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Intrastriatal Injection of Autologous Blood or Clostridial Collagenase as Murine Models of Intracerebral Hemorrhage
Published on: July 3, 2014
Folic acid alleviates neuroinflammation after intracerebral hemorrhage by epigenetically regulating the
Background:
Excessive neuroinflammation exacerbates secondary brain injury after intracerebral hemorrhage (ICH). Adenosine monophosphate deaminase 2 (AMPD2) has been linked to immune regulation, but its role and mechanism in ICH-related neuroinflammation remain unclear. Emerging evidence underscores the importance of epigenetic modifications in post-ICH inflammation. This study aimed to determine whether AMPD2 contributes to neuroinflammation and whether folic acid (FA), a key methyl donor, attenuates inflammatory damage through epigenetic regulation of AMPD2.
Methods:
Bisulfite pyrosequencing was used to detect the DNA methylation level of AMPD2 in patients and experimental models. The function of AMPD2 and the role of FA were investigated using a mouse model of ICH and lipopolysaccharide (LPS)-stimulated microglia. The interaction between AMPD2 and deoxycytidine kinase (DCK) and its pathway activity were assessed using gain-and-loss-of-function assays, NF-κB regulation assays, and co-immunoprecipitation (Co-IP) assays. Furthermore, the methylation inhibitor 5-azacytidine (5-AZA) was used to validate the epigenetic mechanism of FA.
Results:
AMPD2 expression was significantly upregulated after ICH, a phenomenon negatively correlated with its DNA methylation levels. AMPD2 knockdown attenuated neuroinflammation and improved neurological outcomes, whereas AMPD2 overexpression exacerbated inflammatory responses. FA treatment suppressed AMPD2 expression by promoting its DNA methylation, thereby mitigating neuroinflammation and neuronal injury. Mechanistically, AMPD2 interacted with DCK and promoted its ubiquitin proteasome dependent degradation, leading to disinhibition of the NF-κB pathway and enhanced release of pro inflammatory cytokines such as IL 1β and IL 6. Inhibition of NF-κB or rescue of DCK expression reversed the pro inflammatory effects of AMPD2.
Conclusions:
This study explore that AMPD2 promotes inflammation by binding to DCK and facilitating its ubiquitination and reveals the mechanism that FA improves neurological function after ICH by altering the DNA methylation level in the promoter region of AMPD2 gene. thereby improving the recovery of neurological function through AMPD2/DCK/NF-κB signaling pathway.