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

Abstract

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.

Inhibition of VEGFR‐2 by SU5416 increases neonatally glutamate‐induced neuronal damage in the cerebral motor cortex and hippocampus

“…[6,9,12] Moreover, the vascular remodeling mediated by VEGF may be neuropathological, as has been suggested mainly in epilepsy, [8,38] where the expression levels of several proteins in the VEGF pathway appeared to be increased in cerebral tissues from patients with drug-resistant temporal lobe epilepsy. [16,18,43] Finally, the increased blood-brain barrier permeability observed in adult animals after neonatal MSG treatment was recently reported to be reversed by the VEGFR-2 inhibitor SU5416, [27] highlighting the important role of VEGFR-2…”

“…[ 6,9,12 ] Moreover, the vascular remodeling mediated by VEGF may be neuropathological, as has been suggested mainly in epilepsy, [ 8,38 ] where the expression levels of several proteins in the VEGF pathway appeared to be increased in cerebral tissues from patients with drug‐resistant temporal lobe epilepsy. [ 16,18,43 ] Finally, the increased blood‐brain barrier permeability observed in adult animals after neonatal MSG treatment was recently reported to be reversed by the VEGFR‐2 inhibitor SU5416, [ 27 ] highlighting the important role of VEGFR‐2 signaling not only in the acute phase of excitotoxicity damage but also in long‐term alterations. Therefore, the modulation of VEGFR‐2 activation should be more widely studied because it might be useful in the treatment of several neurodegenerative disorders and diseases characterized by excitotoxicity.…”

“…Neonatal MSG treatment increases brain glutamate levels, triggering excitotoxicity, and degenerative processes that are associated with several short-and long-term neurological disorders, [23] including changes in the protein expression profile of some markers of the VEGF system and in blood-brain barrier permeability, [13,27] among others. Therefore, this study was designed to better understand both the degenerative processes triggered by excitotoxicity in the neonatal stage and the role of the VEGF system.…”

“…3037, Tocris Bioscience)/kg of b.w. as previously described [27,28] on PD 5 and 7 (SU group); and (4) subcutaneously injected with MSG as described above and with 10 mg of SU5416/kg of b.w. on PD 5 and 7, 30 min before MSG administration (MSG + SU group).…”

Oral Administration of Lactobacillus Inhibits the Permeability of Blood-Brain and Gut Barriers in a Parkinsonism Model

“…centrifuged at 16,060 × g for 15 min at 4 °C; the supernatants were recovered and mixed with 95% ethanol to precipitate residual proteins and stabilize the fluorescent signal. SF fluorescence was measured in a fluorescent plate reader (Ex: 485 nm; Em: 525 nm)[18,19].…”