Brain as a potential target for antisense oligonucleotide treatment of hypertensive disease. Experimental study on the hypertensive ISIAH rat strain Conference Abstracts
Conference |
2018 Americas Conference on Medical Imaging and Clinical Research 23-25 Dec 2018 , Panama |
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Journal |
Basic & Clinical Pharmacology & Toxicology
ISSN: 1742-7835 , E-ISSN: 1742-7843 |
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Output data | Year: 2018, Volume: 124, Number: SI, Article number : 007, Pages count : 2 | ||||||||
Authors |
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Affiliations |
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Funding (2)
1 | Russian Science Foundation | 16-15-10073 |
2 | The Ministry of Education and Science of the Russian Federation | 14.621.21.0015 (RFMEFI62117X0015) |
Abstract:
Objectives: Brain is directly involved in the pathogenesis of the hypertensive disease. The in vivo metabolome study of the hypothalamus in the hypertensive ISIAH rats revealed distinct changes in metabolites related to the energy and excitatory brain processes. Significant changes in norepinephrine and dopamine concentrations in the hypothalamus and the brain stem of the ISIAH rats were also found. Then, continuous brain intraventricular infusion of the blocker of the angiotensin‐converting enzyme (ACE) by implanted micropumps produced a sustained fall in blood pressure (BP). This prompted us to study the effect of antisense oligodeoxyribonucleotides (ODN) targeted to mRNA of the ACE gene (ACE‐mRNA) on the BP in the ISIAH rats.
Methods: To study the antisense ODN effect on BP in the hypertensive ISIAH rats, we synthesized the Si˜NH2·ODN nanocomposite, amino‐containing silicon nanoparticles bearing oligodeoxyribonucleotide targeted to ACE‐mRNA. Si˜NH2·ODN was administered to rats by inhalation (100 μM for ODN), and BP was measured (tail‐cuff method) two days before and 14 days after inhalation. To study the distribution of the nanocomposite in the body, ODN was labeled with the Cy7.5 dye. The Si˜NH2·ODN(Cy7.5) nanocomposite (2 μM for ODN) was inhaled by the SCID hairless mice. The body distribution was detected by the fluorescent emission computed tomography immediately after inhalation, then 24 h, 72 h, and two weeks after inhalation.
Results: After inhalation, the BP of the ISIAH rats decreased on average by 20 mm/Hg for two weeks. The use of a scrambled oligonucleotide in the Si˜NH2·ODN nanocomposite had no effect. The distribution of the inhaled nanocomposite in the mice body demonstrated its predominant accumulation in the gastrointestinal tract. However, some amount of the ODN (Cy7.5) penetrated the blood‐brain barrier and was observed in the brain stem. The signal in the brain increased during 24 h after inhalation, and then decreased 1.4 and 2.4 times after three and seven days, respectively. The full excretion of the labeled sample from the body occurred during two weeks.
Conclusions:
● Inhalation of Si˜NH2·ODN nanocomposite by hypertensive ISIAH rats produced two‐week long BP decrease.
●Inhaled Si˜NH2·ODN nanocomposite containing antisense ODN against ACE‐mRNA may reach the brain structures in the rodents.
●The results indicate a potential role of the brain renin‐angiotensin system in the pathogenesis of stress‐induced hypertension simulated by the ISIAH rat strain.
Cite:
Levina A.S.
, Zarytova V.F.
, Repkova M.N.
, Klimov O.L.
, Seryapina A.A.
, Shikina N.V.
, Shevelev O.B.
, Markel A.L.
Brain as a potential target for antisense oligonucleotide treatment of hypertensive disease. Experimental study on the hypertensive ISIAH rat strain
Basic & Clinical Pharmacology & Toxicology. 2018. V.124. NSI. 007 :1-2. WOS
Brain as a potential target for antisense oligonucleotide treatment of hypertensive disease. Experimental study on the hypertensive ISIAH rat strain
Basic & Clinical Pharmacology & Toxicology. 2018. V.124. NSI. 007 :1-2. WOS
Identifiers:
Web of science | WOS:000452533800008 |
Citing:
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