Telmisartan protects against cognitive decline via up-regulation of brain-derived neurotrophic factor/tropomyosin-related kinase B in hippocampus of hypertensive rats

Open ArchivePublished:September 04, 2012DOI:https://doi.org/10.1016/j.jjcc.2012.08.004

      Summary

      Background and purpose

      Cognitive decline may occur as a result of hypertension, and is dependent on the function of hippocampus. Brain-derived neurotrophic factor (BDNF) mediated by angiotensin II-induced oxidative stress protects against cell death in hippocampus. Angiotensin II receptor blocker (ARB), candesartan, activates BDNF in the hippocampus. Furthermore, peroxisome proliferator-activated receptor (PPAR)-gamma activation in the brain prevents brain damage. Telmisartan, a unique ARB with PPAR-gamma stimulating activity, protects against cognitive decline partly because of PPAR-gamma activation. The aim of the present study was to determine whether telmisartan protects against cognitive decline via up-regulation of BDNF and its receptor tropomyosin-related kinase B (TrkB) in the hippocampus of hypertensive rats, partly because of PPAR-gamma activation.

      Methods and results

      We divided stroke-prone spontaneously hypertensive rats (SHRSPs), as hypertensive and vascular dementia model rats, into five groups, telmisartan-treated (TLM), TLM + GW9662, a PPAR-gamma inhibitor, -treated (T + G), GW9662-treated (GW), TLM + ANA-12, a TrkB antagonist, -treated (T + A), and vehicle-treated SHRSPs (VEH). After the treatment for 28 days, systolic blood pressure did not change in all groups. However, BDNF expression in the hippocampus was significantly higher in TLM than in VEH to a greater extent than in T + G. Cognitive performance was significantly higher in TLM than in VEH to a greater extent than in T + G, and was not different between T + A, GW, and VEH.

      Conclusion

      Telmisartan protects against cognitive decline via up-regulation of BDNF/TrkB in the hippocampus of SHRSPs, partly because of PPAR-gamma activation independent of blood pressure-lowering effect.

      Keywords

      Introduction

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      Nonhypotensive dose of telmisartan attenuates cognitive impairment partially due to peroxisome proliferator-activated receptor-gamma activation in mice with chronic cerebral hypoperfusion.
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      • Nishimura R.
      • Fujiwara M.
      Telmisartan, a partial agonist of peroxisome proliferator-activated receptor γ, improves impairment of spatial memory and hippocampal apoptosis in rats treated with repeated cerebral ischemia.
      ]. However, it has not been determined whether telmisartan has protective effects on cognitive decline via up-regulation of BDNF/TrkB in the hippocampus.
      Combined with these previous studies, we had the hypothesis that the beneficial effects of telmisartan on cognition are not only because of its established effect of antihypertensive and systemic blockade of AT1R but also because of the benefits on BDNF in the hippocampus via PPAR-gamma agonistic effect in hypertension. The aim of the present study was to determine whether telmisartan protects against cognitive decline via up-regulation of BDNF/TrkB in the hippocampus of stroke-prone spontaneously hypertensive rats (SHRSPs) as hypertensive and vascular dementia model rats [
      • Kimura S.
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      ], partly because of PPAR-gamma activation. Previous studies have demonstrated that ARBs have benefits on brain damage and vascular inflammation in SHRSPs [
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      ]. Telmisartan also has anti-oxidant effects in vasculature [
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      ] and brain [
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      Sympathoinhibition caused by orally administered telmisartan through inhibition of the AT1 receptor in the rostral ventrolateral medulla of hypertensive rats.
      ] of SHRSPs. We divided SHRSPs into five groups, telmisartan-treated (TLM), TLM + GW9662, a PPAR-gamma antagonist, -treated (T + G), GW9662-treated (GW), TLM + N-[2-[[(hexahydro-2-oxo-1H-azepin-3-yl) amino] carbonyl] phenyl]-benzothiophene-2-carboxamide (ANA-12), a TrkB antagonist, -treated (T + A), and vehicle-treated SHRSPs (VEH). Cognitive function was assessed by the Morris water maze test, which has been widely used as a test of spatial memory and cognition [
      • Morris R.
      Development of a water-maze procedure for studying spatial learning in the rat.
      ].

      Methods

       Animals

      This study was reviewed and approved by the committee on ethics of Animal Experiments, Kyushu University Graduate School of Medical Sciences, and conducted according to the Guidelines for Animal Experiments of Kyushu University. Male SHRSPs (12–14 weeks), weighing 350–425 g and fed standard feed were used (SLC Japan, Hamamatsu, Japan). They were housed individually in a temperature-controlled room (22–23 °C) with a 12-h/12-h light-dark cycle (lights on at 7:00 AM). We divided SHRSPs into 5 groups: TLM, T + G, T + A, GW, and VEH (n = 5 for each). Systolic blood pressure and heart rate were measured daily using the tail-cuff method (BP-98 A; Softron, Tokyo, Japan).

       Oral administration of drugs

      SHRSPs were treated for 4 weeks. TLM group was administered telmisartan (1 mg/kg/day, Sigma Aldrich, St. Louis, MO, USA). GW group was administered GW9662 (1 mg/kg/day, Sigma Aldrich). T + G group was administered telmisartan (1 mg/kg/day) plus GW9662 (1 mg/kg/day). T + A group was administered telmisartan (1 mg/kg/day) plus ANA-12 (0.5 mg/kg/day, Sigma Aldrich). VEH group was administered 0.5% methylcellulose. All drugs were dissolved in 0.5% methylcellulose and administered by gastric gavage every day. The dose of telmisartan was selected as a low dose and non-depressor dose [
      • Kobayashi N.
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      • Nomura M.
      • Hirata H.
      • Machida Y.
      • Shinoda M.
      • Suzuki N.
      • Matsuoka H.
      Cardioprotective mechanism of telmisartan via PPAR-γ-eNOS pathway in Dahl salt-sensitive hypertensive rats.
      ,
      • Wagner J.
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      • Ganten D.
      Effects of AT1 receptor blockade on blood pressure and the renin–angiotensin system in spontaneously hypertensive rats of the stroke prone strain.
      ]. The dose of GW9662 was according to the previous studies examining the partial effect of telmisartan on PPAR-gamma activation [
      • Washida K.
      • Ihara M.
      • Nishio K.
      • Fujita Y.
      • Maki T.
      • Yamada M.
      • Takahashi J.
      • Wu X.
      • Kihara T.
      • Ito H.
      • Toshimoto H.
      • Takahashi R.
      Nonhypotensive dose of telmisartan attenuates cognitive impairment partially due to peroxisome proliferator-activated receptor-gamma activation in mice with chronic cerebral hypoperfusion.
      ,
      • Kobayashi N.
      • Ohno T.
      • Yoshida K.
      • Fukushima H.
      • Mamada Y.
      • Nomura M.
      • Hirata H.
      • Machida Y.
      • Shinoda M.
      • Suzuki N.
      • Matsuoka H.
      Cardioprotective mechanism of telmisartan via PPAR-γ-eNOS pathway in Dahl salt-sensitive hypertensive rats.
      ]. The dose of ANA-12 was determined to blockade BDNF according to a previous study [
      • Cazorla M.
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      • Rognan D.
      Identification of a low-molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice.
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       Western blotting analysis

      To obtain the hippocampus tissues, the rats were deeply anesthetized with sodium pentobarbital (100 mg/kg IP) and perfused transcardially with PBS (150 mol/L NaCl, 3 mmol/L KCl, and 5 nmol/L phosphate; pH 7.4, 4 °C). The brains were removed quickly, and the hippocampus tissues obtained according to a rat brain atlas were homogenized and sonicated in a lysing buffer containing 40 mmol/L HEPES, 1% Triton X-100, 10% glycerol, and 1 mmol/L phenylmethanesulfonyl fluoride. The tissue lysate was centrifuged at 6000 rpm for 5 min at 4 °C with a microcentrifuge. The lysate was collected, and protein concentration was determined with a BCA protein assay kit (Pierce, Rockford, IL, USA). An aliquot of 20 μg of protein from each sample was separated on 12% SDS-polyacrylamide gel. Proteins were subsequently transferred onto polyvinylidene difluoride membranes (Immobilon-P membrane; Millipore, Billarica, MA, USA). Membranes were incubated for 2 h with a rabbit polyclonal antiserum against BDNF (1:1000; Abcam, Cambridge, UK) or α-tubulin (1:1000; Cell Signaling, Danvers, MA, USA). Membranes were then washed and incubated with a horseradish peroxidase–conjugated horse anti-mouse IgG antibody (1:10,000) for 40 min. Immunoreactivity was detected by enhanced chemiluminescence autoradiography (plus Western blotting detection kit; GE Healthcare Bio-Sciences AB, Uppsala, Sweden), and was expressed as the ratio to α-tubulin protein.

       Analysis of cognitive function

      Spatial learning and memory function of the rats were investigated with the Morris water maze test in a circular pool filled with water at a temperature of 25.0 ± 1 °C [
      • Morris R.
      Development of a water-maze procedure for studying spatial learning in the rat.
      ]. In the hidden platform test, a transparent platform was submerged 1 cm below the water level. Swimming paths were tracked with a camera fixed on the ceiling of the room and stored in a computer. All the procedures of the Morris water maze were performed for 7 days. A pre-training session was carried out at day 0, in which animals were given 60 s free swimming without the platform. In the hidden-platform test for 4 days, the rats were given 2 trials (1 session) on day 1 and 4 trials (2 sessions) per day on days 2, 3, and 4. The initial trial interval was about 30 min and the inter-session interval was 2 h. During each trial, the rats were released from four pseudo-randomly assigned starting points and allowed to swim for 60 s. After mounting the platform, the rats were allowed to remain there for 15 s, and were then placed in the home cage until the start of the next trial. If a rat was unable to find the platform within 60 s, it was guided to the platform and allowed to rest on the platform for 15 s. Probe trials were performed at day 5. In the probe trial, the hidden platform was removed and the rats was released from the right quadrant and allowed to swim freely for 60 s. The time spent in the target quadrant, where the platform had been located during training, and the time spent in the other quadrants were measured. In the visible-platform test which was performed at day 6, the platform was elevated above the water surface and placed in a different position.

       Statistical analysis

      All values are expressed as mean ± SEM. Comparisons between any two mean values were performed using Bonferroni's correction for multiple comparisons. ANOVA was used to compare all the parameters in all groups. Differences were considered to be statistically significant at a p-value of <0.05.

      Results

       Physiological data

      Systolic blood pressure and heart rate were not changed in TLM, T + G, GW, T + A, and VEH after the treatments (Table 1). Body weight, dairy calorie intake, and water intake were also not different in all groups (Table 1).
      Table 1Physiological data.
      VEHTLMT + GT + AGW
      SBP (mmHg)240 ± 28228 ± 17229 ± 16231 ± 19243 ± 21
      HR (bpm)338 ± 30331 ± 26340 ± 29343 ± 30329 ± 37
      BW (g)282 ± 15280 ± 14288 ± 17276 ± 19291 ± 22
      Calorie intake (Kcal/day)77 ± 574 ± 872 ± 478 ± 674 ± 9
      Water intake (ml/day)32 ± 429 ± 430 ± 530 ± 328 ± 5
      Data are expressed as the mean ± SEM.
      SBP, systolic blood pressure; HR, heart rate; BW, body weight; VEH, vehicle; TLM, telmisartan; T + G, telmisartan + GW9662; T + A, telmisartan + ANA-12; GW, GW9662; n = 5 for each.

       Expression of BDNF in the hippocampus

      The expression of BDNF in the hippocampus was significantly higher in TLM than in VEH (Fig. 1). The up-regulation of BDNF in the hippocampus in TLM was attenuated in T + G, but not in T + A (Fig. 1). However, the expression of BDNF in the hippocampus was not different between GW and VEH (Fig. 1).
      Figure thumbnail gr1
      Fig. 1Expression of BDNF in the hippocampus in each group. BDNF/α-tubulin expression was expressed relative to that in VEH which was assigned a value of 1. *p < 0.05 versus VEH, +p < 0.05 in T + G versus TLM, n = 5 for each. BDNF, brain-derived neurotrophic factor; VEH, vehicle; TLM, telmisartan; T + G, telmisartan + GW9662; T + A, telmisartan + N-[2-[[(hexahydro-2-oxo-1H-azepin-3-yl) amino] carbonyl] phenyl]-benzothiophene-2-carboxamide (ANA-12); GW, GW9662.

       Morris water maze test

      In the hidden platform test, escape latency was significantly lower in TLM than in VEH to a greater extent than in T + G (Fig. 2), and was not different between in VEH, GW, and T + A (Fig. 2). In the probe test, TLM resulted in significantly more time in the target quadrant as compared with VEH, GW, and T + A to a greater extent than in T + G (Fig. 3). In the visible platform test, there were no significant differences in escape latency among all of the groups.
      Figure thumbnail gr2
      Fig. 2Escape latency in the hidden platform test of Morris water maze. *p < 0.05 versus VEH, +p < 0.05 in T + G versus TLM, n = 5 for each. VEH, vehicle; TLM, telmisartan; T + G, telmisartan + GW9662; T + A, telmisartan + N-[2-[[(hexahydro-2-oxo-1H-azepin-3-yl) amino] carbonyl] phenyl]-benzothiophene-2-carboxamide (ANA-12); GW, GW9662.
      Figure thumbnail gr3
      Fig. 3Time in the target quadrant of the probe test of Morris water maze. *p < 0.05 versus VEH, +p < 0.05 in T + G versus TLM, n = 5 for each. VEH, vehicle; TLM, telmisartan; T + G, telmisartan + GW9662; T + A, telmisartan + N-[2-[[(hexahydro-2-oxo-1H-azepin-3-yl) amino] carbonyl] phenyl]-benzothiophene-2-carboxamide (ANA-12); GW, GW9662.

      Discussion

      In the present study, we have demonstrated two major findings. First, telmisartan has a protective effect on the cognitive decline via up-regulation of BDNF/TrkB in the hippocampus of SHRSPs without depressor effect. Second, co-administration of a PPAR-gamma antagonist with telmisartan partially attenuated the telmisartan-mediated protective effect on the cognitive decline. These results suggest that telmisartan has a possibility of protective effect against cognitive decline via activation of BDNF/TrkB through blockade of AT1R and part activation of PPAR-gamma in the hippocampus of SHRSPs independent of blood pressure-lowering effect.
      In the hippocampus, BDNF protects against ischemic cell damage [
      • Ito H.
      • Takemori K.
      • Suzuki T.
      Role of angiotensin II type 1 receptor in the leucocytes and endothelial cells of brain microvessels in the pathogenesis of hypertensive cerebral injury.
      ]. Angiotensin II blocks long-term potentiation in the hippocampus [
      • Beck T.
      • Lindholm D.
      • Castren E.
      • Wree A.
      Brain-derived neurotrophic factor protects against ischemic cell damage in rat hippocampus.
      ,
      • Denny J.B.
      • Polan-Curtain J.
      • Wayner M.J.
      • Armstrong D.L.
      Angiotensin II blocks hippocampal long-term potentiation.
      ,
      • Wayner M.J.
      • Armstrong D.L.
      • Polan-Curtain J.L.
      • Denny J.B.
      Role of angiotensin II and AT1 receptors in hippocampal LTP.
      ,
      • Gard P.R.
      The role of angiotensin II in cognition and behavior.
      ,
      • De Bundel D.
      • Demaegdt H.
      • Lahoutte T.
      • Cavelier V.
      • Kersemans K.
      • Ceulemans A.G.
      • Vauquelin G.
      • Clinckers R.
      • Vanderheyden P.
      • Michotte Y.
      • Smolders I.
      Involvement of the AT1 receptor subtype in the effects of angiotensin IV and LVVhaemorphin 7 on hippocampal neurotransmitter levels and spatial working memory.
      ], and induces superoxide-dependent down regulation of BDNF [
      • Chan S.H.
      • Wu C.W.
      • Chang A.Y.
      • Hsu K.S.
      • Chan J.Y.
      Transcriptional upregulation of brain-derived neurotrophic factor in rostral ventrolateral medulla by angiotensin II: significant in superoxide homeostasis and neural regulation of arterial pressure.
      ]. In the present study, low-dose telmisartan caused the protective effect against cognitive decline with the increase in BDNF expression in hippocampus of SHRSPs, and the effects were attenuated by TrkB antagonist. These results suggest that telmisartan has a protective effect on the cognitive decline via up-regulation of BDNF/TrkB in the hippocampus of SHRSPs without a depressor effect. Among ARBs, candesartan at sub-hypotensive and renin–angiotensin system blocking dose affords neuroprotection after focal ischemia, associated with increased activity of the BDNF [
      • Krikov M.
      • Thone-Reineke C.
      • Muller S.
      • Villringer A.
      • Unger T.
      Candesartan but not ramipril pretreatment improves outcome after stroke and stimulates neurotrophin BDNF/TrkB system in rats.
      ]. Interestingly, ramipril at sub-hypotensive, hypotensive, and renin–angiotensin system blocking doses showed no significant neuroprotective effects [
      • Krikov M.
      • Thone-Reineke C.
      • Muller S.
      • Villringer A.
      • Unger T.
      Candesartan but not ramipril pretreatment improves outcome after stroke and stimulates neurotrophin BDNF/TrkB system in rats.
      ]. Oxidative stress and/or antioxidant deficiency cause cognitive decline [
      • Berr C.
      • Balansard B.
      • Arnaud J.
      • Roussel A.M.
      • Alperovitch A.
      Cognitive decline is associated with systemic oxidative stress: the EVA study. Etude du Vieillissement Arterial.
      ], and oxidative stress in hippocampus impairs cognitive function [
      • Sato H.
      • Takahashi T.
      • Sumitani K.
      • Takatsu H.
      • Urano S.
      Glucocorticoid generates ROS to induce oxidative injury in the hippocampus, leading to impairment of cognitive function of rats.
      ]. Combining the previous studies with our results in the present study, we consider that the telmisartan-induced up-regulation of BDNF/TrkB is caused by the blockade of AT1R-induced superoxide in the hippocampus, and that ARBs have a potential to be preferable agents for the treatment of hypertension with the protection against cognitive decline via up-regulation of BDNF/TrkB in the hippocampus.
      We also demonstrated that, in the present study, telmisartan-induced protection against cognitive decline via up-regulation of BDNF/TrkB in the hippocampus was partially attenuated by co-administration of PPAR-gamma antagonist with telmisartan. In a previous study, low-dose telmisartan without depressor effect protected against focal brain ischemia partly through activation of PPAR-gamma as well as AT1R blockade [
      • Iwanami J.
      • Mogi M.
      • Tsukuda K.
      • Min L.J.
      • Sakata A.
      • Jing F.
      • Iwai M.
      • Horiuchi M.
      Low dose of telmisartan prevents ischemic brain damage with peroxisome proliferator-activated receptor-gamma activation in diabetic mice.
      ]. Telmisartan improves memory impairment and reduces neural apoptosis in hippocampus via a PPAR-gamma-dependent anti-apoptotic mechanism in rats with repeated cerebral ischemia [
      • Haraguchi T.
      • Iwasaki K.
      • Takasaki K.
      • Uchida K.
      • Naito T.
      • Nogami A.
      • Kubota K.
      • Shindo T.
      • Uchida N.
      • Katsurabayashi S.
      • Mishima K.
      • Nishimura R.
      • Fujiwara M.
      Telmisartan, a partial agonist of peroxisome proliferator-activated receptor γ, improves impairment of spatial memory and hippocampal apoptosis in rats treated with repeated cerebral ischemia.
      ]. In other studies, co-administration of PPAR-gamma antagonist had no effect on the losartan-mediated reduction in ischemic area [
      • Haraguchi T.
      • Iwasaki K.
      • Takasaki K.
      • Uchida K.
      • Naito T.
      • Nogami A.
      • Kubota K.
      • Shindo T.
      • Uchida N.
      • Katsurabayashi S.
      • Mishima K.
      • Nishimura R.
      • Fujiwara M.
      Telmisartan, a partial agonist of peroxisome proliferator-activated receptor γ, improves impairment of spatial memory and hippocampal apoptosis in rats treated with repeated cerebral ischemia.
      ,
      • Iwanami J.
      • Mogi M.
      • Tsukuda K.
      • Min L.J.
      • Sakata A.
      • Jing F.
      • Iwai M.
      • Horiuchi M.
      Low dose of telmisartan prevents ischemic brain damage with peroxisome proliferator-activated receptor-gamma activation in diabetic mice.
      ]. Our results are comparable with those previous studies, and suggest that telmisartan could exert protective effects against cognitive decline via up-regulation of BDNF/TrkB in the hippocampus through AT1R blockade and partly PPAR-gamma stimulation. Interestingly, in the present study, PPAR-gamma antagonist alone did not change cognitive performance and the expression of BDNF in the hippocampus. There is a possibility that AT1R blockade has a synergistic effect of PPAR-gamma activation. If so, ARB with partial PPAR-gamma agonist, telmisartan, has a potential to be a preferable agent for the treatment of hypertension with the protection against cognitive decline via up-regulation of BDNF/TrkB in the hippocampus.
      The protective effect against cognitive decline is not specific in telmisartan among ARBs. Candesartan has a positive effect on cognitive decline in hypertensive patients [
      • Saxby B.K.
      • Harrington F.
      • Wesnes K.A.
      • McKeith I.G.
      • Ford G.A.
      Candesartan and cognitive decline in older patients with hypertension a substudy of the SCOPE trial.
      ] or diabetic model [
      • Toda S.
      • Kamat P.K.
      • Awasthi H.
      • Singh N.
      • Raghubir R.
      • Nath C.
      • Hanif K.
      Candesartan improves memory decline in mice: involvement of AT1 receptors in memory deficit induced by intracerebral streptozotocin.
      ], and also significantly reduced the incidence and progression of dementia [
      • Li N.C.
      • Lee A.
      • Whitmer R.A.
      • Kivipelto M.
      • Lawler E.
      • Kazis L.E.
      • Wolozin B.
      Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis.
      ]. In SHRSPs, candesartan improves hippocampal CA1 neuron cell reduction, and superoxide production in the hippocampus [
      • Kim-Mitsuyama S.
      • Yamamoto E.
      • Tanaka E.
      • Zhan Y.
      • Izumiya Y.
      • Ioroi T.
      • Wanibuchi H.
      • Iwao H.
      Critical role of angiotensin II in excess salt-induced brain oxidative stress of stroke-prone spontaneously hypertensive rats.
      ]. In the brain, AT1R-induced superoxide decreases BDNF [
      • Chan S.H.
      • Wu C.W.
      • Chang A.Y.
      • Hsu K.S.
      • Chan J.Y.
      Transcriptional upregulation of brain-derived neurotrophic factor in rostral ventrolateral medulla by angiotensin II: significant in superoxide homeostasis and neural regulation of arterial pressure.
      ]. Both telmisartan and candesartan are reported to reduce oxidative stress via blockade of AT1R in the brain [
      • Hirooka Y.
      • Sagara Y.
      • Kishi T.
      • Sunagawa K.
      Oxidative stress and central cardiovascular regulation. Pathogenesis of hypertension and therapeutic aspects-.
      ,
      • Tsuchihashi T.
      • Kagiyama S.
      • Matsumura K.
      • Abe I.
      • Fujishima M.
      Effects of chronic oral treatment with imidapril and TCV-116 on the responsiveness to angiotensin II in ventrolateral medulla of SHR.
      ,
      • Pelosch N.
      • Hosomi N.
      • Ueno M.
      • Masugata H.
      • Murao K.
      • Hitomi H.
      • Nakao D.
      • Kobori H.
      • Nishiyama A.
      • Kohno M.
      Systemic candesartan reduces brain angiotensin II via downregulation of brain renin–angiotensin system.
      ]. Although candesartan was not examined in the present study, we consider that the protective effect against cognitive decline via up-regulation of BDNF/TrkB in the hippocampus is also caused by candesartan, not only telmisartan among ARBs, through the blockade of AT1R in the hippocampus. However, the change in permeability of the blood–brain barrier by ARBs has not been well assessed to date. Ischemic brain damage enhances blood–brain barrier permeability and penetration of ARBs into the brain, and blood–brain barrier is disrupted in SHRSPs [
      • Ueno M.
      • Sakamoto H.
      • Liao Y.J.
      • Onodera M.
      • Huang C.L.
      • Miyanaka H.
      • Nakagawa T.
      Blood–brain barrier disruption in the hypothalamus of young adult spontaneously hypertensive rats.
      ,
      • Lippoldt A.
      • Kniesel U.
      • Liebner S.
      • Kalbacher H.
      • Kirsch T.
      • Wolburg H.
      • Haller H.
      Structural alterations of tight junctions are associated with loss of polarity in stroke-prone spontaneously hypertensive rat blood–brain barrier endothelial cells.
      ]. Telmisartan is expected to readily shift to organs compared with other ARBs, due to its high lipid solubility [
      • Gohlke P.
      • Weiss S.
      • Jansen A.
      • Wienen W.
      • Stangier J.
      • Rascher W.
      • Culman J.
      • Unger T.
      AT1 receptor antagonist telmisartan administered peripherally inhibits central responses to angiotensin II in conscious rats.
      ,
      • Maillard M.P.
      • Perregaux C.
      • Centeno C.
      • Stangier J.
      • Wienen W.
      • Brunner H.R.
      • Burnier M.
      In vitro and in vivo characterization of the activity of telmisartan: an insurmountable angiotensin II receptor antagonist.
      ]. Moreover, telmisartan is a unique ARB with a partial PPAR-gamma agonistic property [
      • Benson S.C.
      • Pershadsingh H.A.
      • Ho C.I.
      • Chittiboyina A.
      • Desai P.
      • Pravenec M.
      • Qi N.
      • Wang J.
      • Avery M.A.
      • Kurtz T.W.
      Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity.
      ]. From the results obtained in the present study, AT1R blockade with PPAR-gamma agonist is considered to be preferable to the protection against cognitive decline via up-regulation of BDNF/TrkB in the hippocampus.
      Although the present study could demonstrate a beneficial effect of low-dose telmisartan on cognitive function, depressor dose of telmisartan could not provide positive effect on cognition in previous clinical studies [
      • Diener H.C.
      • Sacco R.L.
      • Yusuf S.
      • Cotton D.
      • Ounpuu S.
      • Lawton W.A.
      • Palesch Y.
      • Martin R.H.
      • Albers G.W.
      • Bath P.
      • Bornstein N.
      • Chan B.P.
      • Chen St
      • Cunha L.
      • Dahlof B.
      • et al.
      Effects of aspirin plus extended release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention regimen for Effectively Avoiding Second Stroke (PRoFESS) trial: a double-blind, active, and placebo-controlled study.
      ,
      • Anderson C.
      • Teo K.
      • Gao P.
      • Arima H.
      • Dans A.
      • Unger T.
      • Commerford P.
      • Dyal L.
      • Schumacher H.
      • Pogue J.
      • Paolasso E.
      • Holwerda N.
      • Chazova I.
      • Binbrek A.
      • Young J.
      • et al.
      Renin–angiotensin system blockade and cognitive function in patients at high risk of cardiovascular disease: analysis of data from the ONTARGET and TRANSCEND studies.
      ]. This discrepancy could not be due to the difference in the dose of telmisartan, because the beneficial effects in the present study were obtained with the low and not depressor dose of telmisartan. We could not fully clarify the reasons of the discrepancy in the present study. We used the Morris water maze test in SHRSPs to evaluate cognitive function instead of the shuttle avoidance test. A spatial working memory task, such as Morris water maze test, depends on hippocampus function [
      • Moser M.B.
      • Trommald M.
      • Andersen P.
      An increase in dendritic spine density on hippocampal CA1 pyramidal cells following spatial learning in adult rats suggests the formation of new synapses.
      ,
      • Barnes C.A.
      Spatial learning and memory processes: the search for their neurobiological mechanisms in the rat.
      ]. Because we focused on cognitive performance via BDNF/TrkB in the hippocampus of SHRSPs, we used the Morris water maze test. However, it has not been determined whether other cognitive function tests could obtain similar beneficial effects in other models, such as Alzheimer, diabetes, or cardiovascular disease models. We consider that the cognitive decline in cardiovascular diseases has various clinical backgrounds, and that multi-targeted therapy by combination of agents is necessary to protect against cognitive decline. In these aspects, AT1R blockade with PPAR-gamma agonist, telmisartan, might be considered to be preferable among ARBs.

      Limitations

      There are several limitations in the present study. First, we could not determine the dose dependency of telmisartan and not demonstrate the direct data indicating that telmisartan penetrates blood–brain barrier and reaches the hippocampus. Telmisartan used in the present study was at a low and not depressor dose, and we consider that the higher and depressor dose of telmisartan would provide more beneficial effects. It is necessary in a further study to determine whether the telmisartan-induced depressor effect is synergistic to the present results or not, and to measure the concentration of telmisartan in the hippocampus. Second, we did not quantify superoxide in the hippocampus, and did not determine whether telmisartan reduced superoxide in the hippocampus. Furthermore, we examined only cognitive function and BDNF expression in the hippocampus in the present study, and we did not examine the brain damage in the other areas and vascular inflammation. Previously many studies have already demonstrated that ARBs could prevent brain damage [
      • Saavedra J.M.
      • Sanchez-Lemus E.
      • Benicky J.
      Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: Therapeutic implications.
      ,
      • Haraguchi T.
      • Iwasaki K.
      • Takasaki K.
      • Uchida K.
      • Naito T.
      • Nogami A.
      • Kubota K.
      • Shindo T.
      • Uchida N.
      • Katsurabayashi S.
      • Mishima K.
      • Nishimura R.
      • Fujiwara M.
      Telmisartan, a partial agonist of peroxisome proliferator-activated receptor γ, improves impairment of spatial memory and hippocampal apoptosis in rats treated with repeated cerebral ischemia.
      ,
      • Mogi M.
      • Li J.M.
      • Tsukuda K.
      • Iwanami J.
      • Min L.J.
      • Sakata A.
      • Fujita T.
      • Iwai M.
      • Horiuchi M.
      Telmisartan prevented cognitive decline partly due to PPAR-gamma activation.
      ,
      • Tsukuda K.
      • Mogi M.
      • Iwanami J.
      • Min L.J.
      • Sakata A.
      • Jing F.
      • Iwai M.
      • Horiuchi M.
      Cognitive deficit in amyloid-beta-injected mice was improved by pretreatment with a low dose of telmisartan partly because of peroxisome proliferator-activated receptor-gamma activation.
      ,
      • Iwanami J.
      • Mogi M.
      • Tsukuda K.
      • Min L.J.
      • Sakata A.
      • Jing F.
      • Iwai M.
      • Horiuchi M.
      Low dose of telmisartan prevents ischemic brain damage with peroxisome proliferator-activated receptor-gamma activation in diabetic mice.
      ] and vascular inflammation [
      • Hamaguchi R.
      • Takemori K.
      • Inoue T.
      • Masuno K.
      • Uto H.
      Short-term treatment of stroke-prone spontaneously hypertensive rats with AT1 receptor blocker protects against hypertensive end-organ damage by prolonged inhibition of the renin–angiotensin system.
      ,
      • Takemori K.
      • Inoue T.
      • Ito H.
      Possible role of nitric oxide generated by leukocytes in the pathogenesis of hypertensive cerebral edema in stroke-prone spontaneously hypertensive rats.
      ,
      • Ito H.
      • Takemori K.
      • Suzuki T.
      Role of angiotensin II type 1 receptor in the leucocytes and endothelial cells of brain microvessels in the pathogenesis of hypertensive cerebral injury.
      ]. Telmisartan also has benefits in SHRSP [
      • Kagota S.
      • Tada Y.
      • Nejime N.
      • Nakamura K.
      • Kunitomo M.
      • Shinozuka K.
      Telmisartan provides protection against development of impaired vasodilation independently of metabolic effects in SHRSP.Z-Lepr(fa)/IzmDmcr rats with metabolic syndrome.
      ], and anti-oxidant effects in the brain [
      • Kishi T.
      • Hirooka Y.
      • Sunagawa K.
      Sympathoinhibition caused by orally administered telmisartan through inhibition of the AT1 receptor in the rostral ventrolateral medulla of hypertensive rats.
      ,
      • Hirooka Y.
      • Sagara Y.
      • Kishi T.
      • Sunagawa K.
      Oxidative stress and central cardiovascular regulation. Pathogenesis of hypertension and therapeutic aspects-.
      ]. Because of these previous studies, we consider that the benefits of ARBs on brain damage and vascular inflammation are established, and focused on only cognitive function and BDNF expression in the hippocampus in the present study. Third, we did not perform histochemical experiments to determine the expression of PPAR-gamma and changes in CA1 neuron in the hippocampus, and performed only pharmacological inhibition of PPAR-gamma or BDNF/TrkB in the hippocampus. Although previous studies suggested the expression of PPAR-gamma in the hippocampus of cerebral-ischemia models [
      • Haraguchi T.
      • Iwasaki K.
      • Takasaki K.
      • Uchida K.
      • Naito T.
      • Nogami A.
      • Kubota K.
      • Shindo T.
      • Uchida N.
      • Katsurabayashi S.
      • Mishima K.
      • Nishimura R.
      • Fujiwara M.
      Telmisartan, a partial agonist of peroxisome proliferator-activated receptor γ, improves impairment of spatial memory and hippocampal apoptosis in rats treated with repeated cerebral ischemia.
      ,
      • Gahring L.C.
      • Persiyanov K.
      • Days E.L.
      • Rogers S.W.
      Age-related loss of neuronal nicotinic receptor expression in the aging mouse hippocampus corresponds with cyclooxygenase-2 and PPAR-gamma expression and is altered by long-term NS398 administration.
      ] and GW9662 or ANA-12 have been used as reasonable agents to inhibit PPAR-gamma or TrkB [
      • Haraguchi T.
      • Iwasaki K.
      • Takasaki K.
      • Uchida K.
      • Naito T.
      • Nogami A.
      • Kubota K.
      • Shindo T.
      • Uchida N.
      • Katsurabayashi S.
      • Mishima K.
      • Nishimura R.
      • Fujiwara M.
      Telmisartan, a partial agonist of peroxisome proliferator-activated receptor γ, improves impairment of spatial memory and hippocampal apoptosis in rats treated with repeated cerebral ischemia.
      ,
      • Washida K.
      • Ihara M.
      • Nishio K.
      • Fujita Y.
      • Maki T.
      • Yamada M.
      • Takahashi J.
      • Wu X.
      • Kihara T.
      • Ito H.
      • Toshimoto H.
      • Takahashi R.
      Nonhypotensive dose of telmisartan attenuates cognitive impairment partially due to peroxisome proliferator-activated receptor-gamma activation in mice with chronic cerebral hypoperfusion.
      ,
      • Kobayashi N.
      • Ohno T.
      • Yoshida K.
      • Fukushima H.
      • Mamada Y.
      • Nomura M.
      • Hirata H.
      • Machida Y.
      • Shinoda M.
      • Suzuki N.
      • Matsuoka H.
      Cardioprotective mechanism of telmisartan via PPAR-γ-eNOS pathway in Dahl salt-sensitive hypertensive rats.
      ,
      • Cazorla M.
      • Prémont J.
      • Mann A.
      • Girard N.
      • Kellendonk C.
      • Rognan D.
      Identification of a low-molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice.
      ,
      • Wang D.
      • Hirase T.
      • Nitto T.
      • Soma M.
      • Node K.
      Eicosapentaenoic acid increases cytochrome P-450 2J2 gene expression and epoxyeicosatrienoic acid production via peroxisome proliferator-activated receptor γ in endothelial cells.
      ], It would strengthen the results of the present study to determine the expression of PPAR-gamma and changes in CA1 neuron in the hippocampus and to do the specific PPAR-gamma or BDNF/TrkB-targeting methods (such as gene transfer methods) locally in the hippocampus.

      Conclusion

      Telmisartan has a possibility of protective effect against cognitive decline via activation of BDNF/TrkB through blockade of AT1R and part activation of PPAR-gamma in the hippocampus of SHRSPs independent of blood pressure-lowering effect, which might not be a class effect of ARBs. These results could provide a new aspect that telmisartan may be more effective to prevent cognitive decline compared with other ARBs, and might contribute to improve quality of life in hypertensive patients.

      Conflict of interest

      None.

      Acknowledgments

      This study was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science ( 22790709 ) and, in part, a Kimura Memorial Foundation Research Grant .

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