The Role of Nrf2 in Maintaining the Integrity of the Blood-Brain Barrier

Academic Background

The blood-brain barrier (BBB) is a crucial barrier between the central nervous system (CNS) and the peripheral blood circulation, composed of endothelial cells, pericytes, smooth muscle cells, astrocytes, and neurons. The primary function of the BBB is to selectively control the passage of small molecules, metabolites, and cells, maintaining the homeostasis of the brain’s internal environment while protecting it from pathogens, inflammation, injury, and diseases. The integrity of the BBB is essential for preventing various neurological disorders, and its dysfunction is closely related to neurodegenerative diseases, stroke, traumatic brain injury, and other conditions.

In recent years, research has shown that oxidative stress and inflammation are major factors leading to BBB dysfunction. Nrf2 (Nuclear factor erythroid-related factor 2) is a key regulator of cellular antioxidant and anti-inflammatory responses, capable of modulating the expression of approximately 250 genes through the antioxidant response elements (ARE). These genes are involved in glutathione and thioredoxin antioxidant defense systems, iron metabolism, drug metabolism, and more. The loss of Nrf2 activity can impair BBB integrity, increase the expression of inflammatory markers, and exacerbate the progression of neurodegenerative diseases. Therefore, studying the role of Nrf2 in maintaining BBB integrity is of great significance for developing therapeutic strategies for neurological disorders.

Source of the Paper

This review paper was co-authored by Eduardo Cazalla, Antonio Cuadrado, and Ángel Juan García-Yagüe, affiliated with the Autonomous University of Madrid (UAM), the Instituto de Investigaciones Biomédicas “Sols-Morreale,” and the Instituto de Investigación Sanitaria La Paz (Idipaz) in Spain. The paper was published in 2024 in the journal Fluids and Barriers of the CNS under the title Role of the transcription factor Nrf2 in maintaining the integrity of the blood-brain barrier.

Main Content of the Paper

1. Mechanisms of Nrf2 in BBB Integrity

Nrf2 is a core regulator of cellular antioxidant and anti-inflammatory responses, activating a series of antioxidant and anti-inflammatory genes by modulating ARE sequences. The loss of Nrf2 activity leads to impaired BBB integrity and increased expression of inflammatory markers, such as vascular adhesion molecules and pro-inflammatory cytokines. Studies have shown that Nrf2 maintains BBB integrity by regulating the expression of tight junction (TJ) and adherens junction proteins. For example, Nrf2 can upregulate the expression of claudin-5 and VE-cadherin, thereby enhancing the barrier function of the BBB.

2. Role of Nrf2 in Neurodegenerative Diseases

Nrf2 exhibits protective effects in various neurodegenerative diseases. For instance, in Alzheimer’s disease (AD), Nrf2 can mitigate the toxicity of amyloid-β (Aβ), reduce Aβ plaque accumulation, and promote Aβ clearance. Additionally, Nrf2 can reduce tau protein phosphorylation by regulating the expression of autophagy-related genes, thereby protecting BBB integrity.

In Parkinson’s disease (PD), Nrf2 protects BBB integrity by modulating astrocyte function, reducing oxidative stress and inflammatory responses. Nrf2 also mitigates the toxic effects of α-synuclein on endothelial cells by regulating its degradation.

3. Role of Nrf2 in Cerebrovascular Diseases

Nrf2 also demonstrates protective effects in cerebrovascular diseases. For example, in ischemic stroke, Nrf2 can reduce oxidative stress and inflammation by modulating the HIF-1α signaling pathway, thereby protecting BBB integrity. Nrf2 also reduces BBB permeability by regulating the expression of tight junction proteins, alleviating cerebral edema and neuronal damage.

4. Role of Nrf2 in Diabetes-Related BBB Damage

Both hyperglycemia and hypoglycemia can lead to BBB dysfunction, and Nrf2 plays a critical protective role in this process. Hyperglycemia increases mitochondrial ROS production, leading to increased BBB permeability, while Nrf2 can reduce ROS production by regulating the expression of antioxidant enzymes, thereby protecting BBB integrity. Hypoglycemia downregulates Nrf2 expression, resulting in BBB dysfunction, but Nrf2 activation can partially restore BBB barrier function.

5. Role of Nrf2 in Smoking and Sepsis-Related BBB Damage

Smoking and sepsis both lead to BBB dysfunction, and Nrf2 plays a key protective role in these processes. Smoking increases ROS production, leading to increased BBB permeability, while Nrf2 can reduce ROS production by regulating the expression of antioxidant enzymes, thereby protecting BBB integrity. Sepsis increases inflammatory responses, leading to BBB dysfunction, while Nrf2 can reduce inflammation by regulating the expression of inflammatory factors, thereby protecting BBB integrity.

Significance and Value of the Paper

This review paper systematically summarizes the role of Nrf2 in maintaining BBB integrity, particularly its protective mechanisms under various pathological conditions such as neurodegenerative diseases, cerebrovascular diseases, diabetes, smoking, and sepsis. The paper not only provides new insights into the molecular mechanisms of BBB dysfunction but also offers a theoretical basis for developing therapeutic strategies for neurological disorders. As a potential therapeutic target, Nrf2 has broad clinical application prospects, especially in antioxidant and anti-inflammatory treatments.

Highlights of the Paper

1. Multiple Protective Mechanisms of Nrf2: Nrf2 not only protects the BBB by regulating the expression of antioxidant and anti-inflammatory genes but also enhances BBB barrier function by regulating the expression of tight junction and adherens junction proteins.
2. Protective Role of Nrf2 in Various Diseases: The paper elaborates on the protective role of Nrf2 in multiple pathological conditions, including neurodegenerative diseases, cerebrovascular diseases, diabetes, smoking, and sepsis, providing theoretical support for the clinical application of Nrf2.
3. Potential Applications of Nrf2 Activators: The paper also introduces various Nrf2 activators, such as plant-derived isothiocyanates, triterpenoids, and curcumin, which have shown significant efficacy in protecting BBB integrity.

Conclusion

This review paper systematically summarizes the role of Nrf2 in maintaining BBB integrity, particularly its protective mechanisms under various pathological conditions. As a potential therapeutic target, Nrf2 has broad clinical application prospects, especially in antioxidant and anti-inflammatory treatments. Future research can further explore the clinical applications of Nrf2 activators, providing new strategies for the treatment of neurological disorders.