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Piezo1 suppression reduces demyelination after intracerebral hemorrhage
Jie Qu1, Hang-Fan Zong2, Yi Shan1
1Department of Emergency, The Sixth Medical Center of Chinese PLA General Hospital, Beijing, China.
Abstract:
Piezo1 is a mechanically-gated calcium channel. Recent studies have shown that Piezo1, a mechanically-gated calcium channel, can attenuate both psychosine- and lipopolysaccharide-induced demyelination. Because oligodendrocyte damage and demyelination occur in intracerebral hemorrhage, in this study, we investigated the role of Piezo1 in intracerebral hemorrhage. We established a mouse model of cerebral hemorrhage by injecting autologous blood into the right basal ganglia and found that Piezo1 was largely expressed soon (within 48 hours) after intracerebral hemorrhage, primarily in oligodendrocytes. Intraperitoneal injection of Dooku1 to inhibit Piezo1 resulted in marked alleviation of brain edema, myelin sheath loss, and degeneration in injured tissue, a substantial reduction in oligodendrocyte apoptosis, and a significant improvement in neurological function. In addition, we found that Dooku1-mediated Piezo1 suppression reduced intracellular endoplasmic reticulum stress and cell apoptosis through the PERK-ATF4-CHOP and inositol-requiring enzyme 1 signaling pathway. These findings suggest that Piezo1 is a potential therapeutic target for intracerebral hemorrhage, as its suppression reduces intracellular endoplasmic reticulum stress and cell apoptosis and protects the myelin sheath, thereby improving neuronal function after intracerebral hemorrhage.
Insights
In intracerebral hemorrhage, the Piezo1 channel is expressed in oligodendrocytes. Inhibiting Piezo1 with Dooku1 alleviates brain damage and improves neurological function by reducing cell apoptosis.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Piezo1, a mechanically-gated calcium channel, is known to protect against demyelination.
- Oligodendrocyte damage and demyelination are key features of intracerebral hemorrhage (ICH).
Purpose of the Study:
- To investigate the role of Piezo1 in the context of intracerebral hemorrhage.
- To determine if Piezo1 inhibition could be a therapeutic strategy for ICH.
Main Methods:
- A mouse model of intracerebral hemorrhage was created by injecting autologous blood.
- Piezo1 expression was assessed post-ICH.
- The Piezo1 inhibitor Dooku1 was administered intraperitoneally.
- Brain edema, myelin sheath loss, oligodendrocyte apoptosis, neurological function, and endoplasmic reticulum stress pathways were evaluated.
Main Results:
- Piezo1 expression was significantly upregulated in oligodendrocytes within 48 hours of ICH.
- Dooku1 treatment markedly reduced brain edema, myelin loss, and tissue degeneration.
- Inhibition of Piezo1 substantially decreased oligodendrocyte apoptosis and improved neurological deficits.
- Dooku1 suppressed intracellular endoplasmic reticulum stress and apoptosis via the PERK-ATF4-CHOP and IRE1 pathways.
Conclusions:
- Piezo1 plays a critical role in the pathophysiology of intracerebral hemorrhage.
- Suppression of Piezo1 offers a promising therapeutic approach for ICH by protecting myelin and improving neuronal function.
- Targeting Piezo1 may mitigate endoplasmic reticulum stress and cell death following brain hemorrhage.
