Isoflurane-Induced Postoperative Neurovascular and Cognitive Dysfunction Is Associated with VEGF Overexpression in Aged Rats
Postoperative cognitive dysfunction (POCD) is a common complication in older adults; however, its aetiology remains unclear. Although vascular endothelial growth factor (VEGF) is associated with blood–brain barrier (BBB) disorders and neurological disease, its role in POCD is unknown. Here, we investigated the effect of brain VEGF inhibition on isoflurane-induced cognitive impairment in an aged rat model of POCD. VEGF protein expression was increased in the hippocampus after isoflurane exposure, suggesting that inhalation anaesthesia induces hippocampal VEGF protein overexpression in aged rats. Pretreatment with 2 mg/kg RB-222, an anti-VEGF neutralizing antibody, may partially abolish the degradation of occludin protein in cerebral capillaries, thereby maintaining the ultrastructural and functional integrity of the hippocampal BBB. Inhibition of VEGF also significantly attenuated the isoflurane-induced cognitive deficits in the Morris water maze task. Together, our findings show, for the first time, that elevated expression of brain VEGF after isoflurane exposure contributes to POCD in aged rats. Therefore, therapeutic strategies involving VEGF should take into consideration its role in the pathogenesis of POCD.
KeywordsIsoflurane Postoperative cognitive dysfunction Vascular endothelial growth factor Blood–brain barrier
YYC and XYG conceived and designed the experiments; YYC, ZQL and NY performed the experiments; YYC and ZQL analysed the data; YYC and XYG wrote the paper. All authors read and approved the final manuscript.
This work was supported by grants from the National Natural Science Foundation of China (Nos. 81600933), Shanghai Pudong New District Science and Technology Development Fund Medical and Health Project of China (No. PKJ2018-Y56), and the Hundred Faculty Talent Pool Program at Shanghai University of Medicine & Health Sciences in China.
Compliance with Ethical Standards
Ethics Approval and Consent to Participate
Our research was performed with the approval of the Peking University Biomedical Ethics Committee Experimental Animal Ethics Branch (Approval No. 20150041).
Consent for Publication
All named authors have given consent for publication.
The authors declare that they have no competing interests.
- Cao Y, Ni C, Li Z, Li L, Liu Y, Wang C et al (2015) Isoflurane anesthesia results in reversible ultrastructure and occludin tight junction protein expression changes in hippocampal blood-brain barrier in aged rats. Neurosci Lett 587:51–56. https://doi.org/10.1016/j.neulet.2014.12.018 CrossRefGoogle Scholar
- Gruber BL, Marchese MJ, Kew R (1995) Angiogenic factors stimulate mast-cell migration. Blood 86(7):2488–2493Google Scholar
- Kimura R, Nakase H, Tamaki R, Sakaki T (2005) Vascular endothelial growth factor antagonist reduces brain edema formation and venous infarction. Stroke 36(6):1259–1263. https://doi.org/10.1161/01.STR.0000165925.20413.14 CrossRefGoogle Scholar
- Li ZQ, Rong XY, Liu YJ, Ni C, Tian XS, Mo N et al (2013) Activation of the canonical nuclear factor-kappaB pathway is involved in isoflurane-induced hippocampal interleukin-1beta elevation and the resultant cognitive deficits in aged rats. Biochem Biophys Res Commun 438(4):628–634. https://doi.org/10.1016/j.bbrc.2013.08.003 CrossRefGoogle Scholar
- Liu ZG, Xia ZY, Chen XD, Luo T (2010) Isoflurane induces expression of vascular endothelial growth factor through activating protein kinase C in myocardial cells. Chin J Traumatol 13(5):284–288Google Scholar
- Monk TG, Weldon BC, Garvan CW, Dede DE, van der Aa MT, Heilman KM, Gravenstein JS (2008) Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology 108(1):18–30. https://doi.org/10.1097/01.anes.0000296071.19434.1e CrossRefGoogle Scholar
- Ni C, Tan G, Luo A, Qian M, Tang Y, Zhou Y et al (2013) Melatonin premedication attenuates isoflurane anesthesia-induced beta-amyloid generation and cholinergic dysfunction in the hippocampus of aged rats. Int J Neurosci 123(4):213–220. https://doi.org/10.3109/00207454.2012.742895 CrossRefGoogle Scholar
- Takahashi T, Fujimura M, Koyama M, Kanazawa M, Usuki F, Nishizawa M, Shimohata T (2017) Methylmercury causes blood-brain barrier damage in rats via upregulation of vascular endothelial growth factor expression. PLoS One 12(1):e0170623. https://doi.org/10.1371/journal.pone.0170623 CrossRefGoogle Scholar
- Wu, X., Lu, Y., Dong, Y., Zhang, G., Zhang, Y., Xu, Z., . . . Xie, Z. (2012). The inhalation anesthetic isoflurane increases levels of proinflammatory TNF-alpha, IL-6, and IL-1beta. Neurobiol Aging, 33(7), 1364–1378. https://doi.org/10.1016/j.neurobiolaging.2010.11.002 CrossRefGoogle Scholar