Abstract
BackgroundFour traditional Korean medicinal herbs which act in retarding the aging process, Polygonum multiflorum Thunb., Rehmannia glutinosa (Gaertn) Libosch., Polygala tenuifolia Willd., and Acorus gramineus Soland., were prepared by systematic investigation of Dongeuibogam (Treasured Mirror of Eastern Medicine), published in the early 17th century in Korea. This study was performed to evaluate beneficial effects of four herbal mixture extract (PMC-12) on hippocampal neuron and spatial memory.MethodsHigh performance liquid chromatography (HPLC) analysis was performed for standardization of PMC-12. Cell viability, lactate dehydrogenase, flow cytometry, reactive oxygen species (ROS), and Western blot assays were performed in HT22 hippocampal cells and immunohistochemistry and behavioral tests were performed in a mouse model of focal cerebral ischemia in order to observe alterations of hippocampal cell survival and subsequent memory function.ResultsIn the HPLC analysis, PMC-12 was standardized to contain 3.09 % 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside, 0.35 % 3′,6-disinapoyl sucrose, and 0.79 % catalpol. In HT22 cells, pretreatment with PMC-12 resulted in significantly reduced glutamate-induced apoptotic cell death. Pretreatment with PMC-12 also resulted in suppression of ROS accumulation in connection with cellular Ca2+ level after exposure to glutamate. Expression levels of phosphorylated p38 mitogen-activated protein kinases (MAPK) and dephosphorylated phosphatidylinositol-3 kinase (PI3K) by glutamate exposure were recovered by pretreatment with either PMC-12 or anti-oxidant N-acetyl-L-cysteine (NAC). Expression levels of mature brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP response element binding protein (CREB) were significantly enhanced by treatment with either PMC-12 or NAC. Combination treatment with PMC-12, NAC, and intracellular Ca2+ inhibitor BAPTA showed similar expression levels. In a mouse model of focal cerebral ischemia, we observed higher expression of mature BDNF and phosphorylation of CREB in the hippocampus and further confirmed improved spatial memory by treatment with PMC-12.ConclusionsOur results suggest that PMC-12 mainly exerted protective effects on hippocampal neurons through suppression of Ca2+-related ROS accumulation and regulation of signaling pathways of p38 MAPK and PI3K associated with mature BDNF expression and CREB phosphorylation and subsequently enhanced spatial memory.
Highlights
Four traditional Korean medicinal herbs which act in retarding the aging process, Polygonum multiflorum Thunb., Rehmannia glutinosa (Gaertn) Libosch., Polygala tenuifolia Willd., and Acorus gramineus Soland., were prepared by systematic investigation of Dongeuibogam (Treasured Mirror of Eastern Medicine), published in the early 17th century in Korea
Post-treatment with PMC-12 followed by middle cerebral artery occlusion (MCAO) surgery resulted in a significant increase in the number of double-positive cells of pCREB/ neuronal nuclei (NeuN) or mature brain-derived neurotrophic factor (BDNF)/NeuN in the CA1 and dentate gyrus (DG) region of the ipsilateral hippocampus compared to the MCAO group (Fig. 7). These results suggest a possible association of the protective effects of PMC-12 with neuronal mature BDNF expression and cAMP response element binding protein (CREB) phosphorylation in the hippocampus of MCAO mice
HT22 hippocampal cells for selection of functional herbs on memory impairment, among many herbal candidates, we found that Polygonum multiflorum exhibited prominent neuroprotective effects
Summary
Four traditional Korean medicinal herbs which act in retarding the aging process, Polygonum multiflorum Thunb., Rehmannia glutinosa (Gaertn) Libosch., Polygala tenuifolia Willd., and Acorus gramineus Soland., were prepared by systematic investigation of Dongeuibogam (Treasured Mirror of Eastern Medicine), published in the early 17th century in Korea. Hippocampal neuronal death is a major factor in the progress of memory impairment in many brain disorders [2, 3]. Prevention of hippocampal neuronal deaths provides a potential new therapeutic strategy to ameliorate memory and cognitive impairment of many neurological disorders. HT22 hippocampal cell line, which lacks a functional glutamate receptor, is valuable for studying molecular mechanism of memory deficits [2, 4]. Exposure of HT22 hippocampal cells to glutamate shows neurotoxicity through oxidative stress rather than N-methyl-D-aspartate receptor-mediated excitotoxicity [5,6,7]. Death of hippocampal cell following oxidative stress and accumulation of ROS play a role in learning and memory impairment of brain disorders [11]
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