Nrf2 activator peptide protects the brain from cerebral vascular dysfunction in alcohol ingestion
Bibhuti B Saikia1, Saleena Alikunju2, Yemin A Poovanthodi1
1JFK Neuroscience Institute, Hackensack Meridian Health JFK University Medical Center, Edison, New Jersey, USA.
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.
Insights
Nrf2 peptide (NP) treatment protected against alcohol-induced neurovascular damage by restoring oxidant-antioxidant balance and reducing blood-brain barrier disruption and inflammation in mice.
Area of Science:
- Neuroscience
- Toxicology
- Biochemistry
Background:
- Alcohol consumption causes neuroinflammation and blood-brain barrier (BBB) damage.
- Oxidative signaling is a key mechanism in alcohol-induced neurovascular injury.
- Targeting oxidative stress pathways offers a potential therapeutic strategy.
Purpose of the Study:
- To investigate the neuroprotective effects of enhancing nuclear factor E2-related factor 2 (Nrf2) activity.
- To evaluate a novel Nrf2 activator peptide (NP) for alleviating alcohol-mediated neurovascular damage.
- To assess NP's role in antioxidant defense, BBB integrity, and neuroinflammation.
Main Methods:
- Administration of Nrf2 activator peptide (NP) or control peptide subcutaneously to alcohol-ingested mice.
- Evaluation of oxidant-antioxidant balance, ICAM-1 expression, BBB damage, and leukocyte infiltration.
- Validation of NP effects in Nrf2 knock-out (Nrf2-/-) mice.
Main Results:
- NP treatment preserved oxidant-antioxidant balance in alcohol-ingested mice.
- NP downregulated ICAM-1 expression and mitigated BBB damage and leukocyte infiltration.
- Therapeutic effects of NP were confirmed in Nrf2 knock-out models, highlighting Nrf2's crucial role.
Conclusions:
- Nrf2 peptide (NP) demonstrates significant neurovascular protective effects against alcohol-induced injury.
- NP regulates oxidant-antioxidant balance, reduces oxidative stress-induced BBB disruption, and limits immune cell transmigration.
- Targeting Nrf2 with NP represents a promising therapeutic approach for alcohol-related neurovascular impairments.
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