Endocannabinoid and hematological responses to pre- and post-therapeutic exercises in liver transplant patients.

Am J Clin Exp Immunol 2024;13(6):259-271 www.ajcei.us /ISSN:2164-7712/AJCEI0162249 Original Article Endocannabinoid and hematological responses to pre- and post-therapeutic exercises in liver transplant patients Abdullah Nasser AlShahrani1, Thamir Al-Khlaiwi1, Sultan Ayoub Meo1, Intisar Ahmad Siddiqui2, Bandar Alghanem3,4, Feras Almourfi3,4 Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia; 2Department of Dental Education, College of Dentistry, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia; 3Medical Research Core Facility and Platforms, King Abdullah International Medical Research Centre, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia; 4King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia 1 Received November 25, 2024; Accepted December 17, 2024; Epub December 25, 2024; Published December 30, 2024 Abstract: Endocannabinoids (eCBs) play a crucial role in regulating the pathophysiological progression of chronic liver disease through hepatic cannabinoid receptor 2 (CB2). According to the literature, various treatment options are available for liver disease patients, including transplantation and physical activity both before and after the procedure. The aim of this study is to assess the response of endocannabinoids to pre- and post-therapeutic exercises in liver transplant patients (LTx). This analytical case-control longitudinal study was conducted on patients aged 18-70 at King Fahad Specialist Hospital in Dammam, Saudi Arabia. Participants were divided into two groups: an intervention group of LTx patients (n = 26) and a control group of end-stage liver disease patients (n = 23) who were not candidates for liver transplantation (LT). Blood samples were collected before the initiation of preoperative exercises, one month before LT, and three months after LT following postoperative exercises. The median arachidonoyl ethanolamide (AEA) levels in the control group were comparatively higher after therapeutic exercises compared to before; however, the Wilcoxon signed-rank test showed no significant differences (P = 0.212). In the LTx group, the median difference in AEA between pre- and post-therapeutic exercises was marginally significant (P = 0.091). Additionally, the Wilcoxon signed-rank test revealed a highly significant increase in median 2-arachidonoylglycerol (2-AG) levels after therapeutic exercises compared to before in the LTx group (P = 0.049), while the control group showed no significant change in post- vs. pre-therapeutic exercise median 2-AG levels (P = 0.346). The study’s findings revealed an increased concentration of 2-AG after therapeutic exercises in LTx patients but not in the control group, while AEA levels were elevated after therapeutic exercises in both groups. The effect of post-therapeutic exercises on hematological and biochemical markers was significant between the control and LTx groups, particularly concerning platelet count, total bilirubin, total protein, albumin/globulin ratio, international normalized ratio, and calcium levels. Keywords: Endocannabinoid system, endocannabinoids, cannabinoid receptors, pre- and post-therapeutic exercises, liver transplantation Introduction The endocannabinoid system (ECS) was first identified in the late 1980s during research on cannabis, which led to the discovery of this complex cell-signaling system in the body [1]. The ECS is an intercellular communication system recognized as a neurotransmission system [2]. The liver plays a vital role in metabolizing and breaking down both endocannabinoids (eCBs) and exogenous cannabinoids, such as those found in cannabis. This metabolic process is essential for clearing cannabinoids from the body, which in turn influences their effects on various physiological processes [3]. The ECS is composed of several key components: enzymes, cannabinoid receptors, and eCBs. Enzy- https://doi.org/10.62347/FNLX9490 Endocannabinoid and exercises mes play a crucial role in maintaining a delicate balance in the system, preventing excessive signaling while also contributing to the regulation of various physiological processes beyond the endocannabinoid system itself [4]. The second most important components of the ECS are cannabinoid receptors type 1 (CB1) and type 2 (CB2), which belong to the family of 7-transmembrane G-protein-coupled receptors, specifically the Gi/o class [4]. CB1 receptors are widely distributed throughout the brain, particularly in the hippocampus, basal ganglia, neocortex, and brainstem. They are also present, though to a lesser extent, in the lungs, testes, skeletal muscles, liver, pancreas, and adipose tissues. CB1 receptors are involved in regulating immune responses, metabolism, inflammation, and various physiological functions specific to each tissue type. CB2 receptors are predominantly located outside the nervous system, in tissues such as the liver, cardiovascular system, skeletal muscles, gastrointestinal tract, and immune system. CB2 receptors are also expressed in immune cells, including progenitor cells, T and B lymphocytes, and macrophages, as well as in lymph nodes and the thymus. Owing to their more restricted distribution, CB2 receptors are primarily found in immune-related cells and certain peripheral tissues, including the liver and adipose tissue. Therefore, activation of CB2 triggers immunomodulatory effects [5]. The most studied eCBs are arachidonoyl ethanolamide (anandamide)����������������������� ���������������������� (AEA) and 2-arachidonoylglycerol (2-AG) [4]. The metabolite 2-AG is derived from diacylglycerol and functions as a full agonist with moderate affinity for cannabinoid receptors. It is also hydrolyzed by monoacylglycerol lipase [5]. AEA acts as a partial agonist of cannabinoid receptors and is produced from N-arachidonoyl phosphatidylethanolamine by the enzyme N-acyl-phosphatidylethanolamine phospholipase D-like esterase [6]. Several studies have shown that exercise increases levels of eCBs, including anandamide, which acts as a vasodilator and enhances blood flow during physical activity [7, 8]. Furthermore, both eCBs and external cannabinoids have bronchodilatory properties, indicating that the ECS may play a role in enhancing respiratory function during exercise [8]. Elevated levels of eCBs in the bloodstream have been commonly associated with aerobic 260 exercise [9]. Researchers reviewed studies examining the effects of exercise on endocannabinoid levels and their impact on various physiological and psychological factors. Evidence shows that moderate exercise intensity increases blood levels of AEA and 2-AG, leading to reduced anxiety, decreased pain, and improved well-being. Regular or daily exercise helps maintain ECS balance and manage stress levels [10]. eCBs play a crucial role in regulating the pathophysiological mechanisms, particularly in the progression of chronic liver disease, thr (...truncated)