The Korean Society of Applied Pharmacology 2010; 18(1): 39-47  
Synergistic Increase of BDNF Release from Rat Primary Cortical Neuron by Combination of Several Medicinal Plant-Derived Compounds
Se Jin JEON1, Haerang BAK1, Jungeun SEO1, Kyung Ja KWON2,3, Young Sun KANG2, Hee Jin KIM4, Jae Hoon CHEONG4, Jong Hoon RYU5, Kwang Ho KO1, and Chan Young SHIN2,3,*
1Department of Pharmacology, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, 2Institute for Biomedical Sciences and Technology and Institute of Functional Genomics, Konkuk University, 3Department of Pharmacology and Research Institute of Medical Sciences, School of Medicine, Konkuk University, Seoul 143-701, 4Department of Pharmacy, Sahmyook University, Seoul 139-742, 5Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea
Chan Young SHIN
Received: November 3, 2009; Revised: January 10, 2010; Accepted: January 11, 2010; Published online: January 31, 2010.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor involved in neuronal differentiation, plasticity, survival and regeneration. BDNF draws massive attention mainly due to the potential as a therapeutic target in neurological diseases such as depression and Alzheimer's disease. In a primary screening for the natural compounds enhancing BDNF release from cultured rat primary cortical neuron, we found that compounds such as baicalein, tanshinone IIa, cinnamic acid, epiberberine, genistein and wogonin among many others increased BDNF release. All the compounds at 0.1 ?M of concentration barely showed stimulatory effect on BDNF induction, however, their combination (mixture 1; baicalein, tanshinone IIa and cinnamic acid, mixture 2; epiberberine, genistein and wogonin) showed synergistic increase in BDNF release as well as mRNA and protein expression. The level of BDNF expression was comparable to the maximum BDNF stimulation attainable by a positive control oroxylin A (20 ?M) without cell toxicity as determined by MTT analysis. Both mixtures synergistically increased the phosphorylation of extracellular signal-regulated kinase (ERK) as well as cAMP response element binding protein (CREB), an immediate and essential regulator of BDNF expression. Similar to these results, mixture of these compounds synergistically inhibited the up-regulation of inducible nitric oxide synthase (iNOS) induced by lipopolysaccharide treatments in rat primary astrocytes. These results suggest that the combinatorial treatment of natural compounds in lower concentration might be a useful strategy to obtain sufficient BDNF stimulation in neurological disease condition such as depression, while minimizing potential side effects and toxicity of higher concentration of a single compound.
Keywords: BDNF, Cortical neuron, CREB, ERK, Synergism

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