Anti-PD-1 treatment protects against seizure by suppressing sodium channel function
© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd..
AIMS: Although programmed cell death protein 1 (PD-1) typically serves as a target for immunotherapies, a few recent studies have found that PD-1 is expressed in the nervous system and that neuronal PD-1 might play a crucial role in regulating neuronal excitability. However, whether brain-localized PD-1 is involved in seizures and epileptogenesis is still unknown and worthy of in-depth exploration.
METHODS: The existence of PD-1 in human neurons was confirmed by immunohistochemistry, and PD-1 expression levels were measured by real-time quantitative PCR (RT-qPCR) and western blotting. Chemoconvulsants, pentylenetetrazol (PTZ) and cyclothiazide (CTZ), were applied for the establishment of in vivo (rodents) and in vitro (primary hippocampal neurons) models of seizure, respectively. SHR-1210 (a PD-1 monoclonal antibody) and sodium stibogluconate (SSG, a validated inhibitor of SH2-containing protein tyrosine phosphatase-1 [SHP-1]) were administrated to investigate the impact of PD-1 pathway blockade on epileptic behaviors of rodents and epileptiform discharges of neurons. A miRNA strategy was applied to determine the impact of PD-1 knockdown on neuronal excitability. The electrical activities and sodium channel function of neurons were determined by whole-cell patch-clamp recordings. The interaction between PD-1 and α-6 subunit of human voltage-gated sodium channel (Nav1.6) was validated by performing co-immunostaining and co-immunoprecipitation (co-IP) experiments.
RESULTS: Our results reveal that PD-1 protein and mRNA levels were upregulated in lesion cores compared with perifocal tissues of surgically resected specimens from patients with intractable epilepsy. Furthermore, we show that anti-PD-1 treatment has anti-seizure effects both in vivo and in vitro. Then, we reveal that PD-1 blockade can alter the electrophysiological properties of sodium channels. Moreover, we reveal that PD-1 acts together with downstream SHP-1 to regulate sodium channel function and hence neuronal excitability. Further investigation suggests that there is a direct interaction between neuronal PD-1 and Nav1.6.
CONCLUSION: Our study reveals that neuronal PD-1 plays an important role in epilepsy and that anti-PD-1 treatment protects against seizures by suppressing sodium channel function, identifying anti-PD-1 treatment as a novel therapeutic strategy for epilepsy.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:30 |
|---|---|
| Enthalten in: |
CNS neuroscience & therapeutics - 30(2024), 4 vom: 28. Apr., Seite e14504 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Yang, Yuling [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 16.04.2024 Date Revised 29.04.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1111/cns.14504 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM363966897 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM363966897 | ||
| 003 | DE-627 | ||
| 005 | 20240430231938.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1111/cns.14504 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1393.xml |
| 035 | |a (DE-627)NLM363966897 | ||
| 035 | |a (NLM)37904722 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Yang, Yuling |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Anti-PD-1 treatment protects against seizure by suppressing sodium channel function |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 16.04.2024 | ||
| 500 | |a Date Revised 29.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd. | ||
| 520 | |a AIMS: Although programmed cell death protein 1 (PD-1) typically serves as a target for immunotherapies, a few recent studies have found that PD-1 is expressed in the nervous system and that neuronal PD-1 might play a crucial role in regulating neuronal excitability. However, whether brain-localized PD-1 is involved in seizures and epileptogenesis is still unknown and worthy of in-depth exploration | ||
| 520 | |a METHODS: The existence of PD-1 in human neurons was confirmed by immunohistochemistry, and PD-1 expression levels were measured by real-time quantitative PCR (RT-qPCR) and western blotting. Chemoconvulsants, pentylenetetrazol (PTZ) and cyclothiazide (CTZ), were applied for the establishment of in vivo (rodents) and in vitro (primary hippocampal neurons) models of seizure, respectively. SHR-1210 (a PD-1 monoclonal antibody) and sodium stibogluconate (SSG, a validated inhibitor of SH2-containing protein tyrosine phosphatase-1 [SHP-1]) were administrated to investigate the impact of PD-1 pathway blockade on epileptic behaviors of rodents and epileptiform discharges of neurons. A miRNA strategy was applied to determine the impact of PD-1 knockdown on neuronal excitability. The electrical activities and sodium channel function of neurons were determined by whole-cell patch-clamp recordings. The interaction between PD-1 and α-6 subunit of human voltage-gated sodium channel (Nav1.6) was validated by performing co-immunostaining and co-immunoprecipitation (co-IP) experiments | ||
| 520 | |a RESULTS: Our results reveal that PD-1 protein and mRNA levels were upregulated in lesion cores compared with perifocal tissues of surgically resected specimens from patients with intractable epilepsy. Furthermore, we show that anti-PD-1 treatment has anti-seizure effects both in vivo and in vitro. Then, we reveal that PD-1 blockade can alter the electrophysiological properties of sodium channels. Moreover, we reveal that PD-1 acts together with downstream SHP-1 to regulate sodium channel function and hence neuronal excitability. Further investigation suggests that there is a direct interaction between neuronal PD-1 and Nav1.6 | ||
| 520 | |a CONCLUSION: Our study reveals that neuronal PD-1 plays an important role in epilepsy and that anti-PD-1 treatment protects against seizures by suppressing sodium channel function, identifying anti-PD-1 treatment as a novel therapeutic strategy for epilepsy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Nav1.6 | |
| 650 | 4 | |a PD‐1 receptor | |
| 650 | 4 | |a epilepsy | |
| 650 | 4 | |a sodium channel | |
| 650 | 7 | |a Programmed Cell Death 1 Receptor |2 NLM | |
| 650 | 7 | |a Sodium Channels |2 NLM | |
| 650 | 7 | |a camrelizumab |2 NLM | |
| 650 | 7 | |a 73096E137E |2 NLM | |
| 650 | 7 | |a Antibodies, Monoclonal, Humanized |2 NLM | |
| 650 | 7 | |a NAV1.6 Voltage-Gated Sodium Channel |2 NLM | |
| 700 | 1 | |a Chen, Zhiyun |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Shize |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Guoxiang |e verfasserin |4 aut | |
| 700 | 1 | |a Wan, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Jiangning |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Min |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yulong |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xu |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yun |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t CNS neuroscience & therapeutics |d 2008 |g 30(2024), 4 vom: 28. Apr., Seite e14504 |w (DE-627)NLM17958930X |x 1755-5949 |7 nnns |
| 773 | 1 | 8 | |g volume:30 |g year:2024 |g number:4 |g day:28 |g month:04 |g pages:e14504 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1111/cns.14504 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 30 |j 2024 |e 4 |b 28 |c 04 |h e14504 | ||