Castañeda-Cabral José Luis, Orozco-Suárez Sandra A, Beas-Zárate Carlos, Fajardo-Fregoso Blanca F, Flores-Soto Mario E, Ureña-Guerrero Mónica E
Departamento de Biología Celular y Molecular, Centro Universitario de Ciencias Biológicas y Agropecuarias (CUCBA), Universidad de Guadalajara, Zapopan, Jalisco, México.
Unidad de Investigación Médica en Enfermedades Neurológicas, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Ciudad de México, México.
J Biochem Mol Toxicol. 2023 May;37(5):e23315. doi: 10.1002/jbt.23315. Epub 2023 Feb 2.
Vascular endothelial growth factor (VEGF) exerts neuroprotective or proinflammatory effects, depending on what VEGF forms (A-E), receptor types (VEGFR1-3), and intracellular signaling pathways are involved. Neonatal monosodium glutamate (MSG) treatment triggers neuronal death by excitotoxicity, which is commonly involved in different neurological disorders, including neurodegenerative diseases. This study was designed to evaluate the effects of VEGFR-2 inhibition on neuronal damage triggered by excitotoxicity in the cerebral motor cortex (CMC) and hippocampus (Hp) after neonatal MSG treatment. MSG was administered at a dose of 4 g/kg of body weight (b.w.) subcutaneously on postnatal days (PD) 1, 3, 5, and 7, whereas the VEGFR-2 inhibitor SU5416 was administered at a dose of 10 mg/kg b.w. subcutaneously on PD 5 and 7, 30 min before the MSG treatment. Neuronal damage was assessed using hematoxylin and eosin staining, fluoro-Jade staining, and TUNEL assay. Additionally, western blot assays for some proteins of the VEGF-A/VEGFR-2 signaling pathway (VEGF-A, VEGFR-2, PI3K, Akt, and iNOS) were carried out. All assays were performed on PD 6, 8, 10, and 14. Inhibition of VEGFR-2 signaling by SU5416 increases the neuronal damage induced by neonatal MSG treatment in both the CMC and Hp. Moreover, neonatal MSG treatment increased the expression levels of the studied VEGF-A/VEGFR-2 signaling pathway proteins, particularly in the CMC. We conclude that VEGF-A/VEGFR-2 signaling pathway activation could be part of the neuroprotective mechanisms that attempt to compensate for neuronal damage induced by neonatal MSG treatment and possibly also in other conditions involving excitotoxicity.
血管内皮生长因子（VEGF）发挥神经保护或促炎作用，这取决于所涉及的VEGF形式（A - E）、受体类型（VEGFR1 - 3）以及细胞内信号通路。新生大鼠谷氨酸单钠（MSG）处理通过兴奋性毒性引发神经元死亡，兴奋性毒性通常与包括神经退行性疾病在内的不同神经系统疾病有关。本研究旨在评估VEGFR - 2抑制对新生大鼠MSG处理后大脑运动皮层（CMC）和海马体（Hp）中兴奋性毒性引发的神经元损伤的影响。在出生后第1、3、5和7天，以4 g/kg体重（b.w.）的剂量皮下注射MSG，而在出生后第5和7天，在MSG处理前30分钟，以10 mg/kg b.w.的剂量皮下注射VEGFR - 2抑制剂SU5416。使用苏木精和伊红染色、荧光金染色和TUNEL测定法评估神经元损伤。此外，还对VEGF - A/VEGFR - 2信号通路的一些蛋白质（VEGF - A、VEGFR - 2、PI3K、Akt和iNOS）进行了蛋白质印迹分析。所有测定均在出生后第6、8、10和14天进行。SU5416对VEGFR - 2信号的抑制增加了新生大鼠MSG处理在CMC和Hp中诱导的神经元损伤。此外，新生大鼠MSG处理增加了所研究的VEGF - A/VEGFR - 2信号通路蛋白质的表达水平，特别是在CMC中。我们得出结论，VEGF - A/VEGFR - 2信号通路的激活可能是试图补偿新生大鼠MSG处理诱导的神经元损伤以及可能在其他涉及兴奋性毒性的情况下的神经保护机制的一部分。
