Article ; Online: In vivo
2024 Volume 32, Issue 4, Page(s) 413–422
Abstract: Background: Blocking Transient Receptor Potential Melastatin 4 (TRPM4) in rodents by our antibody M4P has shown to attenuate cerebral ischaemia-reperfusion injury. Since M4P does not interact with human TRPM4, the therapeutic potential of blocking human ...
Abstract | Background: Blocking Transient Receptor Potential Melastatin 4 (TRPM4) in rodents by our antibody M4P has shown to attenuate cerebral ischaemia-reperfusion injury. Since M4P does not interact with human TRPM4, the therapeutic potential of blocking human TRPM4 remains unclear. We developed a monoclonal antibody M4M that inhibited human TRPM4 in cultured cells. However, M4M has no effect on stroke outcome in wild-type rats. Therefore, M4M needs to be evaluated on animal models expressing human TRPM4. Methods: We generated a humanised rat model using the CRISPR/Cas technique to knock-in (KI) the human TRPM4 antigen sequence. Results: In primary neurons from human TRPM4 KI rats, M4M binds to hypoxic neurons, but not normoxic nor wild-type neurons. Electrophysiological studies showed that M4M blocked ATP depletion-induced activation of TRPM4 and inhibited hypoxia-associated cell volume increase. In a stroke model, administration of M4M reduced infarct volume in KI rats. Rotarod test and Neurological deficit score revealed improvement following M4M treatment. Conclusion: M4M selectively binds and inhibits hypoxia-induced human TRPM4 channel activation in neurons from the humanised rat model, with no effect on healthy neurons. Use of M4M in stroke rats showed functional improvements, suggesting the potential for anti-human TRPM4 antibodies in treating acute ischaemic stroke patients. |
---|---|
MeSH term(s) | Rats ; Humans ; Animals ; Stroke/drug therapy ; Transient Receptor Potential Channels/therapeutic use ; Antibodies, Monoclonal/pharmacology ; Brain Ischemia/drug therapy ; TRPM Cation Channels/metabolism ; Reperfusion Injury/drug therapy ; Hypoxia |
Chemical Substances | Transient Receptor Potential Channels ; Antibodies, Monoclonal ; TRPM Cation Channels ; TRPM4 protein, human ; TRPM4 protein, rat |
Language | English |
Publishing date | 2024-02-12 |
Publishing country | England |
Document type | Journal Article |
ZDB-ID | 1187110-6 |
ISSN | 1029-2330 ; 1061-186X |
ISSN (online) | 1029-2330 |
ISSN | 1061-186X |
DOI | 10.1080/1061186X.2024.2313522 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
Zs.A 4481: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG) |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.