Glutamate Neonatal Excitotoxicity Modifies VEGF-A, VEGF-B, VEGFR-1 and VEGFR-2 Protein Expression Profiles During Postnatal Development of the Cerebral Cortex and Hippocampus of Male Rats

Castañeda‐Cabral, José Luis; Beas‐Zárate, Carlos; Gudiño-Cabrera, Graciela; Ureña‐Guerrero, Mónica E.

doi:10.1007/s12031-017-0952-7

Cited by 14 publications

(20 citation statements)

References 60 publications

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“…The delivery of VEGF directly or through viral vectors using different routes (intramuscular, intracerebroventricular, intrathecal or into the spinal cord parenchyma) considerably reduces the symptoms of the disease in murine models of ALS ( Azzouz et al, 2004 ; Storkebaum et al, 2005 ; Dodge et al, 2010 ; Wang et al, 2016 ) and also protects motoneurons from excitotoxic-induced cell death ( Tovar-y-Romo et al, 2007 ; Tovar-y-Romo and Tapia, 2010 ). In this respect, an increase in VEGF and its main receptor (VEGFR-2) has also been described in cerebral motor cortex and hippocampus of postnatal rats following glutamate excitotoxic treatment, which could contribute to neuroprotection mechanisms ( Castañeda-Cabral et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Vascular Endothelial Growth Factor (VEGF) Prevents the Downregulation of the Cholinergic Phenotype in Axotomized Motoneurons of the Adult Rat

Acosta¹,

Morcuende²,

Silva-Hucha³

et al. 2018

Front. Mol. Neurosci.

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Vascular endothelial growth factor (VEGF) was initially characterized by its activity on the vascular system. However, there is growing evidence indicating that VEGF also acts as a neuroprotective factor, and that its administration to neurons suffering from trauma or disease is able to rescue them from cell death. We questioned whether VEGF could also maintain damaged neurons in a neurotransmissive mode by evaluating the synthesis of their neurotransmitter, and whether its action would be direct or through its well-known angiogenic activity. Adult rat extraocular motoneurons were chosen as the experimental model. Lesion was performed by monocular enucleation and immediately a gelatine sponge soaked in VEGF was implanted intraorbitally. After 7 days, abducens, trochlear, and oculomotor nuclei were examined by immunohistochemistry against choline acetyltransferase (ChAT), the biosynthetic enzyme of the motoneuronal neurotransmitter acetylcholine. Lesioned motoneurons exhibited a noticeable ChAT downregulation which was prevented by VEGF administration. To explore whether this action was mediated via an increase in blood vessels or in their permeability, we performed immunohistochemistry against laminin, glucose transporter-1 and the plasmatic protein albumin. The quantification of the immunolabeling intensity against these three proteins showed no significant differences between VEGF-treated, axotomized and control animals. Therefore, the present data indicate that VEGF is able to sustain the cholinergic phenotype in damaged motoneurons, which is a first step for adequate neuromuscular neurotransmission, and that this action seems to be mediated directly on neurons since no sign of angiogenic activity was evident. These data reinforces the therapeutical potential of VEGF in motoneuronal diseases.

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Section: Introductionmentioning

confidence: 99%

Vascular Endothelial Growth Factor (VEGF) Prevents the Downregulation of the Cholinergic Phenotype in Axotomized Motoneurons of the Adult Rat

Acosta¹,

Morcuende²,

Silva-Hucha³

et al. 2018

Front. Mol. Neurosci.

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“…Previous studies demonstrated that neonatal MSG treatment modifies the developmental expression profile of ligands and receptors of the VEGF system and one of the lasting effects of the treatment is increased VEGFR‐2 expression in the Hp (Castañeda‐Cabral et al, 2017). In this study, we found that the VEGFR‐2 protein in MSG‐treated animals was significantly overexpressed in all studied regions, except for the Hyp (Figure 1d).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the systemic administration of monosodium glutamate (MSG) to newborn rats during the first postnatal week of life is a well‐known excitotoxicity model that affects several brain regions and neurotransmission systems (Gudiño‐Cabrera et al, 2014; López‐Pérez et al, 2005; Rivera‐Cervantes et al, 2009; Ureña‐Guerrero, Orozco‐Suárez, López‐Pérez, Flores‐Soto, & Beas‐Zárate, 2009). This model also increases the VEGF expression in neurons and glial cells (Vázquez‐Valls et al, 2011) and modifies the developmental expression profiles of ligands and receptors of the VEGF system, including VEGFR‐2 (Castañeda‐Cabral, Beas‐Zárate, Gudiño‐Cabrera, & Ureña‐Guerrero, 2017). However, it is not known whether the excitotoxic process induced by neonatal MSG treatment changes BBB properties in the adult brain.…”

Section: Introductionmentioning

confidence: 99%

Neonatal excitotoxicity modifies blood‐brain barrier properties increasing its susceptibility to hypertonic shock in adulthood

Fajardo-Fregoso¹,

Castañeda‐Cabral²,

Beas‐Zárate³

et al. 2020

Intl J of Devlp Neuroscience

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Early responses to a neurological excitotoxic process include blood‐brain barrier (BBB) impairment and overexpression of vascular endothelial growth factor (VEGF), but the long‐term effects of excitotoxicity on the BBB properties remain unknown. To assess this, we induced an excitotoxic process on male rats by neonatal monosodium glutamate (MSG) treatment. At postnatal day (PD) 60, we measured the expression level of structural proteins of the BBB and the VEGF type‐2 receptor (VEGFR‐2) protein in the cerebral motor cortex (CMC), striatum (STR), hippocampus (Hp), entorhinal cortex (Ent), and hypothalamus (Hyp). We also measured BBB permeability in the same cerebral regions. Neonatal MSG treatment significantly reduced the protein expression level of claudin‐5 in the CMC, and of ZO‐1 in the CMC and Hp, and increased the expression level of plasmalemmal vesicle‐associated protein in the CMC, and of VEGFR‐2 in all regions except for the Hyp. BBB permeability was significantly higher in all studied regions of MSG‐treated animals after hypertonic shock (HS). The increased BBB permeability observed in the MSG‐treated animals after HS was reversed by VEGFR‐2 inhibition with SU5416. We conclude that neonatal excitotoxicity leads to lasting impairment on BBB properties in adulthood, increasing its susceptibility to HS that could be regulated by VEGFR‐2 activity inhibition.

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“…One common event that occurs after the induction of a variety of different types of brain insult, such as excitotoxicity, vessels occlusion or seizures, is an increase in VEGF of Flk-1 expression in motoneurons or in glial cells (Lennmyr et al 1998;Croll et al 2004;McCloskey et al 2008;Nicoletti et al 2008;Castañeda-Cabral et al 2017). This upregulation has been related to neuroprotection, and avoidance of motoneurons degeneration.…”

Section: Introductionmentioning

confidence: 99%

Sources and lesion-induced changes of VEGF expression in brainstem motoneurons

et al. 2020

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Motoneurons of the oculomotor system show lesser vulnerability to neurodegeneration compared to other cranial motoneurons, as seen in amyotrophic lateral sclerosis (ALS). The overexpression of vascular endothelial growth factor (VEGF) is involved in motoneuronal protection. As previously shown, motoneurons innervating extraocular muscles present a higher amount of VEGF and its receptor Flk-1 compared to facial or hypoglossal motoneurons. Therefore, we aimed to study the possible sources of VEGF to brainstem motoneurons, such as glial cells and target muscles. We also studied the regulation of VEGF in response to axotomy in ocular, facial, and hypoglossal motor nuclei. Basal VEGF expression in astrocytes and microglial cells of the cranial motor nuclei was low. Although the presence of VEGF in the different target muscles for brainstem motoneurons was similar, the presynaptic element of the ocular neuromuscular junction showed higher amounts of Flk-1, which could result in greater efficiency in the capture of the factor by oculomotor neurons. Seven days after axotomy, a clear glial reaction was observed in all the brainstem nuclei, but the levels of the neurotrophic factor remained low in glial cells. Only the injured motoneurons of the oculomotor system showed an increase in VEGF and Flk-1, but such an increase was not detected in axotomized facial or hypoglossal motoneurons. Taken together, our findings suggest that the ocular motoneurons themselves upregulate VEGF expression in response to lesion. In conclusion, the low VEGF expression observed in glial cells suggests that these cells are not the main source of VEGF for brainstem motoneurons. Therefore, the higher VEGF expression observed in motoneurons innervating extraocular muscles is likely due either to the fact that this factor is more avidly taken up from the target muscles, in basal conditions, or is produced by these motoneurons themselves, and acts in an autocrine manner after axotomy.

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Glutamate Neonatal Excitotoxicity Modifies VEGF-A, VEGF-B, VEGFR-1 and VEGFR-2 Protein Expression Profiles During Postnatal Development of the Cerebral Cortex and Hippocampus of Male Rats

Cited by 14 publications

References 60 publications

Vascular Endothelial Growth Factor (VEGF) Prevents the Downregulation of the Cholinergic Phenotype in Axotomized Motoneurons of the Adult Rat

Vascular Endothelial Growth Factor (VEGF) Prevents the Downregulation of the Cholinergic Phenotype in Axotomized Motoneurons of the Adult Rat

Neonatal excitotoxicity modifies blood‐brain barrier properties increasing its susceptibility to hypertonic shock in adulthood

Sources and lesion-induced changes of VEGF expression in brainstem motoneurons

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