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PHAREP 71 1–6 Pharmacological Reports xxx (2014) xxx–xxx

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Pharmacological Reports journal homepage: www.elsevier.com/locate/pharep

Original research article

Telmisartan attenuates cognitive impairment caused by chronic stress in rats Dominik Wincewicz, Jan J. Braszko * Department of Clinical Pharmacology, Medical University of Bialystok, Białystok, Poland

A R T I C L E I N F O

Article history: Received 21 June 2013 Received in revised form 8 November 2013 Accepted 26 November 2013 Available online xxx Keywords: Angiotensin II ARB Cognitive impairment Restraint stress Telmisartan

A B S T R A C T

Background: The potential effect of chronic treatment with telmisartan, an angiotensin type 1 receptor blocker (ARB) and partial agonist of peroxisome proliferator – activated receptor g (PPARg), on stressrelated disorders is a matter of considerable interest. The existing data suggest that angiotensin II (Ang II) plays a major role in exaggerated sympathetic and hormonal response to stress. Enhanced formation of Ang II and increased AT1 receptor activity is associated with devastating impact of stress on central nervous system, which may trigger many psychiatric disorders such as depression, schizophrenia or post-traumatic stress disorder. Some of the anti-stress effects of ARBs have already been proven but these on the stress-induced cognitive impairment were examined only for candesartan. In this study, we tested a hypothesis that blockade of stress response by another ARB telmisartan alleviates the negative effect of prolonged restraint stress on cognitive functions of male Wistar rats. Methods: The preventive action of long-lasting treatment with telmisartan (1 mg/kg body weight) against impairment caused by chronic stress (2 h daily for 21 days) on recall was evaluated in a passive avoidance (PA) situation and object recognition test (ORT). Locomotor activity and anxiety behavior were tested respectively, in an open field and an elevated plus-maze. Results: The results of this study indicate that telmisartan diminishes deleterious effects of chronic restraint stress on memory in a statistically significant manner (p < 0.01) in both, PA situation and ORT. Conclusion: It appears that telmisartan may constitute a new therapeutic option in a stress-related cognitive impairment. ß 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Introduction The most important outcome of prolonged psychological stress includes impairment of learning and memory that is accompanied by neuronal damage and reorganization in the cognition-related brain structures [1,2]. Despite the well-known involvement of stress as a key factor in development of neuropsychological dysfunctions, no clinically effective therapeutic strategy has yet been found. Since prolonged emotional pressure becomes an inseparable factor of our everyday life, safe and effective prevention against its negative impact is an urgent priority. Response to stressful stimuli triggers inseparable and correlated activity of the hypothalamic-pituitary-adrenal (HPA) axis, the reninangiotensin system (RAS) and sympathetic-adrenal medulla system [3]. Angiotensin II (Ang II), the main effector peptide of RAS, apart

* Corresponding author. E-mail address: [email protected] (J.J. Braszko).

from being well known vasoconstrictor, is involved in stress-related information signaling [4]. Ang II is highly concentrated in hippocampus [5], a limbic structure associated with the formation and recall of spatial memories [6]. Physiologically, Ang II excites hippocampal CA1 pyramidal neurons [7] and modulates the induction of hippocampal LTP [8]. Pathophysiological response to stressful stimuli exceeding adaptive mechanisms include increased brain Ang II activity, amplified AT1 receptor expression in the HPA axis which is associated with higher HPA activation, and enhanced peripheral RAS activity [9]. Noteworthy, it has been proven that the expression of Ang II receptors increases after chronic restraint stress [10]. The blockade of brain AT1 receptors ameliorates the response to stress, decreases sympathetic activation [11], prevents somatic stress disorders such as gastric ulceration [12], and decreases anxiety-related behavior [13]. The preclinical experimental data described above is increasingly supported by clinical evidence. Recently, accumulating data associate decrease of cognitive performance with high blood pressure [14]. Moreover, some clinical trials point to angiotensin

http://dx.doi.org/10.1016/j.pharep.2013.11.002 1734-1140/ß 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Please cite this article in press as: Wincewicz D, Braszko JJ. Telmisartan attenuates cognitive impairment caused by chronic stress in rats. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2013.11.002

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antagonists i.e. ACEIs and ARBs as potentially beneficial in prevention of cognitive decline [15]. Accordingly, a clinically proven significant reduction in the incidence and progression of memory impairment was archived with ARBs [16]. One of the most commonly used ARB, with constantly increasing popularity, is telmisartan. Because of its well-known pharmacologic properties, including the longest half-life among all ARBs [17], telmisartan might be considered as superior cardioprotective drug in patients with hypertension. Interestingly, telmisartan is also the most lipophilic agent among ARBs, therefore it most readily crosses the brain-blood barrier (BBB) to cause central AT1 receptor blockade [18]. Due to the fact that systemic ARB treatment, along with intraventricular injection of Ang II, inhibited the central effects of Ang II on blood pressure, vasopressin secretion and the drinking response in spontaneously hypertensive rats [19], it is reasonable to assume that ARB penetrates into the brain. Since BBB permeability increases due to stress [20], the effect of peripherally administered telmisartan on central response to Ang II, might be sufficient to attenuate stressinduced cognitive decline. Moreover, recent in vitro studies indicate that telmisartan is directly neuroprotective [21], but its usefulness in the treatment of inflammatory conditions of the brain needs further support. In this study we tested a hypothesis that telmisartan can protect rats against chronic stress induced cognitive impairment using passive avoidance and object recognition tests. The unspecific influence of potential effects of telmisartan on locomotor activity and anxiety was evaluated in open field and elevated plus-maze, respectively. Materials and methods Animals The experiments were conducted on male Wistar rats, weighing approximately 150 g at the beginning. Animals were housed five to a cage in a temperature (22 8C) and humidity (50–60%) controlled room, on a 12 h:12 h light/dark cycle with light on from 6:00 a.m. Free access to standard laboratory food and tap water was provided. All animals were handled daily for 2 min each until the day of experiment. All the procedures were conducted between 1:00 and 6:00 p.m. A 30 min adaptation period in the experimental room preceded all the tests. All procedures involving animals were approved by the local Ethics Commission for Animal Experimentation. Drugs The specific AT1 receptor antagonist – telmisartan (Boehringer Ingelheim, Germany) was suspended in 0.5% methylcellulose (vehicle) at concentration of 1 mg/ml. Telmisartan or its vehicle was dosed by oral gavage at 1 mg/kg body weight, considered to be a nonhypotensive dose in rats [22,23]. Seventy-two male Wistar rats were randomly assigned to four groups: (1) 18 control rats – receiving 0.5% methylcellulose as a vehicle; (2) 18 rats receiving telmisartan suspended in 0.5% methylcellulose; (3) 18 rats receiving 0.5% methylcellulose subjected to a repeated restraint stress procedure; (4) 18 rats receiving telmisartan suspended in 0.5% methylcellulose subjected the repeated restraint stress procedure. The subjects received either telmisartan or vehicle each day immediately before the stress procedure. Stress procedure Two groups of animals (18 rats each) were subjected to chronic restraint stress [24,25] 2 h daily for 21 days. The restraint was

imposed during the light phase from 13:00 to 15:00 p.m. The restrainer was made of transparent perforated plastic tube, 20 cm long, and 7 cm in diameter. A rat was eased into the restrainer, head first, and once in the tube it was closed with a plexiglass lid. The animals fit tightly into the restrainers and it was not possible for them to move or turn around. Not stressed control rats were at the same time briefly handled and returned to their home cages. All the animals subjected to stress were checked for gastric ulceration on the next day after ending the behavioral tests. Rats were anaesthetized with the mixture of ketamine (50 mg/kg) and xylazine (7.5 mg/kg) injected intraperitoneally and sacrificed. Exposed gastric mucosa was visually examined under the 5 magnification lens for gastric ulceration. No visible signs of injury were found. Behavioral tests All rats underwent behavioral testing next day after ending the chronic drug treatment and repeated stress procedure. Thirty six subjects (assigned to 4 groups) participated in the open field test followed by the passive avoidance test. Performance of another group of 36 rats was estimated in elevated plus-maze which was executed right after object recognition test. Passive avoidance Passive avoidance (PA) behavior was studied in one trial learning, step-trough situation [26], which utilizes the natural preference of rats for dark environment. The apparatus consisted of the platform (250 mm  80 mm) connected to a dark compartment – a metal box (400 mm  400 mm  400 mm) with an opening (60 mm  100 mm) in the middle of the front wall. After a 2 min habituation to the dark compartment, the rat was placed on the illuminated platform and allowed to enter the dark compartment. Two more approach trials were given on the following day with a 2 min interval. At the end of the second trial unavoidable scrambled electric foot-shock (0.3 mA, AC, 2 s) was delivered through the grid floor of the dark compartment (learning trial). Retention of the passive avoidance response was tested 24 h, 48 h and 72 h later by placing the animal on the platform and measuring the latency to re-enter the dark compartment to a maximum of 300 s. Object recognition Object recognition was tested in a wooden box 62 cm long, 38 cm wide and 20 cm high covered with a wire mesh lid. The objects to be discriminated were made of glass or porcelain and existed in duplicate. They appeared to have no natural significance for the rats and they had never been associated with reinforcement. Their weight was such that they could not be displaced by the rats. The procedure was similar to that described previously [27] and may be summarized as follows. All rats were submitted to two habituation sessions, with a 1-h interval, whereby they were allowed 3 min exploration of the apparatus. Twenty-four hours later testing began. The experimental session consisted of two trials, lasting for 3 min and 5 min. In the first trial (T1), rats were exposed to two identical objects A1 and A2. In the second trial (T2), performed 60 min later, rats were exposed to two objects, one of which was duplicate of the familiar object A (A0 ), in order to avoid olfactory traits, and a new object B. From rat to rat, the role (familiar or new object) as well as the relative position of the two objects were counterbalanced and randomly permuted during trial T2. These precautions were taken in order to reduce object and place preference effects. The basic measure was the time spent by the rat in exploring objects during trials T1 and T2. Exploration of

Please cite this article in press as: Wincewicz D, Braszko JJ. Telmisartan attenuates cognitive impairment caused by chronic stress in rats. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2013.11.002

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an object was defined as touching it with the nose. Turning around or sitting on the object was not considered exploratory behavior. From this measure, the following variables were defined: A, the time spent in exploring, respectively, the duplicate of the familiar, and the new object in T2. Object recognition was measured by the variable B  A0 , and total exploration in T2 by B + A0 . Moreover, as B  A0 may be biased by the differences in the overall levels of exploration, the variable B  A0 /B + A0 was also computed. Open field Next day after ending 3 week period of chronic stress and drug administration procedure, animals were tested in an open field for assessment of their locomotor exploratory activity. Open field was a square 100 cm  100 cm white floor divided by eight lines into 25 equal squares and surrounded by a 47 cm high wall [28]. Four plastic bars, 20 cm high, were designed as objects of possible interest for rats. They were fixed perpendicularly, parallel to each other, in four line crossings, in the central area of the floor. A rat was placed in the center of the floor and, following 1 min of adaptation, crossings, rearings and bar approaches were counted manually for 5 min. Elevated ‘plus’ maze Anxiety in rats was evaluated the next day after assessment of their performance in object recognition test. It was measured in an elevated plus-maze (made of gray colored wooden planks) consisted of four arms, 50 cm  10 cm (length  width). Two arms (closed) had 40 cm high walls were covered with removable lid, and two remaining arms (open) had no walls, were arranged such that the open or closed arms were opposite to each other. The maze was elevated to a height of 50 cm from the floor. Rats were placed for 5 min in a pretest arena (60 cm  60 cm  35 cm, constructed of the same material) prior to exposure to the maze. This step allowed facilitation of exploratory behavior. The experimental procedure was similar to that described by Pellow et al. [29]. Immediately after the pretest exposure rats were placed in the center of the elevated plus-maze facing one of the open arms. During the 5 min test period the following measures were taken: the number of entries into the open and closed arms and the time spent in the open and closed arms. An entry was defined as all four feet into one arm. An increase in open arms entries and increase in time spent in open arms were interpreted as indicative of potential anxiolytic activity.

Fig. 1. Effects of chronics stress (daily immobilization for 2 h, 21 days), telmisartan (1 mg./kg p.o., daily) or both in combination, on the latency of the inhibitory avoidance. Results obtained after 24 h. Bars represent means + SEM, n = 9. *p < 0.05 vs. control, telmisartan and stress + telmisartan group.

thus statistically significant differences between the groups. Post hoc comparisons made with Newman–Keuls test revealed that stressed rats re-entered the dark part of the apparatus significantly earlier than all remaining groups (p < 0.05 in all cases). ANOVA of the results obtained after 48 h in the passive avoidance test yielded F(3,32) = 5.604 (p < 0.01; Fig. 2) showing thus statistically significant differences between the groups. Post hoc comparisons made with Newman–Keuls test revealed that stressed rats re-entered the dark part of the apparatus significantly earlier than all remaining groups: control (p < 0.01), treated with telmisartan (p < 0.01), stressed and treated with telmisartan (p < 0.05). ANOVA of the results obtained after 72 h in the passive avoidance test yielded F(3,32) = 7.440 (p < 0.01, Fig. 3) showing thus statistically significant differences between the groups. Post hoc comparisons made with Newman–Keuls test revealed that stressed rats re-entered the dark part of the apparatus significantly earlier than all remaining groups (p < 0.01 in all cases). These results demonstrate that the AT1 receptor blocker, telmisartan, effectively abolished adverse effect of stress on retrieval of passive avoidance behavior. The effect remained for at least 72 h.

Statistical analysis Data were presented as means  standard error of mean (SEM). The results of the experiments were calculated using ANOVA I, followed by Bonferroni test for chosen group comparisons, applied for the results obtained in the open field and elevated plus-maze. ANOVA I followed by the post hoc Newman–Keuls test for multiple comparisons of latencies after 24 h, 48 h and 72 h in the passive avoidance test, object recognition test and body weight gain was used. Levels were deemed significant at p < 0.05. Results Effects of stress and telmisartan on the passive avoidance behavior Passive avoidance behavior was tested 24 h, 48 h and 72 h after delivering adverse stimulus (one learning trial). ANOVA of the results obtained after 24 h in the passive avoidance test yielded F(3,32) = 4.269 (p < 0.05; Fig. 1) showing

Fig. 2. Effects of chronics stress (daily immobilization for 2 h, 21 days), telmisartan (1 mg/kg p.o., daily, 21 days) or both in combination, on the latency of the inhibitory avoidance. Results obtained after 48 h. Bars represent means + SEM, n = 9. *p < 0.05, **p < 0.01 vs. stress group.

Please cite this article in press as: Wincewicz D, Braszko JJ. Telmisartan attenuates cognitive impairment caused by chronic stress in rats. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2013.11.002

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shown). Exposure to chronic restraint stress slightly increased locomotor activity (crossings) and decreased novelty seeking behavior (rearings and bar approaches), but in comparison to control group the differences were not statistically significant. These results demonstrate lack of effect of stress procedure and telmisartan administration on rats’ psychomotor performance. Effects of stress and telmisartan on anxiety behavior in the elevated ‘plus’ maze

Fig. 3. Effects of chronics stress (daily immobilization for 2 h, 21 days), chronic telmisartan (1 mg./kg p.o., daily, 21 days) or both in combination, on the latency of the inhibitory avoidance. Results obtained after 72 h. Bars represent means + SEM, n = 9. *p < 0.01 vs. control, telmisartan and stress + telmisartan group.

Table 1 Effects of stress, telmisartan (1 mg/kg) on the object recognition test. Variables

Control

Telmisartan

Stress

Stress + telmisartan

A A0 B B–A0 B + A0 B–A0 /B + A0

44.1  3.1 21.3  1.6 37.3  3.5 15.4  2.9 60.3  4.7 0.25  0.04

43.4  3.1 12.6  1.8 33.2  5.3 20.7  4.9 45.8  6.2 0.41  0.07

40.1  2.0 25.4  3.9 24.2  2.1 0.78  4.3* 48.1  5.3 0.03  0.09

38  2.9 19.1  1.7 30.8  3.1 11.8  5.83 50  3.7 0.23  0.06

One way ANOVA of all results obtained in the elevated plusmaze revealed no statistically significant differences between the groups in the time spent by rats in the open arms of the elevated plus-maze F(3,32) = 1.367 (p > 0.05) and in the number of open arms entries F(3,32) = 1.854 (p > 0.05; data not shown). Telmisartan treatment caused a slight anxiolytic effect but the differences were not statistically significant. Effects of stress and telmisartan on body weight gain All of the rats gained weight during the course of the study. However, the weight gain in rats treated with telmisartan was significantly (p < 0.05) smaller than in control group. The animals subjected to stress procedure gained significantly (p < 0.001) less weight than not stressed control group. In chronically stressed animals, telmisartan treated rats gained less weight than rats receiving vehicle, but the differences between the groups were not statistically significant (p > 0.05; Table 2).

Discussion

*

p < 0.05 in comparison to control group, n = 9 rats in each group. Values are means  SEM. For further details see text.

Effects of stress and telmisartan on the object recognition test In all groups the time spent in exploring objects A1 and A2 (variable A) was comparable (Table 1). Object recognition memory measured by the difference B–A0 significantly varied between the groups. The rats subjected to stress procedure explored the new, previously unseen object (B) for significantly (p < 0.05) shorter period of time than controls. The negative effect of stress on recognition memory was abolished in the group treated with telmisartan. There were no statistically significant effects of telmisartan treatment on the remaining parameters measured in the object recognition test. Specifically, we observed no changes in habituation (B + A0 ) and no bias of the object recognition scores by the changes in the overall levels of exploration (B–A0 /B + A0 ). Effects of stress and telmisartan on locomotor exploratory activity of rats in the open field One way ANOVA of all results obtained in the open field revealed no statistically significant differences between the groups in crossings F(3,32) = 1.451 (p > 0.05), rearings F(3,32) = 1.912 (p > 0.05), and bar approaches F(3,32) = 0.796 (p > 0.05; data not

The aim of this study was to evaluate preventive effects of telmisartan on post-stress cognitive dysfunctions. Telmisartan effectively restored cognitive functions impaired by stress and decreased forgetfulness examined in passive avoidance and object recognition tests. Interestingly, the effect on retention of avoidance behavior was better preserved in animals receiving telmisartan, although long-term effect remains unknown since the last trial was conducted 72 h after avoidance stimulus. Possible influence of stress-related anxiety [30] was excluded by the results of the elevated plus-maze test. Treatment with telmisartan had only slight anxiolytic effect. Exposure to chronic restraint stress revealed its minor effect on locomotor activity that would not interfere with cognitive performance. In our recent study, following similar protocol of stress procedure and drug administration, it was found that long term treatment with candesartan, another AT1 receptor blocker, effectively counteracted deleterious effects of stress on retrieval of memory [31]. Interestingly, besides the anti-stress effect on cognitive decline achieved with candesartan, a pro-cognitive effect was revealed in non-stressed subjects. This phenomenon can be partially explained by differences in competitive nature of sartans (with respect to Ang II) designated as surmountable/insurmountable antagonism [32]. Candesartan as a slow-dissociating AT1 receptor antagonist produces almost complete depression of AT1 receptor [33], which might lead to higher, in comparison to that

Table 2 Effects of stress and telmisartan (1 mg/kg) on body weight gain. Groups

Day 1

Day 7

Day 14

Day 21

Control Telmisartan Stress Stress + telmisartan

150.2  1.36 149  2.66 151.8  4.60 154.8  1.60

186  2.00 181.2  2.15 167.6  2.62*** 166.4  3.43***

229  1.81 215.4  5.42 185  3.15*** 183.4  5.04***

274.4  6.91 251  9.35* 219  5.83*** 209  6.04***

*p < 0.05, ***p < 0.001 in comparison to control group, n = 9 rats in each group. Values are means  SEM of body weight (mg). For further details see text.

Please cite this article in press as: Wincewicz D, Braszko JJ. Telmisartan attenuates cognitive impairment caused by chronic stress in rats. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2013.11.002

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caused by telmisartan, level of Ang IV, which is known for its procognitive effects [34]. Brain AT1 receptor antagonism has selective and profound influence on brain AT2 receptor expression, and AT1 receptor activity regulates AT2 receptor number, at least in some selected brain areas [11]. Co-localization of AT1 and AT2 angiotensin receptors has never been detected in any brain area and if this co-localization exists in the brain, it is the exception rather than the norm [35]. The possibility of enhancement of cognitive functions generated by indirect stimulation of the AT2 receptors by ARBs cannot be rejected. In a recently published study cognitive functions were improved, in both healthy and a model of Alzheimer disease mice, by direct stimulation of AT2 receptor [36]. Indication of favorable properties of AT2 agonists including anti-inflammatory effects [37] has an undisputable impact in terms of understanding brain angiotensin receptors mechanisms but probably will not become the most effective approach to neurological diseases treatment since AT2 receptor agonists only poorly pass the blood-brain barrier [38]. The data showing that telmisartan, but not losartan or candesartan, attenuates weight gain [39] raise the question of differences between those ARBs in terms of possible effect on energy metabolism. Due to the fact that equivalent hypotensive doses were compared, the metabolic effect may go beyond just blockade of the type 1 angiotensin II receptor. Recent findings indicate that telmisartan is a partial agonist (mixed agonist/ antagonist) of PPARg, an intracellular receptor that is a major regulator of fat cell differentiation [40]. Partial agonists of PPARg may have the capacity to improve glucose and lipid metabolism resulting in a weight gain decrease [41,42]. Accordingly this effect on energy balance might be due to interference with PPARg receptors located in CNS, specifically hypothalamus, which controls food intake [43]. Much smaller effects on PPARg were found among the other clinically approved ARBs, including irbesartan and a metabolite of losartan (EXP3179), that are really not so potent activators of PPARg as telmisartan [44,45]. Direct comparison by investigating changes in serum adiponectin and plasma glucose, as a result of PPARg activation, showed significantly greater effect of telmisartan than candesartan [46]. The significance of PPARg activation with ARBs goes beyond affecting energy metabolism. Activation of these, ubiquitous in CNS, receptors in addition to their anti-diabetic properties prevents neuronal death by reduction of oxidative stress [47] and inflammation [48]. Furthermore, PPARg agonists exert beneficial effects in various CNS disorders including improvement of memory and cognitive function in Alzheimer’s disease [49]. Anti-inflammatory and antioxidant effects of telmisartan exerted by PPARg receptor activation, but not blood pressure-lowering effect, have been associated with preventive role of this drug against cognitive impairment after chronic cerebral ischemia [22]. Since the effect of elevated levels of Ang II and the role of its receptor subtype AT1 in brain infarction are directly correlated with the severity of ischemic injury [50], protective effect of telmisartan in chronic cerebral hypoperfusion is not be confined to the PPARg receptor only. One study appears to support a hypothesis that PPARg stimulation inhibits neuroendocrine responses to stress in restrained rats [51]. In this study, the treatment of psychological stress with rosiglitazone, a pure PPARg agonist, resulted in reduction of heart rate, peak corticosterone levels and c-Fos protein level. Noteworthy, telmisartan restricts cytokine-induced inflammatory signaling by suppression of the tumor necrosis factor-alpha (TNFalpha)-induced activation of nuclear factor (NF)-kappaB in vascular endothelial cells, thereby attenuating cellular inflammation, mainly through AT1 receptor blockade [52]. Because of the fact that PPARg receptors are sparse but still present in normal rat hippocampal neurons [53] and

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up-regulate as a result of oxidative stress, apoptosis and ischemia [54], their signaling path might constitute a new target for the treatment of neurodegenerative disorders. Due to the synergistic effects of AT1 receptor blockade and a potent PPARg activation by telmisartan, an advantage over other ARBs in counteracting deleterious effect of stress on memory was expected. Interestingly our behavioral studies do not indicate telmisartan to be more effective than candesartan in prevention of memory recall decline caused by chronic restraint stress [31]. Therefore, activation of PPARg receptors by telmisartan might not be essential in the curtailment of stress-induced cognitive impairment. Despite the fact that reduction of the stress-induced sympathoadrenal activation seems to be a major mechanism of anti-stress effects of ARBs further investigation into involvement of PPARg receptors appear to be necessary. In conclusion, our results indicate that long term AT1 receptor blockade and PPARg activation with telmisartan might be a step forward in a novel therapeutic approach to cognitive deficits caused by chronic psychological stress. Conflict of interest The authors declare no conflict of interests. Funding Funding for this study was provided by Medical University of Bialystok (133-66867). References [1] Radley JJ, Sisti HM, Rocher AB, Hao J, McCall T, Hof PR, et al. Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex. Neuroscience 2004;125:1–6. [2] Wolf OT. Stress and memory in humans: twelve years of progress. Brain Res 2009;1293:142–54. [3] Yang G, Wan Y, Zhu Y. Angiotensin II – an important stress hormone. Biol Signals 1996;5(1):1–8. [4] Saavedra JM, Benicky J. Brain and peripheral angiotensin II play a major role in stress. Stress 2007;10(2):185–93. [5] Sirett NE, Bray JJ, Hubbard JI. Localization of immunoreactive angiotensin II in the hippocampus and striatum of rat brain. Brain Res 1981;217(2):405–11. [6] Izquierdo I, Medina JH. Memory formation: the sequence of biochemical events in the hippocampus and its connection to activity in other brain structures. Neurobiol Learn Mem 1997;68(3):285–316. [7] Haas HL, Felix D, Celio MR, Inagami T. Angiotensin II in the hippocampus. A histochemical and electrophysiological study. Experientia 1980;36(12): 1394–5. [8] Wayner MJ, Polan-Curtain J, Armstrong DL. Dose and time dependency of angiotensin II inhibition of hippocampal long-term potentiation. Peptides 1995;6:1079–82. [9] Saavedra JM, Sa´nchez-Lemus E, Benicky J. Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: therapeutic implications. Psychoneuroendocrinology 2011;36(1):1–18. [10] Castren E, Saavedra JM. Repeated stress increases the density of angiotensin II binding sites in rat paraventricular nucleus and subfornical organ. Endocrinology 1988;122(1):370–2. [11] Bregonzio C, Seltzer A, Armando I, Pavel J, Saavedra JM. Angiotensin II AT(1) receptor blockade selectively enhances brain AT(2) receptor expression: and abolishes the cold-restraint stress-induced increase in tyrosine hydroxylase mRNA in the locus coeruleus of spontaneously hypertensive rats. Stress 2008;11(6):457–66. [12] Bregonzio C, Armando I, Ando H, Jezova M, Baiardi G, Saavedra JM. Antiinflammatory effects of angiotensin II AT1 receptor antagonism prevent stress-induced gastric injury. Am J Physiol Gastrointest Liver Physiol 2003;285(2):G414–23. [13] Saavedra JM, Armando I, Bregonzio C, Juorio A, Macova M, Pavel J, et al. A centrally acting: anxiolytic angiotensin II AT1 receptor antagonist prevents the isolation stress-induced decrease in cortical CRF1 receptor and benzodiazepine binding. Neuropsychopharmacology 2006;31(6):1123–34. [14] Petrella RJ, Shlyakhto E, Konradi AO, Berrou JP, Sedefdjian A, Pathak A, et al. Blood pressure responses to hypertension treatment and trends in cognitive function in patients with initially difficult-to-treat hypertension: a retrospective subgroup analysis of the Observational Study on Cognitive Function and SBP Reduction (OSCAR) study. J Clin Hypertens 2012;14(2):78–84. [15] Tzourio C, Anderson C, Chapman N, Woodward M, Neal B, MacMahon S, et al. Effects of blood pressure lowering with perindopril and indapamide therapy

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Please cite this article in press as: Wincewicz D, Braszko JJ. Telmisartan attenuates cognitive impairment caused by chronic stress in rats. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2013.11.002