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Neurotherapeutics
Published in: Neurotherapeutics 3/2019

01-07-2019 | Losartan | Original Article

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

Authors: Henning J. Drews, Konstantin Yenkoyan, Ali Lourhmati, Marine Buadze, Daniela Kabisch, Stephan Verleysdonk, Stefan Petschak, Sandra Beer-Hammer, Tigran Davtyan, William H. Frey II, Christoph H. Gleiter, Matthias Schwab, Lusine Danielyan

Published in: Neurotherapeutics | Issue 3/2019

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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.
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Literature
1.
Daulatzai MA. Cerebral hypoperfusion and glucose hypometabolism: key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer’s disease. J Neurosci Res 2017;95:943–72.CrossRef
2.
Kalaria RN, Ballard C. Overlap between pathology of Alzheimer disease and vascular dementia. Alzheimer Dis Assoc Disord 1999;13:S115–23.CrossRefPubMed
3.
Sironi L, Gelosa P, Guerrini U, et al. Anti-inflammatory effects of AT1 receptor blockade provide end-organ protection in stroke-prone rats independently from blood pressure fall. J Pharmacol Exp Ther 2004;311:989–95.CrossRefPubMed
4.
Danielyan L, Klein R, Hanson LR, Buadze M, Schwab M, Gleiter CH, et al. Protective effects of intranasal losartan in the APP/PS1 transgenic mouse model of Alzheimer disease. Rejuvenation Res 2010;13:195–201.CrossRefPubMed
5.
Joglar B, Rodriguez-Pallares J, Rodriguez-Perez AI, Rey P, Guerra MJ, Labandeira-Garcia JL. The inflammatory response in the MPTP model of Parkinson’s disease is mediated by brain angiotensin: relevance to progression of the disease. J Neurochem 2009;109:656–69.CrossRefPubMed
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.CrossRefPubMed
7.
Bhat SA, Goel R, Shukla S, Shukla R, Hanif K. Angiotensin receptor blockade by inhibiting glial activation promotes hippocampal neurogenesis via activation of Wnt/β-catenin signaling in hypertension. Mol Neurobiol 2018;55:5282–98.CrossRefPubMed
8.
Balin BJ, Broadwell RD, Salcman M, El-Kalliny M. Avenues for entry of peripherally administered protein to the central nervous system in mouse, rat, and squirrel monkey. J Comp Neurol 1986;251:260–80.CrossRefPubMed
9.
Dhuria S V., Hanson LR, Frey WH. Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J Pharm Sci 2010;99:1654–73.CrossRef
10.
Thorne RG, Pronk GJ, Padmanabhan V, Frey WH. Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience 2004;127:481–96.CrossRef
11.
Frey WH, Liu J, Chen X, Thorne RG, Fawcett JR, Ala TA, et al. Delivery of125I-NGF to the brain via the olfactory route. Drug Deliv 1997;4:87–92.CrossRef
12.
Hadaczek P, Yamashita Y, Mirek H, Tamas L, Bohn MC, Noble C, et al. The “perivascular pump” driven by arterial pulsation is a powerful mechanism for the distribution of therapeutic molecules within the brain. Mol Ther 2006;14:69–78.CrossRefPubMedPubMedCentral
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.
14.
Schiöth HB, Craft S, Brooks SJ, Frey WH, Benedict C. Brain insulin signaling and Alzheimer’s disease: current evidence and future directions. Mol Neurobiol 2012;46:4–10.CrossRefPubMed
15.
Faraci FM. Protecting against vascular disease in brain. Am J Physiol Heart Circ Physiol 2011.
16.
Knoblach SM, Faden AI. Interleukin-10 improves outcome and alters proinflammatory cytokine expression after experimental traumatic brain injury. Exp Neurol 1998;153:143–51.CrossRefPubMed
17.
Platten M, Youssef S, Hur EM, Ho PP, Han MH, Lanz T V., et al. Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1- and TH17-mediated autoimmunity. Proc Natl Acad Sci 2009;106:14948–53.CrossRefPubMed
18.
Torika N, Asraf K, Cohen H, Fleisher-Berkovich S. Intranasal telmisartan ameliorates brain pathology in five familial Alzheimer’s disease mice. Brain Behav Immun 2017;64:80–90.CrossRefPubMed
19.
Guidoux C, Hauw JJ, Klein IF, Labreuche J, Berr C, Duyckaerts C, et al. Amyloid angiopathy in brain hemorrhage: a postmortem neuropathological-magnetic resonance imaging study. Cerebrovasc Dis 2018;45:124–31.CrossRefPubMed
20.
Bueche CZ, Hawkes C, Garz C, Vielhaber S, Attems J, Knight RT, et al. Hypertension drives parenchymal β-amyloid accumulation in the brain parenchyma. Ann Clin Transl Neurol 2014;1:124–9.CrossRefPubMedPubMedCentral
21.
Takeda S, Sato N, Takeuchi D, Kurinami H, Shinohara M, Niisato K, et al. Angiotensin receptor blocker prevented β-amyloid-induced cognitive impairment associated with recovery of neurovascular coupling. Hypertension 2009;54:1345–52.CrossRefPubMed
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.CrossRefPubMed
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.PubMed
24.
Staudacher T, Pech B, Tappe M, Gross G, Mühlbauer B, Luippold G. Arterial blood pressure and renal sodium excretion in dopamine D3 receptor knockout mice. Hypertens Res 2007;30:93–101.CrossRefPubMed
25.
Yamori Y, Horie R, Akiguchi I, Kihara M, Nara Y, Lovenberg W. Symptomatological classification in the development of stroke in stroke-prone spontaneously hypertensive rats. Jpn Circ J 1982;46:274–83.CrossRefPubMed
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.
27.
Boltze J, Kowalski I, Förschler A, Schmidt U, Wagner D, Lobsien D, et al. The stairway: a novel behavioral test detecting sensomotoric stroke deficits in rats. Artif Organs, vol. 30, 2006, p. 756–63.CrossRefPubMed
28.
Lenhard SC, Strittmatter R, Price WJ, Chandra S, White RF, Barone FC. Brain MRI and neurological deficit measurements in focal stroke: rapid throughput validated with isradipine. Pharmacology 2007;81:1–10.CrossRefPubMed
29.
Tominaga T, Ohnishi ST. Interrelationship of brain edema, motor deficits, and memory impairment in rats exposed to focal ischemia. Stroke 1989;20:513–8.CrossRefPubMed
30.
Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL, Bartkowski H. Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke 1986;17:472–6.CrossRef
31.
Garcia JH, Wagner S, Liu K-F, Hu X-J. Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats: statistical validation. Stroke 1995;26:627–35.CrossRefPubMed
32.
Maguire S, Strittmatter R, Chandra S, Barone FC. Stroke-prone rats exhibit prolonged behavioral deficits without increased brain injury: an indication of disrupted post-stroke brain recovery of function. Neurosci Lett 2004;354:229–33.CrossRefPubMed
33.
Hunter AJ, Hatcher J, Virley D, Nelson P, Irving E, Hadingham SJ, et al. Functional assessments in mice and rats after focal stroke. Neuropharmacology 2000;39:806–16.CrossRefPubMed
34.
Paxinos G WC. The rat brain in stereotaxic coordinates. San Diego: Academic Press 1998:400.
35.
Held F, Morris AWJ, Pirici D, Niklass S, Sharp MMG, Garz C, et al. Vascular basement membrane alterations and β-amyloid accumulations in an animal model of cerebral small vessel disease. Clin Sci 2017;131:1001–13.CrossRefPubMed
36.
Roybon L, Deierborg T, Brundin P, Li JY. Involvement of Ngn2, Tbr and NeuroD proteins during postnatal olfactory bulb neurogenesis. Eur J Neurosci 2009;29:232–43.CrossRefPubMed
37.
Chakroborty S, Kim J, Schneider C, West AR, Stutzmann GE. Nitric oxide signaling is recruited as a compensatory mechanism for sustaining synaptic plasticity in Alzheimer’s disease mice. J Neurosci 2015;35:6893–902.CrossRefPubMedPubMedCentral
38.
Dulak J, Józkowicz A, Dembinska-Kiec A, Guevara I, Zdzienicka A, Zmudzinska-Grochot D, et al. Nitric oxide induces the synthesis of vascular endothelial growth factor by rat vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2000;20:659–66.CrossRefPubMed
39.
Yamada S, Ishima T, Hayashi M, Tomita T, Hayashi E. Muscarinic cholinoceptors and choline acetyltransferase activity in the hypothalamus of spontaneously hypertensive rats. Life Sci 1984;34:2151–8.CrossRefPubMed
40.
Sharp SI, Francis PT, Elliott MSJ, Kalaria RN, Bajic N, Hortobagyi T, et al. Choline acetyltransferase activity in vascular dementia and stroke. Dement Geriatr Cogn Disord 2009;28:233–8.CrossRefPubMed
41.
Brands MW, Banes-Berceli AKL, Inscho EW, Al-Azawi H, Allen AJ, Labazi H. Interleukin 6 knockout prevents angiotensin II hypertension: role of renal vasoconstriction and janus kinase 2/signal transducer and activator of transcription 3 activation. Hypertension 2010;56:879–84.CrossRefPubMedPubMedCentral
42.
Tilleux S, Hermans E. Neuroinflammation and regulation of glial glutamate uptake in neurological disorders. J Neurosci Res 2007;85:2059–70.CrossRefPubMed
43.
Ogunshola OO, Antoniou X. Contribution of hypoxia to Alzheimer’s disease: is HIF-1α a mediator of neurodegeneration? Cell Mol Life Sci 2009;66:3555–63.CrossRefPubMed
44.
Gemba T, Matsunaga K, Ueda M. Changes in extracellular concentration of amino acids in the hippocampus during cerebral ischemia in stroke-prone SHR, stroke-resistant SHR and normotensive rats. Neurosci Lett 1992;135:184–8.CrossRefPubMed
45.
Azegami T, Yuki Y, Hayashi K, Hishikawa A, Sawada SI, Ishige K, et al. Intranasal vaccination against angiotensin II type 1 receptor and pneumococcal surface protein A attenuates hypertension and pneumococcal infection in rodents. J Hypertens 2018;36:387–94.CrossRefPubMed
46.
Yamamoto E, Tamamaki N, Nakamura T, Kataoka K, Tokutomi Y, Dong YF, et al. Excess salt causes cerebral neuronal apoptosis and inflammation in stroke-prone hypertensive rats through angiotensin II-induced NADPH oxidase activation. Stroke 2008;39:3049–56.CrossRefPubMed
47.
McCabe C, Gallagher L, Gsell W, Graham D, Dominiczak AF, MacRae IM. Differences in the evolution of the ischemic penumbra in stroke-prone spontaneously hypertensive and Wistar-Kyoto rats. Stroke 2009;40:3864–8.CrossRefPubMedPubMedCentral
48.
Sharma S, Yang B, Xi X, Grotta JC, Aronowski J, Savitz SI. IL-10 directly protects cortical neurons by activating PI-3 kinase and STAT-3 pathways. Brain Res 2011;1373:189–94.CrossRefPubMed
49.
Miyamoto N, Zhang N, Tanaka R, Liu M, Hattori N, Urabe T. Neuroprotective role of angiotensin II type 2 receptor after transient focal ischemia in mice brain. Neurosci Res 2008;61:249–56.CrossRefPubMed
50.
Schreiber S, Drukarch B, Garz C, Niklass S, Stanaszek L, Kropf S, et al. Interplay between age, cerebral small vessel disease, parenchymal amyloid-β, and tau pathology: Longitudinal studies in hypertensive stroke-prone rats. J Alzheimers Dis, vol. 42, 2014, p. S205–15.CrossRefPubMed
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.
52.
Chiarini A, Whitfield J, Bonafini C, Chakravarthy B, Armato U, Dal Prà I. Amyloid-β25-35, an amyloid-β1-42surrogate, and proinflammatory cytokines stimulate VEGF-A secretion by cultured, early passage, normoxic adult human cerebral astrocytes. J Alzheimers Dis 2010;21:915–26.CrossRefPubMed
53.
Park SY, Chae CB. Toxic levels of amyloid beta peptide do not induce VEGF synthesis. Mol Cell 2007;24:69–75.
54.
Russo I, Caracciolo L, Tweedie D, Choi SH, Greig NH, Barlati S, et al. 3,6′-Dithiothalidomide, a new TNF-α synthesis inhibitor, attenuates the effect of Aβ1-42intracerebroventricular injection on hippocampal neurogenesis and memory deficit. J Neurochem 2012;122:1181–92.CrossRefPubMedPubMedCentral
55.
Kimura T, Nguyen PTH, Ho SA, Tran AH, Ono T, Nishijo H. T-817MA, a neurotrophic agent, ameliorates the deficits in adult neurogenesis and spatial memory in rats infused i.c.v. with amyloid-ß peptide. Br J Pharmacol 2009;157:451–63.CrossRefPubMedPubMedCentral
56.
Ishrat T, Pillai B, Soliman S, Fouda AY, Kozak A, Johnson MH, et al. Low-dose candesartan enhances molecular mediators of neuroplasticity and subsequent functional recovery after ischemic stroke in rats. Mol Neurobiol 2015;51:1542–53.CrossRefPubMed
57.
Thomas T, Miners S, Love S. Post-mortem assessment of hypoperfusion of cerebral cortex in Alzheimer’s disease and vascular dementia. Brain 2015;138:1059–69.CrossRefPubMed
58.
Ando H, Zhou J, Macova M, Imboden H, Saavedra JM, Angiotensin II AT1receptor blockade reverses pathological hypertrophy and inflammation in brain microvessels of spontaneously hypertensive rats. Stroke 2004;35:1726–31.CrossRefPubMed
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.
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.
61.
Isono N, Imamura Y, Ohmura K, Ueda N, Kawabata S, Furuse M, et al. Transthyretin concentrations in acute stroke patients predict convalescent rehabilitation. J Stroke Cerebrovasc Dis 2017;26:1375–82.CrossRefPubMed
62.
Torika N, Asraf K, Apte RN, Fleisher-Berkovich S. Candesartan ameliorates brain inflammation associated with Alzheimer’s disease. CNS Neurosci Ther 2018;24:231–42.CrossRefPubMedPubMedCentral
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.
Metadata
Title
Intranasal Losartan Decreases Perivascular Beta Amyloid, Inflammation, and the Decline of Neurogenesis in Hypertensive Rats
Authors
Henning J. Drews
Konstantin Yenkoyan
Ali Lourhmati
Marine Buadze
Daniela Kabisch
Stephan Verleysdonk
Stefan Petschak
Sandra Beer-Hammer
Tigran Davtyan
William H. Frey II
Christoph H. Gleiter
Matthias Schwab
Lusine Danielyan
Publication date
01-07-2019
Publisher
Springer International Publishing
Published in
Neurotherapeutics / Issue 3/2019
Print ISSN: 1933-7213
Electronic ISSN: 1878-7479
DOI
https://doi.org/10.1007/s13311-019-00723-6

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