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1.
Phytother Res ; 38(6): 2619-2640, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38488455

RESUMEN

Salidroside, a principal bioactive component of Rhodiola crenulata, is neuroprotective across a wide time window in stroke models. We investigated whether salidroside induced neurogenesis after cerebral ischemia and aimed to identify its primary molecular targets. Rats, subjected to transient 2 h of middle cerebral artery occlusion (MCAO), received intraperitoneal vehicle or salidroside ± intracerebroventricular HSC70 inhibitor VER155008 or TrkB inhibitor ANA-12 for up to 7 days. MRI, behavioural tests, immunofluorescent staining and western blotting measured effects of salidroside. Reverse virtual docking and enzymatic assays assessed interaction of salidroside with purified recombinant HSC70. Salidroside dose-dependently decreased cerebral infarct volumes and neurological deficits, with maximal effects by 50 mg/kg/day. This dose also improved performance in beam balance and Morris water maze tests. Salidroside significantly increased BrdU+/nestin+, BrdU+/DCX+, BrdU+/NeuN+, BrdU-/NeuN+ and BDNF+ cells in the peri-infarct cortex, with less effect in striatum and no significant effect in the subventricular zone. Salidroside was predicted to bind with HSC70. Salidroside dose-dependently increased HSC70 ATPase and HSC70-dependent luciferase activities, but it did not activate HSP70. HSC70 immunoreactivity concentrated in the peri-infarct cortex and was unchanged by salidroside. However, VER155008 prevented salidroside-dependent increases of neurogenesis, BrdU-/NeuN+ cells and BDNF+ cells in peri-infarct cortex. Salidroside also increased BDNF protein and p-TrkB/TrkB ratio in ischemic brain, changes prevented by VER155008 and ANA-12, respectively. Additionally, ANA-12 blocked salidroside-dependent neurogenesis and increased BrdU-/NeuN+ cells in the peri-infarct cortex. Salidroside directly activates HSC70, thereby stimulating neurogenesis and neuroprotection via BDNF/TrkB signalling after MCAO. Salidroside and similar activators of HSC70 might provide clinical therapies for ischemic stroke.


Asunto(s)
Isquemia Encefálica , Factor Neurotrófico Derivado del Encéfalo , Glucósidos , Proteínas del Choque Térmico HSC70 , Infarto de la Arteria Cerebral Media , Neurogénesis , Fármacos Neuroprotectores , Fenoles , Ratas Sprague-Dawley , Transducción de Señal , Animales , Fenoles/farmacología , Fenoles/química , Glucósidos/farmacología , Neurogénesis/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Ratas , Masculino , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Isquemia Encefálica/tratamiento farmacológico , Proteínas del Choque Térmico HSC70/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína Doblecortina , Rhodiola/química , Receptor trkB/metabolismo , Modelos Animales de Enfermedad , Azepinas , Benzamidas
2.
Eur J Med Chem ; 209: 112935, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33097301

RESUMEN

Salidroside [(2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-(4-hydroxyphenethoxy)tetrahy-dro-2H-pyran-3,4,5-triol] is an antioxidant, anti-inflammatory and neuroprotective agent, but its drug-like properties are unoptimized and its mechanism of actions is uncertain. We synthesized twenty-six novel derivatives of salidroside and examined them in CoCl2-treated PC12 cells using MTT assay. pOBz, synthesized by esterifying the phenolic hydroxyl group of salidroside with benzoyl chloride, was one of five derivatives that were more cytoprotective than salidroside, with an EC50 of 0.038 µM versus 0.30 µM for salidroside. pOBz was also more lipophilic, with log P of 1.44 versus -0.89 for salidroside. Reverse virtual docking predicted that pOBz would bind strongly with monoamine oxidase (MAO) B by occupying its entrance and substrate cavities, and by interacting with the inter-cavity gating residue Ile199 and Tyr435 of the substrate cavity. Enzymatic studies confirmed that pOBz competitively inhibited the activity of purified human MAO-B (Ki = 0.041 µM versus Ki = 0.92 µM for salidroside), and pOBz was highly selective for MAO-B over MAO-A. In vivo, pOBz inhibited cerebral MAO activity after middle cerebral artery occlusion with reperfusion in rats, and it reduced cerebral infarct volume, improved neurological function and NeuN expression, and inhibited complement C3 expression and apoptosis. Our results suggest that pOBz is a structurally novel type of competitive and selective MAO-B inhibitor, with potent neuroprotective properties after cerebral ischemia-reperfusion injury in rats.


Asunto(s)
Glucósidos/síntesis química , Inhibidores de la Monoaminooxidasa/síntesis química , Monoaminooxidasa/metabolismo , Fármacos Neuroprotectores/síntesis química , Fenoles/síntesis química , Daño por Reperfusión/tratamiento farmacológico , Secuencia de Aminoácidos , Animales , Apoptosis/efectos de los fármacos , Transporte Biológico , Barrera Hematoencefálica/metabolismo , Complemento C3/metabolismo , Evaluación Preclínica de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Glucósidos/farmacología , Humanos , Masculino , Simulación del Acoplamiento Molecular , Inhibidores de la Monoaminooxidasa/farmacología , Fármacos Neuroprotectores/farmacología , Células PC12 , Fenoles/farmacología , Unión Proteica , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad
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