Role of Cholesterol Metabolic Enzyme CYP46A1 and Its Metabolite 24S-Hydroxycholesterol in Ischemic Stroke.

Autor:	Sun H; Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA., Yang T; Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA., Simon RP; Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA., Xiong ZG; Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA., Leng T; Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA.
Jazyk:	angličtina
Zdroj:	Stroke [Stroke] 2024 Oct; Vol. 55 (10), pp. 2492-2501. Date of Electronic Publication: 2024 Sep 03.
DOI:	10.1161/STROKEAHA.124.047803
Abstrakt:	Background: For several decades, it has been recognized that overactivation of the glutamate-gated N-methyl-D-aspartate receptors (NMDARs) and subsequent Ca 2+ toxicity play a critical role in ischemic brain injury. 24S-hydroxycholesterol (24S-HC) is a major cholesterol metabolite in the brain, which has been identified as a potent positive allosteric modulator of NMDAR in rat hippocampal neurons. We hypothesize that 24S-HC worsens ischemic brain injury via its potentiation of the NMDAR, and reducing the production of 24S-HC by targeting its synthetic enzyme CYP46A1 provides neuroprotection. Methods: We tested this hypothesis using electrophysiological, pharmacological, and transgenic approaches and in vitro and in vivo cerebral ischemia models. Results: Our data show that 24S-HC potentiates NMDAR activation in primary cultured mouse cortical neurons in a concentration-dependent manner. At 10 µmol/L, it dramatically increases the steady-state currents by 51% and slightly increases the peak currents by 20%. Furthermore, 24S-HC increases NMDA and oxygen-glucose deprivation-induced cortical neuronal injury. The increased neuronal injury is largely abolished by NMDAR channel blocker MK-801, suggesting an NMDAR-dependent mechanism. Pharmacological inhibition of CYP46A1 by voriconazole or gene knockout of Cyp46a1 dramatically reduces ischemic brain injury. Conclusions: These results identify a new mechanism and signaling cascade that critically impacts stroke outcome: CYP46A1 → 24S-HC → NMDAR → ischemic brain injury. They offer proof of principle for further development of new strategies for stroke intervention by targeting CYP46A1 or its metabolite 24S-HC. Competing Interests: Dr Leng discloses the pending patent US Application No. 18/527,676. The other authors report no conflicts.
Databáze:	MEDLINE
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