Nitric Oxide Participates in the Brain Ischemic Tolerance Induced by Intermittent Hypobaric Hypoxia in the Hippocampal CA1 Subfield in Rats
Previous studies have shown that intermittent hypobaric hypoxia (IH) preconditioning protected neurons survival from brain ischemia. However, the mechanism remains to be elucidated. The present study explored the role of nitric oxide (NO) in the process by measuring the expression of NO synthase (NOS) and NO levels. Male Wistar rats (100) were randomly assigned into four groups: sham group, IH + sham group, ischemia group and IH + ischemia group. Rats for IH preconditioning were exposed to hypobaric hypoxia mimicking 5000 m high-altitude (PB = 404 mmHg, PO2 = 84 mmHg) 6 h/day, once daily for 28 days. Global brain ischemia was established by four-vessel occlusion that has been created by Pulsinelli. Rats were sacrificed at 7th day after the ischemia for neuropathological evaluation by thionin stain. In addition, the expression of neuronal NOS (nNOS), inducible NOS (iNOS), and NO content in the hippocampal CA1 subfield were measured at 2nd day and 7th day after the ischemia. Results revealed that global brain ischemia engendered delayed neuronal death (DND), both nNOS and iNOS expression up-regulated, and NO content increased in the hippocampal CA1 subfield. IH preconditioning reduced neuronal injury induced by the ischemia, and prevented the up-regulation of NOS expression and NO production. In addition, l-NAME + ischemia group was designed to detect whether depressing NO production could alleviate the DND. Pre-administration of l-NAME alleviated DND induced by the ischemia. These results suggest that IH preconditioning plays a protective role by inhibiting the over expression of NOS and NO content after brain ischemia.
KeywordsIntermittent hypobaric hypoxia Global brain ischemia Nitric oxide synthase Nitric oxide Hippocampal CA1 subfield
Bilateral common carotid arteries
Delayed neuronal death
Intermittent hypobaric hypoxia
Inducible nitric oxide synthase
N-nitro-l-arginine methyl ester
Nitric oxide synthase
Neuronal nitric oxide synthase
The present study was supported by the National Natural Science Foundation of China (Nos. 81771253, 31271149 and 81271454), Natural Science Foundation of Hebei Province, China (No. H2015206492) and College Students’ innovation experiment program (USIP201503A).
Compliance with Ethical Standards
Conflict of interest
We declare no conflicts of interest in this study.
All procedures performed in studies involving animals were in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Laboratory Animal Care of Hebei Medical University.
- 2.Wang J, Zhang S, Ma H, Yang S, Liu Z, Wu X, Wang S, Zhang Y, Liu Y (2017) Chronic intermittent hypobaric hypoxia pretreatment ameliorates ischemia-induced cognitive dysfunction through activation of ERK1/2-creb-bdnf pathway in anesthetized mice. Neurochem Res 42(2):501–512CrossRefPubMedGoogle Scholar
- 10.Shapshak P (2012) Single nucleotide polymorphisms (SNPs) for genome wide association studies (GWAS) and molecule of the month Nitric Oxide Synthase, multiple interactive pathways for three similar genes, Nitric Oxide Synthase-1,-2,-3(NOS-1,-2,-3). Bioinformation 8(11):496–497CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Liu ZJ, Chen C, Li XR, Ran YY, Xu T, Zhang Y, Geng XK, Zhang Y, Du HS, Leak RK, Ji XM, Hu XM (2016) Remote ischemic preconditioning-mediated neuroprotection against stroke is associated with significant alterations in peripheral immune responses. CNS Neurosci Ther 22(1):43–52CrossRefPubMedGoogle Scholar
- 29.Lee KF, Chen JH, Teng CC, Shen CH, Hsieh MC, Lu CC, Lee KC, Lee LY, Chen WP, Chen CC, Huang WS, Kuo HC (2014) Protective effects of Hericium erinaceus mycelium and its isolated erinacine a against ischemia-injury-induced neuronal cell death via the inhibition of iNOS/p38 MAPK and nitrotyrosine. Int J Mol Sci 15(9):15073–15089CrossRefPubMedPubMedCentralGoogle Scholar
- 34.Zhang M, Gong JX, Wang JL, Jiang MY, Li L, Hu YY, Qi J, Zhang LY, Zhao H, Cui X, Xian XH, Li WB (2017) p38 MAPK participates in the mediation of GLT-1 up-regulation during the induction of brain ischemic tolerance by cerebral ischemic preconditioning. Mol Neurobiol 54(1):58–71CrossRefPubMedGoogle Scholar
- 37.Zeng WX, Han YL, Zhu GF, Huang LQ, Deng YY, Wang QS, Jiang WQ, Wen MY, Han QP, Xie D, Zeng HK (2017) Hypertonic saline attenuates expression of notch signaling and proinflammatory mediators in activated microglia in experimentally induced cerebral ischemia and hypoxic bv-2 microglia. BMC Neurosci 18(1):32CrossRefPubMedPubMedCentralGoogle Scholar
- 49.Shi Q, Liu X, Wang N, Zheng X, Ran J, Liu Z, Fu J, Zheng J (2017) 1400W ameliorates acute hypobaric hypoxia/reoxygenation-induced cognitive deficits by suppressing the induction of inducible nitric oxide synthase in rat cerebral cortex microglia. Behav Brain Res 319:188–199CrossRefPubMedGoogle Scholar
- 50.Balez R, Ooi L (2015) Getting to no Alzheimer’s disease: neuroprotection versus neurotoxicity mediated by nitric oxide. Oxid Med Cell Longev 2016(4):1–8Google Scholar