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Influence of type 1 diabetes on basal and agonist-induced permeability of the blood-brain barrier.

ABSTRACT: Type 1 diabetes mellitus (T1D) impairs endothelial nitric oxide synthase (eNOS)-dependent responses of cerebral arterioles. However, the influence of T1D on another critical aspect of endothelial cell function in the cerebral microcirculation, i.e., regulation of permeability of the blood-brain barrier (BBB), remains largely unknown. Our goal was to examine basal and agonist-induced changes in permeability of the BBB in nondiabetic and type 1 diabetic (streptozotocin; 50 mg/kg IP) rats. On the day of the experiment (2-3 months after streptozotocin), a craniotomy was made over the parietal cortex in nondiabetic and diabetic rats. We measured the permeability of the BBB (FITC-dextran-10K) under basal conditions and during application of histamine. We also measured diameter of cerebral arterioles in response to histamine in the absence and presence of NG-monomethyl-L-arginine (L-NMMA). We found that basal permeability of the BBB was elevated in T1D and application of histamine did not produce a further increase in permeability. In contrast, basal permeability of the BBB was minimal in nondiabetics and histamine produced an increase in permeability. In addition, histamine-induced arteriolar dilation was less in diabetics than in nondiabetics, and vasodilation to histamine was inhibited by L-NMMA. Our findings suggest that T1D-induced endothelial dysfunction leads to an increase in basal permeability of the BBB, but decreases the ability of the endothelium of the BBB to respond to an important inflammatory mediator. Thus, T1D impairs two critical aspects of endothelial cell function in the cerebral microcirculation, i.e., basal and agonist-induced changes in permeability of the BBB and arteriolar dilation.

SUBMITTER: Mayhan WG

PROVIDER: S-EPMC4760440 | biostudies-other | 2015 Dec

REPOSITORIES: biostudies-other

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Project description:BackgroundType 2 diabetes mellitus (T2DM) is a chronic metabolic dysfunction characterized by progressive insulin resistance and hyperglycaemia. Increased blood-brain barrier (BBB) permeability is a critical neurovascular complication of T2DM that adversely affects the central nervous system homeostasis and function. Histone deacetylase 3 (HDAC3) has been reported to be elevated in T2DM animals and may promote neuroinflammation; however, its involvement in the BBB permeability of T2DM has not been investigated. In this study, we tested our hypothesis that HDAC3 expression and activity are increased in the T2DM mouse brain. Inhibition of HDAC3 may ameliorate T2DM-induced BBB permeability through Nrf2 activation.MethodsT2DM (db/db, leptin receptor-deficient), genetic non-hyperglycemic control (db/+), and wild-type male mice at the age of 16 weeks were used in this study. HDAC3 expression and activity, Nrf2 activation, and BBB permeability and junction protein expression were examined. The effects of HDAC3 activity on BBB permeability were tested using highly selective HDAC3 inhibitor RGFP966. In primary cultured human brain microvascular endothelial cells (HBMEC), hyperglycemia (25 mM glucose) plus interleukin 1 beta (20 ng/ml) (HG-IL1β) served as T2DM insult in vitro. The effects of HDAC3 on transendothelial permeability were investigated by FITC-Dextran leakage and trans-endothelial electrical resistance, and the underlying molecular mechanisms were investigated using Western blot, q-PCR, co-immunoprecipitation, and immunocytochemistry for junction protein expression, miR-200a/Keap1/Nrf2 pathway regulation.ResultsHDAC3 expression and activity were significantly increased in the hippocampus and cortex of db/db mice. Specific HDAC3 inhibition significantly ameliorated BBB permeability and junction protein downregulation in db/db mice. In cultured HBMEC, HG-IL1β insult significantly increased transendothelial permeability and reduced junction protein expression. HDAC3 inhibition significantly attenuated the transendothelial permeability and junction protein downregulation. Moreover, we demonstrated the underlying mechanism was at least in part attributed by HDAC3 inhibition-mediated miR-200a/Keap1/Nrf2 signaling pathway and downstream targeting junction protein expression in T2DM db/db mice.ConclusionsOur experimental results show that HDAC3 might be a new therapeutic target for BBB damage in T2DM.

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Influence of type 1 diabetes on basal and agonist-induced permeability of the blood-brain barrier.

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