# Nrf2 activator peptide protects the brain from cerebral vascular dysfunction in alcohol ingestion

## TL;DR

This study shows that a Nrf2 activator peptide can protect the brain from alcohol-induced damage by reducing oxidative stress and blood-brain barrier disruption.

## Contribution

The study introduces a novel Nrf2 activator peptide as a potential therapeutic for alcohol-related neurovascular injury.

## Key findings

- NP treatment preserved the oxidant-antioxidant balance and reduced BBB damage.
- NP mitigated leukocyte infiltration into the brain following alcohol ingestion.
- NP's effects were validated in Nrf2-knockout mice, confirming its Nrf2-dependent mechanism.

## Abstract

Oxidative signaling is a central mechanism in alcohol-induced injury and has strong implications for blood-brain barrier (BBB) dysregulation and neuroinflammation. Here, by targeting oxidative signaling, we hypothesized an innovative approach to develop a clinically relevant therapeutic strategy for alleviating alcohol-mediated neurovascular damage. To accomplish this, we enhanced the endogenous activity of nuclear factor E2–related factor 2 (Nrf2) by treatment with a Nrf2 activator III TAT peptide (Nrf2 peptide [NP]) and investigated the neuroprotective role of Nrf2 in promoting antioxidant defense properties and reducing BBB damage and transmigration of leukocytes to the brain following alcohol ingestion. We administered the NP subcutaneously to alcohol-ingested mice and evaluated its therapeutic potential in alleviating alcohol-associated neurovascular impairments. We compared the results with those seen in animals treated with control peptide (random sequence with TAT). The studies showed that the NP treatment preserved the oxidant-antioxidant balance, downregulated ICAM-1 and its receptors, and mitigated BBB damage and leukocyte infiltration into the brain. We validated the effect of the NP in Nrf2-knockout (Nrf2−/−) mice. Thus, this study demonstrates that NP exerts neurovascular protective effects by regulating the oxidant-antioxidant balance, reducing oxidative stress–induced BBB disruption, and limiting transmigration of immune cells to the brain in a mouse model of alcohol ingestion.

In this study, we developed a therapeutic strategy to reduce alcohol-induced neurovascular damage by enhancing Nrf2 activity with an activator peptide, showing its role in boosting antioxidant defenses and reducing blood-brain barrier damage and leukocyte migration.