Silibinin Prevents Autophagic Cell Death upon Oxidative Stress in Cortical Neurons and Cerebral Ischemia-Reperfusion Injury

Abstract

Neuronal apoptosis and oxidative stress are involved in most of the neurodegenerative diseases, promoting neuron survival is critical for therapy. Silibinin (SLB), which is derived from the seeds of Silybinisus laborinum L., has been widely used as an antioxidant. Here we tested the neuroprotective effects of SLB and the involved molecular mechanisms. We demonstrated that SLB promoted neuron viability upon hydrogen peroxide (H2O2) challenge and reduced hypoxia/ischemia injury in the middle cerebral artery occlusion (MCAO) mouse model. SLB reversed the decreased level of procaspase-3 and balanced Bcl-2 and Bax expression upon H2O2 insult to inhibit cell apoptosis. Furthermore, SLB suppressed the activation of autophagy by decreasing microtubule-associated protein 1 light chain 3 (LC3-II) and Beclin-1 levels under oxidative stress accordingly. SLB phosphorylated protein kinase B (Akt-1) at Ser473 in a time- and dose-dependent manner. The inhibitor for phosphoinositide-3-kinase (PI3K) wortmannin abrogated SLB-induced phosphorylation of Akt-1 and mTOR, decreased the suppression of autophagy, and therefore abolished SLB-mediated neuroprotection. All the data suggested that SLB protected neurons by inhibiting both the mitochondrial and autophagic cell death pathways. This study opens new avenues for the use of SLB in treatment of central nervous system (CNS) diseases in which oxidative stress plays a major role in disease pathogenesis. Given that it occurs naturally with low toxicity and pleiotropic effects that benefit the nervous system, SLB acts potentially as a novel therapy for ischemic injury.

Lutein Attenuates Both Apoptosis and Autophagy upon Cobalt (II) Chloride-Induced Hypoxia in Rat Műller Cells

“…Most importantly, there is increasing evidence that inhibition of autophagy is protective in various in vivo I/R models [38–40]. Moreover, several in vitro studies also demonstrated that suppression of both apoptosis and autophagy enhanced cell survival [22,41]. Apart from apoptosis, CoCl 2 -induced hypoxia also triggered autophagy in rat cardiomyoblasts (H9c2) and retinal ganglion cells (RGC-5) cell line [22,42].…”

Protective Effects of Gastrodin Against Autophagy‐Mediated Astrocyte Death

“…PI3K/AKT functions upstream of mTOR and is altered in the AD and PD animal models (Heras‐Sandoval et al , ). PI3K–AKT–mTOR is activated by silibinin treatment to protect neurons against the apoptosis induced by hydrogen peroxide (H 2 O 2 ) in vitro and in the middle cerebral artery occlusion or MCAO animal model (Wang et al , ). In addition, the brain‐specific and multifunctional insulin‐like growth factor‐1 (IGF‐1) protein protects neurons from excitotoxicity induced by NMDA treatment via the activation of the PI3K–AKT–mTOR signaling pathway (Wang et al , ).…”

Z‐Guggulsterone attenuates astrocytes‐mediated neuroinflammation after ischemia by inhibiting toll‐like receptor 4 pathway

“…; Wang et al . ). The neurological scores were defined as follows: 0, no neurological dysfunction; 1, failure to extend left forelimb fully; 2, circling to the contralateral side; 3, falling to the left side; 4, no spontaneous locomotor activity.…”

“…Neurological examination and infarct assessment Neurological deficits were evaluated by an experimenter who was blinded to the group information at 3 days after the MCAO procedure with a 5-point scale system reported previously (Longa et al 1989;Wang et al 2016). The neurological scores were defined as follows: 0, no neurological dysfunction; 1, failure to extend left forelimb fully; 2, circling to the contralateral side; 3, falling to the left side; 4, no spontaneous locomotor activity.…”