Intranasal Losartan Decreases Perivascular Beta Amyloid, Inflammation, and the Decline of Neurogenesis in Hypertensive Rats
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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 WordsAngiotensin Angiotensin receptor blocker Hemorrhagic stroke Intranasal Cerebral amyloid angiopathy Alzheimer’s disease
We wish to thank Claudia Müller, Barbara Proksch, and Michael Glaser for excellent technical assistance.
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.
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The authors declare that they have no conflict of interest.
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- 6.Fournier A, Oprisiu-Fournier R, Serot JM, Godefroy O, Achard JM, Faure S, et al. Prevention of dementia by antihypertensive drugs: how AT1-receptor-blockers and dihydropyridines better prevent dementia in hypertensive patients than thiazides and ACE-inhibitors. Expert Rev Neurother 2009;9:1413–31.CrossRefGoogle Scholar
- 13.Danielyan L, Schafer R, von Ameln-Mayerhofer A, Buadze M, Geisler J, Klopfer T, et al. Intranasal delivery of cells to the brain. Eur J Cell Biol 2009.Google Scholar
- 15.Faraci FM. Protecting against vascular disease in brain. Am J Physiol Heart Circ Physiol 2011.Google Scholar
- 22.Kimura Y, Kitagawa K, Oku N, Kajimoto K, Kato H, Tanaka M, et al. Blood pressure lowering with valsartan is associated with maintenance of cerebral blood flow and cerebral perfusion reserve in hypertensive patients with cerebral small vessel disease. J Stroke Cerebrovasc Dis 2010;19:85–91.CrossRefGoogle Scholar
- 23.Bennai F, Morsing P, Paliege A, Ketteler M, Mayer B, Tapp R, et al. Normalizing the expression of nitric oxide synthase by low-dose AT1 receptor antagonism parallels improved vascular morphology in hypertensive rats. J Am Soc Nephrol 1999;10 Suppl 1:S104–15.Google Scholar
- 26.Albert FW, Shchepina O, Winter C, Römpler H, Teupser D, Palme R, et al. Phenotypic differences in behavior, physiology and neurochemistry between rats selected for tameness and for defensive aggression towards humans. Horm Behav 2008.Google Scholar
- 34.Paxinos G WC. The rat brain in stereotaxic coordinates. San Diego: Academic Press 1998:400.Google Scholar
- 51.Kwakowsky A, Potapov K, Kim S, Peppercorn K, Tate WP, Ábrahám IM. Treatment of beta amyloid 1-42 (Aβ1-42)-induced basal forebrain cholinergic damage by a non-classical estrogen signaling activator in vivo. Sci Rep 2016;6.Google Scholar
- 53.Park SY, Chae CB. Toxic levels of amyloid beta peptide do not induce VEGF synthesis. Mol Cell 2007;24:69–75.Google Scholar
- 59.Alemi M, Gaiteiro C, Ribeiro CA, Santos LM, Gomes JR, Oliveira SM, et al. Transthyretin participates in beta-amyloid transport from the brain to the liver- involvement of the low-density lipoprotein receptor-related protein 1? Sci Rep 2016;6.Google Scholar
- 60.González-Marrero I, Giménez-Llort L, Johanson CE, Carmona-Calero EM, Castañeyra-Ruiz L, Brito-Armas JM, et al. Choroid plexus dysfunction impairs beta-amyloid clearance in a triple transgenic mouse model of Alzheimer’s disease. Front Cell Neurosci 2015;9.Google Scholar
- 63.Torika N, Asraf K, Danon A, Apte RN, Fleisher-Berkovich S. Telmisartan modulates glial activation: in vitro and in vivo studies. PLoS One 2016;11.Google Scholar