Treadmill exercise training alleviates diabetes-induced depressive-like behavior and cognitive impairment by improving hippocampal CA1 neurons injury in db/db mice
Introduction
Diabetes mellitus (DM) is one of the most prevalent chronic metabolic diseases in almost all countries across the world. With economic and social development, as well as changes in dietary habits and an increase in sedentary lifestyles, the incidence of DM has been increasing and has gradually showing a younger trend in recent years (Saeedi et al., 2019). With the increasing number of diabetic patients, diabetes-related cognitive impairment has been gaining increasing attention, which manifests in worse learning, slower processing speed, and memory and attention capabilities decreasing, and serves as a transitional stage between cognitively normal and Alzheimer's disease (Gold et al., 2007, Moran et al., 2021). Clinical and experimental evidence strongly suggests that persistent hyperglycemia, particularly type 2 diabetes mellitus (T2DM), results in a progressive impairment of brain neuronal function (Sima and Li, 2005, Stranahan et al., 2008). Patients with DM are more likely to develop depressive symptoms, such as depressed mood, sleep problems, and suicidal ideation, than those without DM (Islam et al., 2015). Epidemiological studies have revealed that nearly one in every four adults with T2DM suffers from depression, a rate that is significantly greater than the rate reported in non-diabetic patients (Khaledi et al., 2019). The hippocampus is a critical tissue that is impacted by diabetes mellitus and is believed to have an essential role in depressive disorders and cognitive processes (Ho et al., 2013). Meanwhile, the CA1 area was revealed to represent a significant output structure of the hippocampus network (Chai et al., 2017). Excitatory neurons in the CA1 area of the hippocampus are more affected than excitatory neurons in other parts of the hippocampus (Beguin et al., 2013). Changes in CA1 morphology are linked to depression (Bedrosian et al., 2011), as well as to learning and memory(Moser et al., 1994).
It is generally accepted that oxidative stress is increased in diabetes, which is a main contributor to diabetic complications (Barone et al., 2021). Oxidative stress is generated by an imbalance between reactive oxygen species (ROS) production and antioxidant capacity. NADPH oxidase 2 (NOX2) is a major source of ROS and has been shown to be constitutively produced in neurons and significantly increased in the brains of patients with modest cognitive deficits (Ansari and Scheff, 2011). Although the hippocampus is a vital region for numerous types of learning and memory, it is extremely vulnerable to oxidative stress. Several recent investigations have demonstrated that oxidative stress in the hippocampus is a significant contributing factor to diabetes-induced cognitive dysfunction (Adedara et al., 2019, Gocmez et al., 2019). Rammal and colleagues reported that they discovered oxidative stress in the hippocampus of anxious male mice and that when oxidative stress was suppressed, depression symptoms improved (Rammal et al., 2008). According to Yürüker et al., oxidative stress is associated with hippocampal neuronal apoptosis and that lowering the level of ROS efficiently inhibits hippocampus neuronal apoptosis and restores hippocampus neural function (Yürüker et al., 2015). In addition, increasing evidence indicates that diabetic-induced cognitive impairment is increasingly linked to inflammation, which may play a role in its development (Pei and Sun, 2018, Stringhini et al., 2013). In diabetic mice, this inflammatory reaction has been linked to the loss of hippocampus neurons and cognitive impairment (Ye et al., 2018). One of the most important regulators of the inflammatory response is the inflammasome. The nucleotide binding and oligomerization domain-like (Nod) receptor family pyrin domain-containing 3 (NLRP3) inflammasome has been extensively investigated and is comprised of the NLRP3 sensor protein, the adaptor protein ASC, and the effector protein Caspase-1 (Xu et al., 2018). It is widely established that NADPH oxidase-derived ROS accumulation is a major pathway for NLRP3 inflammasome activation (Moon et al., 2016). Once active, the NLRP3 inflammasome forms a complex with the cysteine protease Caspase-1 and the adaptor protein ASC, resulting in Caspase-1 cleavage and activation. Activated Caspase-1 can process pro-IL-1β into its mature form IL-1β, which plays a vital role in the development and progression of CNS disorders. On the whole, hippocampal neurons, particularly within the CA1 region, are more susceptible to hyperglycemia-induced oxidative stress, promoting the generation and accumulation of ROS, so as to promote apoptosis (Huang et al., 2020) and inflammation (Blaser et al., 2016) through different signaling pathways. Furthermore, it appears as though oxidative stress, apoptosis, and inflammation are in a vicious loop, exacerbating one another and promoting disease progression.
It is well known that aerobic exercise training is an effective therapy for both the prevention and treatment of T2DM and its complications. Aerobic exercise training is an important part of rehabilitation, and it has been shown to be useful in the prevention of metabolically induced neurodegenerative diseases (Bertram et al., 2016, Law et al., 2020). However, little is focused on the effects of treadmill aerobic exercise on the progression of diabetes-induced behavioral abnormalities associated with depression and cognitive impairments in db/db mice. Thus, we performed a comprehensive study in db/db mice, a well-characterized rodent model of T2DM, to determine the effect of treadmill aerobic exercise on diabetes-related neurobehavioral deficits and the underlying mechanisms of this beneficial effect. Based on the previous findings and pre-experiment results, we hypothesize that treadmill exercise training can ameliorate hippocampus injury by suppressing oxidative stress-induced apoptosis and NLRP3 inflammasome activation, thereby improving diabetes-induced depressive-like behavior and cognitive impairment in db/db mice.
Section snippets
Experimental animals and study design
Six-week-old male db/db (C57BLKS/J-leprdb/leprdb) mice and age-matched db/m (C57BLKS/J-leprdb/m) mice were purchased from the Model Animal Research Center of Nanjing University (Nanjing, China). All animals were housed in the specific pathogen free level animal room (12 h/12 h light-dark cycle; temperature 24 ± 2 °C; relative humidity 55 ± 5%) of the Animal Experimental Center of Xuzhou Medical University. All animal experiments were approved by the Experimental Animal Ethics Committee of
Effects of treadmill exercise training on body weight, fasting blood glucose, and insulin resistance in db/db mice
Throughout the experimental period, the body weight, FBG, and plasma insulin levels of db/db mice grew and remained considerably higher than those of non-diabetic db/m control mice (Fig. 1A, B, and E). All of these characteristics of db/db mice are consistent with previous reports on this diabetic animal model. We observed that from week 4 until the end of the experiment, the db/db-TET mice's body weight reduced significantly compared to that of the db/db mice in the model control group.
Discussion
Numerous investigations have shown numerous shared pathogenic mechanisms between diabetes and neurodegenerative disorders (Hölscher, 2020, Morsi et al., 2018, Su and Dai, 2016). With the rise of type 2 diabetes mellitus, diabetes-related cognitive dysfunction and depressive-like behavior are increasing and receiving increasing attention. Impairment of hippocampal structure and function is at the heart of neurological symptoms caused by type 2 diabetes, and changes in hippocampal structure and
CRediT authorship contribution statement
Zhongyuan Zhou: Conceptualization, Methodology, Data curation, Writing – original draft. Meng Wang: Methodology, Data curation. Chengyu Huang: Software, Validation. Yan Li: Visualization. Lin Gao: Investigation. Yandong Zhu: Supervision. Changjiang Ying: Writing – review & editing. Xiaoyan Zhou: Writing – review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgment
This research was funded by the Postgraduate Research and Practice Innovation Program of Jiangsu Province (No. KYCX21_2674).
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