, did not require microglial STING expression. In contrast, activation by specific agonists (ADU-S100, 35 nmol) significantly alleviated male mice, but female mice. mice leads to increase proinflammatory cytokines may counteract analgesic effect ADU-S100. Microglial expression type I interferon-ß (IFN-ß) signaling were required for effects Mechanistically, downstream TANK-binding kinase 1 (TBK1) production IFN-ß, partly account observed. These findings suggest could be potential therapeutic intervention pain, particularly males.

Language: Английский

Citations

9
Nrf2 Ameliorates Sevoflurane-Induced Cognitive Deficits in Aged Mice by Inhibiting Neuroinflammation in the Hippocampus DOI
Junhua Li, Jinfeng Li, Yafang Liu

et al.

Molecular Neurobiology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

Language: Английский

Citations

0
LAMP2A-mediated neuronal hyperexcitability by enhancing NKAβ1 degradation underlies depression-induced allodynia DOI Creative Commons
Yuxin Zhang,

Huanghui Wu,

Qian Zhang

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(4), P. 115489 - 115489

Published: April 1, 2025

Language: Английский

Citations

0
GDPD3 Deficiency Alleviates Neuropathic Pain and Reprograms Macrophagic Polarization Through PGE2 and PPARγ Pathway DOI Creative Commons
Wenqian Li,

Youjia Fan,

Haizhen Lan

et al.

Neurochemical Research, Journal Year: 2024, Volume and Issue: 49(8), P. 1980 - 1992

Published: May 20, 2024

Abstract The complex mechanism of neuropathic pain involves various aspects both central and peripheral conduction pathways. An effective cure for therefore remains elusive. We found that deficiency the gene Gdpd3 , encoding a lysophospholipase D enzyme, alleviates inflammatory responses in dorsal root ganglia (DRG) mice under reduces PE (20:4) PGE2 DRG. had stronger analgesic effect on than Celecoxib, nonsteroidal anti-inflammatory drug. also interferes with polarization macrophages, switching from M1 towards M2 phenotype. PPARγ/ FABP4 pathway was screened by RNA sequencing as functional related deficient BMDMs stimulated LPS. Both protein mRNA levels PPARγ GDPD3 were higher those litter control mice. However, GW9962 (inhibitor PPARγ) could reverse reprogramming macrophages caused deficiency. Therefore, our study suggests exerts relieving neuroinflammation DRG phenotype to M2, which mediated through pathway.

Language: Английский

Citations

1
Tiam1-mediated maladaptive plasticity underlying morphine tolerance and hyperalgesia DOI

Changqun Yao,

Xing Fang, Qin Ru

et al.

Brain, Journal Year: 2024, Volume and Issue: 147(7), P. 2507 - 2521

Published: April 4, 2024

Opioid pain medications, such as morphine, remain the mainstay for treating severe and chronic pain. Prolonged morphine use, however, triggers analgesic tolerance hyperalgesia (OIH), which can last a long period after withdrawal. How induces these detrimental side effects remains unclear. Here, we show that OIH are mediated by Tiam1-coordinated synaptic structural functional plasticity in spinal nociceptive network. Tiam1 is Rac1 GTPase guanine nucleotide exchange factor promotes excitatory synaptogenesis modulating actin cytoskeletal dynamics. We found prolonged treatment activated dorsal horn ablation from neurons eliminated antinociceptive OIH. At same time, pharmacological blockade of Tiam1-Rac1 signalling prevented development reserved established increased dendritic spine density NMDA receptor activity neurons, both required Tiam1. Furthermore, co-administration inhibitor NSC23766 was sufficient to abrogate management. These findings identify Tiam1-mediated maladaptive network an underlying cause maintenance provide promising therapeutic target reduce prolong use

Language: Английский

Citations

1
Presynaptic Rac1 in the hippocampus selectively regulates working memory DOI Open Access
Jaebin Kim, Edwin Bustamante, Péter Sótonyi

et al.

Published: June 28, 2024

One of the most extensively studied members Ras superfamily small GTPases, Rac1 is an intracellular signal transducer that remodels actin and phosphorylation signaling networks. Previous studies have shown Rac1-mediated associated with hippocampal-dependent working memory longer-term forms learning can modulate both pre- postsynaptic plasticity. How these different cognitive functions plasticity mediated by are linked, however, unclear. Here, we show spatial selectively impaired following expression a genetically encoded Rac1-inhibitor at presynaptic terminals, while processes affected inhibition sites. To investigate regulatory mechanisms this process, leveraged new advances in mass spectrometry to identify proteomic post-translational landscape signaling. We identified serine/threonine kinases phosphorylated cytoskeletal synaptic vesicle proteins enriched active Rac1. The sites positions likely effects on vesicles. Consistent this, also report changes distribution morphology vesicles ultrastructure inhibition. Overall, study reveals previously unrecognized role provides insights into its potential mechanisms.

Language: Английский

Citations

1
A rapid and dynamic role for FMRP in the plasticity of adult neurons DOI Creative Commons

Daniel G. Gundermann,

Seana Lymer,

Justin Blau

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 3, 2023

Fragile X syndrome (FXS) is a neuro-developmental disorder caused by silencing

Language: Английский

Citations

3
Presynaptic Rac1 in the hippocampus selectively regulates working memory DOI Creative Commons
Jaebin Kim, Edwin Bustamante, Péter Sótonyi

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 19, 2024

Abstract One of the most extensively studied members Ras superfamily small GTPases, Rac1 is an intracellular signal transducer that remodels actin and phosphorylation signaling networks. Previous studies have shown Rac1-mediated associated with hippocampal-dependent working memory longer-term forms learning can modulate both pre- postsynaptic plasticity. How these different cognitive functions plasticity mediated by are linked, however, unclear. Here, we show spatial selectively impaired following expression a genetically encoded Rac1-inhibitor at presynaptic terminals, while processes affected inhibition sites. To investigate regulatory mechanisms this process, leveraged new advances in mass spectrometry to identify proteomic post-translational landscape signaling. We identified serine/threonine kinases phosphorylated cytoskeletal synaptic vesicle proteins enriched active Rac1. The sites positions likely effects on vesicles. Consistent this, also report changes distribution morphology vesicles ultrastructure inhibition. Overall, study reveals previously unrecognized role provides insights into its potential mechanisms.

Language: Английский

Citations

0