Browse > Article
http://dx.doi.org/10.4062/biomolther.2010.18.1.039

Synergistic Increase of BDNF Release from Rat Primary Cortical Neuron by Combination of Several Medicinal Plant-Derived Compounds  

Jeon, Se-Jin (Department of Pharmacology, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University)
Bak, Hae-Rang (Department of Pharmacology, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University)
Seo, Jung-Eun (Department of Pharmacology, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University)
Kwon, Kyung-Ja (Institute for Biomedical Sciences and Technology and Institute of Functional Genomics, Konkuk University)
Kang, Young-Sun (Institute for Biomedical Sciences and Technology and Institute of Functional Genomics, Konkuk University)
Kim, Hee-Jin (Department of Pharmacy, Sahmyook University)
Cheong, Jae-Hoon (Department of Pharmacy, Sahmyook University)
Ryu, Jong-Hoon (Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University)
Ko, Kwang-Ho (Department of Pharmacology, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University)
Shin, Chan-Young (Institute for Biomedical Sciences and Technology and Institute of Functional Genomics, Konkuk University)
Publication Information
Biomolecules & Therapeutics / v.18, no.1, 2010 , pp. 39-47 More about this Journal
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 $0.1{\mu}M$ 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 ($20{\mu}M$) 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;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
Times Cited By Web Of Science : 1  (Related Records In Web of Science)
Times Cited By SCOPUS : 1
연도 인용수 순위
1 Angelucci, F., Brene, S. and Mathe, A. A. (2005). BDNF in schizophrenia, depression and corresponding animal models. Mol. Psychiatry 10, 345-352.   DOI
2 Bhat, N. R., Zhang P, Lee J. C. and Hogan E. L. (1998). Extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases regulate inducible nitric oxide synthase and tumor necrosis factor-alpha gene expression in endotoxin-stimulated primary glial cultures. J Neurosci. 18,1633-1641.   DOI
3 Bibel, M. and Barde, Y. A. (2000). Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system. Genes Dev. 14, 2919-2937.   DOI
4 Chen, S. O., Fang, S. H., Shih, D. Y., Chang, T. J. and Liu, J. J. (2009). Recombinant core proteins of Japanese encephalitis virus as activators of the innate immune response. Virus Genes 38, 10-18.   DOI
5 Conner, J. M., Lauterborn, J. C., Yan, Q., Gall, C. M. and Varon, S. (1997). Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport. J. Neurosci. 17, 2295-2313.   DOI
6 Duman, R. S., Heninger, G. R. and Nestler, E. J. (1997). A molecular and cellular theory of depression. Arch. Gen. Psychiatry 54, 597-606.   DOI   ScienceOn
7 Ernfors, P., Van De Water, T., Loring, J. and Jaenisch, R. (1995). Complementary roles of BDNF and NT-3 in vestibular and auditory development. Neuron 14, 1153-1164.   DOI
8 Feng, H. L., Leng, Y., Ma, C. H., Zhang, J., Ren, M. and Chuang, D. M. (2008). Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model. Neuroscience 155, 567-572.   DOI
9 Ha, S. and Redmond, L. (2008). ERK mediates activity dependent neuronal complexity via sustained activity and CREB-mediated signaling. Dev. Neurobiol. 68, 1565-1579.   DOI
10 Hemmings, S. M., Kinnear, C. J., Van der Merwe, L., Lochner, C., Corfield, V. A., Moolman-Smook, J. C. and Stein, D. J. (2008). Investigating the role of the brain-derived neurotrophic factor (BDNF) val66met variant in obsessive-compulsive disorder (OCD). World J. Biol. Psychiatry 9, 126-134.   DOI
11 Liu, C., Wu, J., Gu, J., Xiong, Z., Wang, F., Wang, J., Wang, W. and Chen, J. (2007). Baicalein improves cognitive deficits induced by chronic cerebral hypoperfusion in rats. Pharmacol. Biochem. Behav. 86, 423-430.   DOI   ScienceOn
12 Kim, D. H., Jeon, S. J., Son, K. H., Jung, J. W., Lee, S., Yoon, B. H., Choi, J. W., Cheong, J. H., Ko, K. H. and Ryu, J. H. (2006). Effect of the flavonoid, oroxylin A, on transient cerebral hypoperfusion-induced memory impairment in mice. Pharmacol. Biochem. Behav. 85, 658-668.   DOI
13 Kim, S. R. and Kim, Y. C. (2000). Neuroprotective phenylpropanoid esters of rhamnose isolated from roots of Scrophularia buergeriana. Phytochemistry 54, 503-509.   DOI
14 Liu, C., Lin, N., Wu, B. and Qiu, Y. (2009). Neuroprotective effect of memantine combined with topiramate in hypoxic-ischemic brain injury. Brain Res. 1282, 173-182.   DOI
15 Maekawa, T., Sakura, H., Kanei-Ishii, C., Sudo, T., Yoshimura, T., Fujisawa, J., Yoshida, M. and Ishii, S. (1989). Leucine zipper structure of the protein CRE-BP1 binding to the cyclic AMP response element in brain. EMBO. J. 8, 2023-2028.
16 Piao, H. Z., Jin, S. A., Chun, H. S., Lee, J. C. and Kim, W. K. (2004). Neuroprotective effect of wogonin: potential roles of inflammatory cytokines. Arch. Pharm. Res. 27, 930-936.   DOI
17 Cramer, T., Juttner, S., Plath, T., Mergler, S., Seufferlein, T., Wang, T. C., Merchant, J. and Hocker, M. (2008). Gastrin transactivates the chromogranin A gene through MEK-1/ERK- and PKC-dependent phosphorylation of Sp1 and CREB. Cell Signal 20, 60-72.   DOI
18 Cui, Q., Zhang, J., Zhang, L., Li, R. and Liu, H. (2009). Angelica injection improves functional recovery and motoneuron maintenance with increased expression of brain derived neurotrophic factor and nerve growth factor. Curr. Neurovasc. Res. 6, 117-123.   DOI
19 Duman, R. S. (2002). Pathophysiology of depression: the concept of synaptic plasticity. Eur. Psychiatry 17 Suppl 3, 306-310.   DOI
20 Rumajogee, P., Madeira, A., Verge, D., Hamon, M. and Miquel, M. C. (2002). Up-regulation of the neuronal serotoninergic phenotype in vitro: BDNF and cAMP share Trk B-dependent mechanisms. J. Neurochem. 83, 1525-1528.   DOI
21 Sairanen, M., Lucas, G., Ernfors, P., Castren, M. and Castren, E. (2005). Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. J. Neurosci. 25, 1089-1094.   DOI
22 Sasaki, T., Dai, X. Y., Kuwata, S., Fukuda, R., Kunugi, H., Hattori, M. and Nanko, S. (1997). Brain-derived neurotrophic factor gene and schizophrenia in Japanese subjects. Am. J. Med. Genet. 74, 443-444.   DOI
23 Jung, H. A., Min, B. S., Yokozawa, T., Lee, J. H., Kim, Y. S. and Choi, J. S. (2009). Anti-Alzheimer and antioxidant activities of Coptidis Rhizoma alkaloids. Biol. Pharm. Bull. 32, 1433-1438.   DOI
24 Hofer, M., Pagliusi, S. R., Hohn, A., Leibrock, J. and Barde, Y. A. (1990). Regional distribution of brain-derived neurotrophic factor mRNA in the adult mouse brain. EMBO. J. 9, 2459-2464.
25 Huang, E. J. and Reichardt, L. F. (2001). Neurotrophins: roles in neuronal development and function. Annu. Rev. Neurosci. 24, 677-736.   DOI
26 Imming, P., Sinning, C. and Meyer, A. (2006). Drugs, their targets and the nature and number of drug targets. Nat. Rev. Drug Discov. 5, 821-834.   DOI
27 Yamashita, K., Kotani, Y., Nakajima, Y., Shimazawa, M., Yoshimura, S., Nakashima, S., Iwama, T. and Hara, H. (2007). Fasudil, a Rho kinase (ROCK) inhibitor, protects against ischemic neuronal damage in vitro and in vivo by acting directly on neurons. Brain Res. 1154, 215-224.   DOI
28 Yu, H. L., Li, L., Zhang, X. H., Xiang, L., Zhang, J., Feng, J. F. and Xiao, R. (2009). Neuroprotective effects of genistein and folic acid on apoptosis of rat cultured cortical neurons induced by beta-amyloid 31-35. Br. J. Nutr. 102, 655-662.   DOI
29 Yu, X. Y., Lin, S. G., Zhou, Z. W., Chen, X., Liang, J., Liu, P. Q., Duan, W., Chowbay, B., Wen, J. Y., Li, C. G. and Zhou, S. F. (2007). Role of P-glycoprotein in the intestinal absorption of tanshinone IIA, a major active ingredient in the root of Salvia miltiorrhiza Bunge. Curr. Drug Metab. 8, 325-340.   DOI
30 Mu, X., He, G., Cheng, Y., Li, X., Xu, B. and Du, G. (2009). Baicalein exerts neuroprotective effects in 6-hydroxydopamine-induced experimental parkinsonism in vivo and in vitro. Pharmacol. Biochem. Behav. 92, 642-648.   DOI
31 Novikova, L. N., Novikov, L. N. and Kellerth, J. O. (2000). BDNF abolishes the survival effect of NT-3 in axotomized Clarke neurons of adult rats. J. Comp. Neurol. 428, 671-680.   DOI
32 Ozan, E., Okur, H., Eker, C., Eker, O. D., Gonul, A. S. and Akarsu, N. (2010). The effect of depression, BDNF gene val66met polymorphism and gender on serum BDNF levels. Brain Res. Bull. 15, 61-65.
33 Park, J., Koito, H., Li, J. and Han, A. (2009). Microfluidic compartmentalized co-culture platform for CNS axon myelination research. Biomed. Microdevices 11, 1145-1153.   DOI
34 Xia, W. J., Yang, M., Fok, T. F., Li, K., Chan, W. Y., Ng, P. C., Ng, H. K., Chik, K. W., Wang, C. C., Gu, G. J., et al. (2005). Partial neuroprotective effect of pretreatment with tanshinone IIA on neonatal hypoxia-ischemia brain damage. Pediatr. Res 58, 784-790.   DOI
35 Soppet, D., Escandon, E., Maragos, J., Middlemas, D. S., Reid, S. W., Blair, J., Burton, L. E., Stanton, B. R., Kaplan, D. R., Hunter, T., et al. (1991). The neurotrophic factors brainderived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor. Cell 65, 895-903.   DOI
36 Wagner, H. and Ulrich-Merzenich, G. (2009). Synergy research: approaching a new generation of phytopharmaceuticals.Phytomedicine 16, 97-110.   DOI
37 Wang, Z., Hu, S. Y., Lei, D. L. and Song, W. X. (2006). Effect of chronic stress on PKA and P-CREB expression in hippocampus of rats and the antagonism of antidepressors. Zhong Nan Da Xue Xue Bao Yi Xue Ban 31, 767-771.
38 Zuccato, C. and Cattaneo, E. (2009). Brain-derived neurotrophic factor in neurodegenerative diseases. Nat. Rev. Neurol. 5, 311-322.   DOI
39 Sato, K., Suematsu, A., Nakashima, T., Takemoto-Kimura, S., Aoki, K., Morishita, Y., Asahara, H., Ohya, K., Yamaguchi, A., Takai, T. (2006). Regulation of osteoclast differentiation and function by the CaMK-CREB pathway. Nat. Med. 12, 1410-1416.   DOI
40 Hu, Y. and Russek, S. J. (2008). BDNF and the diseased nervous system: a delicate balance between adaptive and pathological processes of gene regulation. J. Neurochem. 105, 1-17.   DOI
41 Lyden, P. D., Jackson-Friedman, C., Shin, C. and Hassid, S. (2000). Synergistic combinatorial stroke therapy: A quantal bioassay of a GABA agonist and a glutamate antagonist. Exp. Neurol. 163, 477-489.   DOI