Beneficial effect of (–)Schisandrin B against 3‐nitropropionic acid‐induced cell death in PC12 cells

Abstract

Huntington's disease (HD) is characterized by the dysfunction of mitochondrial energy metabolism, which is associated with the functional impairment of succinate dehydrogenase (mitochondrial complex II), and pyruvate dehydrogenase (PDH). Treatment with 3-nitropropionic acid (3-NP), a potent irreversible inhibitor of succinate dehydrogenase, replicates most of the pathophysiological features of HD. In the present study, we investigated the effect of (-)schisandrin B [(-)Sch B, a potent enantiomer of schisandrin B] on 3-NP-induced cell injury in rat differentiated neuronal PC12 cells. The 3-NP caused cell necrosis, as assessed by lactate dehydrogenase (LDH) leakage, and mitochondrion-dependent cell apoptosis, as assessed by caspase-3 and caspase-9 activation, in differentiated PC12 cells. The cytotoxicity induced by 3-NP was associated with a depletion of cellular reduced glutathione (GSH) as well as the activation of redox-sensitive c-Jun N-terminal kinase (JNK) pathway and the inhibition of PDH. (-)Sch B pretreatment (5 and 15 μM) significantly reduced the extent of necrotic and apoptotic cell death in 3-NP-challenged cells. The cytoprotection afforded by (-)Sch B pretreatment was associated with the attenuation of 3-NP-induced GSH depletion as well as JNK activation and PDH inhibition. (-)Sch B pretreatment enhanced cellular glutathione redox status and ameliorated the 3-NP-induced cellular energy crisis, presumably by suppressing the activated JNK-mediated PDH inhibition, thereby protecting against necrotic and apoptotic cell death in differentiated PC12 cells.

Schisandrin B as a Hormetic Agent for Preventing Age-Related Neurodegenerative Diseases

“…On the other hand, the well-established mitochondrial antioxidant and mitoenergetic sparing properties of Sch B make it a particularly promising candidate for promoting brain health. Results from our recent investigation have further demonstrated that Sch B treatment can attenuate the oxidative stress induced by 3-nitroproponic acid, a potent irreversible inhibitor of mitochondrial succinate dehydrogenase that has been used in experimental models of HD, in differentiated PC12 cells and prevent the oxidative stress-induced energy crisis by suppressing the activation of the JNK signaling pathway and the consequent inhibition of PDH [ 76 ], a key bioenergetic enzyme which bridges anaerobic and aerobic brain energy metabolism. This observation supports the role of Sch B in enhancing glucose utilization in the brain.…”

Schisandrin B protects PC12 cells against oxidative stress of neurodegenerative diseases

“…In addition, Sch B showed neuroprotective effects against focal cerebral ischemic injury in Sprague-Dawley rats [8,9]. Further, Sch B improved paraquat-induced oxidative stress in the rat adrenal pheochromocytoma cell line (PC12 cells) [10,11]. The above studies indicated that Sch B might play a positive role in the therapy of neurodegenerative diseases.…”

Schisandrin B Enhances Glutathione Redox Cycling and Protects Against β-amyloid-induced Apoptosis in Human Neuroblastoma SH-SY5Y Cells: A Comparative Study of Various Phytochemicals

“…Oxidative stress has been recognized as a determining factor in causing neuronal cell death in Alzheimer's disease [10,21]. ()Sch B, a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, has been shown to induce an antioxidant response in various organs of rodents and in cultured cell lines, including neuronal cells [5,16,22].…”

“…a class of non-flavonoid polyphenolics) in the fruit of Schisandra chinensis, was found to produce nonspecific protection against tissue oxidant injury in various organs of rodents, presumably by up-regulating the glutathione redox cycling [5][6][7]. Previous studies have also demonstrated that ()Sch B, a potent stereoisomer of Sch B that amounts to 80% of the stereoisomers [8], increases the resistance of neuronal cells to paraquat-and 3-nitroponoic acid-induced oxidative stress through reducing the extent of oxidant-induced reduced glutathione (GSH) depletion, indicative of enhanced glutathione redox cycling [9,10]. It is therefore of pharmacological interest to examine whether ()Sch B can counteract oxidative stress-induced neuronal cell apoptosis, which has been implicated in the development of Alzheimer's disease.…”