SMND‐309, a Novel Derivate of Salvianolic Acid B, Attenuates Apoptosis and Ameliorates Mitochondrial Energy Metabolism in Rat Cortical Neurons

Abstract

SMND-309, a novel compound (2E)-2-{6-[(E)-2-carboxyvinyl]-2,3-dihydroxyphenyl}-3-(3,4-dihydroxyphenyl) acrylic acid, is a new derivate of salvianolic acid B. The present study elucidates the effects of SMND-309 on the cultured rat cortical neuron damage induced by oxygen-glucose deprivation. The results show that SMND-309 treatment obviously attenuates apoptosis and ameliorates mitochondrial energy metabolism in rat cortical neurons by increasing cell survival rate, mitochondrial antioxidant enzyme activities, mitochondrial respiratory enzymes activities, mitochondrial respiratory control ratio and the adenosine triphosphate content, and by decreasing mitochondrial malondialdehyde content, lactate dehydrogenase release, intracellular Ca 2+ level and caspase-3 activity in a concentration-dependent manner. Moreover, SMND-309 exhibits significantly higher potency as compared to salvianolic acid B. These findings indicate that SMND-309 has a protective potential against cerebral ischaemic injury and its protective effects may be due to the suppression of intracellular Ca 2+ elevation and caspase-3 activity, and improvement of mitochondrial energy metabolism and antioxidant property.Danshen, the dried root of Salvia miltiorrhiza Bunge (Labiatae), is a traditional Chinese medicine commonly used for the treatment of cardiovascular diseases, such as angina pectoris, myocardial infarction and stroke [1]. The content of danshen can be separated into lipid-soluble and watersoluble fractions. Its lipid-soluble fraction contains more than 30 diterpenoid tanshinones; the major active constituents include tanshinone I, IIA and IIB, cryptotanshinone, dihydrotanshinone I, methylenetanshinone, and isotanshinone IIA [2,3]. The putative active components of its aqueous extract are salvianolic acid B, danshensu, lithospermic acids, protocatechuic acid, and rosemarinic acid [4][5][6]. Salvianolic acid B is the most abundant and bioactive member of the salvianolic acids in danshen [7]. It was assigned as the marker species for danshen in the Chinese Pharmacopoeia. In animal studies, salvianolic acid B has been shown to possess many of the actions of the danshen herb. Hence, it was reported to possess hepatoprotective and antifibrogenic effects [8], inhibit platelet aggregation and improve cerebral blood flow [9], enhance angiogenic processes [10,11], and protect against injury in the skin, heart and brain caused by ischaemia reperfusion, possibly by reducing lipid peroxides, scavenging free radicals and improving energy metabolism [12][13][14][15][16]. Therefore, since March 2005, salvianolic acid B has been approved by the Chinese State Food and Drug Administration as a neuroprotective agent for the treatment of acute cerebral infarction (State Drug Permit Doc: Z20050249).We have recently described the structure of a novel degradation product in rat brain after oral administration of salvianolic acid B with the chemical name (2E)-2-{6-[(E)-2-carboxyvinyl]-2,3-dihydroxyphenyl}-3-(3,4-dihydroxyphenyl) acrylic acid (Chinese pa...

Salvianolic acid B inhibits low-density lipoprotein oxidation and neointimal hyperplasia in endothelium-denuded hypercholesterolaemic rabbits

“…The main pharmacological activities of Sal B include inhibition of lipopolysaccharide (LPS)‐inducible COX‐2 in human aortic smooth muscle cells (HASMCs) via JNK and ERK suppression,17 reduction of MMP‐2 and MMP‐9 in cholesterol‐fed mice and LPS‐stimulated HASMCs,18 reduction of leucocyte adhesion to human aortic endothelial cells (HAECs)19 and attenuation of ischaemia–reperfusion injury 20, 21. Additionally, administration of Sal B resulted in an improvement in regional cerebral blood flow in the ischaemic cerebral hemisphere in rats,20, 22 attenuation of apoptosis in rat cortical neurons23 and neuroprotection in cerebral ischaemia 24. Furthermore, Sal B has also been shown to protect endothelial cells from oxidative stress,25 to inhibit TGF‐β1‐induced myofibroblast transition and restore epithelial morphology26 and to inhibit platelet aggregation and adhesion under flow conditions 27…”

Salvianolic acid B inhibits mitochondrial dysfunction by up-regulating mortalin

“…Previous studies reported that SalB is effective in inhibiting hepatocellular apoptosis by regulating apoptotic-related factors in the mitochondrial death pathway. SalB is also involved in ameliorating mitochondrial energy metabolism 9 10 . In living cells, mitochondria are relevant sources of reactive oxygen species.…”

Molecular Pharmacology of Rosmarinic and Salvianolic Acids: Potential Seeds for Alzheimer’s and Vascular Dementia Drugs

“…A summary of in vitro effects that attributes to the potential therapeutic effects of salvianolic acid derivatives are shown in Table 1 [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. By assessing the β-secretase (β-site amyloid precursor protein (APP) cleaving enzyme or BACE1) and γ-secretase inhibitory activity, a selective effect against BACE1 was demonstrated for SA-B [ 32 ].…”