Huperzine A Ameliorates Cognitive Deficits and Oxidative Stress in the Hippocampus of Rats Exposed to Acute Hypobaric Hypoxia

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• 作者：Qinghai Shi (1) qinghaishi@gmail.com
  Jianfeng Fu (1) dxpjf@163.com
  Di Ge (1)
  Yan He (1)
  Jihua Ran (1)
  Zhengxiang Liu (1)
  Jing Wei (1)
  Tong Diao (1)
  Youfang Lu (1)
• 关键词：Huperzine A &#8211 ; Acute hypobaric hypoxia &#8211 ; Cognitive functions &#8211 ; Hippocampus &#8211 ; Oxidative stress &#8211 ; Apoptosis
• 刊名：Neurochemical Research
• 出版年：2012
• 出版时间：September 2012
• 年：2012
• 卷：37
• 期：9
• 页码：2042-2052
• 全文大小：555.0 KB
• 参考文献：1. Virues-Ortega J, Buela-Casal G, Garrido E et al (2004) Neuropsychological functioning associated with high-altitude exposure. Neuropsychol Rev 14:197–224
  2. Squire LR (1992) Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol Rev 99:195–231
  3. Roach RC, Hackett PH (2001) Frontiers of hypoxia research: acute mountain sickness. J Exp Biol 204:3161–3170
  4. Maiti P, Singh SB, Sharma AK et al (2006) Hypobaric hypoxia induces oxidative stress in rat brain. Neurochem Int 49:709–716
  5. Maiti P, Singh SB, Mallick B et al (2008) High altitude memory impairment is due to neuronal apoptosis in hippocampus, cortex and striatum. J Chem Neuroanat 36:227–238
  6. Shi QH, Fu JF, Ge D et al (2012) Acute hypobaric hypoxia stress induces cognitive impairment in rats. Xibei Guofang Yixue Zazhi 33:4–7
  7. Wang R, Zhang HY, Tang XC (2001) Huperzine a attenuates cognitive dysfunction and neuronal degeneration caused by beta-amyloid protein-(1–40) in rat. Eur J Pharmacol 421:149–156
  8. Wang T, Tang XC (1998) Reversal of scopolamine-induced deficits in radial maze performance by (−)-huperzine a: comparison with e2020 and tacrine. Eur J Pharmacol 349:137–142
  9. Xu SS, Gao ZX, Weng Z et al (1995) Efficacy of tablet huperzine-a on memory, cognition, and behavior in alzheimer’s disease. Zhongguo Yao Li Xue Bao 16:391–395
  10. Ye JW, Cai JX, Wang LM et al (1999) Improving effects of huperzine a on spatial working memory in aged monkeys and young adult monkeys with experimental cognitive impairment. J Pharmacol Exp Ther 288:814–819
  11. Zhang RW, Tang XC, Han YY et al (1991) drug evaluation of huperzine a in the treatment of senile memory disorders. Zhongguo Yao Li Xue Bao 12:250–252
  12. Wang J, Zhang HY, Tang XC (2010) Huperzine a improves chronic inflammation and cognitive decline in rats with cerebral hypoperfusion. J Neurosci Res 88:807–815
  13. Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11:47–60
  14. Wang LS, Zhou J, Shao XM et al (2002) Huperzine a attenuates cognitive deficits and brain injury in neonatal rats after hypoxia-ischemia. Brain Res 949:162–170
  15. Jayalakshmi K, Singh SB, Kalpana B et al (2007) N-acetyl cysteine supplementation prevents impairment of spatial working memory functions in rats following exposure to hypobaric hypoxia. Physiol Behav 92:643–650
  16. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254
  17. Cathcart R, Schwiers E, Ames BN (1983) Detection of picomole levels of hydroperoxides using a fluorescent dichlorofluorescein assay. Anal Biochem 134:111–116
  18. Dousset JC, Trouilh M, Foglietti MJ (1983) Plasma malonaldehyde levels during myocardial infarction. Clin Chim Acta 129:319–322
  19. Hissin PJ, Hilf R (1976) A fluorometric method for determination of oxidized and reduced glutathione in tissues. Anal Biochem 74:214–226
  20. Barhwal K, Singh SB, Hota SK et al (2007) Acetyl-l-carnitine ameliorates hypobaric hypoxic impairment and spatial memory deficits in rats. Eur J Pharmacol 570:97–107
  21. Wang YE, Feng J, Lu WH et al (1988) Pharmacokinetics of huperzine a in rats and mice. Zhongguo Yao Li Xue Bao 9:193–196
  22. Wang LM, Han YF, Tang XC (2000) Huperzine a improves cognitive deficits caused by chronic cerebral hypoperfusion in rats. Eur J Pharmacol 398:65–72
  23. Lu WH, Shou J, Tang XC (1988) Improving effect of huperzine a on discrimination performance in aged rats and adult rats with experimental cognitive impairment. Zhongguo Yao Li Xue Bao 9:11–15
  24. Cheng DH, Ren H, Tang XC (1996) Huperzine a, a novel promising acetylcholinesterase inhibitor. NeuroReport 8:97–101
  25. Muthuraju S, Maiti P, Solanki P et al (2010) Cholinesterase inhibitors ameliorate spatial learning deficits in rats following hypobaric hypoxia. Exp Brain Res 203:583–592
  26. Sastre J, Pallardo FV, Vina J (2000) Mitochondrial oxidative stress plays a key role in aging and apoptosis. IUBMB Life 49:427–435
  27. Savitha S, Tamilselvan J, Anusuyadevi M et al (2005) Oxidative stress on mitochondrial antioxidant defense system in the aging process: role of dl-alpha-lipoic acid and l-carnitine. Clin Chim Acta 355:173–180
  28. Schild L, Reinheckel T, Reiser M et al (2003) Nitric oxide produced in rat liver mitochondria causes oxidative stress and impairment of respiration after transient hypoxia. FASEB J 17:2194–2201
  29. Magalhaes J, Ascensao A, Soares JM et al (2005) Acute and severe hypobaric hypoxia increases oxidative stress and impairs mitochondrial function in mouse skeletal muscle. J Appl Physiol 99:1247–1253
  30. Watson BD (1993) Evaluation of the concomitance of lipid peroxidation in experimental models of cerebral ischemia and stroke. Prog Brain Res 96:69–95
  31. Li RC, Row BW, Kheirandish L et al (2004) Nitric oxide synthase and intermittent hypoxia-induced spatial learning deficits in the rat. Neurobiol Dis 17:44–53
  32. Rauchova H, Koudelova J, Drahota Z et al (2002) Hypoxia-induced lipid peroxidation in rat brain and protective effect of carnitine and phosphocreatine. Neurochem Res 27:899–904
  33. Koudelova J, Rauchova H, Vokurkova M (2006) Activity of lactate dehydrogenase in serum and cerebral cortex of immature and mature rats after hypobaric hypoxia. Neurochem Res 31:915–919
  34. Yunoki M, Kawauchi M, Ukita N et al (1998) Effects of lecithinized sod on sequential change in sod activity after cerebral contusion in rats. Acta Neurochir Suppl 71:142–145
  35. Wang R, Tang XC (2005) Neuroprotective effects of huperzine a. A natural cholinesterase inhibitor for the treatment of alzheimer’s disease. Neurosignals 14:71–82
  36. Perry G, Castellani RJ, Hirai K et al (1998) Reactive oxygen species mediate cellular damage in alzheimer disease. J Alzheimers Dis 1:45–55
  37. Titus AD, Shankaranarayana Rao BS, Harsha HN et al (2007) Hypobaric hypoxia-induced dendritic atrophy of hippocampal neurons is associated with cognitive impairment in adult rats. Neuroscience 145:265–278
  38. Ruan YW, Ling GY, Zhang JL et al (2003) Apoptosis in the adult striatum after transient forebrain ischemia and the effects of ischemic severity. Brain Res 982:228–240
  39. Mayer B, Oberbauer R (2003) Mitochondrial regulation of apoptosis. News Physiol Sci 18:89–94
  40. Alnemri ES, Livingston DJ, Nicholson DW et al (1996) Human ice/ced-3 protease nomenclature. Cell 87:171
  41. Thornberry NA, Lazebnik Y (1998) Caspases: enemies within. Science 281:1312–1316
  42. Li P, Nijhawan D, Budihardjo I et al (1997) Cytochrome c and datp-dependent formation of apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479–489
  43. Zhou J, Tang XC (2002) Huperzine a attenuates apoptosis and mitochondria-dependent caspase-3 in rat cortical neurons. FEBS Lett 526:21–25
• 作者单位：1. Clinical Laboratory Diagnostic Center, Urumqi General Hospital of PLA, Urumqi, 830000 Xinjiang, China
• ISSN：1573-6903

文摘

Acute exposure to high altitudes can cause neurological dysfunction due to decreased oxygen availability to the brain. In this study, the protective effects of Huperzine A on cognitive deficits along with oxidative and apoptotic damage, due to acute hypobaric hypoxia, were investigated in male Sprague–Dawley rats. Rats were exposed to simulated hypobaric hypoxia at 6,000 m in a specially fabricated animal decompression chamber while receiving daily Huperzine A orally at the dose of 0.05 or 0.1 mg/kg body weight. After exposure to hypobaric hypoxia for 5 days, rats were trained in a Morris Water Maze for 5 consecutive days. Subsequent trials revealed Huperzine A supplementation at a dose of 0.1 mg/kg body weight restored spatial memory significantly, as evident from decreased escape latency and path length to reach the hidden platform, and the increase in number of times of crossing the former platform location and time spent in the former platform quadrant. In addition, after exposure to hypobaric hypoxia, animals were sacrificed and biomarkers of oxidative damage, such as reactive oxygen species, lipid peroxidation, lactate dehydrogenase activity, reduced glutathione, oxidized glutathione and superoxide dismutase were studied in the hippocampus. Expression levels of pro-apoptotic proteins (Bax, caspase-3) and anti-apoptotic protein (Bcl-2) of hippocampal tissues were evaluated by Western blotting. There was a significant increase in oxidative stress along with increased expression of apoptotic proteins in hypoxia exposed rats, which was significantly improved by oral Huperzine A at 0.1 mg/kg body weight. These results suggest that supplementation with Huperzine A improves cognitive deficits, reduces oxidative stress and inhibits the apoptotic cascade induced by acute hypobaric hypoxia.