DL-3-n-butylphthalide improved physical and learning and memory performance of rodents exposed to acute and chronic hypobaric hypoxia

Gang Xu; Yi-Kun Shi; Bin-Da Sun; Lu Liu; Guo-Ji E; Shu He; Jian-Yang Zhang; Bao Liu; Qiu Hu; Jian Chen; Yu-Qi Gao; Er-Long Zhang

doi:10.1186/s40779-021-00314-7

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DL-3-n-butylphthalide improved physical and learning and memory performance of rodents exposed to acute and chronic hypobaric hypoxia

RESEARCH | Updated：2023-02-28

- DL-3-n-butylphthalide improved physical and learning and memory performance of rodents exposed to acute and chronic hypobaric hypoxia
- Military Medical Research Vol. 9, Issue 1, Pages: 1-11(2022)
- Affiliations：
  
  1.Institute of Medicine and Equipment for High Altitude Region, College of High Altitude Military Medicine, Army Medical University, Number 30, Gaotanyan Street, District of Shapingba, Chongqing 400038, China
  2.Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Chongqing 400038, China
  3.Key Laboratory of High Altitude Medicine, People’s Liberation Army, Chongqing 400038, China
- Author bio：
  
  * gaoy66@yahoo.com;
  loong0810@sina.com
- Funds：
- DOI：10.1186/s40779-021-00314-7
  CLC：
- Published：2022-02
- Accepted：
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Xu et al.: DL-3-n-butylphthalide improved physical and learning and memory performance of rodents exposed to acute and chronic hypobaric hypoxia. Mil Med Res, 2021, 8: 23.
DOI：

Xu et al.: DL-3-n-butylphthalide improved physical and learning and memory performance of rodents exposed to acute and chronic hypobaric hypoxia. Mil Med Res, 2021, 8: 23. DOI： 10.1186/s40779-021-00314-7.

摘要

Abstract

Background:

Studies have revealed the protective effect of DL-3-n-butylphthalide (NBP) against diseases associated with ischemic hypoxia. However

the role of NBP in animals with hypobaric hypoxia has not been elucidated. This study investigated the effects of NBP on rodents with acute and chronic hypobaric hypoxia.

Methods:

Sprague-Dwaley rats and Kunming mice administered with NBP (0

120

and 240 mg/kg for rats and 0

180

and 360 mg/kg for mice) were placed in a hypobaric hypoxia chamber at 10

000 m and the survival percentages at 30 min were determined. Then

the time and distance to exhaustion of drug-treated rodents were evaluated during treadmill running and motor-driven wheel-track treadmill experiments

conducted at 5800 m for 3 days or 20 days

to evaluate changes in physical functions. The frequency of active escapes and duration of active escapes were also determined for rats in a shuttle-box experiment

conducted at 5800 m for 6 days or 27 days

to evaluate changes in learning and memory function. ATP levels were measured in the gastrocnemius muscle and malonaldehyde (MDA)

superoxide dismutase (SOD)

hydrogen peroxide (H

)

glutathione peroxidase (GSH-Px)

and lactate were detected in sera of rats

and routine blood tests were also performed.

Results:

Survival analysis at 10

000 m indicated NBP could improve hypoxia tolerance ability. The time and distance to exhaustion for mice (NBP

90 mg/kg) and time to exhaustion for rats (NBP

120 and 240 mg/kg) significantly increased under conditions of acute hypoxia compared with control group. NBP treatment also significantly increased the time to exhaustion for rats when exposed to chronic hypoxia. Moreover

240 mg/kg NBP significantly increased the frequency of active escapes under conditions of acute hypoxia. Furthermore

the levels of MDA and H

decreased but those of SOD and GSH-Px in the sera of rats increased under conditions of acute and chronic hypoxia. Additionally

ATP levels in the gastrocnemius muscle significantly increased

while lactate levels in sera significantly decreased.

Conclusion:

NBP improved physical and learning and memory functions in rodents exposed to acute or chronic hypobaric hypoxia by increasing their anti-oxidative capacity and energy supply.

关键词

Keywords

references

Yan X . Cognitive impairments at high altitudes and adaptation . High Alt Med Biol . 2014 ; 15 ( 2 ): 141 - 5 . https://doi.org/10.1089/ham.2014.1009 https://doi.org/10.1089/ham.2014.1009 .

Zhang G , Zhou SM , Zheng SJ , Liu FY , Gao YQ . Astragalus on the anti-fatigue effect in hypoxic mice . Int J Clin Exp Med . 2015 ; 8 ( 8 ): 14030 - 5 .

Lague SL . High-altitude champions: birds that live and migrate at altitude . J Appl Physiol . 2017 ; 123 ( 4 ): 942 - 50 . https://doi.org/10.1152/japplphysiol.00110.2017 https://doi.org/10.1152/japplphysiol.00110.2017 .

Naeije R . Physiological adaptation of the cardiovascular system to high altitude . Prog Cardiovasc Dis . 2010 ; 52 ( 6 ): 456 - 66 . https://doi.org/10.1016/j.pcad.2010.03.004 https://doi.org/10.1016/j.pcad.2010.03.004 .

Taylor AT . High-altitude illnesses: physiology, risk factors, prevention, and treatment . Rambam Maimonides Med J . 2011 ; 2 ( 1 ): e0022 . https://doi.org/10.5041/RMMJ.10022 https://doi.org/10.5041/RMMJ.10022 .

Basnyat B , Murdoch DR . High-altitude illness . Lancet . 2003 ; 361 ( 9373 ): 1967 - 74 . https://doi.org/10.1016/S0140-6736(03)13591-X https://doi.org/10.1016/S0140-6736(03)13591-X .

Liu B , Chen J , Zhang L , Gao Y , Cui J , Zhang E , et al . IL-10 dysregulation in acute mountain sickness revealed by transcriptome analysis . Front Immunol . 2017 ; 8 : 628 . https://doi.org/10.3389/fimmu.2017.00628 https://doi.org/10.3389/fimmu.2017.00628 .

Liao WT , Liu B , Chen J , Cui JH , Gao YX , Liu FY , et al . Metabolite modulation in human plasma in the early phase of acclimatization to hypobaric hypoxia . Sci Rep . 2016 ; 6 ( 1 ): 22589 . https://doi.org/10.1038/srep22589 https://doi.org/10.1038/srep22589 .

Dosek A , Ohno H , Acs Z , Taylor AW , Radak Z . High altitude and oxidative stress . Respir Physiol Neurobiol . 2007 ; 158 ( 2–3 ): 128 - 31 . https://doi.org/10.1016/j.resp.2007.03.013 https://doi.org/10.1016/j.resp.2007.03.013 .

Liu CL , Liao SJ , Zeng JS , Lin JW , Li CX , Xie LC , et al . DL-3-n-butylphthalide prevents stroke via improvement of cerebral microvessels in RHRSP . J Neurol Sci . 2007 ; 260 ( 1–2 ): 106 - 13 . https://doi.org/10.1016/j.jns.2007.04.025 https://doi.org/10.1016/j.jns.2007.04.025 .

Wang S , Ma F , Huang L , Zhang Y , Peng Y , Xing C , et al . DL-3-n-Butylphthalide (NBP): a promising therapeutic agent for ischemic stroke . CNS Neurol Disord Drug Targets . 2018 ; 17 ( 5 ): 338 - 47 . https://doi.org/10.2174/1871527317666180612125843 https://doi.org/10.2174/1871527317666180612125843 .

Niu XL , Jiang X , Xu GD , Zheng GM , Tang ZP , Yin N , et al . DL-3-n-butylphthalide alleviates vascular cognitive impairment by regulating endoplasmic reticulum stress and the Shh/Ptch1 signaling-pathway in rats . J Cell Physiol . 2019 ; 234 ( 8 ): 12604 - 14 . https://doi.org/10.1002/jcp.27332 https://doi.org/10.1002/jcp.27332 .

Sun Y , Cheng X , Wang H , Mu X , Liang Y , Luo Y , et al . DL-3-n-butylphthalide promotes neuroplasticity and motor recovery in stroke rats . Behav Brain Res . 2017 ; 329 : 67 - 74 . https://doi.org/10.1016/j.bbr.2017.04.039 https://doi.org/10.1016/j.bbr.2017.04.039 .

Min JJ , Huo XL , Xiang LY , Qin YQ , Chai KQ , Wu B , et al . Protective effect of DL-3-n-butylphthalide on learning and memory impairment induced by chronic intermittent hypoxia-hypercapnia exposure . Sci Rep . 2014 ; 4 : 5555 .

Lu G , Ding D , Shi M . Acute adaptation of mice to hypoxic hypoxia . Biol Signals Recept . 1999 ; 8 ( 4–5 ): 247 - 55 . https://doi.org/10.1159/000014594 https://doi.org/10.1159/000014594 .

Xu G , Gao YQ , Gao YX , Wu G , Zhang JY , Gao WX . An improved formula for standard hypoxia tolerance time (STT) to evaluate hypoxic tolerance in mice . Mil Med Res . 2018 ; 5 ( 1 ): 33 . https://doi.org/10.1186/s40779-018-0180-7 https://doi.org/10.1186/s40779-018-0180-7 .

Wang CC , Ding L , Zhang LY , Shi HH , Xue CH , Chi NQ , et al . A pilot study on the effects of DHA/EPA-enriched phospholipids on aerobic and anaerobic exercises in mice . Food Funct . 2020 ; 11 ( 2 ): 1441 - 54 . https://doi.org/10.1039/C9FO02489A https://doi.org/10.1039/C9FO02489A .

Zaretsky DV , Kline H , Zaretskaia MV , Rusyniak DE . Automatic analysis of treadmill running to estimate times to fatigue and exhaustion in rodents . PeerJ . 2018 ; 6 : e5017 . https://doi.org/10.7717/peerj.5017 https://doi.org/10.7717/peerj.5017 .

Hou X , Xu H , Chen W , Zhang N , Zhao Z , Fang X , et al . Neuroprotective effect of dimethyl fumarate on cognitive impairment induced by ischemic stroke . Ann Transl Med . 2020 ; 8 ( 6 ): 375 . https://doi.org/10.21037/atm.2020.02.10 https://doi.org/10.21037/atm.2020.02.10 .

Irarrazaval S , Allard C , Campodonico J , Perez D , Strobel P , Vasquez L , et al . Oxidative stress in acute hypobaric hypoxia . High Alt Med Biol . 2017 ; 18 ( 2 ): 128 - 34 . https://doi.org/10.1089/ham.2016.0119 https://doi.org/10.1089/ham.2016.0119 .

Murray AJ . Energy metabolism and the high-altitude environment . Exp Physiol . 2016 ; 101 ( 1 ): 23 - 7 . https://doi.org/10.1113/EP085317 https://doi.org/10.1113/EP085317 .

Murray AJ , Montgomery HE , Feelisch M , Grocott MPW , Martin DS . Metabolic adjustment to high-altitude hypoxia: from genetic signals to physiological implications . Biochem Soc Trans . 2018 ; 46 ( 3 ): 599 - 607 . https://doi.org/10.1042/BST20170502 https://doi.org/10.1042/BST20170502 .

Bailey DM , Brugniaux JV , Filipponi T , Marley CJ , Stacey B , Soria R , et al . Exaggerated systemic oxidativeinflammatory-nitrosative stress in chronic mountain sickness is associated with cognitive decline and depression . J Physiol . 2019 ; 597 ( 2 ): 611 - 29 . https://doi.org/10.1113/JP276898 https://doi.org/10.1113/JP276898 .

Lefranois R , Gautier H , Pasquis P . Ventilatory oxygen drive in acute and chronic hypoxia . Respir Physiol . 1968 ; 4 ( 2 ): 217 - 28 . https://doi.org/10.1016/0034-5687(68)90053-4 https://doi.org/10.1016/0034-5687(68)90053-4 .

Bartsch P , Swenson ER . Clinical practice: acute high-altitude illnesses . N Engl J Med . 2013 ; 368 ( 24 ): 2294 - 302 . https://doi.org/10.1056/NEJMcp1214870 https://doi.org/10.1056/NEJMcp1214870 .

West JB . Physiological effects of chronic hypoxia . N Engl J Med . 2017 ; 376 ( 20 ): 1965 - 71 . https://doi.org/10.1056/NEJMra1612008 https://doi.org/10.1056/NEJMra1612008 .

Mazzeo RS , Bender PR , Brooks GA , Butterfield GE , Groves BM , Sutton JR , et al . Arterial catecholamine responses during exercise with acute and chronic high-altitude exposure . Am J Phys . 1991 ; 261 ( 4 Pt 1 ): E419 - 24 .

Smith SM , Friedle SA , Watters JJ . Chronic intermittent hypoxia exerts CNS region-specific effects on rat microglial inflammatory and TLR4 gene expression . PLoS One . 2013 ; 8 ( 12 ): e81584 . https://doi.org/10.1371/journal.pone.0081584 https://doi.org/10.1371/journal.pone.0081584 .

Macri MA , Dalessandro N , Di Giulio C , Di Iorio P , Di Luzio S , Giuliani P , et al . Region-specific effects on brain metabolites of hypoxia and hyperoxia overlaid on cerebral ischemia in young and old rats: a quantitative proton magnetic resonance spectroscopy study . J Biomed Sci . 2010 ; 17 ( 1 ): 14 . https://doi.org/10.1186/1423-0127-17-14 https://doi.org/10.1186/1423-0127-17-14 .

Zhu M , Xu M , Zhang K , Li J , Ma H , Xia G , et al . Effect of acute exposure to hypobaric hypoxia on learning and memory in adult Sprague-Dawley rats . Behav Brain Res . 2019 ; 367 : 82 - 90 . https://doi.org/10.1016/j.bbr.2019.03.047 https://doi.org/10.1016/j.bbr.2019.03.047 .

Qaid E , Zakaria R , Sulaiman SF , Yusof NM , Shafin N , Othman Z , et al . Insight into potential mechanisms of hypobaric hypoxia-induced learning and memory deficit - lessons from rat studies . Hum Exp Toxicol . 2017 ; 36 ( 12 ): 1315 - 25 . https://doi.org/10.1177/0960327116689714 https://doi.org/10.1177/0960327116689714 .

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