Markus Regina P, Sousa Kassiano S, Ulrich Henning, Ferreira Zulma S
Laboratory of Chronopharmacology, Department of Physiology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil.
Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil.
Purinergic Signal. 2025 Feb;21(1):99-112. doi: 10.1007/s11302-024-10037-8. Epub 2024 Jul 20.
In mammal's pineal glands, ATP interacts with the high-affinity P2Y and the low-affinity P2X7 receptors. ATP released from sympathetic nerve terminals potentiates noradrenaline-induced serotonin N-acetyltransferase (Snat) transcription, N-acetylserotonin (NAS), and melatonin (MLT) synthesis. Circulating melatonin impairs the expression of adhesion molecules in endothelial cells, blocking the migration of leukocytes. Acute defence response induced by pathogen- and danger/damage-associated molecular patterns (PAMPs and DAMPs) triggers the NF-κB pathway in pinealocytes and blocks the transcription of Snat. Therefore, the darkness hormone is not released, and neutrophils and monocytes migrate to the lesion sites. ATP released in high amounts from apoptotic and death cells was considered a DAMP, and the blockage of P2X7 receptors was tested as a new class of drugs for treating brain damage. However, this is not a simple equation. High ATP injected in a lateral ventricle blocked MLT, but not NAS, synthesis as it impairs the transcription of acetyl serotonin N-methyltransferase. NAS is released in the plasma and the cerebral spinal fluid. NAS also blocks the rolling and adhesion of leukocytes to endothelial cells. Otherwise, it is metabolised specifically in each brain area to provide the requested concentration of MLT as a neuroprotector. As observed in physiological conditions, high extracellular ATP, different from the other DAMPs, reports the environmental light/dark cycle rhythm because NAS substitutes MLT as the nocturnal chemical indicator, the darkness hormone. Thus, blocking the P2X7R should not be considered a universal therapy for improving acute strokes, as MLT and ATP are partners in health and disease.
在哺乳动物的松果体中，三磷酸腺苷（ATP）与高亲和力的P2Y受体和低亲和力的P2X7受体相互作用。交感神经末梢释放的ATP增强去甲肾上腺素诱导的血清素N-乙酰转移酶（Snat）转录、N-乙酰血清素（NAS）和褪黑素（MLT）的合成。循环中的褪黑素会损害内皮细胞中黏附分子的表达，阻止白细胞的迁移。由病原体及危险/损伤相关分子模式（PAMPs和DAMPs）引发的急性防御反应会触发松果体细胞中的核因子κB（NF-κB）通路，并阻断Snat的转录。因此，黑暗激素无法释放，中性粒细胞和单核细胞会迁移到损伤部位。凋亡细胞和死亡细胞大量释放的ATP被认为是一种DAMP，而对P2X7受体的阻断作为一类新型药物用于治疗脑损伤进行了测试。然而，情况并非如此简单。向侧脑室注射高剂量的ATP会阻断MLT的合成，但不会阻断NAS的合成，因为它会损害乙酰血清素N-甲基转移酶的转录。NAS会释放到血浆和脑脊液中。NAS还会阻断白细胞在内皮细胞上的滚动和黏附。否则，它会在每个脑区进行特异性代谢，以提供所需浓度的MLT作为神经保护剂。正如在生理条件下所观察到的，与其他DAMPs不同，高细胞外ATP反映了环境光/暗周期节律，因为NAS替代MLT作为夜间化学指标，即黑暗激素。因此，不应将阻断P2X7R视为改善急性中风的通用疗法，因为MLT和ATP在健康和疾病中都是相互关联的。
