Fluorescein Permeability of the Blood–Brain Barrier Is Enhanced in Juvenile- but Not Young Adult-Onset Type 1 Diabetes in Rats

Tsuneoka, Yousuke; Nishimura, Tsubasa; Oka, Jun-Ichiro

doi:10.1248/bpb.b21-00248

Cited by 2 publications

(1 citation statement)

References 26 publications

(36 reference statements)

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“…In type 2 diabetes mellitus model Bio-Breeding Zucker diabetic rat (BBZDR)/Wor rats, it is found that more than 84% of the brain regions show increased BBB permeability, while the cerebellum and midbrain do not change significantly [ 18 ]. In juvenile-onset diabetic rat models, the BBB permeability of hippocampus and striatum increases, but no change is observed in the frontal cortex and hypothalamus [ 19 ]. In a diet-induced obese model of type 2 diabetes mellitus, BBB damage mainly occurs in the hypothalamus and hippocampus [ 20 ].…”

Section: Diabetes Damages Glia and Vascular Cells Of Bbbmentioning

confidence: 99%

Glial and Vascular Cell Regulation of the Blood-Brain Barrier in Diabetes

Yan

Zuo

et al. 2022

Diabetes Metab J

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As a structural barrier, the blood-brain barrier (BBB) is located at the interface between the brain parenchyma and blood, and modulates communication between the brain and blood microenvironment to maintain homeostasis. The BBB is composed of endothelial cells, basement membrane, pericytes, and astrocytic end feet. BBB impairment is a distinguishing and pathogenic factor in diabetic encephalopathy. Diabetes causes leakage of the BBB through downregulation of tight junction proteins, resulting in impaired functioning of endothelial cells, pericytes, astrocytes, microglia, nerve/glial antigen 2-glia, and oligodendrocytes. However, the temporal regulation, mechanisms of molecular and signaling pathways, and consequences of BBB impairment in diabetes are not well understood. Consequently, the efficacy of therapies diabetes targeting BBB leakage still lags behind the requirements. This review summarizes the recent research on the effects of diabetes on BBB composition and the potential roles of glial and vascular cells as therapeutic targets for BBB disruption in diabetic encephalopathy.

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Section: Diabetes Damages Glia and Vascular Cells Of Bbbmentioning

confidence: 99%

Glial and Vascular Cell Regulation of the Blood-Brain Barrier in Diabetes

Yan

Zuo

et al. 2022

Diabetes Metab J

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Hepatic Ischemia-Reperfusion Impairs Blood-Brain Barrier Partly Due to Release of Arginase From Injured Liver

Zhu

Zhou

et al. 2021

Front. Pharmacol.

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Aim: Hepatic ischemia-reperfusion (HIR) induces remote organs injury, including the brain. The homeostasis of the brain is maintained by the blood-brain barrier (BBB); thus, we aimed to investigate whether HIR impaired BBB and attempted to elucidate its underlying mechanism.Methods: Cell viability of human cerebral microvascular endothelial cells (hCMEC/D3) was measured following 24 h incubation with a serum of HIR rat undergoing 1 h ischemia and 4 h reperfusion, liver homogenate, or lysate of primary hepatocytes of the rat. The liver homogenate was precipitated using (NH4)2SO4 followed by separation on three columns and electrophoresis to identify the toxic molecule. Cell activity, apoptosis, proliferation, cell cycle, and expressions of proteins related to cell cycle were measured in hCMEC/D3 cells incubated with identified toxic molecules. HIR rats undergoing 1 h ischemia and 24 h reperfusion were developed to determine the release of an identified toxic molecule. BBB function was indexed as permeability to fluorescein and brain water. Endothelial cell proliferation and expressions of proteins related to the cell cycle in cerebral microvessels were measured by immunofluorescence and western blot.Results: Toxic molecule to BBB in the liver was identified to be arginase. Arginase inhibitor nor-NOHA efficiently attenuated hCMEC/D3 damage caused by liver homogenate and serum of HIR rats. Both arginase and serum of HIR rats significantly lowered arginine (Arg) in the culture medium. Arg addition efficiently attenuated the impairment of hCMEC/D3 caused by arginase or Arg deficiency, demonstrating that arginase impaired hCMEC/D3 via depriving Arg. Both arginase and Arg deficiency damaged hCMEC/D3 cells by inhibiting cell proliferation, retarding the cell cycle to G1 phase, and downregulating expressions of cyclin A, cyclin D, CDK2, and CDK4. HIR notably increased plasma arginase activity and lowered Arg level, increased the BBB permeability accompanied with enhanced brain water, and decreased the proliferative cells (marked by Ki67) in cerebral microvessels (marked by CD31) and protein expressions of cyclin A, cyclin D, CDK2 and CDK4 in isolated brain microvessels. Oral supplement of Arg remarkably attenuated these HIR-induced alterations.Conclusion: HIR leads to substantial release of arginase from the injured liver and then deprives systemic Arg. The Arg deficiency further impairs BBB via inhibiting the proliferation of brain microvascular endothelial cells by cell cycle arrest.

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Fluorescein Permeability of the Blood–Brain Barrier Is Enhanced in Juvenile- but Not Young Adult-Onset Type 1 Diabetes in Rats

Cited by 2 publications

References 26 publications

Glial and Vascular Cell Regulation of the Blood-Brain Barrier in Diabetes

Glial and Vascular Cell Regulation of the Blood-Brain Barrier in Diabetes

Hepatic Ischemia-Reperfusion Impairs Blood-Brain Barrier Partly Due to Release of Arginase From Injured Liver

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