Intranasal Losartan Decreases Perivascular Beta Amyloid, Inflammation, and the Decline of Neurogenesis in Hypertensive Rats
Autor: | William H. Frey, Sandra Beer-Hammer, Henning Johannes Drews, Stefan Petschak, Matthias Schwab, Stephan Verleysdonk, Lusine Danielyan, Marine Buadze, Daniela Kabisch, Ali Lourhmati, T. Davtyan, Christoph H. Gleiter, Konstantin Yenkoyan |
---|---|
Rok vydání: | 2019 |
Předmět: |
Male
0301 basic medicine medicine.medical_specialty Angiotensin receptor Amyloid beta Neurogenesis Neuroprotection Losartan Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Rats Inbred SHR Internal medicine medicine Animals Pharmacology (medical) Administration Intranasal Neuroinflammation Inflammation Pharmacology Amyloid beta-Peptides Dose-Response Relationship Drug biology business.industry medicine.disease Rats Stroke Transthyretin 030104 developmental biology Endocrinology Hypertension biology.protein Original Article Neurology (clinical) Cerebral amyloid angiopathy business Angiotensin II Type 1 Receptor Blockers Glymphatic System 030217 neurology & neurosurgery medicine.drug |
Zdroj: | Neurotherapeutics |
ISSN: | 1878-7479 1933-7213 |
Popis: | 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-019-00723-6) contains supplementary material, which is available to authorized users. |
Databáze: | OpenAIRE |
Externí odkaz: |