Abstract
The endocannabinoid system, through cannabinoid (CB) receptors, is involved in memory-related responses, as well as in processes that may affect cognition, like oxidative stress processes. The purpose of the experiments was to investigate the impact of CB1 and CB2 receptor ligands on the long-term memory stages in male Swiss mice, using the passive avoidance (PA) test, as well as the influence of these compounds on the level of oxidative stress biomarkers in the mice brain. A single injection of a selective CB1 receptor antagonist, AM 251, improved long-term memory acquisition and consolidation in the PA test in mice, while a mixed CB1/CB2 receptor agonist WIN 55,212-2 impaired both stages of cognition. Additionally, JWH 133, a selective CB2 receptor agonist, and AM 630, a competitive CB2 receptor antagonist, significantly improved memory. Additionally, an acute administration of the highest used doses of JWH 133, WIN 55,212-2, and AM 630, but not AM 251, increased total antioxidant capacity (TAC) in the brain. In turn, the processes of lipids peroxidation, expressed as the concentration of malondialdehyde (MDA), were more advanced in case of AM 251. Thus, some changes in the PA performance may be connected with the level of oxidative stress in the brain.
Highlights
It has been widely reported that intense oxidative stressrelated processes in the brain are one of the main causal factors involved in the impairment in cognitive functions through two critical changes in the brain
One-way analysis of variance (ANOVA) revealed that administration of the acute ip doses of CB receptor ligands had no statistically significant effect on the locomotor activity as compared with the appropriate control vehicle-injected groups (for CB2 receptor agonist, JWH 133: F(4, 45) = 0.1459, p = 0.9639; for CB2 receptor antagonist, AM 630: F(5, 54) = 1.720, p = 0.1458; for CB1/CB2 receptor agonist, WIN 55,212-2: F(3, 36) = 1.138, p = 0.3468; and for CB1 receptor antagonist, AM 251: F(4, 45) = 2.464, p = 0.0585) (Tables 1(a), 1(b), 1(c), and 1(d), resp.)
What is interesting is that we revealed that an acute systemic pretraining or posttraining administration of a mixed CB1/CB2 receptor agonist, WIN 55,212-2, at the dose of 1.0 mg/kg, impaired cognitive processes in the passive avoidance (PA) test but at the same time increased the level of total antioxidant capacity (TAC) in the brain showing certain antioxidant properties
Summary
It has been widely reported that intense oxidative stressrelated processes in the brain are one of the main causal factors involved in the impairment in cognitive functions through two critical changes in the brain. The formation of ROS and other free radicals during metabolism is an important and normal process that is ideally compensated by an elaborate endogenous antioxidant system. Excessive radical production and their accumulation result in oxidative stress, which has been implicated in mechanisms responsible for oxidative injury of neurons by causing damage of cell structures, including lipids, membranes, and proteins [1]. The central nervous system (CNS) is very susceptible to oxidative stress. It contains large amounts of free-radical generating iron and substances like ascorbate, glutamate, and unsaturated fatty acids that undergo redox-reaction leading to radical formation [3]. Malondialdehyde (MDA), the product of lipid peroxidation, is a neuronal toxin and may impair protein function [4]
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