Nrf2 activator peptide protects the brain from cerebral vascular dysfunction in alcohol ingestion
Bibhuti Ballav Saikia, Saleena Alikunju, Yemin A. Poovanthodi, Zayan Kassim, P.M. Abdul Muneer
Bibhuti Ballav Saikia, Saleena Alikunju, Yemin A. Poovanthodi, Zayan Kassim, P.M. Abdul Muneer
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Research Article Neuroscience Vascular biology

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

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.

Authors

Bibhuti Ballav Saikia, Saleena Alikunju, Yemin A. Poovanthodi, Zayan Kassim, P.M. Abdul Muneer

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Figure 8

Nrf2 peptide attenuates BBB permeability and the transmigration of leukocytes to the brain in alcohol ingestion.

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Nrf2 peptide attenuates BBB permeability and the transmigration of leuko...
(A and B) Graphical representation of BBB permeability showing the leakage of Evans blue (EB; 5 μM) (A) and sodium fluorescein (NaFl; 5 μM) (B) in mice fed with CD or ED with CP or NP treatments (n = 6 per group). (C) Transmigration of leukocytes was analyzed by infusion of cultured GFP monocytes (green) through the jugular vein of mice; immunostaining images show colocalization with Mac-1 (red). The second panel in each row shows selected, enlarged, and colocalized staining of GFP and Mac-1. The third and fourth panels of each row show GFP and Mac-1 staining, respectively. Scale bars: 400 μm in first panel of each row; 80 μm in second, third, and fourth panels. In second panels, the colocalized yellow cells are infused GFP cells stained with Mac-1 (yellow arrows); and red-stained cells (Mac-1 alone) are endogenous blood cells (white arrows). (D and E) Quantitative analysis of the number of GFP+ (D) and Mac-1+ (E) cells. Data are shown as mean ± SD. Statistically significant, *P < 0.05 and ***P < 0.001 vs. their representative control groups (CD) in WT and Nrf2–/–. @P < 0.05, @@P < 0.001, and @@@P < 0.001 vs. representative groups in WT animals. Statistical analysis was performed by 3-way ANOVA with Bonferroni’s post hoc test.