Resveratrol prevents brain edema, blood–brain barrier permeability, and altered aquaporin profile in autism animal model

Abstract

Autism spectrum disorder can present a plethora of clinical conditions associated with the disorder, such as greater brain volume in the first years of life in a significant percentage of patients. We aimed to evaluate the brain water content, the blood–brain barrier permeability, and the expression of aquaporin 1 and 4, and GFAP in a valproic acid‐animal model, assessing the effect of resveratrol. On postnatal day 30, Wistar rats of the valproic acid group showed greater permeability of the blood–brain barrier to the Evans blue dye and a higher proportion of brain water volume, prevented both by resveratrol. Prenatal exposition to valproic acid diminished aquaporin 1 in the choroid plexus, in the primary somatosensory area, in the amygdala region, and in the medial prefrontal cortex, reduced aquaporin 4 in medial prefrontal cortex and increased aquaporin 4 levels in primary somatosensory area (with resveratrol prevention). Valproic acid exposition also increased the number of astrocytes and GFAP fluorescence in both primary somatosensory area and medial prefrontal cortex. In medial prefrontal cortex, resveratrol prevented the increased fluorescence. Finally, there was an effect of resveratrol per se on the number of astrocytes and GFAP fluorescence in the amygdala region and in the hippocampus. Thus, this work demonstrates significant changes in blood–brain barrier permeability, edema formation, distribution of aquaporin 1 and 4, in addition to astrocytes profile in the animal model of autism, as well as the use of resveratrol as a tool to investigate the mechanisms involved in the pathophysiology of autism spectrum disorder.

Pathology and Astrocytes in Autism

“… 54 In a valproic acid (VPA) animal model of ASD, there was an increase in the number of astrocytes and GFAP in medial prefrontal cortex and primary somatosensory cortex on postnatal day 30. 55 In contrast, some other studies showed no change in GFAP protein in anterior cingulate grey matter, amygdala, and anterior and dorsolateral prefrontal white matter of postmortem ASD brains. 30 , 51 , 56 Other proteins expressed by astrocytes are also changed in ASD.…”

“…AQP4 is mainly responsible for eliminating water from the cerebral parenchyma as well as supporting potassium buffering. 55 , 55 In addition, there was a reduction in AQP4 protein in the cerebellum and an increase of connexin (cnx) 43, a gap junction protein located in astrocytes, in BA9 of postmortem ASD brains. 57 Beside buffering ions and neurotransmitters concentration, cnx43 is responsible for regulating cellular growth and cell-cell adhesion.…”

GABAergic synaptic transmission and cortical oscillation patterns in the primary somatosensory area of a valproic acid rat model of autism spectrum disorder

“…We considered the statistical power of 80%, the effect size (0.85 for in vivo electrophysiology and 0.8 for in vitro electrophysiology) and α = 0.05 (two‐tailed). The effect size was based on previous in vivo and in vitro experiments of our group (Pasquetti et al, 2019) and previous studies showing the effect of RSV‐ and VPA‐treated rats (Bambini‐Junior et al, 2014; Deckmann et al, 2021; Fontes‐Dutra et al, 2018; Hirsch et al, 2018; Santos‐Terra et al, 2022; Santos‐Terra, Deckmann, Schwingel, et al, 2021), where smaller sample sizes were used to find a significant difference between groups. Parametric data from in vitro electrophysiology were analysed by two‐way ANOVA followed by the Tukey post hoc test.…”

“…Strikingly, resveratrol ( trans ‐3,5,4′‐trihydroxystilbene, RSV), a polyphenol with anti‐inflammatory and antioxidant properties, is capable of modulating cytokines, chemokines and JAK/STAT pathways (de Sá Coutinho et al, 2018), as well as SIRT enzymes, which also contribute to its anti‐inflammatory effects (Kalliora et al, 2019). Previous work from our group showed that RSV was capable of preventing many VPA‐induced alterations from behavioural to molecular level (Bambini‐Junior et al, 2014; Deckmann et al, 2021; Fontes‐Dutra et al, 2018; Santos‐Terra et al, 2022; Santos‐Terra, Deckmann, Schwingel, et al, 2021). When administered in pregnant rats of the VPA animal model of ASD, RSV was able to prevent not only the cortical displacement of PV + interneurons in PSSA (Fontes‐Dutra et al, 2018) but also of PV + , SST + and CB + GABAergic interneurons in the medial prefrontal cortex (mPFC) of the offspring (Santos‐Terra et al, 2022), highlighting its neuroprotective role in early stages of neurodevelopment.…”

Resveratrol Mitigates Oxygen and Glucose Deprivation-Induced Inflammation, NLRP3 Inflammasome, and Oxidative Stress in 3D Neuronal Culture

“…Resveratrol is a naturally occurring polyphenolic compound found in many plants, such as grapes and blueberries, capable of crossing the blood-brain barrier (BBB) [ 22 , 23 ]. Numerous studies have shown that resveratrol acts through AMPK signaling [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ].…”