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Blood‑brain barrier dysfunction in epilepsy: Mechanisms, therapeutic strategies and future orientation (Review)

  • Authors:
    • Na Huang
    • Yawen Huang
    • Zhenyuan Deng
    • Shuya Qi
    • Wei Zhang
    • Yuanyuan Liu
    • Guohe Tan
  • View Affiliations / Copyright

    Affiliations: Institute of Neuroscience and Guangxi Key Laboratory of Brain Science, Department of Human Anatomy, School of Basic Medical Sciences, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530016, P.R. China, Guangxi Key Laboratory of Regenerative Medicine, Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co‑constructed by the Province and Ministry, Nanning, Guangxi Zhuang Autonomous Region 530016, P.R. China
    Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 136
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    Published online on: July 3, 2025
       https://doi.org/10.3892/ijmm.2025.5577
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Abstract

The blood‑brain barrier (BBB) is a crucial structure for maintaining homeostasis within the central nervous system, and its integrity plays a pivotal role in the onset and progression of epilepsy. Epileptic seizures can disrupt the molecular architecture of the BBB, including the loss of tight junction proteins, activation of matrix metalloproteinases and dysfunction of supporting cells. Various pathological changes, such as transmembrane transport disorders, upregulation of platelet‑derived growth factor receptor β and vascular endothelial growth factor signalling pathways, and activation of astrocytes and microglia, accompany these alterations. These modifications exacerbate the entry of toxic molecules (such as albumin) into the brain parenchyma, triggering neuroinflammation and neuronal damage, thereby establishing a vicious cycle of epilepsy, BBB disruption and recurrent epilepsy. Consequently, repairing or protecting the BBB is a novel strategy for controlling epileptic seizures and treating drug‑resistant epilepsy. Consequently, compared with current treatment approaches that primarily focus on suppressing neuronal excitability, repairing or protecting the BBB is a novel strategy for controlling epileptic seizures and treating drug‑resistant epilepsy. Drugs such as botulinum, levetiracetam and angiotensin receptor blockers show the potential for BBB protection. The development of nanomaterials can enhance drug concentrations in affected areas, thereby offering new avenues for refractory epilepsy. The present study systematically reviews the critical role of the BBB in the pathogenesis of epilepsy, untangles the complex association between BBB dysfunction and the course of the disease, aims to deepen our understanding of the molecular mechanisms underlying BBB damage, and explores new approaches for epilepsy prevention and treatment from a BBB perspective. This review provides a theoretical foundation and research direction for the development of diagnostic and treatment strategies that are safer and more effective than current standard therapies.
View Figures

Figure 1

Physiological structure and molecular
characteristics of the BBB. (A) The BBB is composed primarily of
BMECs connected by TJs and is encased by a basal lamina, pericytes,
astrocytic end-feet and narrow extracellular spaces. (B) BMECs are
connected by TJs complexes formed by proteins such as claudins,
occludins, ZO-1, ZO-2, ZO-3 and junctional adhesion molecules.
These complexes tightly regulate non-specific substance transport,
ensuring the low permeability of the BBB. (C) Pericytes are
essential for BBB functionality. PDGFRβ receptors on pericytes
interact with PDGF-BB secreted by BMECs, facilitating
vascularisation. Pericytes release ANGPT-1, which supports BMEC
development and maintains BBB stability. Pericytes modulate
inflammatory responses by releasing both pro-inflammatory
chemokines and anti-inflammatory cytokines. (D) Astrocytes form
expanded end-feet surrounding the outer basal surface of BMECs and
establish close connections with them. These end-feet are rich in
AQP4 and ion channels, which contribute to blood flow regulation,
ion homeostasis and nutritional support. Astrocytes also produce
cytokines, such as ANGPT-1 and SHH, to enhance BBB integrity by
upregulating TJ proteins and modulating BMEC transport properties.
BBB, blood-brain barrier; TJ, tight junction; ZO-1, zona occludens
protein 1; ANGPT-1, angiopoietin-1; PDGFRβ, platelet-derived growth
factor receptor β; PDGF-BB, platelet-derived growth factor-BB; SHH,
sonic hedgehog; AQP4, aquaporin 4; JAM, junctional adhesion
molecule.

Figure 2

Functional changes of the BBB in the
epileptic brain. Following epilepsy, the expression of TJ proteins,
including occludin, ZO-1 and claudin-8, in BBB endothelial cells,
as well as the KV7.5 ion channel in endothelial cells, is reduced
significantly. In status epilepticus, enrichment of a large amount
of glutamate in the brain leads to N-methyl-D-aspartate activation
in endothelial cells and further increases the intracellular
Ca2+ concentration, leading to excitotoxicity, abnormal
expression and function of TJs, and increased permeability of the
BBB. The upregulation of ABC transporters, such as P-glycoprotein
and breast cancer resistance protein, in vascular endothelial cells
limits the brain penetration of anti-seizure drugs and is closely
related to drug-resistant epilepsy. Following seizures, the
expression levels of the VEGF/VEGFR signalling pathway in glial and
endothelial cells are upregulated, the expression of the TJ protein
ZO-1 is inhibited and MMPs are activated, which destroys the
vascular endothelial extracellular matrix and degrades TJ proteins.
Seizures cause pericyte rearrangement and PDGFRβ overexpression,
further compromising BBB integrity. The activation of astrocytes
and microglia enhances electrical synaptic coupling and promotes
the release of pro-inflammatory mediators, thereby increasing BBB
permeability. BBB, blood-brain barrier; TJ, tight junction; ZO-1,
zona occludens protein 1; ABC, ATP-binding cassette; VEGF, vascular
endothelial growth factor; VEGFR, VEGF receptor; MMP, matrix
metalloproteinase; PDGFRβ, platelet-derived growth factor receptor
β; JAM, junctional adhesion molecule.

Figure 3

Interplay between BBB damage and
epileptogenesis. Epilepsy leads to neurotransmitter imbalances,
abnormal remodelling of cerebral blood vessels and abnormal changes
in ion channels, thereby destroying the BBB. Epilepsy can cause
microglial activation, which releases a number of pro-inflammatory
mediators, and the long-term inflammatory response leads to
increased BBB permeability. BBB damage exacerbates the inflammatory
response through various pathways and accumulates harmful
substances in the brain, thereby promoting the occurrence and
development of epilepsy. BBB, blood-brain barrier; VEGF, vascular
endothelial growth factor.

Figure 4

Mechanisms of epilepsy progression
caused by BBB damage. Serum albumin leakage caused by BBB damage is
a key factor in epileptogenesis. After serum albumin enters the
brain parenchyma, it binds to TGF-β receptors on astrocytes,
resulting in a decrease in the expression of Kir4.1 and AQP4,
disrupting potassium and water balance, lowering the excitability
threshold and activating the associated signalling cascade. This
may eventually lead to seizures, and the exuded serum albumin can
be absorbed by neurons, causing neurons to die and dissolve.
Furthermore, when the BBB is compromised, immune cells from the
periphery infiltrate brain tissue to release pro-inflammatory
factors, such as tumor necrosis factor-α, interleukin-1β, high
mobility group box-1 and toll-like receptor 4. These mediators can
activate glial cells in the brain, such as microglia and
astrocytes, and promote them to release more pro-inflammatory
factors, aggravate neuronal damage, increase neuronal excitability
and reduce the threshold of seizures. These pro-inflammatory
factors can further aggravate the destruction of the BBB structure.
BBB dysfunction increases the permeability of blood vessels,
resulting in a severe local inflammatory response, which jointly
promotes the transport of a large amount of iron from the blood to
the brain parenchyma, causing iron overload. Oxidative stress
caused by iron overload causes further neuronal damage. The
accumulation of iron activates microglia and astrocytes, releases a
large number of pro-inflammatory factors, aggravates neuronal
damage, reduces the threshold of seizures and promotes the
development of epilepsy. Additionally, BBB disruption allows plasma
components such as fibrinogen, thrombin and haemoglobin to enter
the brain, further promoting neuronal death and aggravating seizure
progression. BBB, blood-brain barrier; TGF-β, transforming growth
factor-β; AQP4, aquaporin 4; Kir4.1, inwardly rectifying potassium
channel 4.1.

Figure 5

Novel treatment strategies for
epilepsy based on BBB regulation. Emerging strategies for treating
epilepsy have focused on restoring BBB integrity and improving drug
delivery. Restoring the damaged BBB and eliminating the negative
effects caused by BBB dysfunction (such as anti-inflammatory
therapy) may be key strategies for the treatment of epilepsy, such
as the vitexin derivative VB-001, potassium channel modulators,
levetiracetam, flavonoids and high mobility group box-1
antagonists. Cell therapies using induced pluripotent stem
cell-derived pericytes to replace dysfunctional pericyte function
may potentially restore the BBB. Focused ultrasound combined with
microbubbles, which instantaneously opens the BBB, is a promising
non-invasive technique that plays an important role in targeted
delivery therapy. Nanomaterial drug delivery systems can pass
through the BBB and play an important role in treating epilepsy.
BBB, blood-brain barrier; ASD, anti-seizure drug.

Figure 6

BBB-based basic research to clinical
translation. Basic research on BBB damage in preclinical and
clinical trials to explore BBB-based treatments for epilepsy. BBB,
blood-brain barrier; TJ, tight junction; ABC, ATP-binding cassette;
LEV, levetiracetam; ARB, angiotensin receptor blocker; miR,
microRNA; rHu-EPO, recombinant human erythropoietin; HMGB1, high
mobility group box-1.
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Copy and paste a formatted citation
Spandidos Publications style
Huang N, Huang Y, Deng Z, Qi S, Zhang W, Liu Y and Tan G: Blood‑brain barrier dysfunction in epilepsy: Mechanisms, therapeutic strategies and future orientation (Review). Int J Mol Med 56: 136, 2025.
APA
Huang, N., Huang, Y., Deng, Z., Qi, S., Zhang, W., Liu, Y., & Tan, G. (2025). Blood‑brain barrier dysfunction in epilepsy: Mechanisms, therapeutic strategies and future orientation (Review). International Journal of Molecular Medicine, 56, 136. https://doi.org/10.3892/ijmm.2025.5577
MLA
Huang, N., Huang, Y., Deng, Z., Qi, S., Zhang, W., Liu, Y., Tan, G."Blood‑brain barrier dysfunction in epilepsy: Mechanisms, therapeutic strategies and future orientation (Review)". International Journal of Molecular Medicine 56.3 (2025): 136.
Chicago
Huang, N., Huang, Y., Deng, Z., Qi, S., Zhang, W., Liu, Y., Tan, G."Blood‑brain barrier dysfunction in epilepsy: Mechanisms, therapeutic strategies and future orientation (Review)". International Journal of Molecular Medicine 56, no. 3 (2025): 136. https://doi.org/10.3892/ijmm.2025.5577
Copy and paste a formatted citation
x
Spandidos Publications style
Huang N, Huang Y, Deng Z, Qi S, Zhang W, Liu Y and Tan G: Blood‑brain barrier dysfunction in epilepsy: Mechanisms, therapeutic strategies and future orientation (Review). Int J Mol Med 56: 136, 2025.
APA
Huang, N., Huang, Y., Deng, Z., Qi, S., Zhang, W., Liu, Y., & Tan, G. (2025). Blood‑brain barrier dysfunction in epilepsy: Mechanisms, therapeutic strategies and future orientation (Review). International Journal of Molecular Medicine, 56, 136. https://doi.org/10.3892/ijmm.2025.5577
MLA
Huang, N., Huang, Y., Deng, Z., Qi, S., Zhang, W., Liu, Y., Tan, G."Blood‑brain barrier dysfunction in epilepsy: Mechanisms, therapeutic strategies and future orientation (Review)". International Journal of Molecular Medicine 56.3 (2025): 136.
Chicago
Huang, N., Huang, Y., Deng, Z., Qi, S., Zhang, W., Liu, Y., Tan, G."Blood‑brain barrier dysfunction in epilepsy: Mechanisms, therapeutic strategies and future orientation (Review)". International Journal of Molecular Medicine 56, no. 3 (2025): 136. https://doi.org/10.3892/ijmm.2025.5577
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