Morphological Changes of Cortical and Hippocampal Neurons After Treatment with VEGF and Bevacizumab

Overview

Journal CNS Neurosci Ther

Specialties Neurology
Pharmacology

Date 2016 Feb 11

PMID 26861512

Citations 9

Authors

Pauline Latzer

Uwe Schlegel

Carsten Theiss

Affiliations

Soon will be listed here.

Abstract

Aims: Vascular endothelial growth factor (VEGF) is a hallmark of glioblastoma multiforme (GBM) and plays an important role in brain development and function. Recently, it has been reported that treatment of GBM patients with bevacizumab, an anti-VEGF antibody, may cause a decline in neurocognitive function and compromise quality of life. Therefore, we investigated the effects of VEGF and bevacizumab on the morphology and on survival of neurons and glial cells.

Methods: Dissociated cortical and hippocampal cell cultures of juvenile rats were treated with VEGF, bevacizumab, and VEGF + bevacizumab. Neuronal and glial cell viability was analyzed, and the morphology of neurons was objectified by morphometric analysis.

Results: In cortical cultures, bevacizumab significantly decreased the number of neurons after 20 days and the number of glial cells subsequent 30 days. Additionally, an increase in the dendritic length of cortical neurons was obvious after 10 days of incubation with bevacizumab, but returned to control level after 30 days. In hippocampal cultures, cell viability was not affected by bevacizumab; however, dendritic length increased at day 10, but decreased after long-term treatment.

Conclusion: Therefore, bevacizumab obviously has a cytotoxic effect in cortical cultures and decreases the dendritic length in hippocampal neurons after long-term treatment.

Citing Articles

Beyond vessels: unraveling the impact of VEGFs on neuronal functions and structure.

Aksan B, Mauceri D J Biomed Sci. 2025; 32(1):33.

PMID: 40050849 PMC: 11884128. DOI: 10.1186/s12929-025-01128-8.

Hippocampus-Avoidance Whole-Brain Radiation Therapy Is Efficient in the Long-Term Preservation of Hippocampal Volume.

Popp I, Rau A, Kellner E, Reisert M, Fennell J, Rothe T Front Oncol. 2021; 11:714709.

PMID: 34490112 PMC: 8417356. DOI: 10.3389/fonc.2021.714709.

Update on Chemotherapeutic Approaches and Management of Bevacizumab Usage for Glioblastoma.

Funakoshi Y, Hata N, Kuga D, Hatae R, Sangatsuda Y, Fujioka Y Pharmaceuticals (Basel). 2020; 13(12).

PMID: 33339404 PMC: 7766528. DOI: 10.3390/ph13120470.

Expression and Significance of MicroRNA155 in Serum of Patients with Cerebral Small Vessel Disease.

Guo Y, Li D, Li J, Yang N, Wang D J Korean Neurosurg Soc. 2020; 63(4):463-469.

PMID: 32156102 PMC: 7365280. DOI: 10.3340/jkns.2019.0179.

Mitochondrial-associated impairments of temozolomide on neural stem/progenitor cells and hippocampal neurons.

Lomeli N, Di K, Pearre D, Chung T, Bota D Mitochondrion. 2020; 52:56-66.

PMID: 32045717 PMC: 7415494. DOI: 10.1016/j.mito.2020.02.001.

References

Stupp R, Hegi M, Mason W, van den Bent M, Taphoorn M, Janzer R . Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009; 10(5):459-66. DOI: 10.1016/S1470-2045(09)70025-7. View

Gilbert M, Dignam J, Armstrong T, Wefel J, Blumenthal D, Vogelbaum M . A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014; 370(8):699-708. PMC: 4201043. DOI: 10.1056/NEJMoa1308573. View

Soker S, Takashima S, Miao H, Neufeld G, Klagsbrun M . Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell. 1998; 92(6):735-45. DOI: 10.1016/s0092-8674(00)81402-6. View

Hohman T, Bell S, Jefferson A . The role of vascular endothelial growth factor in neurodegeneration and cognitive decline: exploring interactions with biomarkers of Alzheimer disease. JAMA Neurol. 2015; 72(5):520-9. PMC: 4428948. DOI: 10.1001/jamaneurol.2014.4761. View

Hao T, Rockwell P . Signaling through the vascular endothelial growth factor receptor VEGFR-2 protects hippocampal neurons from mitochondrial dysfunction and oxidative stress. Free Radic Biol Med. 2013; 63:421-31. PMC: 3756493. DOI: 10.1016/j.freeradbiomed.2013.05.036. View

Romano M, Biagioni F, Besozzi G, Carrizzo A, Vecchione C, Fornai F . Effects of bevacizumab on neuronal viability of retinal ganglion cells in rats. Brain Res. 2012; 1478:55-63. DOI: 10.1016/j.brainres.2012.08.014. View

Cariboni A, Hickok J, Rakic S, Andrews W, Maggi R, Tischkau S . Neuropilins and their ligands are important in the migration of gonadotropin-releasing hormone neurons. J Neurosci. 2007; 27(9):2387-95. PMC: 6673474. DOI: 10.1523/JNEUROSCI.5075-06.2007. View

Taiana M, Lombardi R, Porretta-Serapiglia C, Ciusani E, Oggioni N, Sassone J . Neutralization of schwann cell-secreted VEGF is protective to in vitro and in vivo experimental diabetic neuropathy. PLoS One. 2014; 9(9):e108403. PMC: 4182455. DOI: 10.1371/journal.pone.0108403. View

Lamalice L, Houle F, Jourdan G, Huot J . Phosphorylation of tyrosine 1214 on VEGFR2 is required for VEGF-induced activation of Cdc42 upstream of SAPK2/p38. Oncogene. 2004; 23(2):434-45. DOI: 10.1038/sj.onc.1207034. View

10.

Gerber H, McMurtrey A, Kowalski J, Yan M, Keyt B, Dixit V . Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem. 1998; 273(46):30336-43. DOI: 10.1074/jbc.273.46.30336. View

11.

Kreisl T, Kim L, Moore K, Duic P, Royce C, Stroud I . Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2008; 27(5):740-5. PMC: 2645088. DOI: 10.1200/JCO.2008.16.3055. View

12.

Oosthuyse B, Moons L, Storkebaum E, Beck H, Nuyens D, Brusselmans K . Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet. 2001; 28(2):131-8. DOI: 10.1038/88842. View

13.

Jin K, Mao X, Greenberg D . Vascular endothelial growth factor stimulates neurite outgrowth from cerebral cortical neurons via Rho kinase signaling. J Neurobiol. 2005; 66(3):236-42. DOI: 10.1002/neu.20215. View

14.

Lefebvre J, Sanes J, Kay J . Development of dendritic form and function. Annu Rev Cell Dev Biol. 2015; 31:741-77. DOI: 10.1146/annurev-cellbio-100913-013020. View

15.

Licht T, Goshen I, Avital A, Kreisel T, Zubedat S, Eavri R . Reversible modulations of neuronal plasticity by VEGF. Proc Natl Acad Sci U S A. 2011; 108(12):5081-6. PMC: 3064368. DOI: 10.1073/pnas.1007640108. View

16.

Pan Z, Fukuoka S, Karagianni N, Guaiquil V, Rosenblatt M . Vascular endothelial growth factor promotes anatomical and functional recovery of injured peripheral nerves in the avascular cornea. FASEB J. 2013; 27(7):2756-67. PMC: 3688738. DOI: 10.1096/fj.12-225185. View

17.

Kim B, Choi M, Kim Y, Park H, Lee H, Yun C . Vascular endothelial growth factor (VEGF) signaling regulates hippocampal neurons by elevation of intracellular calcium and activation of calcium/calmodulin protein kinase II and mammalian target of rapamycin. Cell Signal. 2008; 20(4):714-25. DOI: 10.1016/j.cellsig.2007.12.009. View

18.

Chinot O, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R . Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014; 370(8):709-22. DOI: 10.1056/NEJMoa1308345. View

19.

Fournier N, Lee B, Banasr M, Elsayed M, Duman R . Vascular endothelial growth factor regulates adult hippocampal cell proliferation through MEK/ERK- and PI3K/Akt-dependent signaling. Neuropharmacology. 2012; 63(4):642-52. PMC: 3392414. DOI: 10.1016/j.neuropharm.2012.04.033. View

20.

Cvetanovic M, Patel J, Marti H, Kini A, Opal P . Vascular endothelial growth factor ameliorates the ataxic phenotype in a mouse model of spinocerebellar ataxia type 1. Nat Med. 2011; 17(11):1445-7. PMC: 3287040. DOI: 10.1038/nm.2494. View