The Impact of Some Modulators of the Renin-Angiotensin System on the Scopolamine-Induced Memory Loss Mice Model

Abstract

As some of the renin-angiotensin-aldosterone system (RAAS)-dependent mechanisms underlying the cognitive performance modulation could include oxidative balance alterations, in this study we aimed to describe some of the potential interactions between RAAS modulators (Losartan and Ramipril) and oxidative stress in a typical model of memory impairment. In this study, 48 white male Swiss mice were divided into six groups and received RAAS modulators (oral administration Ramipril 4 mg/kg, Losartan 20 mg/kg) and a muscarinic receptors inhibitor (intraperitoneal injection scopolamine, 0.5 mg/kg) for 8 consecutive days. Then, 24 h after the last administration, the animals were euthanized and whole blood and brain tissues were collected. Biological samples were then processed, and biochemical analysis was carried out to assess superoxide dismutase and glutathione activities and malondialdehyde concentrations. In the present experimental conditions, we showed that RAAS modulation via the angiotensin-converting enzyme inhibition (Ramipril) and via the angiotensin II receptor blockage (Losartan) chronic treatments could lead to oxidative stress modulation in a non-selective muscarinic receptors blocker (scopolamine) animal model. Our results showed that Losartan could exhibit a significant systemic antioxidant potential partly preventing the negative oxidative effects of scopolamine and a brain antioxidant potential, mainly by inhibiting the oxidative-stress-mediated cellular damage and apoptosis. Ramipril could also minimize the oxidative-mediated damage to the lipid components of brain tissue resulting from scopolamine administration. Both blood serum and brain changes in oxidative stress status were observed following 8-day treatments with Ramipril, Losartan, scopolamine, and combinations. While the serum oxidative stress modulation observed in this study could suggest the potential effect of RAAS modulation and scopolamine administration on the circulatory system, blood vessels endothelia, and arterial tension modulation, the observed brain tissues oxidative stress modulation could lead to important information on the complex interaction between renin-angiotensin and cholinergic systems.

Keywords: Losartan; RAAS; Ramipril; antioxidant effect; blood serum; brain; cognitive functions; mice model; oxidative stress; scopolamine.

Figure 1

Renin–angiotensin–aldosterone system modulators and the implication of oxidative stress in cognitive processes.

Figure 2

Schematic representation of the experimental design.

Figure 3

Total superoxide dismutase specific activity in blood serum and brain extracts in scopolamine-induced memory loss mice models treated with RAS modulators (CMC-Na = sodium carboxymethyl cellulose; LOS = Losartan; RAM = Ramipril; SCO = scopolamine). Results were expressed as means ± SEM (n = 8, for each group, (a)—** p < 0.01, ^‡ p = 0.056, ^‡‡ p = 0.06; (b)—* p < 0.05, ** p < 0.01, ^‡ p = 0.06, ^‡‡ p = 0.056).

Figure 4

Cellular glutathione peroxidase specific activity in brain extracts in scopolamine-induced memory loss mice models treated with RAS modulators (CMC-Na = sodium carboxymethyl cellulose; LOS = Losartan; RAM = Ramipril; SCO = scopolamine). Results were expressed as means ± SEM (n = 8, for each group, * p < 0.05, ** p < 0.01, ^‡ p = 0.051).

Figure 5

Malondialdehyde concentration in blood serum and brain extracts of the RAS-modulated scopolamine-induced memory loss mice models (CMC-Na = sodium carboxymethyl cellulose; LOS = Losartan; RAM = Ramipril; SCO = scopolamine). Results were expressed as means ± SEM (n = 8, for each group, (a)—* p < 0.05, ^‡ p = 0.06; (b)—* p < 0.05, ** p < 0.01, ^‡ p = 0.06).

Figure 6

Correlative analysis of biochemical markers determined from brain extracts (CMC-Na = sodium carboxymethyl cellulose; LOS = Losartan; RAM = Ramipril; SCO = scopolamine). Results were expressed as means ± SEM (n = 8, for each group, Pearson’s correlation, r = Pearson coefficient, p = p-value).