Protective Properties Of GLP-1 And Associated Peptide Hormones in Neurodegenerative Disorders Part 2

6 | GLP-1 MIMETICS HAVE ANTI-INFLAMMATORY PROPERTIES

Progressive neurodegenerative diseases as well as stroke induce a chronic inflammation response in the brain (Clark & Vissel, 2018; de Oliveira Manoel & Macdonald, 2018; Ferrari & Tarelli, 2011; Lukiw & Bazan, 2000). 

As the trend of population aging continues to intensify, degenerative diseases have become a topic of great concern. Many people believe that memory will gradually weaken with age. However, this is not the case. The memory of most elderly people does not change significantly under the influence of degenerative diseases.

Degenerative diseases usually affect neural tissue, leading to problems such as intellectual decline and cognitive dysfunction. For example, Alzheimer's disease is a common degenerative disease that causes the death and atrophy of neurons in the brain, thereby affecting functions such as learning, movement, thinking, and memory. So, how much impact do degenerative diseases have on memory?

The latest research shows that the impact of degenerative diseases on memory is not absolute. Although these diseases may affect the memory of the elderly to a certain extent, this impact is not necessarily fatal or irreversible. On the contrary, many elderly people can still maintain good memory after suffering from degenerative diseases, and can even improve their memory through active self-management and treatment measures.

For example, the elderly can maintain good memory by developing healthy living habits. Measures such as maintaining moderate exercise, eating a balanced diet, getting enough sleep, and maintaining social activities and learning activities can effectively reduce the impact of degenerative diseases on memory.

In addition, the elderly can also enhance their memory through continuous learning and training. Such as doing memory training, learning new knowledge, playing intellectual games, participating in social activities, etc., can help the elderly maintain the vitality and sensitivity of their memory. In this way, even if the elderly suffer from degenerative diseases, their memory can still be maintained at a relatively good level.

In summary, there is no necessary connection between degenerative diseases and memory, and we can protect and enhance memory through a series of effective measures. The elderly should maintain a positive and confident attitude, seize every opportunity in life, participate more in social and learning activities, and vigorously cultivate their memory ability so that even if they suffer from degenerative diseases, they can live a fulfilling, pleasant, and happy life. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because Cistanche has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche can also promote the growth and repair of nerve cells, thereby enhancing the connectivity and function of neural networks. These effects can help improve memory, learning ability, and thinking speed, and can also prevent the occurrence of cognitive dysfunction and neurodegenerative diseases.

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This secondary downstream process causes further neurodegenerative effects via the activation of immune cells such as microglia in the brain. These cells release pro-inflammatory cytokines and free radicals such as nitric oxide (NO), which is neurotoxic (Ayasolla et al., 2004). 

The neurodegenerative effects of chronic inflammation play a major role in disease progression (Arnon & Aharoni, 2009) and research for anti-inflammatory drugs for such conditions is ongoing (Aisen, 2002; Cole et al., 2004; Griffin, 2008; Lee et al., 2010). 

It is therefore of great interest to note that GLP-1 mimetics have anti-inflammatory properties. Several studies demonstrated that both activated microglia and activated astrocytes, which take part in the immune/inflammation response, induce GLP-1 receptor expression. 

GLP-1 treatment prevented an endotoxin-induced release of IL-1β by these cells (Chowen et al., 1999; Iwai et al., 2006; Ohshima et al., 2015). IL-1ß is pro-inflammatory and reduces neuronal transmission while increasing apoptosis-related signaling (Rothwell & Hopkins, 1995). 

Furthermore, exendin-4 can reduce monocyte adhesion to the aortic endothelium in an inflammation response in atherosclerosis and also prevents lipopolysaccharide (LPS)-induced cytokine and chemokine release (Arakawa et al., 2010) and can prevent an increase in microvascular permeability (Dozier et al., 2009). 

We tested the effects of the GLP-1 analog liraglutide in the APP/PS1 mouse model of Alzheimer's disease, which develops a chronic inflammation response in the brain. 

The liraglutide reduced the numbers of activated microglia and astroglia (McClean et al., 2011; McClean & Holscher, 2014b). As this may be an indirect effect due to the reduction of amyloid in the brain that can reduce the inflammation response, we followed up this study with a second study that measured the effects of liraglutide on inflammation only. 

X-ray exposure is known to induce an inflammation response. The expression of pro-inflammatory cytokines and nitric oxide synthase after x-ray exposure to the brains of mice was significantly reduced by liraglutide (Parthasarathy & Holscher, 2013b). 

Furthermore, liraglutide reduced the level of activated micro- and astroglia and the levels of the pro-inflammatory cytokines in an inflammation study induced by intracerebroventricular (i.c.v.) injection of palmitate (Barreto-Vianna et al., 2017). 

Another study testing liraglutide in the 5xFAD mouse model of Alzheimer's disease showed clear anti-inflammatory effects by reducing activated glial levels (Paladugu et al., 2021). Importantly, liraglutide showed clear anti-inflammatory properties in a primate study where amyloid oligomers had been injected into the cerebral ventricle to induce an inflammatory response. 

Treatment with liraglutide reduced inflammation, reduced loss of synapses, improved cognition, and re-sensitized insulin signaling (Batista et al., 2018; Lourenco et al., 2013). 

In animal models of Parkinson's disease, GLP-1 receptor agonists show the same anti-inflammatory properties. In the MPTP mouse model of Parkinson's disease, we and others found that the activation of microglia and the increase of proinflammatory cytokines in the brain were much reduced by GLP-1 receptor agonists (Feng et al., 2018; Liu, Jalewa, et al., 2015; Zhang et al., 2015, 2018, 2019). 

In the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease, we furthermore found a reduction of the inflammation response induced by the toxin (Jalewa et al., 2017; Zhang et al., 2020).

7 | GLP-1 MIMETICS ARE NEUROPROTECTIVE IN ANIMAL MODELS OF ALZHEIMER'S DISEASE

In several rodent models of Alzheimer's disease, GLP-1 receptor agonists were found to be neuroprotective. The GLP-1 receptor agonist exendin-4 (exenatide) showed protective effects in a triple transgenic mouse model that expresses human mutated amyloid beta precursor protein (APP), presenilin-1 (PSEN1) and microtubule-associated protein tau (MAPT) genes that are related to early-onset Alzheimer's disease and frontotemporal dementia (FTD) (Li et al., 2010). Liraglutide (Victoza) (Courrèges et al., 2008) displayed neuroprotective effects in the tgAPP/PS1 mouse model of Alzheimer's disease. 

Memory loss, impaired synaptic transmission (long-term potentiation; LTP) in the hippocampus, synapse loss, chronic inflammation in the brain, the amyloid plaque load in the cortex, and total amyloid levels in the cortex were much reduced (McClean et al., 2011). 

In a triple tgAPP/PS1/tau mouse model, liraglutide improved learning and memory, decreased levels of hyperphosphorylated tau and tangles, increased ERK phosphorylation, and decreased JNK phosphorylation, both kinases that are involved in inflammation. 

Liraglutide furthermore decreased the number of degenerative neurons in the hippocampus and cortex (Chen et al., 2017). In other studies, liraglutide had neuroprotective effects in 14- to 16-month-old APP/PS1 mice, indicating that treatment even at more progressed stages of Alzheimer's disease may still have benefits (McClean & Holscher, 2014a). 

In a chronic 8-month-long study, liraglutide reduced key pathological markers of Alzheimer's disease such as memory impairment, synaptic loss, reduced load of amyloid plaques, and chronic inflammation in the brain and therefore has the potential to be used as a prophylactic treatment (McClean et al., 2015). Other studies were able to reproduce the protective effects of liraglutide in mouse models of Alzheimer's disease (Holubova et al., 2018; Parthasarathy & Holscher, 2013a; Qi et al., 2016; Salles et al., 2020). 

The GLP-1 receptor agonist lixisenatide (Lyxumia®) has comparable protective effects in the APP/PS1 model (McClean & Holscher, 2014b). Liraglutide furthermore showed protective effects in the APP/PS1/tau Alzheimer's disease model and in a rat model where amyloid is injected into the brain (Cai et al., 2014). 

One study failed to find neuroprotective effects of liraglutide in two Alzheimer's disease mouse models. The reason for this may be that the study contained several flaws. For instance, a transgenic mouse model that expresses the London APP mutation was used, which develops predominately intracellular amyloid aggregates and very few extracellular plaques (Dewachter et al., 2000). 

Unfortunately, the authors measured only amyloid plaques and no biomarkers for inflammation or growth factor signaling in this model and found that liraglutide had no effects on the plaque load (Hansen et al., 2016). 

Liraglutide showed protective effects in the human P301L mutated tau gene-expressing mouse, a model of frontotemporal lobe dementia. Liraglutide reduces motor impairments and the amount of tangles and hyperphosphorylated tau in the brain (Hansen, Fabricius, et al., 2015). 

In the accelerated senescence SAMP8 mouse model, liraglutide improved memory formation and reduced neuronal loss in the hippocampus (Hansen, Barkholt, et al., 2015). 

Liraglutide furthermore improved insulin desensitization and chronic inflammation in the brain induced by the injection of amyloid oligomers into the cortex of cynomolgus monkeys. 

The level of synaptic markers was also protected from the effects of amyloid in the brain, indicating that synaptic loss was prevented (Batista et al., 2018; Lourenco et al., 2013). Importantly, GLP-1 receptor agonists can normalize neuronal progenitor cell proliferation and neurogenesis in the hippocampus of mice (During et al., 2003; Hamilton et al., 2011; Hunter & Holscher, 2012; Li et al., 2010; McClean et al., 2011; Parthasarathy & Holscher, 2013a; Porter, Irwin, et al., 2010; Porter, Kerr, et al., 2010). 

Another important physiological role of GLP-1 mimetics is that it protects cells against endoplasmic reticulum stress toxicity and autophagy impairments (Panagaki et al., 2017; Sharma et al., 2013).

8 | GLP-1 MIMETICS SHOW PROTECTIVE EFFECTS IN ANIMAL MODELS OF PARKINSON'S DISEASE

The GLP-1 mimetic exendin-4 showed good protective effects in several animal models of Parkinson's disease. In the 6-OHDA lesion model in the rat, the drug protected dopamine neurons and improved motor activity (Bertilsson et al., 2008; Harkavyi et al., 2008). 

Exendin-4 had similar protective effects in the MPTP mouse model of Parkinson's disease (Kim et al., 2009; Li et al., 2009). In a separate study, exendin-4 had good protective effects in the rotenone rat model of Parkinson's disease. 

Rotenone is a pesticide that can induce Parkinson's disease in humans (Aksoy et al., 2017). Both liraglutide and lixisenatide are protective in the MPTP mouse model of Parkinson's disease. 

Motor coordination was improved and neurons in the substantia nigra (SN) were protected by both drugs. Proapoptotic mitochondrial BAX/BAD levels were reduced, whereas insulin-related second messenger signaling was normalized (Liu, Jalewa, et al., 2015). Recently, the long-acting protease-resistant GLP-1 analog semaglutide (Ozempic®) has been brought to the market as a treatment for type 2 diabetes mellitus (Dhillon, 2018). 

In the MPTP mouse model of Parkinson's disease, semaglutide was found to have good neuroprotective properties on motor activity, dopamine levels, dopamine neurons in the SN and reducing inflammation as well as the levels of α-synuclein (Zhang et al., 2018; Zhang et al., 2019). 

These encouraging preclinical results suggest that GLP-1 analogs are a viable strategy for treating Parkinson's disease (Bae & Song, 2017; Candeias et al., 2015; Hölscher, 2018; Wicinski
et al., 2019).

9 | GLP-1 MIMETICS ARE PROTECTIVE IN ANIMAL MODELS OF EPILEPSY

We tested the GLP-1 analog liraglutide in the lithium–pilocarpine animal model of epilepsy. Treatment once daily for 7 days after the induction of epilepsy reduced the chronic inflammation response in the brain as shown by reduced numbers of activated microglia and astrocytes and reduced levels of TNF-a and IL-1ß in the hippocampus. 

The marker for mitochondrial apoptosis BAX (Bcl-2-like protein 4) was reduced and the mitochondrial survival factor anti-apoptotic protein (Bcl-2) was enhanced by liraglutide (Wang et al., 2018). Another study tested liraglutide in two different animal models of epilepsy, the mouse intrahippocampal kainic acid (KA) model of temporal lobe epilepsy and the WAG/Rij rat model of absence epileptogenesis. 

Liraglutide reduced the development of spontaneous seizures in kainate-induced epilepsy. Memory impairment and anxiety-like behavior in the open field were improved. 

In the forced swim test, liraglutide displayed antidepressant effects. Liraglutide did not modify the epileptogenic process underlying the development of absence seizures in WAG/Rij rats but showed antidepressants in the forced swim test (Citraro et al., 2019). 

Another study compared the antiepileptic drug levetiracetam with the effects of liraglutide, either in separate groups or in combination. In the pentylenetetrazol (PTZ) kindling model, levetiracetam had anti-epileptic properties as expected, but enhanced depressive-like behavior in rats. Levetiracetam furthermore induced a prodepressant effect and impaired avoidance-memory retention in nonpentylenetetrazol-treated controls. 

Liraglutide delayed but did not prevent full epilepsy. The liraglutide prevented the depressive-like behavior induced by pentylenetetrazol kindling and by pentylenetetrazol + levetiracetam treatment. 

The levetiracetam + liraglutide combination protected against pentylenetetrazol-induced anxiety and impairments in locomotion and cognition. The levetiracetam + liraglutide combination furthermore had anti-oxidative and anti-inflammatory effects and reduced nitrite levels and lipid peroxidation in the brain, while increasing levels of reduced glutathione. 

Liraglutide on its own or levetiracetam + liraglutide as a combination increased hippocampal brain-derived neurotrophic factor (BDNF) levels (de Souza et al., 2019). 

In a separate study testing the effects of liraglutide in the pentylenetetrazol kindling mouse model, pretreatment with liraglutide prevented the seizure severity, normalized behavioral activity, and cognition, reduced oxidative stress and altered levels of neurotransmitters such as glutamate, dopamine/noradrenaline and serotonin in mouse brains. 

The expression of the GLP-1 receptor in the brain was upregulated, too (Koshal & Kumar, 2016b). The same group tested liraglutide in a different model of epilepsy, the corneal mouse model, where kindling was induced by electrical stimulation. 

Measuring the same parameters as in their first study, they found the same profile of improvements and neuroprotective effects in the brain (Koshal & Kumar, 2016a). 

In a Dravet syndrome mouse model, which is a refractory form of epilepsy typically caused by heterozygous mutations of the Scn1a gene for the voltage-gated sodium channel Nav1.1, liraglutide significantly alleviated seizures recorded in the electroencephalogram (EEG). Cognitive impairments were improved and the number of necrotic neurons in the hippocampus was reduced by the drug. 

The apoptosis kinase caspase-3 was downregulated and mTOR activity improved. This demonstrates that apoptosis was reduced and growth factor signaling improved. In addition, mitochondria were protected by lowering BAX levels and enhancing Bcl-2 levels (Liu et al., 2020). See Koshal et al. (2018) for a review on this subject.

10 | GLP-1 EFFECTS IN STROKE AND REPERFUSION INJURY

A good body of evidence exists in the literature that GLP-1 receptor agonists have protective effects on the cardiovascular system and stroke and ischemia. 

The anti-inflammatory properties and the neuroprotective effects of these drugs indicate that these drugs may be useful in treating stroke victims. Exendin-4 showed good neuroprotection in a transient middle cerebral artery occlusion (MCAO) stroke model in rats. 

It was found that exendin-4 reduced the brain area that degenerated after the stroke had been induced. In a functional score of motor activity, the drug-treated group performed better (Li et al., 2009). In a transient cerebral ischemia model in gerbils, the effect of exendin-4 treatment was measured in the hippocampal CA1 region. 

It was found that GLP-1 receptor expression was increased after 1 day and GLP-1 receptor immunoreactivity was found not only in pyramidal neurons but also in astrocytes and GABA interneurons. Exendin-4 reversed the ischemia-induced hyperactivity, reduced neuronal loss, and also reduced microglial inflammatory activation in a dose-dependent manner (Lee et al., 2011). 

In a rat MCAO stroke reperfusion study, both semaglutide and liraglutide were tested. Liraglutide injected as a bolus reduced brain infarct size by up to 90% and improved neurological scores in a dose-dependent manner. 

Semaglutide and liraglutide when administered s.c. reduced the brain infarct size by 63% and 48%, respectively, and improved motor scores at 72-h post-surgery (Basalay et al., 2019). 

In diabetic rats, an upregulation of protein level of inducible nitric oxide synthase (iNOS) and NADPH oxidase and a suppression of endothelial nitric oxide synthase (eNOS) expression were found in carotid arteries of diabetic stroke model rats. 

Lixisenatide was able to reduce the inflammation response and upregulate eNOS expression. The expression of iNOS and NADPH oxidase was reduced and neurological tests showed an improvement in motor skills (Abdel-Latif et al., 2018). 

A further study tested the neuroprotective effect of exendin-4 after focal cerebral ischemia induction. The drug reduced infarct volume and improved motor impairment. 

It also reduced oxidative stress, induction of inflammation response, and neuronal death after reperfusion (Teramoto et al., 2011). In an MCAO stroke study testing the effects of exendin-4 in diabetic rats, neuronal death in the cortex was much reduced by the drug. Additionally, there was a reduction in microglial infiltration and an increase in stroke-induced neural stem cell proliferation and neuroblast formation (Darsalia et al., 2012). 

A separate study confirmed these results (Li et al., 2009). Exendin-4 furthermore was protective when applied post-MCAO stroke even in healthy and diabetic mice. The inflammation response in the brain was reduced, too (Darsalia et al., 2014). 

Human recombinant GLP-1 had been tested in the same model and showed similar protective effects (Jiang et al., 2016). A study testing exendin-4 and liraglutide in an MCAO stroke model in diabetic db/db mice also showed good neuroprotective effects (Li, Liu, Jou, & Wang, 2016). In a study testing the effects of exendin-4 in an MCAO stroke mouse model, animals were treated in addition to the coagulation inhibitor warfarin. 

Neurodegeneration by MCAO-induced stroke was much reduced and warfarin-associated hemorrhagic transformation was reduced in the mice, too. Activation of microglia and levels of pro-inflammatory cytokines in the brain were much reduced by the drug. 

In addition, the PI3K/Akt/GSK-3β second messenger signaling cascade that is activated by insulin was functionally improved (Chen et al., 2016). Liraglutide had comparable protective properties in an MCAO stroke rat model. 

Apoptosis and oxidative stress were reduced in the brain, liraglutide normalized Akt and extracellular signal-regulated kinases (ERK) activity and kinases associated with inflammation c-junNH2-terminal kinase (JNK) and p38 were reduced in activity (Zhu et al., 2016). 

We tested semaglutide in the MCAO rat model. Semaglutide-treated animals showed reduced scores of neurological impairments in several motor and grip strength tasks. 

The cerebral infarction size was reduced and the loss of neurons in the hippocampal areas CA1 and CA3 and the dentate gyrus was much reduced. Chronic inflammation as seen in levels of activated microglia and the activity of the p38 MAPK/MKK/c-Jun/NF-κB p65 inflammation signaling pathway was reduced. In addition, improved growth factor signaling as shown in levels of activated ERK1 and IRS-1, and a reduction in the apoptosis signaling pathway C-raf, ERK2, Bcl-2/BAX, and caspase-3 was observed. 

Neurogenesis has also been normalized in the dentate gyrus (Yang et al., 2019). Importantly, the effects of GLP-1 on cardiovascular parameters were found to be independent of blood glucose levels. 

In a study testing liraglutide along a metformin group in diabetic rats, it was found that metformin did not show comparable neuroprotective properties as liraglutide did, even though both drugs effectively controlled blood glucose levels (Filchenko et al., 2018).

11 | CLINICAL TRIALS TESTING CARDIOVASCULAR RISK FACTORS

In a double-blind, placebo-controlled clinical trial testing liraglutide in people with type 2 diabetes mellitus and cardiovascular risks (LEADER trial), the effects on cardiovascular events were tested. A total of 9340 patients were observed for 3.8 years. 

Fewer patients died from cardiovascular causes in the liraglutide group (Marso et al., 2016). In a separate double-blind, placebo-controlled clinical trial testing the GLP-1 receptor agonist dulaglutide (REWIND trial), 9900 people with type 2 diabetes mellitus and cardiovascular risk factors were monitored for 2 years and tested every 6 months for the composite primary outcome of stroke, myocardial infarction or death from cardiovascular or unknown causes. 

The trial showed a reduced risk of developing cardiovascular impairments and as a secondary outcome, the risk of developing cognitive impairment was reduced by 14% by dulaglutide (Cukierman-Yaffe et al., 2020). 

For further details on this topic, please consult the reviews (Darsalia et al., 2018; Erbil et al., 2019; Groeneveld et al., 2016; Maskery et al., 2021). 

In conclusion, when considering the detailed information on molecular changes induced by GLP-1 receptor agonists observed in animal studies and the range of neuroprotective properties in stroke and ischemia found in clinical studies, the evidence is strong that such drugs may help reduce the cytotoxic effects that evolve in the brain after stroke.

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