Indole-3-propionic Acid Attenuates HI-Related Blood–Brain Barrier Injury in Neonatal Rats by Modulating the PXR Signaling Pathway

Abstract

The blood−brain barrier (BBB) is an important physiological barrier of the human body contributing to maintaining brain homeostasis and normal function. Hypoxic-ischemic (HI)-related brain injury is one of the main causes of neonatal acute morbidity and chronic disability. The previous research of our group confirmed that there was serious BBB destruction during HI brain injury. However, at present, the protection strategy of BBB is very limited, and further research on the protection mechanism is warranted. Indole-3-propionic acid (IPA) is a bacterial metabolism with anti-inflammatory and antioxidant properties, having neuroprotective effects and protective effects on the mucosal barrier. However, the role of IPA in BBB is not clear. In this research, we demonstrated the protective effect of IPA on BBB disruption from HI brain injury and hypothesized that it involves the amelioration of inflammation, oxidative stress, and MMP activation, thereby inhibiting apoptosis of rat brain microvascular endothelial cells (rBMECs). We demonstrated that expression levels of several inflammatory markers, including iNOS, TNF-α, IL-6, and IL-1β, were significantly increased from HI damage or OGD injury. However, IPA treatment inhibited the increase significantly. Moreover, we demonstrated that IPA reduced intracellular ROS levels and MMP activation in rBMECs from OGD injury. Further research on the underlying detailed molecular mechanisms suggested that IPA attenuates inflammation by inhibiting NF-κB signaling. Finally, we investigated the mechanism of the relationship between PXR activation and NF-κB inhibition. The results suggested overexpression of PXR in rBMECs could significantly counteract the decrease of junction proteins and downregulate the increased p-IκB-α and p-NF-κB from OGD injury. However, the protective effects of IPA were reversed by antagonists of the PXR. Taken together, IPA might mitigate HI-induced damage of the BBB and the protective effect may be exerted through modulating the PXR signaling pathway.

Circulating (poly)phenol metabolites in the brain: unveiling in vitro and in vivo blood-brain barrier transport

“…Also kaempferol attenuated LPS-induced BBB dysfunction by counteracting the increase of BBB permeability and the degradation of TJs proteins such as occludin-1 and claudin-1, as well as the gap junction protein connexin 43[58]. Regarding metabolites, indole-3-propionic acid was shown to attenuate hypoxic-ischemic-induced BBB leakage in neonatal rats, holding protective effects on rat BMEC cell viability and proliferation, as well as in AJs and TJs proteins modulation[59]. In male Wistar ischemic rats exposed to dusty particulate matter, it was observed that pretreatment with gallic acid reversed BBB leakage and lipid peroxidation[60].…”

Circulating low-molecular-weight (poly)phenol metabolites in the brain: unveiling in vitro and in vivo blood–brain barrier transport

“…58 Regarding metabolites, indole-3-propionic acid was shown to attenuate hypoxic-ischemic-induced BBB leakage in neonatal rats, holding protective effects on rat BMEC cell viability and proliferation, as well as in AJs and TJs proteins modulation. 59 In male Wistar ischemic rats exposed to dusty particulate matter, it was observed that pretreatment with gallic acid reversed BBB leakage and lipid peroxidation. 60 Indeed, gallic and caffeic acid were shown to protect against hyperglycemia-induced BBB disruption in bEnd.3 cells, with caffeic acid increasing claudin-5, occludin, ZO-1 and ZO-2.…”

Synbiotic therapy with Clostridium sporogenes and xylan promotes gut-derived indole-3-propionic acid and improves cognitive impairments in an Alzheimer's disease mouse model

“…17 Additionally, due to its anti-inflammatory properties, IPA also demonstrates potential therapeutic benefits for neurodegenerative diseases characterized by chronic inflammation. 18 Furthermore, it holds promise for alleviating AD. Abundant research suggests that tryptophan can be metabolized by gut microorganisms like C. sporogenes into IPA.…”