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Increased Permeability of the Blood-Brain Barrier in a Diabetic Mouse Model (Lepr^db^/db Mice).

ABSTRACT: Type 2 Diabetes Mellitus (T2DM) is linked to multiple complications, including cognitive impairment, and the prevalence of memory-related neurodegenerative diseases is higher in T2DM patients. One possible theory is the alteration of the microvascular and macrovascular environment of the blood-brain barrier (BBB). In this study, we employed different approaches, including RT-PCR, functional pharmacokinetic studies using sodium fluorescein (NaFL), and confocal microscopy, to characterize the functional and molecular integrity of the BBB in a T2DM animal model, leptin receptor-deficient mutant mice (Lepr^db^/db mice). As a result, VCAM-1, ICAM-1, MMP-9, and S100b (BBB-related markers) dysregulation was observed in the Lepr^db^/db animal model compared to littermate wild-type mice. The brain concentration of sodium fluorescein (NaFL) increased significantly in Lepr^db/db untreated mice compared to insulin-treated mice. Therefore, the permeability of NaFL was higher in Lepr^db^/db control mice than in all remaining groups. Identifying the factors that increase the BBB in Lepr^db^/db mice will provide a better understanding of the BBB microvasculature and present previously undescribed findings of T2DM-related brain illnesses, filling knowledge gaps in this emerging field of research.

SUBMITTER: Alshammari MA

PROVIDER: S-EPMC11276738 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Increased Permeability of the Blood-Brain Barrier in a Diabetic Mouse Model (Leprdb/db Mice).

Alshammari Musaad A MA Alshehri Abdulaziz O AO Alqahtani Faleh F Khan Mohammad R MR Bakhrebah Muhammed A MA Alasmari Fawaz F Alshammari Tahani K TK Alsharari Shakir D SD

International journal of molecular sciences 20240716 14

Type 2 Diabetes Mellitus (T2DM) is linked to multiple complications, including cognitive impairment, and the prevalence of memory-related neurodegenerative diseases is higher in T2DM patients. One possible theory is the alteration of the microvascular and macrovascular environment of the blood-brain barrier (BBB). In this study, we employed different approaches, including RT-PCR, functional pharmacokinetic studies using sodium fluorescein (NaFL), and confocal microscopy, to characterize the func ...[more]

PMID: 39063010

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Project description:BackgroundThe blood-brain barrier (BBB) is a semipermeable interface that prevents the non-selective transport into the central nervous system. It controls the delivery of macromolecules fueling the brain metabolism and the immunological surveillance. The BBB permeability is locally regulated depending on the physiological requirements, maintaining the tissue homeostasis and influencing pathological conditions. Given its relevance in vertebrate CNS, it is surprising that little is known about the BBB in Amphibians, some of which are capable of adult CNS regeneration.ResultsThe BBB size threshold of the anuran Xenopus laevis (African clawed toad), as well as two urodele species, Ambystoma mexicanum (axolotl) and Pleurodeles waltl (Iberian ribbed newt), was evaluated under physiological conditions through the use of synthetic tracers. We detected important differences between the analyzed species. Xenopus exhibited a BBB with characteristics more similar to those observed in mammals, whereas the BBB of axolotl was found to be permeable to the 1 kDa tracer. The permeability of the 1 kDa tracer measured in Pleurodeles showed values in between axolotl and Xenopus vesseks. We confirmed that these differences are species-specific and not related to metamorphosis. In line with these results, the tight junction protein Claudin-5 was absent in axolotl, intermediate in Pleurodeles and showed full-coverage in Xenopus vessels. Interestingly, electron microscopy analysis and the retention pattern of the larger tracers (3 and 70 kDa) demonstrated that axolotl endothelial cells exhibit higher rates of macropinocytosis, a non-regulated type of transcellular transport.ConclusionsOur study demonstrated that, under physiological conditions, the blood-brain barrier exhibited species-specific variations, including permeability threshold, blood vessel coverage, and macropinocytosis rate. Future studies are needed to test whether the higher permeability observed in salamanders could have metabolic and immunological consequences contributing to their remarkable regenerative capacity.

Dataset Information

Increased Permeability of the Blood-Brain Barrier in a Diabetic Mouse Model (Lepr^db^/db Mice).

Publications

Increased Permeability of the Blood-Brain Barrier in a Diabetic Mouse Model (<i>Lepr<sup>db</sup></i><sup>/<i>db</i></sup> Mice).

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