Introduction
Traumatic brain injury (TBI), also known as intracranial injury, occurs when a sudden external force injures the brain, leading to neurological impairment. According to the literature, the annual incidence of TBI in the United States is 180–250 cases per 100,000 people a year, and the incidence rate in Europe is 235 cases per 100,000 people a year [1], [2]. Nearly 1.6 million patients with TBI are admitted to the hospital each year, of whom 66,000 die annually [3]. TBI accounts for 15–20% of all types of trauma and has the highest mortality rate among all types of trauma. Severe traumatic brain injury (sTBI) patients have a mortality rate of approximately 30–50%, and there is a relatively high disability rate among survivors. TBI includes primary brain injury, which includes concussion, brain contusion, brain stem injury, diffuse axonal injury, and so on. It also involves secondary brain injury, such as brain edema, subdural hematoma, epidural hematoma, and intracranial hematoma. These brain injuries involve hemorrhagic and ischemic brain injuries, as well as pathological processes such as cerebral edema and the destruction of the blood-brain barrier (BBB). How to improve the therapeutic effect of TBI, reduce mortality and disability, and improve the prognosis of TBI patients has always been the focus of clinical and basic research [4].
TBI is initially a partial injury, but it can cause many secondary injuries within a few hours to several days, that is, secondary brain injury (SBI). A growing body of animal experiments and clinical studies have confirmed that brain damage caused by trauma is not completed immediately after injury but is secondary to brain tissue ischemia, hypoxia, or microenvironment changes [5]. The latter is the main pathological process of brain damage after trauma, and this process is caused by a combination of factors, which is an important cause of neuron death [6]. SBI obviously aggravates the primary brain injury and traumatic brain edema, which is the main cause of neurological dysfunction [7]. In addition to the serious consequences of TBI, cognitive impairment is also one of the most persistent and severe symptoms, usually manifested in both attention and memory. Studies have shown that spatial memory loss occurs after various levels of TBI [8], [9]. However, the exact mechanism of cognitive impairment after TBI is still not very clear. Changes in acetylcholine content, the toxic effects of glutamate, the decline of brain-derived neurotrophic factor (BDNF) levels, and the inflammatory response in the brain tissue injury area are all related to cognitive impairment after TBI. Preventing neuronal necrosis and improving cognitive function are the clinical goals of TBI therapy.
Glucagon like peptide-1 (GLP-1) is a peptide hormone that was first discovered as a regulator of insulin release from β-cells in the pancreas, and it exerts its biological effects through the GLP-1 receptor (GLP-1R) [10]. GLP-1R is widely expressed in the pancreas and extrapancreatic tissues such as the gastrointestinal tract, central nervous system, cardiovascular system, bone marrow, kidney, and lung tissues [11]. After GLP-1 binds to GLP-1R, it activates protease A (PKA), which increases the content of the second messenger cAMP in the cell, which in turn activates the Pac family of guanylate exchange factors regulated by cAMP, thereby increasing the cytoplasmic Ca2+ concentration and the number of islet cells [12]. GLP-1 is of particular interest for its glucose-lowering effect, which accelerates insulin biosynthesis and promotes its rapid secretion through the GLP-1 receptor that directly acts on insulin β-cell membranes or indirectly acts on glucose receptors and sensitive nerves on β cells [10]. Furthermore, GLP-1 also inhibits islet β-cell apoptosis, promotes the proliferation and differentiation of islet β-cells, and regenerates islet β-cells by inducing stem cells to differentiate into insulin-secreting cells [13]. GLP-1R agonists (GLP-1RA) are receiving widespread attention for the treatment of type 2 diabetes [14]. Since the FDA approved Exenatide, the first GLP-1RA in 2005, six GLP-1RAs have been approved for marketing, and many drugs are in various stages of clinical trials [15]. GLP-1RAs also play a protective role in the nervous system and have been shown to prevent and treat Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis by stimulating neural cell differentiation, enhancing synaptic plasticity, and promoting neurotransmitter secretion [16], [17], [18], [19]. However, the recovery effect and mechanism of GLP-1RAs on neurological function and cognitive impairment after TBI are still unclear.
In the present study, we aimed to investigate the effects of GLP-1RA and Exendin-4 (Ex-4) on the recovery from neurological and cognitive function impairment after TBI, and then explored the potential molecular mechanisms involved in this study.
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Animal preparation
Adult male Sprague Dawley (SD) rats weighing 200–250 g were obtained from the Laboratory Animal Center of Tianjin Medical University. The experiment was started in the animal room after approximately 1 week of adaptive breeding. All rats were randomly selected and housed in a 12 h light/dark cycle with controlled temperature (22 ± 2 °C) and humidity (45%) and free access to food and water. All protocols were approved by the Animal Ethics Committee of Tianjin Medical University.
Experimental design of animal models
A total of 78
Ex-4 promotes neurological recovery after TBI
To evaluate whether Ex-4 promoted neurological recovery of rats after TBI, TBI was induced by controlled cortical impact (CCI), and mNSS was then performed at days 0, 1, 3, 7, 14, and 21, respectively. As shown in Fig. 1A, Ex-4 rats displayed lower mNSS scores than TBI-treated animals on day 3 (4.7 ± 1.3 vs. 8.3 ± 1.3; p < 0.001), day 7 (3.1 ± 0.7 vs. 6.1 ± 1.4; p < 0.001), day 14 (2.5 ± 0.5 vs. 4.8 ± 1.4; p < 0.01), and day 21 (2.3 ± 0.7 vs. 3.1 ± 0.7; p < 0.05) after TBI. Moreover, the mNSS
Discussion
Traumatic brain injury (TBI) is one of the main causes of physical and cognitive disabilities [20]. After many years of animal and clinical trials, almost all drugs that have shown efficacy in animal experiments have failed in clinical trials [21]. Therefore, further research on the pathological mechanism of TBI and finding effective neuroprotective agents are the research hotspots of TBI. TBI often causes permanent motor or sensory neurological deficits. In addition, cognitive impairment is
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors’ contributions
J. Z. and T.L. Y.: collection, analysis and interpretation of data; J. Z. and S.X. C.: manuscript writing; S.X. C. and S. Z.: conception and design, interpretation of data, manuscript revision. All authors approved the final version of the manuscript.
Funding
This study is supporting by the National Natural Science Foundation Major Program of China (81891003, 81891004) and the Technology Research Projects of PAL (AWS15J001).
Declaration of Competing Interest
There are no conflicts of interest to disclose for the authors.
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Metabolic disorders on cognitive dysfunction after traumatic brain injury
2022, Trends in Endocrinology and Metabolism
In recent years, GLP-1 receptor agonists, including exendin-4 [68], liraglutide [69], and twinincretin [69], have gained momentum in basic and clinical research. Studies have demonstrated that the drugs can improve cognitive dysfunction in animals after TBI, which may be related to the inhibition of glial inflammation and the promotion of CBF recovery [79,80]. Therefore, further basic research and clinical studies are needed to determine the efficacy and mechanism of action of each antidiabetic agent and to determine the optimal dosage range and time window for administration. View all citing articles on Scopus
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