Korean J Physiol Pharmacol.  2020 Sep;24(5):423-431. 10.4196/kjpp.2020.24.5.423.

Curcumin targets vascular endothelial growth factor viaactivating the PI3K/Akt signaling pathway and improves brainhypoxic-ischemic injury in neonatal rats

Affiliations
  • 1Department of Otolaryngology Head and Neck Surgery, The Second Hospital of Baoding, Baoding 071000,
  • 2Department of Radiology, Affiliated Hospital of Hebei University, Baoding 071000,
  • 3Department of Obstetrics, Affiliated Hospital of Hebei University, Baoding 071000,
  • 4Department of MR Room, Qingyuan District People’’s Hospital, Baoding 071000, China

Abstract

This study aimed to evaluate the effect of curcumin on brain hypoxicischemic(HI) damage in neonatal rats and whether the phosphoinositide 3-kinase(PI3K)/Akt/vascular endothelial growth factor (VEGF) signaling pathway is involved.Brain HI damage models were established in neonatal rats, which received the followingtreatments: curcumin by intraperitoneal injection before injury, insulin-likegrowth factor 1 (IGF-1) by subcutaneous injection after injury, and VEGF by intracerebroventricularinjection after injury. This was followed by neurological evaluation,hemodynamic measurements, histopathological assessment, TUNEL assay,flow cytometry, and western blotting to assess the expression of p-PI3K, PI3K, p-Akt,Akt, and VEGF. Compared with rats that underwent sham operation, rats with brainHI damage showed remarkably increased neurological deficits, reduced right bloodflow volume, elevated blood viscosity and haematocrit, and aggravated cell damageand apoptosis; these injuries were significantly improved by curcumin pretreatment.Meanwhile, brain HI damage induced the overexpression of p-PI3K, p-Akt, and VEGF,while curcumin pretreatment inhibited the expression of these proteins. In addition,IGF-1 treatment rescued the curcumin-induced down-regulated expression of p-PI3K, p-Akt, and VEGF, and VEGF overexpression counteracted the inhibitory effectof curcumin on brain HI damage. Overall, pretreatment with curcumin protectedagainst brain HI damage by targeting VEGF via the PI3K/Akt signaling pathway inneonatal rats.

Keyword

Brain; Curcumin; Hypoxic-ischemic; PI3K/Akt signaling pathway; Vascular endothelial growth factor

Figure

  • Fig. 1 Curcumin improves brain HI damage in neonatal rats (n = 12 per group). (A) HI damage in brain tissues of the sham, HI, and HI + CUR groups by TUNEL staining. (B) Neurological deficits evaluated in the sham, HI, and HI + CUR groups by Longa’s score at 24 h and 72 h after treatment. (C) Histopathological changes of brain tissues in the sham, HI, and HI + CUR groups by H&E staining (×400). (D) Cell apoptosis in brain tissues of the sham, HI, and HI + CUR groups by TUNEL staining (×400). (E) Early and late apoptotic in brain tissues of the sham, HI, and HI + CUR groups by flow cytometry. HI, hypoxic-ischemic injury; CUR, curcumin. **p < 0.01, ***p < 0.001 vs. sham group; ##p < 0.01 vs. HI group.

  • Fig. 2 Curcumin promotes the activation of PI3K/Akt signaling pathway and VEGF expression in neonatal rats with brain HI damage (n = 12 per group). (A) Band intensities from western blots were calculated. (B) The protein expression of p-PI3K, PI3K, p-Akt, Akt, and VEGF in the sham, HI, and HI + CUR groups by western blotting. HI, hypoxic-ischemic injury; CUR, curcumin; VEGF, vascular endothelial growth factor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. **p < 0.01 vs. sham group; ##p < 0.01 vs. HI group.

  • Fig. 3 Inhibitory effect of curcumin on VEGF expression disappears via activating PI3K/Akt signaling pathway in neonatal rats with brain HI damage (n = 12 per group). (A) Band intensities from western blots were calculated. (B) The protein expression of p-PI3K, PI3K, p-Akt, Akt, and VEGF in the sham, HI, HI + CUR and HI + CUR + IGF-1 groups by western blotting. HI, hypoxic-ischemic injury; CUR, curcumin; IGF-1, insulin-like growth factor 1; VEGF, vascular endothelial growth factor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. **p < 0.01 vs. sham group; ##p < 0.01 vs. HI group.

  • Fig. 4 The inhibitory effect of curcumin on brain HI damage is counteracted by VEGF overexpression in neonatal rats (n = 12 per group). (A) The VEGF expression in the sham, HI, HI + CUR, and HI + CUR + ov-VEGF groups by western blotting. (B) HI damage in brain tissues of the sham, HI, HI + CUR, and HI + CUR + ov-VEGF groups by TUNEL staining. (C) Neurological deficits evaluated in the sham, HI, HI + CUR, and HI + CUR + ov-VEGF groups by Longa’s score at 24 h and 72 h after treatment. (D) Histopathological changes of brain tissues in the sham, HI, HI + CUR, and HI + CUR + ov-VEGF groups by H&E staining (×400). (E) Cell apoptosis in the sham, HI, HI + CUR, and HI + CUR + ov-VEGF groups by TUNEL staining (×400). (F) Early and late apoptotic in brain tissues of the sham, HI, HI + CUR, and HI + CUR + ov-VEGF groups by flow cytometry. HI, hypoxic-ischemic injury; CUR, curcumin; VEGF, vascular endothelial growth factor. **p < 0.01 vs. sham group; ##p < 0.01 vs. HI group.


Reference

1. Douglas-Escobar M, Weiss MD. 2015; Hypoxic-ischemic encephalopathy: a review for the clinician. JAMA Pediatr. 169:397–403. DOI: 10.1001/jamapediatrics.2014.3269. PMID: 25685948.
2. Logitharajah P, Rutherford MA, Cowan FM. 2009; Hypoxic-ischemic encephalopathy in preterm infants: antecedent factors, brain imaging, and outcome. Pediatr Res. 66:222–229. DOI: 10.1203/PDR.0b013e3181a9ef34. PMID: 19390490.
Article
3. Kharoshankaya L, Stevenson NJ, Livingstone V, Murray DM, Murphy BP, Ahearne CE, Boylan GB. 2016; Seizure burden and neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy. Dev Med Child Neurol. 58:1242–1248. DOI: 10.1111/dmcn.13215. PMID: 27595841. PMCID: PMC5214689.
Article
4. Lundgren C, Brudin L, Wanby AS, Blomberg M. 2018; Ante- and intrapartum risk factors for neonatal hypoxic ischemic encephalopathy. J Matern Fetal Neonatal Med. 31:1595–1601. DOI: 10.1080/14767058.2017.1321628. PMID: 28486858.
Article
5. Northington FJ, Chavez-Valdez R, Martin LJ. 2011; Neuronal cell death in neonatal hypoxia-ischemia. Ann Neurol. 69:743–758. DOI: 10.1002/ana.22419. PMID: 21520238. PMCID: PMC4000313.
Article
6. Shankaran S. 2012; Hypoxic-ischemic encephalopathy and novel strategies for neuroprotection. Clin Perinatol. 39:919–929. DOI: 10.1016/j.clp.2012.09.008. PMID: 23164187.
Article
7. Dixon BJ, Reis C, Ho WM, Tang J, Zhang JH. 2015; Neuroprotective strategies after neonatal hypoxic ischemic encephalopathy. Int J Mol Sci. 16:22368–22401. DOI: 10.3390/ijms160922368. PMID: 26389893. PMCID: PMC4613313.
8. Ek CJ, D'Angelo B, Baburamani AA, Lehner C, Leverin AL, Smith PL, Nilsson H, Svedin P, Hagberg H, Mallard C. 2015; Brain barrier properties and cerebral blood flow in neonatal mice exposed to cerebral hypoxia-ischemia. J Cereb Blood Flow Metab. 35:818–827. DOI: 10.1038/jcbfm.2014.255. PMID: 25627141. PMCID: PMC4420855.
Article
9. Storkebaum E, Lambrechts D, Carmeliet P. 2004; VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection. Bioessays. 26:943–954. DOI: 10.1002/bies.20092. PMID: 15351965.
Article
10. Silverman WF, Krum JM, Mani N, Rosenstein JM. 1999; Vascular, glial and neuronal effects of vascular endothelial growth factor in mesencephalic explant cultures. Neuroscience. 90:1529–1541. DOI: 10.1016/S0306-4522(98)00540-5. PMID: 10338318.
Article
11. Guo H, Zhou H, Lu J, Qu Y, Yu D, Tong Y. 2016; Vascular endothelial growth factor: an attractive target in the treatment of hypoxic/ischemic brain injury. Neural Regen Res. 11:174–179. DOI: 10.4103/1673-5374.175067. PMID: 26981109. PMCID: PMC4774214.
Article
12. Howes MR, Fang R, Houghton PJ. 2017; Effect of Chinese herbal medicine on Alzheimer's disease. Int Rev Neurobiol. 135:29–56. DOI: 10.1016/bs.irn.2017.02.003. PMID: 28807163.
Article
13. Ip FC, Zhao YM, Chan KW, Cheng EY, Tong EP, Chandrashekar O, Fu GM, Zhao ZZ, Ip NY. 2016; Neuroprotective effect of a novel Chinese herbal decoction on cultured neurons and cerebral ischemic rats. BMC Complement Altern Med. 16:437. DOI: 10.1186/s12906-016-1417-1. PMID: 27814708. PMCID: PMC5097373.
Article
14. Huang L, Chen C, Zhang X, Li X, Chen Z, Yang C, Liang X, Zhu G, Xu Z. 2018; Neuroprotective effect of curcumin against cerebral ischemia-reperfusion via mediating autophagy and inflammation. J Mol Neurosci. 64:129–139. DOI: 10.1007/s12031-017-1006-x. PMID: 29243061.
Article
15. Cui X, Song H, Su J. 2017; Curcumin attenuates hypoxic-ischemic brain injury in neonatal rats through induction of nuclear factor erythroid-2-related factor 2 and heme oxygenase-1. Exp Ther Med. 14:1512–1518. DOI: 10.3892/etm.2017.4683. PMID: 28781627. PMCID: PMC5526188.
Article
16. Huang Y, Mao Y, Li H, Shen G, Nan G. 2018; Knockdown of Nrf2 inhibits angiogenesis by downregulating VEGF expression through PI3K/Akt signaling pathway in cerebral microvascular endothelial cells under hypoxic conditions. Biochem Cell Biol. 96:475–482. DOI: 10.1139/bcb-2017-0291. PMID: 29373803.
Article
17. Ren X, Ma H, Zuo Z. 2016; Dexmedetomidine postconditioning reduces brain injury after brain hypoxia-ischemia in neonatal rats. J Neuroimmune Pharmacol. 11:238–247. DOI: 10.1007/s11481-016-9658-9. PMID: 26932203.
Article
18. Jiang J, Wang W, Sun YJ, Hu M, Li F, Zhu DY. 2007; Neuroprotective effect of curcumin on focal cerebral ischemic rats by preventing blood-brain barrier damage. Eur J Pharmacol. 561:54–62. DOI: 10.1016/j.ejphar.2006.12.028. PMID: 17303117.
Article
19. Rong Z, Pan R, Chang L, Lee W. 2015; Combination treatment with ethyl pyruvate and IGF-I exerts neuroprotective effects against brain injury in a rat model of neonatal hypoxic-ischemic encephalopathy. Int J Mol Med. 36:195–203. DOI: 10.3892/ijmm.2015.2219. PMID: 25999282. PMCID: PMC4494588.
Article
20. Feng Y, Rhodes PG, Bhatt AJ. 2008; Neuroprotective effects of vascular endothelial growth factor following hypoxic ischemic brain injury in neonatal rats. Pediatr Res. 64:370–374. DOI: 10.1203/PDR.0b013e318180ebe6. PMID: 18535483.
Article
21. Belinga VF, Wu GJ, Yan FL, Limbenga EA. 2016; Splenectomy following MCAO inhibits the TLR4-NF-κB signaling pathway and protects the brain from neurodegeneration in rats. J Neuroimmunol. 293:105–113. DOI: 10.1016/j.jneuroim.2016.03.003. PMID: 27049570.
Article
22. Sundar Dhilip Kumar S, Houreld NN, Abrahamse H. 2018; Therapeutic potential and recent advances of curcumin in the treatment of aging-associated diseases. Molecules. 23:835. DOI: 10.3390/molecules23040835. PMID: 29621160. PMCID: PMC6017430.
Article
23. Yu L, Fan Y, Ye G, Li J, Feng X, Lin K, Dong M, Wang Z. 2015; Curcumin inhibits apoptosis and brain edema induced by hypoxia-hypercapnia brain damage in rat models. Am J Med Sci. 349:521–525. DOI: 10.1097/MAJ.0000000000000457. PMID: 25867253.
Article
24. Wang B, Li W, Jin H, Nie X, Shen H, Li E, Wang W. 2018; Curcumin attenuates chronic intermittent hypoxia-induced brain injuries by inhibiting AQP4 and p38 MAPK pathway. Respir Physiol Neurobiol. 255:50–57. DOI: 10.1016/j.resp.2018.05.006. PMID: 29758366.
Article
25. Joseph A, Wood T, Chen CC, Corry K, Snyder JM, Juul SE, Parikh P, Nance E. 2018; Curcumin-loaded polymeric nanoparticles for neuroprotection in neonatal rats with hypoxic-ischemic encephalopathy. Nano Res. 11:5670–5688. DOI: 10.1007/s12274-018-2104-y.
Article
26. Liu L, Zhang W, Wang L, Li Y, Tan B, Lu X, Deng Y, Zhang Y, Guo X, Mu J, Yu G. 2014; Curcumin prevents cerebral ischemia reperfusion injury via increase of mitochondrial biogenesis. Neurochem Res. 39:1322–1331. DOI: 10.1007/s11064-014-1315-1. PMID: 24777807.
Article
27. Zhu HT, Bian C, Yuan JC, Chu WH, Xiang X, Chen F, Wang CS, Feng H, Lin JK. 2014; Curcumin attenuates acute inflammatory injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway in experimental traumatic brain injury. J Neuroinflammation. 11:59. DOI: 10.1186/1742-2094-11-59. PMID: 24669820. PMCID: PMC3986937.
Article
28. Dore-Duffy P, Wang X, Mehedi A, Kreipke CW, Rafols JA. 2007; Differential expression of capillary VEGF isoforms following traumatic brain injury. Neurol Res. 29:395–403. DOI: 10.1179/016164107X204729. PMID: 17626736.
Article
29. Chaitanya GV, Cromer WE, Parker CP, Couraud PO, Romero IA, Weksler B, Mathis JM, Minagar A, Alexander JS. 2013; A recombinant inhibitory isoform of vascular endothelial growth factor164/165 aggravates ischemic brain damage in a mouse model of focal cerebral ischemia. Am J Pathol. 183:1010–1024. DOI: 10.1016/j.ajpath.2013.06.009. PMID: 23906811.
Article
30. Baburamani AA, Castillo-Melendez M, Walker DW. 2013; VEGF expression and microvascular responses to severe transient hypoxia in the fetal sheep brain. Pediatr Res. 73:310–316. DOI: 10.1038/pr.2012.191. PMID: 23222909.
Article
31. Sköld MK, Risling M, Holmin S. 2006; Inhibition of vascular endothelial growth factor receptor 2 activity in experimental brain contusions aggravates injury outcome and leads to early increased neuronal and glial degeneration. Eur J Neurosci. 23:21–34. DOI: 10.1111/j.1460-9568.2005.04527.x. PMID: 16420412.
Article
32. Gotts JE, Chesselet MF. 2005; Vascular changes in the subventricular zone after distal cortical lesions. Exp Neurol. 194:139–150. DOI: 10.1016/j.expneurol.2005.02.001. PMID: 15899251.
Article
33. Moriyama Y, Takagi N, Hashimura K, Itokawa C, Tanonaka K. 2013; Intravenous injection of neural progenitor cells facilitates angiogenesis after cerebral ischemia. Brain Behav. 3:43–53. DOI: 10.1002/brb3.113. PMID: 23532762. PMCID: PMC3607146.
Article
34. Pan Z, Zhuang J, Ji C, Cai Z, Liao W, Huang Z. 2018; Curcumin inhibits hepatocellular carcinoma growth by targeting VEGF expression. Oncol Lett. 15:4821–4826. DOI: 10.3892/ol.2018.7988. PMID: 29552121. PMCID: PMC5840714.
Article
35. Lu CW, Hao JL, Yao L, Li HJ, Zhou DD. 2017; Efficacy of curcumin in inducing apoptosis and inhibiting the expression of VEGF in human pterygium fibroblasts. Int J Mol Med. 39:1149–1154. DOI: 10.3892/ijmm.2017.2944. PMID: 28393179. PMCID: PMC5403353.
Article
36. Li X, Fang Q, Tian X, Wang X, Ao Q, Hou W, Tong H, Fan J, Bai S. 2017; Curcumin attenuates the development of thoracic aortic aneurysm by inhibiting VEGF expression and inflammation. Mol Med Rep. 16:4455–4462. DOI: 10.3892/mmr.2017.7169. PMID: 28791384. PMCID: PMC5647005.
Article
37. Cardona-Gomez GP, Mendez P, Garcia-Segura LM. 2002; Synergistic interaction of estradiol and insulin-like growth factor-I in the activation of PI3K/Akt signaling in the adult rat hypothalamus. Brain Res Mol Brain Res. 107:80–88. DOI: 10.1016/S0169-328X(02)00449-7.
Article
38. Aberg ND, Brywe KG, Isgaard J. 2006; Aspects of growth hormone and insulin-like growth factor-I related to neuroprotection, regeneration, and functional plasticity in the adult brain. ScientificWorldJournal. 6:53–80. DOI: 10.1100/tsw.2006.22. PMID: 16432628. PMCID: PMC5917186.
39. Guan J, Mathai S, Liang HP, Gunn AJ. 2013; Insulin-like growth factor-1 and its derivatives: potential pharmaceutical application for treating neurological conditions. Recent Pat CNS Drug Discov. 8:142–160. DOI: 10.2174/1574889811308020004. PMID: 23597305.
Article
40. Sun L, Huang T, Xu W, Sun J, Lv Y, Wang Y. 2017; Advanced glycation end products promote VEGF expression and thus choroidal neovascularization via Cyr61-PI3K/AKT signaling pathway. Sci Rep. 7:14925. DOI: 10.1038/s41598-017-14015-6. PMID: 29097668. PMCID: PMC5668426.
Article
41. Ye L, Wang X, Cai C, Zeng S, Bai J, Guo K, Fang M, Hu J, Liu H, Zhu L, Liu F, Wang D, Hu Y, Pan S, Li X, Lin L, Lin Z. 2019; FGF21 promotes functional recovery after hypoxic-ischemic brain injury in neonatal rats by activating the PI3K/Akt signaling pathway via FGFR1/β-klotho. Exp Neurol. 317:34–50. DOI: 10.1016/j.expneurol.2019.02.013. PMID: 30802446.
Article
42. Luo Z, Zhang M, Niu X, Wu D, Tang J. 2019; Inhibition of the PI3K/Akt signaling pathway impedes the restoration of neurological function following hypoxic-ischemic brain damage in a neonatal rabbit model. J Cell Biochem. 120:10175–10185. DOI: 10.1002/jcb.28302. PMID: 30614032.
Article
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