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Neurotherapeutics

, Volume 16, Issue 3, pp 725–740 | Cite as

Intranasal Losartan Decreases Perivascular Beta Amyloid, Inflammation, and the Decline of Neurogenesis in Hypertensive Rats

  • Henning J. Drews
  • Konstantin Yenkoyan
  • Ali Lourhmati
  • Marine Buadze
  • Daniela Kabisch
  • Stephan Verleysdonk
  • Stefan Petschak
  • Sandra Beer-Hammer
  • Tigran Davtyan
  • William H. FreyII
  • Christoph H. Gleiter
  • Matthias Schwab
  • Lusine DanielyanEmail author
Original Article

Abstract

The contribution of the local angiotensin receptor system to neuroinflammation, impaired neurogenesis, and amyloid beta (Aβ) accumulation in Alzheimer’s disease (AD) and in hypertension is consistent with the remarkable neuroprotection provided by angiotensin receptor blockers (ARBs) independent of their blood pressure-lowering effect. Considering the causal relationship between hypertension and AD and that targeting cerebrovascular pathology with ARBs does not necessarily require their systemic effects, we tested intranasal losartan in the rat model of chronic hypertension (spontaneously hypertensive stroke-prone rats, SHRSP). Intranasal losartan at a subdepressor dose decreased mortality, neuroinflammation, and perivascular content of Aβ by enhancing key players in its metabolism and clearance, including insulin-degrading enzyme, neprilysin, and transthyretin. Furthermore, this treatment improved neurologic deficits and increased brain IL-10 concentration, hippocampal cell survival, neurogenesis, and choroid plexus cell proliferation in SHRSP. Losartan (1 μM) also reduced LDH release from cultured astroglial cells in response to toxic glutamate concentrations. This effect was completely blunted by IL-10 antibodies. These findings suggest that intranasal ARB treatment is a neuroprotective, neurogenesis-inducing, and Aβ-decreasing strategy for the treatment of hypertensive stroke and cerebral amyloid angiopathy acting at least partly through the IL-10 pathway.

Key Words

Angiotensin Angiotensin receptor blocker Hemorrhagic stroke Intranasal Cerebral amyloid angiopathy Alzheimer’s disease 

Notes

Acknowledgments

We wish to thank Claudia Müller, Barbara Proksch, and Michael Glaser for excellent technical assistance.

Funding Sources

This study was supported by the Dr. Karl-Kuhn Foundation and Interfaculty Centre for Pharmacogenomics and Pharma Research (Grant number 15-0-0), Germany, given to L.D. M.S. was supported in part by the Robert Bosch Stiftung, Stuttgart, Germany.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Supplementary material

13311_2019_723_MOESM1_ESM.pdf (129 kb)
ESM 1 (PDF 128 kb)
13311_2019_723_MOESM2_ESM.pdf (486 kb)
ESM 2 (PDF 486 kb)

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Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2019

Authors and Affiliations

  • Henning J. Drews
    • 1
  • Konstantin Yenkoyan
    • 2
    • 3
  • Ali Lourhmati
    • 1
  • Marine Buadze
    • 1
  • Daniela Kabisch
    • 1
  • Stephan Verleysdonk
    • 4
  • Stefan Petschak
    • 1
  • Sandra Beer-Hammer
    • 5
  • Tigran Davtyan
    • 6
  • William H. FreyII
    • 7
  • Christoph H. Gleiter
    • 1
  • Matthias Schwab
    • 1
    • 2
    • 3
    • 8
    • 9
  • Lusine Danielyan
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Clinical PharmacologyUniversity Hospital of TuebingenTuebingenGermany
  2. 2.Departments of Biochemistry and of Clinical PharmacologyYerevan State Medical UniversityYerevanArmenia
  3. 3.Neuroscience LaboratoryYerevan State Medical UniversityYerevanArmenia
  4. 4.Interfaculty Institute of Biochemistry (IFIB)Eberhard Karls Universität TübingenTuebingenGermany
  5. 5.Department of Pharmacology and Experimental Therapy and Interfaculty Center of Pharmacogenomics and Drug Research (ICePhA)University of TuebingenTuebingenGermany
  6. 6.Analytical Laboratory Branch of E. Gabriyelian Scientific Center of Drug and Medical Technology Expertise of Ministry Health of Armenia YerevanArmenia
  7. 7.Center for Memory & AgingHealthPartners InstituteSt. PaulUSA
  8. 8.Dr. Margarete Fischer-Bosch-Institute of Clinical PharmacologyStuttgartGermany
  9. 9.Department of Pharmacy and BiochemistryUniversity of TuebingenTuebingenGermany

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