Blood-brain barrier disruption

The blood-brain barrier (BBB) can be easily destroyed by stroke, which is one of the main factors responsible for macrophage infiltration and central nervous inflammation.

The blood-brain barrier represents a fundamental limitation in treating neurological disease because it prevents all neuropeptides from reaching the central nervous system (CNS). Currently, there is no efficient method to permanently bypass the blood-brain barrier.

Activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) is thought to cause acute brain injury, but the role remains poorly understood in subarachnoid hemorrhage (SAH).

A study was conducted to evaluate if AMPAR activation induces acute blood-brain barrier disruption after SAH. C57BL/6 male adult mice (n = 117) underwent sham or filament perforation modeling, followed by a random intraperitoneal injection of vehicle or two dosages (1 mg/kg or 3 mg/kg) of a selective non-competitive AMPAR antagonist perampanel (PER) at 30 min post-modeling. The effects were evaluated by mortality, neurological scores, and brain water content at 24-48 h and video electroencephalogram monitoring, immunostaining, and Western blotting at 24 h post-SAH. PER significantly suppressed post-SAH neurological impairments, brain edema, and BBB disruption. SAH developed epileptiform spikes without obvious convulsion, which were also inhibited by PER. Western blotting showed that the expression of AMPAR subunits GluA1 and GluA2 was unchanged after SAH, but they were significantly activated after SAH. PER prevented post-SAH activation of GluA1/2, associated with the suppression of post-SAH induction of tenascin-C, a causative mediator of post-SAH BBB disruption. Meanwhile, intracerebroventricular injection of a subtype-selective GluA1/2 agonist augmented the activation of GluA1/2 and the induction of tenascin-C in brain capillary endothelial cells and aggravated post-SAH BBB disruption without increases in epileptiform spikes. Neurological impairments and brain edema were not correlated with the occurrence of epileptiform spikes. This study first showed that AMPAR plays an important role in the development of post-SAH BBB disruption and can be a novel therapeutic target against it 1).

Zang et al. reported the protective effects of Trelagliptin against BBB injury and macrophage infiltration. The results indicate that the infraction volume, the neurological score, and macrophage infiltration staining with CD68 were increased in middle cerebral artery occlusion (MCAO) mice but significantly reversed by treatment with Trelagliptin. Additionally, Trelagliptin reduced the permeability of the BBB by increasing the expression of the tight junction zonula occludens protein-1 (ZO-1) in the cerebral cortex. In an in vitro hypoxia model of endothelial cells, the increased migration of macrophages, enlarged permeability of endothelial monolayer, downregulation of ZO-1, and elevated expression level of CXCL1 by hypoxic conditions were all reversed by treatment with Trelagliptin in a dose-dependent manner. The results demonstrate that Trelagliptin might mitigate macrophage infiltration by preventing the breakdown of the blood-brain barrier in the brains of MCAO mice 2).

Although ongoing research has yielded some potential options for future glioblastoma therapies, delivery of chemotherapy medications across the BBB remains elusive and has limited the efficacy of these medications 3).

Current strategies for enhancing the delivery of therapies across the BBB to the tumor is discussed, with a distinction made between strategies that seek to disrupt the BBB and those that aim to circumvent it in the article of Azad et al. 4).

Histological investigations have shown that disruption of the blood brain barrier (BBB) is well correlated with the degradation of collagen IV, a major component of the BBB 5). Among other basal lamina proteins, collagen IV is often degraded by metalloproteinase-9 (MMP-9)

Triolein emulsion infusion into the carotid artery has been reported to induce temporary and reversible opening of the blood brain barrier by increasing vascular permeability.

Transmucosal delivery of glial derived neurotrophic factor (GDNF) is equivalent to direct intrastriatal injection at ameliorating the behavioral and immunohistological features of Parkinson disease in a murine model. Mucosal grafting of arachnoid defects is a technique commonly used for endoscopic skull base reconstruction and may represent a novel method to permanently bypass the blood-brain barrier 6).

Kawakita F, Kanamaru H, Asada R, Imanaka-Yoshida K, Yoshida T, Suzuki H. Inhibition of AMPA (α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionate) Receptor Reduces Acute Blood-Brain Barrier Disruption After Subarachnoid Hemorrhage in Mice. Transl Stroke Res. 2021 Aug 3. doi: 10.1007/s12975-021-00934-0. Epub ahead of print. PMID: 34342874.
Zang L, Yang B, Zhang M, Cui J, Ma X, Wei L. Trelagliptin Mitigates Macrophage Infiltration by Preventing the Breakdown of the Blood-Brain Barrier in the Brain of Middle Cerebral Artery Occlusion Mice. Chem Res Toxicol. 2021 Mar 17. doi: 10.1021/acs.chemrestox.0c00323. Epub ahead of print. PMID: 33728903.
Hendricks BK, Cohen-Gadol AA, Miller JC. Novel delivery methods bypassing the blood-brain and blood-tumor barriers. Neurosurg Focus. 2015 Mar;38(3):E10. doi: 10.3171/2015.1.FOCUS14767. PubMed PMID: 25727219.
Azad TD, Pan J, Connolly ID, Remington A, Wilson CM, Grant GA. Therapeutic strategies to improve drug delivery across the blood-brain barrier. Neurosurg Focus. 2015 Mar;38(3):E9. doi: 10.3171/2014.12.FOCUS14758. PubMed PMID: 25727231.
Egashira Y, Zhao H, Hua Y, Keep RF, Xi G. White matter injury after subarachnoid hemorrhage: role of blood-brain barrier disruption and matrix metalloproteinase-9. Stroke. 2015;46(10):2909–2915.
Bleier BS, Kohman RE, Guerra K, Nocera AL, Ramanlal S, Kocharyan AH, Curry WT, Han X. Heterotopic Mucosal Grafting Enables the Delivery of Therapeutic Neuropeptides Across the Blood Brain Barrier. Neurosurgery. 2016 Mar;78(3):448-57. doi: 10.1227/NEU.0000000000001016. PubMed PMID: 26352099.
  • blood-brain_barrier_disruption.txt
  • Last modified: 2021/08/03 20:14
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