Mild Hypercholesterolemia Blunts the Proinflammatory and Prothrombotic Effects of Hypertension on the Cerebral Microcirculation

Rodrigues, S.; Vital, Shantel; Granger, D. Neil

doi:10.1038/jcbfm.2012.194

Cited by 14 publications

(13 citation statements)

References 40 publications

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“…35 Twenty-four hours later, 0.4 mL of blood was obtained by cardiac puncture. Then, the mouse was transcardially perfused with phosphatebuffered saline (100 mmHg) for 5 min.…”

Section: Blood-brain Barrier Dysfunctionmentioning

confidence: 99%

Lipid-Core Nanocapsules Act as a Drug Shuttle Through the Blood Brain Barrier and Reduce Glioblastoma After Intravenous or Oral Administration

Rodrigues¹,

Fiel²,

Shimada³

et al. 2016

j biomed nanotechnol

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Lipid-core nanocapsules (LNC) are formed by an organogel surrounded by poly(epsilon-caprolactone) and stabilized by polysorbate 80. LNCs increase the concentration of drugs in the brain after oral or intravenous administration. We proposed to determine whether the drug is released from the LNC to cross the blood brain barrier (BBB) or the drug-loaded LNCs can cross the BBB to release the drug. We synthesized a Rhodamine B-polymer conjugate to prepare a fluorescent-labeled LNC formulation, and intravital microscopy was used to determine the ability of the LNCs to cross the brain barrier using different administration routes in C57BI/6 mice. A glioblastoma model was used to determine the impact of the LNC as a shuttle for treatment. After pial vessel exposure, intense fluorescence was detected inside the vessels 10 min after intravenous or 20 min after intraperitoneal injections of fluorescent-labeled LNC. The fluorescence was observed in the perivascular tissue after 30 and 60 min, respectively. Increased tissue fluorescence was detected 240 min after oral administration. The integrity of the barrier was determined during the experiments. Normal leukocyte and platelet adhesion to the vessel wall indicated that Rhodamine B-labeled LNC did not cause pial vessel alterations. After intravenous or oral administration, Rhodamine B-labeled LNC-containing co-encapsulated indomethacin and indomethacin ethyl ester exhibited similar behavior in pial vessels, being more efficient in the treatment of mice with glioblastoma than indomethacin in solution. Therefore, we demonstrated that LNCs act as drug shuttles through the BBB, delivering drugs in brain tissue with high efficiency and reducing glioblastoma after intravenous or oral administration.

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“…35 Twenty-four hours later, 0.4 mL of blood was obtained by cardiac puncture. Then, the mouse was transcardially perfused with phosphatebuffered saline (100 mmHg) for 5 min.…”

Section: Blood-brain Barrier Dysfunctionmentioning

confidence: 99%

Lipid-Core Nanocapsules Act as a Drug Shuttle Through the Blood Brain Barrier and Reduce Glioblastoma After Intravenous or Oral Administration

Rodrigues¹,

Fiel²,

Shimada³

et al. 2016

j biomed nanotechnol

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“…Hypertension induced in mice was accompanied by increased leukocyte and platelet adhesion in cerebral venules and was attenuated by mild hypercholesterolemia [11*]. Using mice with transgenic expression of apoA-I and wild-type mice treated with 4F suggested that the beneficial effect of the mild hypercholesterolemia was HDL-mediated [11*].…”

Section: Efficacy Of Apolipoprotein Mimetics In Models Of Diseasementioning

confidence: 99%

“…Using mice with transgenic expression of apoA-I and wild-type mice treated with 4F suggested that the beneficial effect of the mild hypercholesterolemia was HDL-mediated [11*]. …”

Section: Efficacy Of Apolipoprotein Mimetics In Models Of Diseasementioning

confidence: 99%

Apolipoprotein A-I mimetics

Reddy

Navab²,

Anantharamaiah

et al. 2014

Current Opinion in Lipidology

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Purpose of Review To summarize recent publications in the field of apolipoprotein mimetics. Recent Findings Apolipoprotein mimetic peptides continue to show efficacy in a number of animal models of disease and demonstrate properties that make them attractive as potential therapeutic agents. A number of new apolipoprotein mimetics have been described recently. A major site of action of apolipoprotein mimetic peptides was found to be in the small intestine where they decrease the levels of pro-inflammatory bioactive lipids. A major problem related to the use of apolipoprotein mimetic peptides is their cost, particularly those that need to be generated by solid phase synthesis with chemical addition of end blocking groups. Novel approaches to apolipoprotein mimetic therapy have emerged recently that show promise in overcoming these barriers. Summary Despite the recent failure of therapies designed to raise HDL-cholesterol in humans, an approach to therapy using mimetics of HDL and its components continues to show promise.

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“…While it might be expected that risk factor combinations would exert an additive or synergistic effect on the vessel dysfunction elicited by the presence of individual risk factors, recent studies from our laboratory have revealed that mild diet-induced hypercholesterolemia blunts the recruitment of adherent leukocytes and platelets in venules, and protects against the impaired endothelium-dependent dilation in arteries elicited by hypertension(18, 22). It remains unclear whether this protective effect of HCh on HTN-induced vascular dysfunction is also manifested in genetically hypercholesterolemic (e.g, ApoE −/− ) mice placed on a normal diet.…”

Section: Introductionmentioning

confidence: 99%

Hypercholesterolemia blunts the oxidative stress elicited by hypertension in venules through angiotensin II type-2 receptors

Yıldırım

Senchenkova

Granger

2016

Microvascular Research

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OBJECTIVE Hypertension and hypercholesterolemia elicit inflammatory and thrombogenic responses in the microvasculature. However, little is known about whether and how risk factor combinations alter microvascular function. We examined how the actions of HTN+HCh on the microvasculature differ from the responses elicited by either risk factor alone. METHODS Intravital microscopy was used to monitor the adhesion and emigration of leukocytes and dihydrorhodamine oxidation in cremaster muscle venules of wild type mice that were infused with angiotensin II for 2 wks (HTN), placed on a high cholesterol diet (HCD), or both. RESULTS Either HTN or HCh alone enhanced the production of reactive oxygen species and promoted the recruitment of leukocytes in venules. However, the combination of HTN and HCh produced changes in ROS production and leukocyte recruitment that were greatly attenuated compared to HTN alone. The inhibitory effects of HCh on the AngII mediated responses were also observed in genetically-induced HCh (ApoE-deficient mice). Treating HCh + HTN mice with an antagonist to AT2r reversed the HCh-dependent protection against oxidative stress and inflammation during HTN. CONCLUSIONS These findings indicate that HCh blunts the oxidative stress and inflammatory cell recruitment elicited by hypertension in venules through a mechanism that involves AT2 receptor activation.

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Mild Hypercholesterolemia Blunts the Proinflammatory and Prothrombotic Effects of Hypertension on the Cerebral Microcirculation

Cited by 14 publications

References 40 publications

Lipid-Core Nanocapsules Act as a Drug Shuttle Through the Blood Brain Barrier and Reduce Glioblastoma After Intravenous or Oral Administration

Lipid-Core Nanocapsules Act as a Drug Shuttle Through the Blood Brain Barrier and Reduce Glioblastoma After Intravenous or Oral Administration

Apolipoprotein A-I mimetics

Hypercholesterolemia blunts the oxidative stress elicited by hypertension in venules through angiotensin II type-2 receptors

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