Cardiotonic pill attenuates white matter and hippocampal damage via inhibiting microglial activation and downregulating ERK and p38 MAPK signaling in chronic cerebral hypoperfused rat

BMC Complementary and Alternative Medicine

Won Kyung Jeon³  Hyung Won Kang²  In Sun Lee³  Bu Yeo Kim³  Jung-Soo Han¹  Ji Hye Bang³  Ki Mo Lee³ 

[1]Department of Biological Sciences, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea

[2]Department of Neuropsychiatry, College of Oriental Medicine, Won-Kwang University, Iksan 570-749, Republic of Korea

[3]KM-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, Daejeon 305-811, Republic of Korea

关键词: Hippocampus;    White matter;    Microglia;    Inflammation;    Permanent bilateral common carotid artery occlusion;    Cardiotonic pill;   

Others  :  1220496
DOI  :  10.1186/1472-6882-13-334

 received in 2013-08-05, accepted in 2013-11-22,  发布年份 2013

【 摘 要 】

Background

The cardiotonic pill (CP) is a herbal medicine composed of Salvia miltiorrhiza (SM), Panax notoginseng (PN), and Dryobalanops aromatica Gaertner (DAG) that is widely used to treat cardiovascular diseases. The present experiment was conducted to examine the effects of CP on white matter and hippocampal damage induced by chronic cerebral hypoperfusion.

Methods

Chronic cerebral hypoperfusion was induced in male Wistar rats by permanent bilateral common carotid artery occlusion (BCCAo). Daily oral administration of CP (200 mg/kg) began 21 days after BCCAo and continued for 42 days. The levels of microglial activation and myelin basic protein (MBP) were measured in the white matter and hippocampus of rats with chronic BCCAo, and the expression levels of mitogen-activated protein kinases (MAPKs) and inflammatory markers such as cyclooxygenase-2, interleukin-1β, and interleukin-6 were examined.

Results

MBP expression was reduced in the white matter and hippocampal regions of rats that received BCCAo. In contrast, reduced levels of MBP were not observed in BCCAo rats given CP treatments. The administration of CP alleviated microglial activation, the alteration of ERK and p38 MAPK signaling, and inflammatory mediator expression in rats with chronic BCCAo.

Conclusion

These results suggest that CP may have protective effects against chronic BCCAo-induced white matter and hippocampal damage by inhibiting inflammatory processes including microglial activation and proinflammatory mediator expression, and downreguating the hyperphosphorylation of ERK and p38 MAPK signaling.

【 授权许可】

   
2013 Lee et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Moorhouse P, Rockwood K: Vascular cognitive impairment: current concepts and clinical developments. Lancet Neurol 2008, 7(3):246-255.
• [2]de la Torre JC: Is Alzheimer's disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. Lancet Neurol 2004, 3(3):184-190.
• [3]Roman GC, Erkinjuntti T, Wallin A, Pantoni L, Chui HC: Subcortical ischaemic vascular dementia. Lancet Neurol 2002, 1(7):426-436.
• [4]Farkas E, Luiten PG, Bari F: Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain res reviews 2007, 54(1):162-180.
• [5]Marosi M, Rakos G, Robotka H, Nemeth H, Sas K, Kis Z, Farkas T, Lur G, Vecsei L, Toldi J: Hippocampal (CA1) activities in Wistar rats from different vendors. Fundamental differences in acute ischemia. J Neurosci Methods 2006, 156(1–2):231-235.
• [6]O'Sullivan M: Leukoaraiosis. Pract Neurol 2008, 8(1):26-38.
• [7]Jeon WK, Ma J, Choi BR, Han SH, Jin Q, Hwang BY, Han JS: Effects of Fructus mume Extract on MAPK and NF-kappaB Signaling and the Resultant Improvement in the Cognitive Deficits Induced by Chronic Cerebral Hypoperfusion. Evi-based Complement Alter Med : eCAM 2012, 2012:450838.
• [8]Deng Y, Lu J, Sivakumar V, Ling EA, Kaur C: Amoeboid microglia in the periventricular white matter induce oligodendrocyte damage through expression of proinflammatory cytokines via MAP kinase signaling pathway in hypoxic neonatal rats. Brain Pathol 2008, 18(3):387-400.
• [9]Wakita H, Tomimoto H, Akiguchi I, Lin JX, Miyamoto K, Oka N: A cyclooxygenase-2 inhibitor attenuates white matter damage in chronic cerebral ischemia. Neuroreport 1999, 10(7):1461-1465.
• [10]Farkas E, Donka G, de Vos RA, Mihaly A, Bari F, Luiten PG: Experimental cerebral hypoperfusion induces white matter injury and microglial activation in the rat brain. Acta Neuropathol 2004, 108(1):57-64.
• [11]Haddad JJ: Mitogen-activated protein kinases and the evolution of Alzheimer's: a revolutionary neurogenetic axis for therapeutic intervention? Prog Neurobiol 2004, 73(5):359-377.
• [12]Horie Y, Han JY, Mori S, Konishi M, Kajihara M, Kaneko T, Yamagishi Y, Kato S, Ishii H, Hibi T: Herbal cardiotonic pills prevent gut ischemia/reperfusion-induced hepatic microvascular dysfunction in rats fed ethanol chronically. World J Gastroenterol 2005, 11(4):511-515.
• [13]Wei XH, Liu YY, Li Q, Yan L, Hu BH, Pan CS, Li ZX, Chang X, Fan JY, Zhao N, et al.: Treatment with cardiotonic pills((R)) after ischemia-reperfusion ameliorates myocardial fibrosis in rats. Microcirculation 2013, 20(1):17-29.
• [14]Zhao N, Liu YY, Wang F, Hu BH, Sun K, Chang X, Pan CS, Fan JY, Wei XH, Li X, et al.: Cardiotonic pills, a compound Chinese medicine, protects ischemia-reperfusion-induced microcirculatory disturbance and myocardial damage in rats. Am J Physiol Heart Circ Physiol 2010, 298(4):H1166-H1176.
• [15]Cai QY, Chen XS, Zhan XL, Yao ZX: Protective effects of catalpol on oligodendrocyte death and myelin breakdown in a rat model of chronic cerebral hypoperfusion. Neurosci Lett 2011, 497(1):22-26.
• [16]Lim GP, Yang F, Chu T, Chen P, Beech W, Teter B, Tran T, Ubeda O, Ashe KH, Frautschy SA, et al.: Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease. J Neurosci 2000, 20(15):5709-5714.
• [17]Wang F, Liu YY, Liu LY, Guo J, Sun K, Wang CS, Fan JY, Han JY: Inhibition effect of cardiotonic pills on venous thrombosis induced in rat mesentery by photochemical reaction. Clin Hemorheol Microcirc 2006, 34(1–2):131-138.
• [18]Yoshioka H, Niizuma K, Katsu M, Sakata H, Okami N, Chan PH: Consistent injury to medium spiny neurons and white matter in the mouse striatum after prolonged transient global cerebral ischemia. J Neurotrauma 2011, 28(4):649-660.
• [19]Otori T, Katsumata T, Muramatsu H, Kashiwagi F, Katayama Y, Terashi A: Long-term measurement of cerebral blood flow and metabolism in a rat chronic hypoperfusion model. Clin Exp Pharmacol Physiol 2003, 30(4):266-272.
• [20]Cho KO, La HO, Cho YJ, Sung KW, Kim SY: Minocycline attenuates white matter damage in a rat model of chronic cerebral hypoperfusion. J Neurosci Res 2006, 83(2):285-291.
• [21]Wakita H, Tomimoto H, Akiguchi I, Kimura J: Dose-dependent, protective effect of FK506 against white matter changes in the rat brain after chronic cerebral ischemia. Brain Res 1998, 792(1):105-113.
• [22]Miki K, Ishibashi S, Sun L, Xu H, Ohashi W, Kuroiwa T, Mizusawa H: Intensity of chronic cerebral hypoperfusion determines white/gray matter injury and cognitive/motor dysfunction in mice. J Neurosci Res 2009, 87(5):1270-1281.
• [23]Khwaja O, Volpe JJ: Pathogenesis of cerebral white matter injury of prematurity. Arc Dis Child Fetal Neonatal Ed 2008, 93(2):F153-F161.
• [24]Liu R, Wen Y, Perez E, Wang X, Day AL, Simpkins JW, Yang SH: 17beta-Estradiol attenuates blood–brain barrier disruption induced by cerebral ischemia-reperfusion injury in female rats. Brain Res 2005, 1060(1–2):55-61.
• [25]Duan W, Ran H, Zhou Z, He Q, Zheng J: Adenosine A2A receptor deficiency up-regulates cystatin F expression in white matter lesions induced by chronic cerebral hypoperfusion. PloS One 2012, 7(12):e52566.
• [26]Narantuya D, Nagai A, Sheikh AM, Wakabayashi K, Shiota Y, Watanabe T, Masuda J, Kobayashi S, Kim SU, Yamaguchi S: Microglia transplantation attenuates white matter injury in rat chronic ischemia model via matrix metalloproteinase-2 inhibition. Brain Res 2010, 1316:145-152.
• [27]Minami M, Katayama T, Satoh M: Brain cytokines and chemokines: roles in ischemic injury and pain. J Pharmacol Sci 2006, 100(5):461-470.
• [28]Wang J, Zhang HY, Tang XC: Huperzine a improves chronic inflammation and cognitive decline in rats with cerebral hypoperfusion. J Neurosci Res 2010, 88(4):807-815.
• [29]Sweatt JD: The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J Neurochem 2001, 76(1):1-10.
• [30]Jung HW, Son HY, Minh CV, Kim YH, Park YK: Methanol extract of Ficus leaf inhibits the production of nitric oxide and proinflammatory cytokines in LPS-stimulated microglia via the MAPK pathway. Phytother Res 2008, 22(8):1064-1069.
• [31]Choi BR, Kwon KJ, Park SH, Jeon WK, Han SH, Kim HY, Han JS: Alternations of Septal-hippocampal System in the Adult Wistar Rat with Spatial Memory Impairments Induced by Chronic Cerebral Hypoperfusion. Exp Neurobiol 2011, 20(2):92-99.
• [32]Chaparro-Huerta V, Rivera-Cervantes MC, Flores-Soto ME, Gomez-Pinedo U, Beas-Zarate C: Proinflammatory cytokines and apoptosis following glutamate-induced excitotoxicity mediated by p38 MAPK in the hippocampus of neonatal rats. J Neuroimmunol 2005, 165(1–2):53-62.
• [33]Himaya SW, Ryu B, Qian ZJ, Kim SK: Paeonol from Hippocampus kuda Bleeler suppressed the neuro-inflammatory responses in vitro via NF-kappaB and MAPK signaling pathways. Toxicol In Vitro 2012, 26(6):878-887.
• [34]Wakita H, Tomimoto H, Akiguchi I, Kimura J: Protective effect of cyclosporin A on white matter changes in the rat brain after chronic cerebral hypoperfusion. Stroke 1995, 26(8):1415-1422.