|Year : 2015 | Volume
| Issue : 3 | Page : 263-269
Cognitive enhancing effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on learning and memory
VS Nade, LA Kawale, KD Valte, NV Shendye
Department of Pharmacology, M.V.P. Samaj College of Pharmacy, Gangapur Road, Nashik, Maharashtra, India
|Date of Submission||30-Jan-2014|
|Date of Decision||05-Apr-2015|
|Date of Acceptance||12-Apr-2015|
|Date of Web Publication||18-May-2015|
Dr. V S Nade
Department of Pharmacology, M.V.P. Samaj College of Pharmacy, Gangapur Road, Nashik, Maharashtra
Source of Support: None, Conflict of Interest: None
Objective: The present study was designed to investigate cognitive enhancing property of angiotensin-converting enzymes inhibitors (ACEI) and angiotensin receptor blockers (ARBs) in rats.
Materials and Methods: The elevated plus maze (EPM), passive avoidance test (PAT), and water maze test (WMT) were used to assess cognitive enhancing activity in young and aged rats. Ramipril (10 mg/kg, p.o.), perindopril (10 mg/kg, i.p), losartan (20 mg/kg, i.p), and valsartan (20 mg/kg, p.o) were administered to assess their effect on learning and memory. Scopolamine (1 mg/kg, i.p) was used to impair cognitive function. Piracetam (200 mg/kg, i.p) was used as reference drug.
Results: All the treatments significantly attenuated amnesia induced by aging and scopolamine. In EPM, aged and scopolamine-treated rats showed an increase in transfer latency (TL) whereas, ACEI and ARBs showed a significant decrease in TL. Treatment with ACEI and ARBs significantly increased step down latencies and decreased latency to reach the platform in target quadrant in young, aged and scopolamine-treated animals in PAT and WMT, respectively. The treatments inhibited acetylcholinesterase (AChE) enzyme in the brain. Similarly, all the treatments attenuated scopolamine-induced lipid peroxidation and normalize antioxidant enzymes.
Conclusion: The results suggest that the cognitive enhancing effect of ACEI and ARBs may be due to inhibition of AChE or by regulation of antioxidant system or increase in formation of angiotensin IV.
Keywords: Acetylcholinesterase, angiotensin IV, lipid peroxidation, scopolamine
|How to cite this article:|
Nade V S, Kawale L A, Valte K D, Shendye N V. Cognitive enhancing effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on learning and memory. Indian J Pharmacol 2015;47:263-9
|How to cite this URL:|
Nade V S, Kawale L A, Valte K D, Shendye N V. Cognitive enhancing effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on learning and memory. Indian J Pharmacol [serial online] 2015 [cited 2023 Oct 4];47:263-9. Available from: https://www.ijp-online.com/text.asp?2015/47/3/263/157114
| » Introduction|| |
Cholinergic neurons in the central nervous system are degenerated in patient with Alzheimer disease (AD) results into the impairment of memory.  Many attempts have been made to reverse cognitive deficits by alternative treatments.
Renin angiotensin system (RAS) becomes a new target.  Drugs known to interfere with the renin-angiotensin system have been shown to have beneficial cognitive effects and proven as a nootropic. Angiotensin II (Ang II) can decrease cognitive performance. Angiotensin-converting enzymes inhibitors (ACEI) reduce Ang II in the brain which inhibits the release of acetylcholine, whose levels are decreased in AD. , Ang IV is a derivative of Ang II, and it has been shown to enhance acquisition, consolidation and recall in animal models of learning and memory when administered centrally or peripherally.  Ang IV and AT 4 agonists have been postulated to be positively implicated in memory acquisition and retrieval.  Recently, AT 4 has been isolated and has shown to be the insulin-regulated aminopeptidase (IRAP). The distinct facilitating effects of Ang IV on memory have been related to its binding to IRAP. , However, Ang IV-peptides have some limitations in their use as clinically therapeutics because they are rapidly degraded with short half-lives, and they are too large and hydrophilic to penetrate the blood-brain barrier. 
Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARBs) affect RAS and may have an influence on learning and memory. Hence, the present study was designed to evaluate the effect of ACEI (ramipril and perindopril) and ARBs (losartan and valsartan) on learning and memory.
| » Materials and Methods|| |
Wistar strain rats young (age - 8-10 weeks, 90-110 g) and aged (age - 35-38 weeks, weight - 250-280 g) were used for the study. Animals were housed in colony cages and maintained under the standard laboratory environmental conditions; temperature 25 ± 2°C, 12 h light: 12 h dark cycle and 50 ±5% relative humidity with free access to food and water ad libitum. Animals were acclimatized to laboratory conditions before the test. Each group consisted of five (n = 5) animals. All the experiments were carried out during the light period (08:00-16:00 h). The studies were carried out in accordance with the guidelines given by Committee for the Purpose of Control and Supervision of Experiments on Animals, New Delhi (India). The Institutional Animal Ethical Committee approved the protocol of the study (IAEC/2010/01).
Drugs and Chemicals
Piracetam (UCB India Pvt. Ltd., Vapi, Gujarat, India), scopolamine (Sigma-Aldrich, USA), losartan and valsartan (Matrix Labs Ltd., Nasik, India), ramipril and perindopril (Glenmark Research Centre, Nasik, India). Thiobarbituric acid (TBA) (Research-Lab Fine Chem Industries, Mumbai, India), nitroblue tetrazolium chloride (NBT) (Himedia Laboratories Pvt. Ltd., Mumbai, India), 5, 5'-Dithiobis (2-nitro benzoic acid) (DTNB) (Alfa Aesar, A Johnson Mathey Company). Bovine serum albumin (Spectrochem Pvt. Ltd., Mumbai, India). All the chemicals used were of analytical grade and purchased from standard manufacturers.
Animals were divided into eighteen groups (n = 5 for each group) as follows:
Elevated plus maze
The elevated plus maze (EPM) consisted of two open arms (50 cm × 10 cm) crossed with two closed arms (50 cm × 10 cm × 40 cm). The arms were connected together with a central square of 10 cm × 10 cm. The apparatus was elevated to the height of 50 cm in a dimly illuminated room. Animals were placed individually at the end of either of the open arms facing away from the central platform. The time taken by each animal to move from open arm to either of the closed arms was recorded. This duration of time was called transfer latency (TL). If the animal does not enter into any of the enclosed arms within 120 s, it was gently pushed into any of the enclosed arms and TL was considered as 120 s. Later the animal was allowed to explore the plus maze for 5 min and send back to the home cage. TL was then noted on day 8 th and 9 th . TL measured on day 8 th serves as a parameter for acquisition (learning) while TL on day 9 indicates retention (memory). 
Angiotensin-converting enzymes inhibitors and ARBs or standard drugs or vehicle were administered orally for 8 days and TL was noted after 45 min of administration of last dose on 8 th day and again after 24 h, that is, on 9 th day. In scopolamine-treated group, scopolamine (1 mg/kg) was injected i.p. after 45 min of administration of ACEI and ARBs or standard drugs or vehicle and TL was recorded after 45 min of injection of scopolamine on 8 th day and after 24 h, that is, on 9 th day.
Collection of Brain Samples
The animals of the group I, VI, VII, VIII, and IX were sacrificed by cervical decapitation on the 9 th day after TL was measured in EPM. Immediately after decapitation whole brain was carefully removed from the skull. For preparation of brain homogenate, the fresh whole brain was weighed and transferred to a glass homogenizer and homogenized in an ice bath after adding 10 volumes of 0.9% w/v sodium chloride solution. The homogenate was centrifuged at 3000 rpm for 10 min, and the resultant cloudy supernatant liquid was used for estimation of brain acetylcholinesterase (AChE) activity.
Estimation of Brain Cholinesterase
Brain cholinesterase activity was measured by the method of Ellman et al. (1961) with slight modification. The 0.5 ml of the cloudy supernatant liquid was pipetted out into 25 ml volumetric flask and dilution was made with a freshly prepared DTNB solution (10 mg DTNB in 100 ml of Sorenson phosphate buffer, pH 8.0). From the volumetric flask, two 4 ml portions were pipetted out into two test tubes. In the test tubes, 2 drops of eserine solution, 1 ml of substrate solution (75 mg of acetylcholine iodide per 50 ml of distilled water) was pipetted out and incubated for 10 min at 30°C. The solution in the tube containing eserine was used for zeroing the colorimeter. The resulting yellow color is due to the reduction of DTNB by certain substances in the brain homogenate and due to non-enzymatic hydrolysis of the substrate. After calibrating the instrument, change in absorbance per min of the sample was read at 420 nm. Protein estimation was done by folin method. 
Passive Avoidance Test
The term passive avoidance is usually employed to describe experiments in which the animal learns to avoid a noxious event by suppressing a particular behavior. Rats were placed on a rectangular box (50 cm × 50 cm) with electrifiable grid floor. The grid floor was connected to a shock device which delivers scrambled foot shocks. Each rat was placed on the platform, released after raising the cylinder, and the latency to step-down on the grid floor was measured (familiarization). After 10 s of exploration, it was returned to the home cage. Immediately after the animal has descended from the platform, an unavoidable footshock (50 Hz; 1.5 mA; 1s) was applied (learning, day 0). After 24 h of learning trial, the rat was again placed on the platform, and the step-down latency was measured (acquisition, day 1). The test was finished when the animal steps down or remains on the platform (cut-off time: 300s). ACEI and ARBs or standard drugs or vehicle were administered orally for 8 days and step down latency (SDL) was noted after 45 min of administration of last dose on 8 th day and again after 24 h, that is, on 9 th day. In scopolamine-treated group, scopolamine (1 mg/kg) was injected i.p. after 45 min of administration of ACEI and ARBs or standard drug or vehicle and SDL was recorded after 45 min of injection of scopolamine on 8 th day and after 24 h, that is, on 9 th day.  On the 9 th day, after measurement of SDL, the animals of group I, V, XV, XVI, XVII, and XVIII were sacrificed by cervical dislocation and antioxidant parameters such as lipid peroxidation (LPO), superoxide dismutase (SOD), glutathione (GSH), catalase (CAT) levels in the brain were measured.
Biochemical Analysis: Dissection and Homogenization
The brain was removed, rinsed with isotonic saline and weighted. A 10% (w/v) tissue homogenate was prepared in 0.1 M phosphate buffer (pH 7.4). The post nuclear fraction for CAT assay was obtained by centrifugation (Remi - C-30, Remi Industries Ltd., Mumbai, India) of the homogenate at 1000 g for 20 min at 4°C; for other enzyme assays, centrifugation was at 12,000 g for 60 min at 4°C. A Shimadzu - 160A spectrophotometer was used for subsequent assays. 
Catalase activity was assessed by the method of Luck, where the breakdown of H 2 O 2 was measured at 240 nm. Briefly, the assay mixture consisted of 3 ml of H 2 O 2 phosphate buffer (0.0125 M H 2 O 2 ) and 0.05 ml of supernatant of brain homogenate (10%) and the change in the absorbance were measured at 240 nm. The enzyme activity was calculated using the millimolar extension coefficient of H 2 O 2 (0.07). The results were expressed as micromoles of H 2 O 2 decomposed per minute per milligram of protein. 
Superoxide Dismutase Activity
Superoxide dismutase activity was assayed according to the method of Kono, wherein the reduction of NBT chloride was inhibited by the SOD was measured at 560 nm spectrophotometrically. Briefly, the reaction was initiated by the addition of hydroxylamine hydrochloride to the reaction mixture containing NBT and post nuclear fraction of brain homogenate. The results were expressed as units per milligrams of protein, with one unit of enzyme defined as the amount of SOD required to inhibit the rate of reaction by 50%. 
Lipid Peroxidation Assay
The quantitative measurement of LPO in the brain was done by the method of Wills (1966). The amount of malondialdehyde (MDA) formed was measured by reaction with TBA at 532 nm. The results were expressed as nanomoles of MDA per milligram of protein, using the molar extension coefficient of the chromophore (1.56 × 10 5 M −1 cm −1 ). 
The protein content was measured according to the method of Lowry et al., using bovine serum albumin as standard and expressed as μg protein/mg of tissue. To the tissue homogenate distilled water and alkaline copper sulfate were mixed and incubated at room temperature for 15 min. Then phenol reagent was added and incubated for 30 min, and the absorbance at 540 nm was determined spectrophotometrically. 
Water Maze Test
The apparatus is a circular water tank filled to a depth of 20 cm with 25°C water containing 500 ml of milk. Four points equally distributed along the perimeter of the tank serves as starting locations. The tank is divided into four equal quadrants, and a small platform (19 cm height) is located in the center of one of the quadrants. The first experimental day was dedicated to swimming for 60 s in the absence of the platform. During the four subsequent days, the rat was given two trial sessions per day with the platform in place. When rat located the platform, it was permitted to remain on it for 10 s. If the rat did not locate the platform within 120 s, it was placed on the platform for 10 s. The time interval between trial sessions was 30 min. On the day, after the final training trial sessions, rats were individually subjected to a probe trial session in which the platform was removed from the pool, and rats were allowed to swim for 120 s to search for it. The time of swimming was recorded in the pool quadrant where the platform has been previously placed. ACEI and ARBs or standard drug were given for 8 days. Scopolamine (1 mg/kg) was injected i.p. after 45 min of administration of ACEI and ARBs or standard drug and trial was given 45 min of injection of scopolamine. The latency to reach the platform was measured on 8 th and 9 th day. 
Results are expressed as mean ± standard error of the mean, and the statistical analysis of data was done using one-way analysis of variance followed by Dunnett's test. Probability level less of 0.05 was considered statistically significant.
| » Results|| |
Effect of Angiotensin-converting Enzymes Inhibitors and Angiotensin Receptor Blockers on Transfer Latency in Young, Aged and Scopolamine-treated Rats in Elevated Plus Maze
Transfer latency of the 8 th day of drugs treatment reflected learning behavior of animals whereas, TL of the 9 th day of drugs treatment reflected retention of learned task or memory when subjected to EPM test. The young animals treated with ACEI and ARBs showed a reduction in TL on 8 th and 9 th day, indicating significant (P < 0.01) improvement in memory compared with the vehicle group. Aged rats showed higher TL, indicating impairment in learning and memory. Pretreatment with ACEI and ARBs also showed significant (P < 0.01) improvement in memory of aged rats. Administration of scopolamine (1 mg/kg) increased TL on 9 th day indicating impairment in memory (amnesia). The rats treated with ACEI and ARBs for 8 successive days significantly (P < 0.01) reversed the amnesia induced by scopolamine and protected young rats. Piracetam (used as the positive control) significantly improved memory (P < 0.01) of both young and aged rats and reversed amnesia induced by scopolamine. ACEI and ARBs also showed significant improvement memory (P < 0.01) as compared to Piracetam [Table 1].
|Table 1: Effect of ACEI and ARBs on TL in young, aged and scopolamine-treated rats in elevated plus maze |
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Effect of Angiotensin-converting Enzymes Inhibitors and Angiotensin Receptor Blockers on Brain Cholinesterase Activity in Rats
Ramipril, perindopril, losartan, and valsartan showed a remarkable decrease in cholinesterase activity (P < 0.01) in young rats as compared to vehicle group [Figure 1].
|Figure 1: Effect of angiotensin-converting enzymes inhibitors and angiotensin receptor blockers on brain acetylcholinesterase activity in rats: Each column represents mean ± standard error of the mean (n = 5). Groups VI, VII, VIII, and IX compared to Group I. *P < 0.05; **P < 0.01 (one-way analysis of variance followed by Dunnett's test)|
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Effect of Angiotensin-converting Enzymes Inhibitors and Angiotensin Receptor Blockers on Step Down Latencies in Young, Aged and Scopolamine-treated Rats in Passive Avoidance Test
Step down latency of 9 th day indicated the long-term memory of animals. ACEI and ARBs administered to young, and aged rats showed significant (P < 0.01) increase in SDL as compared with their respective vehicle groups. ACEI and ARBs administered for 8 days significantly (P < 0.01) reversed memory deficits due to scopolamine-induced amnesia. Piracetam also showed significant (P < 0.01) improvement in memory in young, aged and scopolamine-treated rats. ACEI and ARBs showed significant (P < 0.01) increase in SDL as compared to Piracetam [Table 2].
|Table 2: Effect of ACEI and ARBs on SDL in young, aged and scopolamine-treated rats in passive avoidance test |
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Lipid peroxidation assay
The level of MDA was significantly increased in scopolamine-treated group, as compared with vehicle-treated group, while administration of ramipril, perindopril, losartan, and valsartan significantly (P < 0.01) brought down the level of MDA as compared with rats treated with scopolamine [Table 3].
|Table 3: Effect of ACEI and ARBs on LPO, SOD, CAT and GSH levels in scopolamine - induced oxidative stress |
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Effect on Brain Superoxide Dismutase and Catalase Levels
The levels of the defensive antioxidant enzymes, SOD and CAT were decreased after scopolamine administration in rats as compared with vehicle-treated group. Pretreatment with ramipril, perindopril, losartan, and valsartan increased levels of SOD and CAT as compared to scopolamine-treated group [Table 3].
Effect on Brain Glutathione Level
The content of GSH was depleted significantly in scopolamine-treated group, as compared with vehicle-treated group, indicating the oxidative stress-induced by scopolamine. On the other hand, the GSH levels were found to be elevated significantly after treatment with ramipril, perindopril, losartan, and valsartan as compared with scopolamine [Table 3].
Effect of Angiotensin-converting Enzymes Inhibitors and Angiotensin Receptor Blockers on Latency to Reach the Platform in Young, Aged and Scopolamine-treated Rats in Water Maze Test
Latency to reach the platform was significantly decreased in young rats treated with ACEI and ARBs compared to vehicle group, suggesting cognitive enhancing effect. In aged rats, the latency to reach the platform was increased, demonstrating memory impairment. Treatment with ACEI and ARBs significantly (P < 0.01) decreased the latency to reach the platform in aged rats. Scopolamine (1 mg/kg) increased the latency to reach the platform on 8 th and 9 th day, reinforcing amnesia in water maze test. Pretreatment with ACEI and ARBs significantly (P < 0.01) decreased latency to reach the platform on 8 th and 9 th day in scopolamine-treated group. ACEI and ARBs significantly (P < 0.01) decreased latency to reach the platform as compared to Piracetam [Table 4].
|Table 4: Effect of ACEI and ARBs on latency to reach the platform in young, aged and scopolamine - treated rats in water maze test |
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| » Discussion|| |
Renin-angiotensin system may provide an alternative for treatment of various cognitive disorders. Renin-angiotensin and aldosterone system plays a major role in the progression of many diseases such as hypertension, atherosclerosis, kidney failure, etc. This system has been demonstrated to be present also in the brain. Vast efforts have been made in investigating its central impact and function. ACEI and ARBs prevent formation and action of Ang II and enhance the formation Ang IV, and it has been proved for its memory enhancing property.  The present study demonstrated that Ang IV receptor facilitate learning and memory by improving the cholinergic system in the brain and by reducing oxidative stress.
In the present investigation, the efficacy of ACEI and ARBs was studied on acquisition and consolidation of memory processes. The effect of ACEI (ramipril and perindopril) and ARBs (losartan and valsartan) were evaluated using EPM, passive avoidance test, and water maze test (WMT). Scopolamine was used as an amnesic agent; scopolamine-induced impairment of the memory is due to cholinergic deficits in certain brain areas and appears to be related to oxidative stress.
Elevated plus maze served as the exteroceptive behavioral model to evaluate memory in rats. The spontaneous alteration in behavior in the EPM is considered to reflect working memory.  Administration of ACE significantly improved memory of rats reflected by diminished TL in young as well as aged rats. Pretreatment with ACEI and ARBs for 8 days significantly reversed memory deficit induced by interoceptive stimuli, that is, scopolamine. Piracetam used as reference drug also decreased TL. Acetylcholine is considered as the most important neurotransmitter involved in the regulation of cognitive functions. According to the cholinergic hypothesis, memory impairments in patients with the senile dementia are due to a selective and irreversible deficiency in the cholinergic functions in the brain. This serves as the rationale for the use of AChE inhibitors for the symptomatic treatment of AD in its early stages. Consequently, AChE has been a potential target for the treatment of AD and prevention strategies. , Cholinergic system in hippocampus plays an important role in memory formation and retrieval. Better performance of ACEI and AT 1 antagonist treated animals in behavioral tests can be attributed to improved cholinergic system due to decreased activity of AChE resulting in increased ACh. Elevated brain Ang II may interfere with acetylcholine release that in turn interferes with cognitive function. Ang II also interferes with potassium mediated release of ACh from cortex slices. AT 1 receptor antagonists selectively prevent the vasoconstrictor action of Ang II and enhance the formation of Ang IV. Ang IV was found to recall of a passive avoidance response and enhance memory. Along with Ang II receptor antagonist, renin inhibitors, and ACEI found to decrease the synthesis of Ang II and in turn increase the synthesis of Ang IV.  Hence, the mechanism of memory enhancement activity of angiotensin antagonists may be due to blocking Ang II receptor, thus potassium mediated release of ACh might be enhanced and facilitation of formation of Ang IV (or) Ang IV like compound and its ligand that acts on the AT 4 receptor subtype to improve performance. 
Therefore, we evaluated the effect of ACEI and ARBs on AChE activity and correlated this activity with its antiamnesic activities. Treatment of ACEI and ARBs significantly inhibited AChE activity.
In order to confirm the effect of ACEI and ARBs on learning and memory, we used passive avoidance task. Scopolamine-treated rats exhibited significantly shorter step-down latencies. ACEI and ARBs treatment showed a significant increase in SDL in young as well as aged animals. Pretreatment with ACEI and ARBs significantly increased SDL in scopolamine-treated group. Thus, ACEI and ARBs significantly reversed the deficit produced by scopolamine. Piracetam used as positive control, also increased the SDL, which is consistent with previous reports.
The ameliorative effects of ACEI and ARBs on learning and memory were investigated in the WMT. The effect of ACEI and ARBs on spatial learning was evaluated using the WMT, which represents a more specific test of spatial memory. A task was developed where rats learn to swim in a water tank to find an escape platform hidden under the water. Learning is reflected on the shorter latencies to escape, the decrease on the length of the path to find the platform and increase in swimming time in target quadrant.  The scopolamine-treated animals showed significantly increase in latency to reach the platform in target quadrant where the platform was placed on the 8 th and 9 th day. Treatment with ACEI and ARBs significantly decreased latency to reach the platform in target quadrant than the other quadrants in doing so animals crossed the target quadrant (quadrant which previously containing the platform) repeatedly than others. Thus, the increased latency to reach the platform induced by scopolamine was significantly reversed by ACEI and ARBs. Piracetam also significantly decreased latency to reach the platform in target quadrant. The results indicated that ACEI and ARBs have significantly improved spatial memory.
Many studies have shown that the oxygen free radicals are implicated in the process of age-related decline in the cognitive performance may be responsible for the development of AD in elderly persons.  El-Sherbiny et al. reported that memory impairment in the scopolamine-induced animal model is associated with increased oxidative stress within rat brain.  It is demonstrated that increased oxidation of lipids, proteins, and deoxyribonucleic acid, alterations in mitochondrial function and a possible role of amyloid beta and its precursor protein in oxidative reaction in experimental models of AD. Strong evidence supporting the involvement of oxidative stress in degenerative changes within the forebrain cholinergic system has been suggested. Scopolamine causes memory impairment and oxidative stress.  NADPH oxidative stress as it uses NADH/NADPH as substrates for the production of superoxide anion and gets activated by binding to Ang II to AT 1 receptor. Thus, ACEI and ARBs were evaluated for antioxidant potential.
The results of the present study demonstrated that administration of all the treatments for 8 days produced significant fall in MDA and restored the activities of SOD, CAT, and GSH. Administration of scopolamine significantly increased MDA level, an important marker for LPO and reduced SOD, CAT, and GSH activities in the brain. Thus, ACEI and ARBs exert a protective effect against oxidative damage induced by scopolamine.
Raghavendra et al., compared the effect of captopril (ACEI) and losartan (a selective AT 1 receptor antagonist) in a step-up shock avoidance (active avoidance) task. The results suggested that both drugs were equally effective in enhancing retention of memory when administered prior to training. They have concluded that the decrease in endogenous Ang II activity in the brain might result in improved cognitive performance. 
In another research, Pederson et al., showed that the intracerebroventricularly infusion of scopolamine hydrobromide to disrupt spatial learning in the circular water maze and followed by administration of the Ang IV analog norleucine 1 -Ang IV (Nle 1 -Ang IV) to restore normal performance. The results suggested that Nle 1 -Ang IV acts to counteract the disruption of spatial learning induced by scopolamine. It has been found that results obtained in this investigation are consistent with those reported earlier. 
The present investigation suggests that ACEI (ramipril and perindopril) and ARBs (losartan and valsartan) showed cognitive enhancing activity by inhibition of AChE activity, and by regulation of the antioxidant system or increase formation of Ang IV. Thus, ACEI and ARBs might offer a useful therapeutic choice in either prevention or the treatment of dementia or other cognitive disorders.
Further it is necessary, to measure Ang IV level in the brain to focus on the mechanism of action of ACEI and ARBs at the molecular level to support the use of these drugs in dementia.
| » Conclusion|| |
The present study indicates that ramipril, perindopril, losartan, and valsartan attenuated scopolamine-induced memory deficit and showed memory enhancing property. ACEI and ARBs may provide a safer alternative for treatment of various cognitive disorders.
| » References|| |
AMyhrer T. Neurotransmitter systems involved in learning and memory in the rat: A meta-analysis based on studies of four behavioral tasks. Brain Res Brain Res Rev 2003;41:268-87.
McKinley MJ, Albiston AL, Allen AM, Mathai ML, May CN, McAllen RM, et al.
The brain renin-angiotensin system: Location and physiological roles. Int J Biochem Cell Biol 2003;35:901-18.
Gard PR. The role of angiotensin II in cognition and behaviour. Eur J Pharmacol 2002;438:1-14.
Amadio M, Govoni S, Alkon DL, Pascale A. Emerging targets for the pharmacology of learning and memory. Pharmacol Res 2004;50:111-22.
Gard PR. Cognitive-enhancing effects of angiotensin IV. BMC Neurosci 2008;9 Suppl 2:S15.
Bohlen V, Halbach O. Angiotensin IV in the central nervous system. Cell Tissue Res 2003;311:1-9.
Wright JW, Stubley L, Pederson ES, Kramár EA, Hanesworth JM, Harding JW. Contributions of the brain angiotensin IV-AT4 receptor subtype system to spatial learning. J Neurosci 1999;19:3952-61.
Albiston AL, McDowall SG, Matsacos D, Sim P, Clune E, Mustafa T, et al.
Evidence that the angiotensin IV (AT (4)) receptor is the enzyme insulin-regulated aminopeptidase. J Biol Chem 2001;276:48623-6.
Wright JW, Harding JW. Important role for angiotensin III and IV in the brain renin-angiotensin system. Brain Res Brain Res Rev 1997;25:96-124.
Jaiswal AK, Bhattacharya SK. Effect of Shilajit on memory, anxiety and brain monoamines in rats. Indian J Pharmacol 1992;2:12-7.
Ellman GL, Courtney KD, Andres V Jr, Feather-Stone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 1961;7:88-95.
Vogel HG, Vogel WH. Drug Discovery and Evaluation: Pharmacological Assays. 2 nd
ed. Germany: Springer-Verlag; 2002. p. 334-6.
Naidu PS, Singh A, Kulkarni SK. Effect of Withania somnifera
root extract on haloperidol-induced orofacial dyskinesia: Possible mechanisms of action. J Med Food 2003;6:107-14.
Luck H. Catalase. In: Bergmeyer HU, editor. Methods of Enzymatic Analysis. New York: Academic Press; 1971. p. 885-93.
Kono Y. Generation of superoxide radical during autoxidation of hydroxylamine and an assay for superoxide dismutase. Arch Biochem Biophys 1978;186:189-95.
Wills ED. Mechanism of lipid peroxide formation in animal tissues. Biochem J 1966;99:667-76.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193:265-75.
Morris R. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 1984;11:47-60.
Joshi H, Parle M. Pharmacological evidences for antiamnesic potentials of Phyllanthus amarus
in mice. Afr J Biomed Res 2000;10:165-73.
Jeong EJ, Lee KY, Kim SH, Sung SH, Kim YC. Cognitive-enhancing and antioxidant activities of iridoid glycosides from Scrophularia buergeriana
in scopolamine-treated mice. Eur J Pharmacol 2008;588:78-84.
Raghavendra V, Chopra K, Kulkarni SK. Comparative studies on the memory-enhancing actions of captopril and losartan in mice using inhibitory shock avoidance paradigm. Neuropeptides 2001;35:65-9.
El-Sherbiny DA, Khalifa AE, Attia AS, Eldenshary Eel-D. Hypericum perforatum
extract demonstrates antioxidant properties against elevated rat brain oxidative status induced by amnestic dose of scopolamine. Pharmacol Biochem Behav 2003;76:525-33.
Pederson ES, Harding JW, Wright JW. Attenuation of scopolamine-induced spatial learning impairments by an angiotensin IV analog. Regul Pept 1998;74:97-103.
[Table 1], [Table 2], [Table 3], [Table 4]
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| ||Drug and Chemical Toxicology. 2021; : 1 |
|[Pubmed] | [DOI]|
||Beneficial effects of angiotensin converting enzyme inhibition on scopolamine-induced learning and memory impairment in rats, the roles of brain-derived neurotrophic factor, nitric oxide and neuroinflammation
| ||Farimah Beheshti, Hamid Reza Akbari, Yousef Baghcheghi, Fatemeh Mansouritorghabeh, Sakineh Sadat Mortazavi Sani, Mahmoud Hosseini |
| ||Clinical and Experimental Hypertension. 2021; 43(6): 505 |
|[Pubmed] | [DOI]|
||Facilitation of TRKB Activation by the Angiotensin II Receptor Type-2 (AT2R) Agonist C21
| ||Liina Laukkanen, Cassiano R. A. F. Diniz, Sebastien Foulquier, Jos Prickaerts, Eero Castrén, Plinio C. Casarotto |
| ||Pharmaceuticals. 2021; 14(8): 773 |
|[Pubmed] | [DOI]|
||Perindopril ameliorates experimental Alzheimer’s disease progression: role of amyloid ß degradation, central estrogen receptor and hyperlipidemic-lipid raft signaling
| ||Basim A. S. Messiha, Mohammed R. A. Ali, Mahmoud M. Khattab, Amira M. Abo-Youssef |
| ||Inflammopharmacology. 2020; 28(5): 1343 |
|[Pubmed] | [DOI]|
||The Brain AT2R—a Potential Target for Therapy in Alzheimer’s Disease and Vascular Cognitive Impairment: a Comprehensive Review of Clinical and Experimental Therapeutics
| ||Heba A. Ahmed, Tauheed Ishrat |
| ||Molecular Neurobiology. 2020; 57(8): 3458 |
|[Pubmed] | [DOI]|