Drucker, a professor in the department of medicine at the University of Toronto’s Temerty Faculty of Medicine and a senior scientist at the Lunenfeld-Tanenbaum Research Institute at Sinai Health, has pioneered research on gut hormones that has led to life-changing therapies for people with type 2 diabetes, obesity and short bowel syndrome.
Now, Drucker’s lab is studying how these same hormones work in the context of other conditions throughout the body, which could result in treatments for an even wider variety of diseases.
Drucker, an inductee to the Canadian Medical Hall of Fame and winner of the Canada Gairdner International Award, is most well-known for his contributions to the discovery of glucagon-like peptides (GLP-1 and GLP-2), gut hormones that help control insulin and balance blood sugar levels, and for the development of related therapies for diabetes, obesity and intestinal failure.
Yet, beyond conventional metabolism, drugs based on GLP-1 can also reduce plaque formation in arteries, or atherosclerosis, and control inflammation in several organs. Plaque and inflammation are linked to heart attack, stroke and other cardiovascular diseases—some of the leading causes of death in people with type 2 diabetes and obesity.
The drugs also show promise for treating liver disease and Alzheimer’s disease.
In a study recently published in JCI Insight, Drucker’s research team investigated the role that specific GLP-1 receptors play to make GLP-1 drugs effective against cardiovascular and liver disease in the aorta and liver of mice.
In the first half of the study, Drucker’s team saw that the GLP-1 drug reduced plaque in the arteries, but the presence or lack of the GLP-1 receptor in blood vessel and immune cells in the aorta did not play a role.
“We’ve ruled out the importance of receptors in these cell types, but we still don’t fully understand how GLP-1 reduces atherosclerosis,” says Drucker.
This negative result was valuable, but the second story the paper told was more novel.
The mice developed fatty liver disease, liver fibrosis and liver inflammation through the same high-fat diet that triggered plaque development in their arteries. The researchers saw that the mice with GLP-1 receptors in specific cells in their livers responded well to the GLP-1 drugs, whereas the “knockout” mice without the GLP-1 receptor in these cells did not—despite both groups losing weight as an effect of the GLP-1 drug.
This outcome suggests that even though weight loss has conventionally been important for GLP-1 action to reduce fat and inflammation in the liver, it may not be the whole story. In, fact GLP-1 may reduce liver inflammation through mechanisms independent of weight loss.
“This paper is the first to show that even though weight loss is the same in both groups of animals that we studied, the animals that were missing the GLP-1 receptor in the immune cells in the liver did not have the same therapeutic benefit,” Drucker says. “It’s really the first paper to show that there’s another element to the story of how GLP-1 works in the liver.”
GLP-1 drugs are already in phase three trials to treat liver diseases such as non-alcoholic steatohepatitis, a more aggressive form of fatty liver disease. So, it was not surprising for the researchers to see that mice treated with GLP-1 drugs saw reduced liver inflammation.
But Drucker said it was exciting to identify GLP-1 receptors in specific immune cells in the liver, which may be necessary to get the full therapeutic effects of GLP-1 drugs to treat fatty liver and liver inflammation. This finding could lead to more targeted and effective treatment options.
Overall, the study is another piece in the puzzle of how GLP-1 works in different areas of the body. But researchers still need a better understanding of how GLP-1 drugs produce their multiple therapeutic benefits in treating diseases.
“If I could figure out how GLP-1 reduces heart attacks and strokes, and I knew where that magic was happening, maybe we could make even better, more targeted GLP-1 therapies to produce more effective medicines,” Drucker says.
Drucker credits his background as a clinician scientist for bringing the perspective of patients and their unmet medical needs into his research. Although he hasn’t been directly involved in patient care for 12 years, he calls his training as a physician and a clinician scientist the “secret sauce” to his research.
“What clinician scientists are really good at is asking the important questions that are directly relevant to human disease,” he says. “I’ve always tried to ask questions that are not just interesting for the sake of basic science, which is important by itself, but also questions that might inform how disease pathophysiology and drugs work clinically.”
He says that what makes the GLP-1 story so exciting is that physicians are able to treat diabetes and obesity by conventionally lowering blood sugar or bodyweight, but also by attacking cardiovascular risk, the number-one cause of death these patients face.
“Until recently, there haven’t been therapies that go beyond lowering blood sugar or reducing bodyweight to actually show there’s a reduction in death,” Drucker says. “GLP-1 therapies are changing the natural history of these diseases.”
Improved disease outcomes may soon extend to other conditions. Emerging data suggest that GLP-1 drugs have an anti-inflammatory effect to treat a wide variety of diseases, and the next frontier could be Alzheimer’s disease now that GLP-1 drugs targeting the condition recently entered phase three trials.
Drucker says that if GLP-1 drugs work to treat Alzheimer’s, it would likely reflect a combination of neuroprotection, improved brain metabolism and reduction of inflammation associated with the condition, which could also improve cognition and slow the course of disease.
“Whether it’s in the pancreas, blood vessels, the liver, or the brain, increased inflammation is a driving component of the pathology of all kinds of different diseases,” he says. “I believe that one reason GLP-1 is the Swiss Army knife of metabolism—that it can do so many different things in so many different organs—is its ability to reduce inflammation.”
Exactly how that happens, however, is still shrouded in mystery, Drucker says.
“There’s a huge amount of uncertainty as to how GLP-1 controls inflammation in different organs in the body, and that’s a major focus for our lab right now.”
Glucagon like peptide-1 (GLP-1) is a 30 or 31 amino acid long peptide hormone mainly secreted by 3 tissues in the human body: enteroendocrine L cells in the distal intestine, alpha cells in the pancreas, and the central nervous system (1). Through its interaction with the GLP-1 receptor (GLP-1R), GLP-1 participates in the regulation of glucose homeostasis. In addition, glucagon like peptide-1 receptor agonists (GLP-1RAs) can be combined with GLP-1Rs, playing the same role as GLP-1.
A variety of GLP-1RAs and analogues, such as exendin-4 and liraglutide, has been used successfully in the treatment of type 2 diabetes mellitus (T2DM) (2). At present, the therapeutic application and potential value of GLP-1RAs in diseases other than diabetes has become a research hotspot. Interestingly, GLP-1RAs have been reported to activate the metabolism of brown fat and increase the energy expenditure in rodents through exercise activities independent of the sympathetic nervous system pathway (3).
Liraglutide has been approved by the United States Food and Drug Administration (FDA) for long-term weight management (4). Moreover, GLP-1RAs have been shown to exert many beneficial effects on vascular endothelial cells. For instance, GLP-1RAs were demonstrated to reduce the risk of cardiovascular events (5) by decreasing the blood pressure (6), improving microvascular function, and reducing inflammation (7).
Further, GLP-1RAs play a neuroprotective effect by stimulating the differentiation of nerve cells and inhibiting neuroinflammation (8), while they were also reported to inhibit liver inflammation (9). These findings indicated that in addition to playing a role in the treatment of diabetes, GLP-1RAs can also be used in the treatment of other diseases, such as certain neurological diseases, cardiovascular diseases (CVDs), and diseases related to metabolic disorders.
Many studies on the correlation between the function of GLP-1RAs and the development and progression of tumors are also underway. Related studies (10) have found that GLP-1RAs can inhibit the PI3K/AKT/mTOR and ERK/MAPK pathways, thereby inhibiting the growth of prostate cancer; however, whether GLP-1RAs increase the risk of pancreatitis remains controversial (11). We here attempted to systematically review the mechanisms of action and therapeutic value of GLP-1RAs.
Brief Introduction and Physiological Function of Glucagon Like Peptide-1 Receptor Agonists
Glucagon like peptide-1 (GLP-1) is the second incretin identified in 1983. The first identified incretin was a gastric inhibitory peptide (GIP) with the activity of inhibiting the secretion of gastric acid, which was isolated from porcine small intestines (12). Briefly, GLP-1 exists in the human body in two active forms, GLP-1 (7-36 amide) and GLP-1 (7-37), with the proportion of GLP-1 (7-36 amide) being higher (8, 9).
The half-life of natural GLP-1 is very short. Depending on the species, the half-life is approximately 1 to 2 min (13). There are two reasons for this: (1) after its recognition by dipeptidyl-peptidase 4 (DPP-4), GLP-1 is cleaved into GLP-1(9-36) amide, which is in a low affinity; (2) kidney clearance. Glucagon like peptide-1 receptor (GLP-1R) is a member of the B family of G protein-coupled receptors.
In the pancreas, the interaction of GLP-1 and GLP-1R is known to mainly act through the cAMP-PKA pathway. More specifically, the interaction of GLP-1 and GLP-1R activates adenylate cyclase (AC), which stimulates the conversion of ATP to cyclic adenosine monophosphate (cAMP), thereby increasing the concentration of cAMP. In turn, cAMP further activates protein kinase A (PKA) and Rap guanine nucleotide exchange factor 4 (RAPGEF4, also known as EPAC2) (14).
The activated PKA can close the ATP-dependent K+ channel and depolarize the cell membrane, while also activate the voltage-dependent Ca2+ channel, causing a Ca2+ inflow and the generation of action potentials (15). In addition, PKA can also promote Ca2+ release by activating inositol triphosphate (IP3). The activated EPAC2 can further activate Ras protein 1 and phospholipase C, which activate the IP3 and diacylglycerol (DAG) pathways and promote the release of Ca2+ (16).
All these pathways eventually lead to an increase in the intracellular Ca2+ concentration, thereby promoting the mitochondrial synthesis of ATP, and the release of insulin particles into the blood through exocytosis. Apart from the pancreas, GLP-1R is also widely distributed in various tissues of the body including the lungs, kidneys, central nervous system, cardiovascular system, gastrointestinal tract, and skin and vagus nerves (17). This distribution breadth of GLP-1R further highlights the diversity and importance of its biological functions.
Glucagon like peptide-1 receptor agonists (GLP-1RAs) are emerging glucose control drugs, which are widely used in the treatment of T2MD in recent years. Due to the wide distribution of GLP-1R, GLP-1RAs also have a wide range of pharmacological effects. At present, existing GLP-1RAs mainly include 2 types: polypeptide and non-polypeptide (18). Based on similarities in their amino acid sequence, peptide agonists are mainly divided into GLP-1 and derivatives and exendin-4 and derivatives.
Common GLP-1RAs are listed in Table 1. In addition to lowering the levels of blood glucose, as shown in Figure 1, GLP-1RAs have also been shown to have a positive effect on multiple human tissues. Liraglutide, which has been approved for reducing the risk of T2MD, has also been found to reduce the risk of major cardiovascular events in adults with established CVDs (19).
Accordingly, the guidelines of the American Diabetes Association recommend it as a second-line drug after metformin, suitable for patients with known atherosclerotic cardiovascular disease (20). Moreover, liraglutide was reported to reduce the abnormal proliferation of hyperglycaemia-induced vascular smooth muscle cells by inhibiting the PI3K/AKT and ERK 1/2 signaling pathways (21). Due to the metabolic regulatory function of GLP-1RAs, they have also been considered for the treatment of other diseases such as obesity, liver disease and other metabolic dysfunction diseases (22).
Classification of GLP-1RAs.
|Name||Listing situation||Molecular formula||Molecular weight|
|Supaglutide||Clinical Trials||Waiting to be published||Waiting to be published|
|PEG-loxenatide||Yes||C210H325N55O69S·(C2H4O)2n||44212.65 ± 4000Da|
In non-alcoholic fatty liver disease (NAFLD) mice (23), liraglutide was shown to inhibit the MKK4/JNK signaling pathway, thereby improving the hypoadiponectinemia-induced inflammatory stress. In addition, GLP-1RAs (24) have also been found to play an active role in the treatment of polycystic ovary syndrome (PCOS).
Besides, the protective and therapeutic effects of GLP-1RAs on the central nervous system have now been confirmed by several studies (25, 26). In particular, they have been reported to stimulate nerve differentiation, enhance synaptic plasticity, promote nerve cell survival, and prevent and treat Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke and other neurological diseases by regulating the expression of some key enzymes and the release of certain neurotransmitters (27). In addition, a number of studies have also shown that GLP-1RAs has a positive effect on the treatment of certain tumors (10).
Effects of Glucagon Like Peptide-1 Receptor Agonists on the Neurological System
Autoradiography of human tissue sections with 125I-labelled GLP-1 (7-36 amide) revealed a high content of GLP-1R in the central nervous system suggesting its potentially important role in the nervous system (28). More specifically, GLP-1R is widely expressed in the periphery of the central nervous system, including the hippocampus, neocortex, hypothalamus, spinal cord and cerebellum (29). In recent years, a variety of mechanisms for the beneficial effects of GLP-1RAs on the brain have been discovered, including the reduction of neuroinflammation and increase of signal transduction in surviving cells. In addition, they have been shown to enhance synaptic transmission and counteract learning deficits (30, 31). A recent study found that exendin-4 could improve the reference memory ability of adult rats (32). The use of GLP-1RAs could promote the proliferation of adult rodent neural stem cells, indicating their role in promoting brain regeneration (33, 34). The therapeutic effect of GLP-1RAs on neurological diseases has been confirmed by several studies.
Effects on Alzheimer’s Disease
Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disease, with unclear aetiology and pathogenesis. Approximately 6-8% of people over the age of 65 suffer from AD; this risk is known to increase with age, and is more common in women (1.5 times compared with men) (35). A study has suggested that the accumulation of amyloid-β (Aβ) deposits triggers a series of pathological processes, such as inflammation, tau angle formation, synaptic dysfunction, and cell death, which lead to neurodegenerative behavior and eventually to the development of dementia (36).
According to some researchers, the abnormal accumulation of Aβ and tau protein is the cause of AD (37, 38). However, some studies have indicated that these are manifestations and not the cause of the disease (39, 40). The main pathological features of AD include the deposition of insoluble Aβ that forms senile plaques, neurofibrillary tangles, and neuronal apoptosis (40). Neurofibrillary tangles have been found in the amygdala, hippocampal structure, parahippocampal gyrus, and temporal cortex of patients with AD, whereas senile plaques have been shown to be distributed throughout the combined neocortex and striatum (41).
Interestingly, AD has been associated with a dysfunction in insulin signaling in the brain. A Rotterdam study has shown that the risk of AD in patients with T2MD is increased by 2-fold (42). Moreover, insulin resistance(IR) has also been reported in the brain of patients with AD. Due to IR, the brain cannot use glucose, thus leading to inflammation and the deposition of plaques and tangles (43).
In an AD mouse model, GLP-1RAs were demonstrated to reduce the levels of AD pathological markers, including oligomeric antibodies and antibody plaque load, reduce the activation of microglia, and improve memory behavior (35, 44, 45). Furthermore, GLP-1RAs were found to protect hippocampal neurons from cell necrosis caused by glutamate, Fe2+ and hypoxia. Calcium is also known to play an important role in neuronal plasticity and neurodegenerative diseases. In a study using cultured rat hippocampal neurons, pre-treatment of nerve cells with GLP-1 resulted in a weakened Ca2+ response to glutamate and weakened membrane depolarization (46).
Whole-cell patch clamp analysis showed that glutamate-induced currents and voltage-dependent calcium channel currents were significantly reduced in GLP-1-pre-treated neurons. Pre-treatment of neurons with GLP-1 significantly reduced the susceptibility of glutamate-induced neuronal death. A basic study suggested that semaglutide protects neurons from Aβ toxicity potentially through the enhancement of autophagy and the inhibition of apoptosis (47).
Zhou et al. found that the protective effect of dulaglutide on learning and memory impairment might be the result of reducing the hyperphosphorylation of tau and neurofilament proteins in a PI3K/AKT/GSK3β signaling pathway-dependent manner (48). Two types of GLP-1RAs, liraglutide and exenatide, were found to be antagonistic to the neurodegeneration and AD progression even in mice without diabetes (35, 49). McClean et al. (35) showed that systemic administration of liraglutide in AD transgenic mice for 8 weeks could prevent memory impairment, neuronal loss, and deterioration of hippocampal synaptic plasticity.
In addition, according to the numbers of activated microglia, liraglutide could significantly reduce both the deposition of amyloid plaques and inflammation (50). Similarly, in rats injected with monoclonal antibodies (mAbs) in the hippocampus, pre-treatment with liraglutide significantly protected from the mAbs-induced damage of spatial memory and long-term potentiation (51). Importantly, liraglutide was not only shown to have a preventive effect, but also reversed some of the key pathological features of late AD in mice (52). Another GLP-1 analogue, exenatide, has also shown promising results against neurodegenerative diseases in a pre-clinical study (53). Conclusively, GLP-1RAs have great research potential in the field of AD treatment.
Effects on Parkinson’s Disease
Parkinson’s disease (PD) is a chronic neurodegenerative disease that affects the central nervous system and the second most common neurodegenerative disease after AD (54). It mainly affects the motor nervous system, and is associated with the loss of Lewy bodies and substantia nigra dopamine neurons (55). The Lewy body is a neuron inclusion body, mainly composed of α-synuclein (56). Dopamine, which acts as a neurotransmitter, is known to play a key role in movement control. However, the reason behind the loss of these dopamine-producing nerve cells remains unclear (57).
The most obvious symptoms of PD in the early stages are tremor, limb stiffness, decreased motor function and abnormal gait. Cognitive and behavioral problems might also manifest. In the late stages of PD, the key molecular pathogenic mechanisms include the misfolding and aggregation of α-synuclein, mitochondrial dysfunction, impaired protein clearance (related to inefficient ubiquitin-proteasome and autophagy-lysosomal systems), neuroinflammation and oxidative stress (57).
To date, no therapeutic approach has been shown to either completely cure PD or delay, stop, and reverse the degeneration and death of dopaminergic neurons (58). Therefore, effective neuroprotective therapies are continuously being pursued. Increasing evidence has demonstrated that GLP-1 analogues can cross the blood-brain barrier, protect dopaminergic neurons in the substantia nigra, and rescue motor activity and cognitive functions in PD animal models (59–61). These findings have strongly supported the hypothesis that the use of GLP-1RAs might be a novel effective treatment for PD.
Disturbance of insulin signaling in diabetic patients might lead to the abnormal expression of αSyn, damage to mitochondrial function, increase in mitochondrial oxidative stress, and down-regulation of the PI3K/AKT pathway, which in turn could promote the occurrence and development of PD (62). Surprisingly, GLP-1RAs, such as liraglutide, lixisenatide, and semaglutide, have showed outstandingly neuroprotective effects on animal models of PD (63, 64).
Bertilsson et al. found that intraperitoneal injection of exendin-4 increased the number of BrdU-positive progenitor cells in the subventricular zone (33), indicating that exendin-4 could compensate for the loss of dopaminergic neurons in the PD model by promoting the formation of substantia nigra neurons. Similarly, in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model, GLP-1 analogues were reported to protect the brain from MPTP-induced pathological effects, such as movement disorders, increased levels of α-synuclein, chronic inflammation in the brain, loss of dopaminergic neurons, oxidative stress, and expression of growth factors (65).
The novel GLP-1RA geniposide was found to up-regulate the expression of β-cell lymphoma 2 (Bcl-2), whereas reduce the activity of caspase 3, thereby protecting dopaminergic neurons in a MPTP mouse model of PD (66). Inflammation is increasingly recognized as a key factor in the pathogenesis of PD (67). Therefore, the regulation of the activity of microglia is believed to play a key role in the neuroinflammation of PD. Positron emission tomography of patients with early PD showed a significant increase in the activation of microglia (68), which might lead to neuron loss in PD and AD (69).
Injection of exendin-4 into rodents after endotoxin and mTP toxin-induced damage to the substantia nigra striatum could prevent the toxin-induced activation of microglia and inhibit the production of pro-inflammatory cytokines (70). Mitochondrial function interference or mitochondrial damage is also one of the mechanisms of pathogenesis of PD (71). Interestingly, GLP-1RAs have also been shown to exert multiple effects on mitochondria.
For example, saxagliptin protected the mitochondrial function in PD rat models by up-regulating complex I and the anti-apoptotic protein Bcl-2 (72), while long-term use of exendin-4 in rodents promoted the function of hippocampal nerves, and improved motor function and behavior (73). Moreover, GLP-1RAs were shown to protect neurons and induce beneficial changes in neuroplasticity in laboratory models of several neurological diseases, including PD (31).
In a pre-clinical trial, patients with moderate PD who received subcutaneous injection of 2 mg exenatide once a week had an advantage of 3.5 points in the mds-updrs exercise scale over the placebo group (74). Zhang et al. found that semaglutide could reverse the decrease in the levels of tyrosine hydroxylase, alleviate inflammation, and increase autophagy, thus protecting dopaminergic neurons in substantia nigra and striatum (75). Another study showed that the incidence of PD diagnosed with T2DM varies greatly depending on the administered diabetes treatment. Compared with other oral hypoglycemic agents, the prevalence of PD when using DPP4 inhibitors and GLP-1RAs was shown to be 36-60% lower (76). These results indicated that GLP-1RAs might play a useful role in the future treatment of PD.
Effects on Stroke
Stroke is the second leading cause of death and the leading cause of disability worldwide. Strokes are mainly divided into hemorrhagic and ischemic strokes caused by blood vessel obstruction. Strokes are mostly caused by arterial occlusion, which in turn leads to cerebral ischemia, brain damage, and then nerve damage and disability. Typical symptoms of stroke include sudden unilateral weakness, numbness or loss of vision, diplopia, changes in speech, ataxia, and non-orthogonal vertigo (77). Atypical symptoms include isolated vertigo, blindness in both eyes, amnesia, agnosia, dysarthria, dysphagia, stridor, headache, hemiplegia, confusion, and changes in consciousness (77).
The pathological mechanism of stroke mainly includes the apoptosis of neurons in the cerebral cortex and striatum. As neurological and medical complications after stroke are not properly predicted, prevented, or dealt with, they are considered to constitute the main cause of the high morbidity and mortality associated with strokes (78). In addition, T2DM is associated with an increased risk of stroke and mortality after stroke (79). Interestingly, GLP-1RA antidiabetic drugs have shown a distinct effect in reducing the incidence of stroke and enhancing neuroprotection in both pre-clinical and clinical studies (80, 81).
A pre-clinical study showed that exendin-4 had a remarkable neuroprotective effect, improving the neurological deficit caused by transient middle cerebral artery occlusion in mice, and reducing neuronal loss and microglial inflammation (82). Acute administration of exendin-4 at the beginning of the stroke or 1 h later was reported to have a significant effect; however, this neuroprotective effect disappeared after 3 h.
The neuroprotective effect of exendin-4 was found to be independent of the glucose-increasing effect, whereas related to increasing the levels of cAMP and reducing oxidative stress and the inflammatory response (83). Relevant studies have found that exendin-4 could mediate the neuroprotective effect on γ-aminobutyric acid neurons in the piriform cortex and striatum and play a neuroprotective role in a cAMP/PKA- and PI3K/AKT-dependent manner after stroke (84, 85). Sato et al. found that intraperitoneal injection of liraglutide 2.5 h after stroke induced neuroprotection in rats, which was related to the up-regulation of vascular endothelial growth factor (VEGF) (86).
A study on the protective mechanism of liraglutide on cortical neurons after ischemia suggested that liraglutide probably reversed the ischemia-induced apoptosis by activating the PI3K/AKT and MAPK pathways (87). Another study on the effect of dulaglutide on stroke showed that dulaglutide reduced the incidence of stroke in middle-aged and elderly people with T2MD and other cardiovascular risk factors, but it cannot reduce the severity of stroke (88). A trial of reperfusion therapy for ischemic stroke indicated that semaglutide, which has a strong GLP-1R-mediated neuroprotective effect, could reduce the infarct size in acute ischemic stroke in non-diabetic rats (89). In addition, the activation of GLP-1R was shown to promote synaptic plasticity and axonal growth (30), and stimulate adult neurogenesis (90). These findings might lay the foundation for the potential regenerative treatment of patients with chronic stroke.
Effects on Chronic Pain
Pain is an unpleasant subjective and emotional experience related to actual or potential tissue damage (91). Pain can be divided into acute and chronic pain (92). Compared with acute pain, chronic pain is known to be much more harmful to the human body (93). Continuous pain can induce more serious pathological reactions in the human body, and even cause shock or death. Therefore, the treatment of chronic pain is even more important. Clinically, treatment drugs for chronic pain are mainly non-steroidal anti-inflammatory analgesics, opioid analgesics, and auxiliary drugs: such as antidepressants and anxiety drugs (94). However, the adverse reactions caused by these drugs often limit their application.
In particular, long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) can cause gastric mucosal damage as they can inhibit mitochondrially encoded cytochrome C oxidase I (MT-CO1, also known as COX-1) and block its protective effect on gastric mucosa. Therefore, the use of NSAIDs is usually associated with damage to the gastrointestinal tract and other systems during treatment, and thus need to be used with caution (95). In recent years, there have been numerous crises caused by the abuse of opioids. The nervous system can quickly develop tolerance to the drug.
Overuse of opioids might lead to serious consequences, such as respiratory depression, addiction, and even death (96, 97). Studies found that intrathecal injection of GLP-1RAs effectively reduced formalin-induced peripheral nerve injury, as well as cancer- and diabetes-induced pain without causing serious adverse reactions. Moreover, it was also reported that long-term injection of geniposide and exenatide did not induce nociceptive tolerance (98, 99). Hence, GLP-1RAs (98) appear to be potential alternatives for the treatment of chronic pain due to their effect in reducing pain while not affecting acute injury. Previous experiments have found that exendin-4 could reduce the pain-induced neuro-inflammatory response through the GLP-1R pathway, thereby promoting the recovery of cognitive function in mice (100). Likewise, the anti-dipeptidyl peptidase-IV GLP-1RA ROSE-010 was shown to effectively relieve the intestinal pain induced by irritable bowel syndrome (101). However, there have been relatively few studies on the mechanism of GLP-1RAs in the treatment of chronic pain.
Surprisingly, a recent study found that liraglutide blocked the lipopolysaccharide-induced visceral allodynia in a NO-dependent manner. It was suggested that this was achieved by inhibiting the production of pro-inflammatory cytokines and reducing the increase in intestinal permeability (102). As shown in Figure 2, following stimulation of GLP-1R by exenatide on microglia, the cAMP/PKA/p38β/CREB signal transduction pathway is activated, promoting the expression of IL-10. Subsequently, the IL-10 receptor/STAT3 signaling pathway in microglia is autocrinally activated, thereby promoting the expression and release of β-endorphin, the latter acts on μ-opioid receptors on neurons to produce analgesic and neuroprotective effects (103–105).
The various aforementioned GLP-1RAs are peptides that are easily hydrolyzed by proteases, thus making their oral use basically ineffective. Therefore, discovering a small molecule GLP-1RA that could be orally administered is a current but extremely challenging research hotspot. Interestingly, W-24 (106), a non-peptide GLP-1RA, has been reported to inhibit inflammatory pain by stimulating the spinal cord GLP-1R for the release of analgesic β-endorphin. Moreover, as a small molecule drug, it could increase the confidence of in-depth research to find oral GLP-1RAs in the treatment of chronic pain.
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419463/
More information: Brent McLean et al, Differential importance of endothelial and hematopoietic cell GLP-1Rs for cardiometabolic vs. hepatic actions of semaglutide, JCI Insight (2021). DOI: 10.1172/jci.insight.153732