Research reportTreadmill exercise improves LPS-induced memory impairments via endocannabinoid receptors and cyclooxygenase enzymes
Introduction
Neuroinflammation has been considered as a very important component in the pathophysiology of neurodegenerative diseases [1,2]. Intraperitoneal injection of lipopolysaccharide leads to degeneration of memory performance by inducing neuroinflammation in the brain [1,3]. The hippocampus, a key structure related to learning and memory, is affected by inflammatory processes of neurodegenerative diseases and endocannabinoid system components [4]. The endocannabinoid system includes two types of receptors (CB1 and CB2) that are activated by a family of endogenous arachidonic acid derivatives, such as anandamide and 2-arachidonoylglycerol. This system is emerging as one of the important therapeutic targets in the brain disorders that it has the ability to modulate a range of aspects of neuronal damage [4,5]. The cannabinoid receptors type1 are expressed mainly in the brain, one of their biological actions being the regulation of synaptic activity [4].The presence of cannabinoid receptor type2 in different parts of the brain, including the hippocampus and amygdala, suggests that they may be involved in learning and memory processes and regulation of mood disorders [5,6]. According to reports, inflammatory conditions stimulate CB2 receptor expression [7]. Two isoforms of cyclooxygenase (COX-1 and COX-2) are also involved in the neuroinflammatory process of neurodegenerative diseases, but their role in the development of neurodegeneration is not fully determined [8]. COX-1 is constitutively expressed throughout the mammalian body and in the brain predominantly in microglia, but COX-2 is expressed in fewer tissues and in the brain in the hippocampal neurons and their dendritic spines [9,10]. Cyclooxygenases (COX-1 and 2) metabolize free arachidonic acid to generate biologically active prostaglandins [10]. In the brain, PGE2 is produced by one of three PGE2 synthase enzymes: one cytosolic PGES (cPGES) and two membrane-associated synthases (mPGES-1 and -2). Of these, mPGES-1 is primarily coupled to COX-2 and its expression is up-regulated following stimulation by a pathological injury factor [11]. Therefore, COX2 and mPGES-1 inhibition may alleviate brain inflammation-induced cognitive impairment [11,12]. Song et al. showed that systemic LPS-induced neuroinflammation increased the expression levels of iNOS and COX2 proteins and was associated with cognitive deficits in the Morris water maze test, but glycyrrhizin consumption reduced the expression levels of these proteins and improved memory deficit [13].
Pharmacological interventions can improve cognitive and memory function following brain injury, but its effects are often temporary and limited, and may have unexpected side effects [14,15]. Therefore, it is believed that non-pharmacological treatments such as physical exercise can help brain function more than medicine-dependent approaches [15]. Regular exercise training improves brain function by increasing neurogenesis, gene expression, synaptic plasticity, and hippocampal cell density, and increases hippocampus-dependent learning and memory [16,17]. In addition, exercise and endocannabinoid activity play an independent role in regulating brain plasticity, and a field of endocannabinoid-exercise interaction is emerging [16]. Regular physical activity increases the hippocampal endocannabinoid signaling [16] and endocannabinoid signaling appears to be essential for the positive effects of exercise on memory. For instance, exercise-induced spatial memory improvement in animals was prevented by simultaneous blockade of the CB1 receptor [18]. There is also scientific evidence to suggest that physical activity affects cognitive function by affecting COX pathway function in the hippocampus [15,19]. Since intraperitoneal injection of LPS, as a laboratory model of neuroinflammation associated with cognitive impairment [20], affects CB receptors [21,22] and COX enzymes [13,20], and given the role of the endocannabinoid system and COX enzymes in memory formation and their susceptibility to exercise [[17], [18], [19]], the question is raised whether physical activity can improve cognitive impairment by modulating these factors in neurodegenerative diseases? Therefore, this study attempts to investigate the effect of treadmill aerobic exercise on the expression of CB receptors and COX enzymes against LPS-induced cognitive disorders in the hippocampus of rats.
Section snippets
Animals
Forty male Wistar rats were purchased from animal center of Pasteur Institute (Tehran, Iran), weighing 180−220 g at the beginning of the experiment. The rats were maintained under standard animal housing conditions (temperature 25 ± 2 °C, 12/12 light-dark cycle) with ad libitum access to food and water. After one week acclimation, animals were randomly allocated into either the saline--treated (Sal) or LPS-treated (LPS) groups; then each group was divided into two subgroups: the sedentary (Sed)
Morris water maze
In this study, hippocampal-dependent spatial learning and memory were tested using the Morris water maze test. The within-group comparison showed that during the 4 consecutive training days, there was a gradual decrease in the escape distance (F(2.3,83.7) = 56.8, P < 0.001) and escape latency (F(2.4,86.1) = 75.43, P < 0.001) for animals from the different groups. Also, there was a significant effect of exercise condition × day interaction (F(2.4,86.1) = 3.98, P = 0.016) in the escape latency
Discussion
The results of this study showed that endurance exercise could impact cognitive function, and improve the peripheral LPS-hampered learning and memory in the treadmill exercise rats in the MWM test. According to reports, exercise has beneficial effects on memory and cognitive function, while inflammation shows the opposite effects [15,28]. LPS-induced neuroinflammation causes neuronal death, neurogenesis inhibition, and synaptic plasticity impairment [3]. LPS also affects the hippocampus and
Conclusions
The results presented in this report indicate that treadmill exercise may improve cognitive function by inducing hippocampal CB1 expression; and may limit the need for high CB2 expression by reducing LPS-induced inflammation. It may also affects neuroinflammation-induced learning and memory impairment by decreasing the trend of elevation of COX2 and mPGES-1 expression in the LPS-treated rats. However, further studies are needed to elucidate the modulatory action of exercise on the
CRediT authorship contribution statement
Azam Moosavi Sohroforouzani: Conceptualization, Formal analysis, Investigation, Writing - original draft. Saeed Shakerian: Supervision, Writing - review & editing, Funding acquisition. Mohsen Ghanbarzadeh: Project administration. Hojjatallah Alaei: Supervision, Writing - review & editing.
Declaration of Competing Interest
None.
Acknowledgement
This research was funded by a grant (EE/97.24.3.17663/SCU.ac.IR) from the Shahid Chamran University of Ahvaz, Iran.
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