Protective Properties Of GLP-1 And Associated Peptide Hormones in Neurodegenerative Disorders Part 4

20 | DUAL GLP-1/GIP RECEPTOR AGONISTS ARE PROTECTIVE IN ANIMAL MODELS OF PARKINSON'S DISEASE

In a direct comparison between GLP-1 analogs, GIP analogs, oxyntomodulin, and DA1-JC, we found that DA1-JC was best at protecting SH-SY5Y cells from rotenone stress (Jalewa et al., 2016). 

Oxyntomodulin is an important endocrine substance that can affect the secretion of gastric acid and gastrointestinal motility, helping us digest food. However, the latest research has found that oxyntomodulin can also have a positive effect on our memory.

First, oxyntomodulin can promote the connection between neurons and improve learning and memory. Studies have found that oxyntomodulin can increase the release of an important neurotransmitter called acetylcholine, which plays an important role in the brain. Acetylcholine can promote the connection between neurons and enhance the excitability of neurons, thereby improving learning and memory.

Second, oxyntomodulin can also promote the growth and repair of neurons. Studies have found that oxyntomodulin can increase the level of an important growth factor called BDNF, which also plays an important role in the brain. BDNF can promote the growth and repair of neurons and enhance the connection between neurons, thereby improving learning and memory.

Finally, oxyntomodulin can also promote sleep and improve the effect of memory consolidation. Studies have found that sleep is very important for memory consolidation, and oxyntomodulin can affect sleep. Oxyntomodulin can reduce the level of a neurotransmitter called histamine in the brain, which can excite people and affect sleep. By reducing the level of histamine, oxyntomodulin can promote sleep and improve the effect of memory consolidation.

Therefore, oxyntomodulin has a positive impact on our memory. By promoting the connection and growth between neurons and improving sleep quality, oxyntomodulin can help us improve our learning and memory abilities. At the same time, we also need to pay attention to maintaining a healthy diet and lifestyle to minimize the risk of excessive gastric acid secretion, thereby maintaining a healthy body and brain. It can be seen that we need to improve our memory, and Cistanche can significantly improve our memory because Cistanche is a traditional Chinese medicine with many unique effects, one of which is to improve memory. The efficacy of Cistanche comes from the various active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc., which can promote brain health in many ways.

Click know supplements to improve memory

The outcome confirms previous studies that demonstrated that GIP can synergistically add to the protective effects of GLP-1 receptor activation. DA1-JC showed protective effects in the MPTP mouse model of Parkinson's disease. The motor impairments were reduced and synapses were protected from stress. Dopamine neurons were protected from MPTP toxicity, too. 

The chronic inflammation in the brain induced by MPTP and BDNF levels in the brain was improved (Cao et al., 2016; Ji, Xue, Lijun, et al., 2016). However, in a direct comparison with single GIP and GLP-1 receptor agonists, DA1-JC did not show improved effects (Li, Liu, Li, & Holscher, 2016; Liu, Jalewa, et al., 2015). We then tested DA1-JC in the 6-OHDA rat model of Parkinson's disease. 

DA1-JC did improve motor activity, however dopamine neurons in the SN were protected from toxicity to some extent. Dopamine levels in the basal ganglia were found to be improved after 6-OHDA treatment but did not reach the levels seen in non-lesioned rats. 

The levels of glial-derived neurotrophic factor (GDNF), a protective growth factor for dopamine neurons (Airaksinen & Saarma, 2002), were improved by DA1-JC, too. Furthermore, Akt and CREB second messenger cell signaling that is associated with growth factor activity had been improved. Autophagy was also normalized by the DA1-JC (Jalewa et al., 2017). 

In a direct comparison, DA3-CH was more effective than liraglutide in the MPTP mouse model of Parkinson's disease. DA3-CH was superior in motor tests and in protecting dopamine neurons (Yuan et al., 2017). In a follow-up experiment, liraglutide, DA1-JC, DA4-JC, and DA5-CH were compared at equal doses in the MPTP model. 

Importantly, the dual agonists DA4-JC and DA5-CH that show enhanced crossing of the BBB offered the best neuroprotection. In rotarod motor tests and grip strength tests, DA5-CH was best in improving motor impairments. 

Dopamine neurons in the SN were better protected by DA5-CH and DA4-JC than by the other peptide drugs. The levels of proinflammatory cytokines were lowest in the animals treated by DA5-CH, and the levels of GDNF in the brain were increased the most by DA4-JC. Synapse protection was highest by DA4-JC and DA5-CH treatment, whereas DA1-JC and liraglutide were not very effective (Figure 2) (Feng et al., 2018). 

In a follow-up study, in a direct comparison between DA5-CH and exendin-4, DA5 was more effective in the MPTP mouse model. When testing different doses, DA5-CH was effective in protecting the brain at much lower doses compared with exendin-4 (Zhang et al., 2020). 

When comparing DA5-CH with liraglutide at equal doses in the same Parkinson's disease animal model, DA5-CH was more effective in reducing lipid peroxidation, reducing the number of apoptotic neurons in the SN, and normalizing autophagy in the SN and striatum. Importantly, mitochondria were protected from mitophagy by reducing the Bax/Bcl-2 ratio (Zhang et al., 2020). 

In a follow-up study, testing DA5-CH in direct comparison with exendin-4 in the 6-OHDA rat model of Parkinson's disease, Da5-CH was more potent in normalizing motor activity, increasing dopamine levels in the striatum, reducing the loss of dopamine neurons in the SN pars compacta, reducing the chronic inflammation response and levels of pro-inflammatory cytokines in the brain, improving mitogenesis and autophagy, normalizing insulin signaling and reducing the amount of α-synuclein (Zhang et al., 2021). 

As exendin-4 has already shown good neuroprotective effects in patients with Parkinson's disease (Cheong et al., 2020), the results are most encouraging and suggest that DA5-CH may be more effective in the clinic.

FIGURE 2 A direct comparison between three dual agonists and liraglutide in the MPTP mouse model of Parkinson's disease (PD). (a) Motor performance in the rotarod test.
The dual agonists DA4-JC and DA5-CH that can penetrate the BBB best were the most effective. *P < .05 compared with controls; # P < .05 compared with the MPTP group; $ P < .05 compared with liraglutide + MPTP group. %P < .05 compared with DA-JC1 + MPTP group, %P < .05 compared with DA1-JC + MPTP group. (b): The grip strength test showed the same outcome. *P < .05 compared with controls; # P < .05 compared with MPTP group; $ P < .05 compared to the liraglutide + MPTP group. %P < .05 compared with DA1-JC + MPTP group. (c) Protection of dopamine neurons in the substantria nigra (SN). Quantification of TH-positive neurons in the SN shows that the dual agonists DA4-JC and DA5-CH were again the most effective. *P < .05 compared with control group; # P < .05 compared to MPTP group; $ P < .05 compared with the Liraglutide group; $ P < .05 compared to the liraglutide group; %P < .05 compared with the DA-JC1 group; %P < .05 compared with the DA-JC1 group. 

Shown are representative images, scale bar = 200 μm. (d) Western blot quantification of pro-inflammatory cytokines and the growth factor glial cell-derived neurotrophic factor (GDNF) in the brain. (a,b) All peptides tested reduced the pro-inflammatory cytokines. (c) DA4-JC was best in normalizing GDNF expression in the brain. Adapted from (Feng et al., 2018).

21 | DUAL GLP-1/GIP RECEPTOR AGONISTS ARE PROTECTIVE IN ALZHEIMER'S DISEASE ANIMAL MODELS

In preclinical studies, DA3-CH showed neuroprotective effects in the APP/PS1 mouse model of Alzheimer's disease. DA3-CH improved learning and memory of water maze tasks and reduced the amyloid plaque load in the brain. Endoplasmic reticulum stress and autophagy biomarker levels were improved by DA3-CH, too (Panagaki et al., 2018). 

In a direct comparison between liraglutide and DA4-JC, the dual agonist was superior in improving memory formation and long-term potentiation of synaptic plasticity in the hippocampus of APP/PS1 mice. Furthermore, DA4-JC was more potent in reducing amyloid plaque levels. Chronic inflammation as shown in microglia activation and levels of pro-inflammatory cytokines was more potently reduced by DA4-JC (Figure 3) (Maskery et al., 2020). 

DA5-CH also showed good protective effects in the APP/PS1 mouse model. DA5-CH improved working and spatial memory and lowered the amyloid plaque and phosphorylated tau protein levels in the brain. In electrophysiology recordings, DA5-CH was able to reverse the impairment of synaptic plasticity (LTP) in the hippocampus. 

Additionally, DA5-CH normalized insulin signaling and PI3K and AKT second messenger signaling (Cao et al., 2018). The i.c.v. streptozotocin (STZ) rat model of insulin desensitization in the brain is considered to be a model of sporadic Alzheimer's disease (Lester-Coll et al., 2006; Moloney et al., 2010; Steen et al., 2005; Talbot et al., 2012). 

Enhancing levels of GLP-1 was effective in reversing insulin desensitization in this model (Knezovic et al., 2018). When testing DA4-JC in the streptozotocin model, drug treatment improved memory formation and decreased the levels of phosphorylated tau in the brain. DA4-JC also reduced the chronic inflammation response. 

Apoptosis and mitophagy were reduced by DA4-JC and insulin signaling was resensitized as shown by reduced levels of phosphor-IRS1Ser1101 levels and elevated phospho-AktSer473 levels in the brain (Shi et al., 2017). In a separate study, DA5-CH showed good neuroprotective effects in the streptozotocin rat model. Tau phosphorylation in the brain was reduced, insulin signaling was normalized and inflammation markers were reduced. 

In EEG recordings, streptozotocin i.c.v. injection reduced theta rhythm and treatment with DA5-CH reversed this impairment (Li et al., 2020). As liraglutide has already shown protective effects in a Phase II clinical trial in Alzheimer's disease patients, the results reported here suggest that DA4-JC and DA5-CH may have superior effects in slowing down disease progression.

FIGURE 3 Comparing the effects of the dual agonist DA4-JC with those of liraglutide side by side in the APP/PS1 model of Alzheimer's disease (AD). (a) Acquisition times for water maze training. The dual agonist improved learning times better than liraglutide. (b) Probe test percentage of target quadrant swim times. In this recall test, DA4-JC was superior in memory consolidation and recall than liraglutide. 

Sample swimming tracks are shown below. (c) Quantification of beta-amyloid plaque loads in the neocortex. DA4-JC was more effective in reducing the amyloid load compared with liraglutide sample micrographs are shown: A = WT; B = APP/PS1 Sal; C = APP/PS1 lira; D = APP/PS1 DA4-JC. Scale bar = 50 μm. (d) Quantification of pro-inflammatory cytokines in the brain. DA4-JC was more effective in reducing the chronic inflammation response. *P < .05; Sample bands are shown. Adapted from (Maskery et al., 2020).

22 | DUAL GLP-1/GIP RECEPTOR AGONISTS ARE PROTECTIVE IN STROKE AND EPILEPSY ANIMAL MODELS

We tested the dual agonist DA1-JC in the MCAO rat reperfusion model and compared it with the GLP-1 analog Val (8)-GLP-1(glu-PAL). Drug-treated groups showed reduced scores of neurological dysfunction, cerebral infarction size, and percentage of apoptotic neurons in the brain. 

In addition, levels of the mitophagy marker Bax and the inflammation marker iNOS were reduced, whereas levels of the mitogenesis marker Bcl-2 were significantly increased. DA1-JC was more effective in protecting against neurodegeneration than Val(8)-GLP-1(glu-PAL), as measures of neurological dysfunction, cerebral infarction size, and expression of Bcl-2 were improved, whereas the percentage of apoptotic neurons and the levels of Bax and iNOS were lower in the DA1-JC group (Han et al., 2016). 

In the pilocarpine-induced epileptogenesis rat model, DA3-CH reduced the activation of microglia and astrocytes and the associated release of the pro-inflammatory cytokines in the brain. 

Furthermore, DA3-CH reduced the levels of the mitochondrial pro-apoptotic protein Bax while increasing the levels of the anti-apoptotic protein Bcl-2. DA3-CH protected neurons from neurotoxicity in the hippocampus area CA1 as evaluated by quantification of neuronal numbers. 

These findings in two different models of neurodegenerative disorders demonstrate the dual GLP-1/GIP agonists have generic neuroprotective properties that suggest that these drugs may be protective in treating these conditions.

23 | CONCLUSION

There is good preclinical evidence that GLP-1 and GIP receptor agonists are neuroprotective in a range of neurodegenerative disorders. 

The observation that they reduce the chronic inflammation response, normalize insulin and other growth factor signaling, enhance energy utilization, and protect mitochondria can explain why these drugs have protective effects in a diverse range of neurodegenerative disorders that all share these pathological features. 

Dual GLP-1/GIP receptor agonists can be more effective than single receptor agonists and the ability to cross the BBB is a key parameter that determines their potency. 

First results from clinical trials in patients with Alzheimer's disease or Parkinson's disease testing GLP-1 receptor agonists show clear protective effects and are a proof of concept that this research strategy is viable. 

Improved drugs that are designed to treat CNS diseases and can cross the BBB at a better rate than GLP-1 receptor agonists that have been developed to remain in the bloodstream for longer times to treat type 2 diabetes mellitus hold promise to be more effective in treating Alzheimer's disease or Parkinson's disease. 

Dual receptor agonists that are designed to cross the BBB are currently the best available candidates for novel treatments for such neurodegenerative disorders.

23.1 | Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in the IUPHAR/BPS Guide to PHARMACOLOGY http://www.guidetopharmacology.org and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20 (Alexander, Christopoulos, et al., 2019; Alexander, Fabbro, et al., 2019; Alexander, Mathie, et al., 2019).

CONFLICT OF INTEREST

The author is a named inventor on patents and patent applications that cover the use of GLP-1, GIP, and dual GLP-1/GIP receptor agonists as treatments for neurodegenerative disorders. The patents are owned by Ulster University and Lancaster University, UK. He is the CSO of the company Kariya Pharmaceuticals.

DATA AVAILABILITY STATEMENT

This is a review and all data included in this paper have been published elsewhere.

REFERENCES

1.Abdel-Latif, R. G., Heeba, G. H., Taye, A., & Khalifa, M. M. A. (2018). Lixisenatide, a novel GLP-1 analog, protects against cerebral ischemia/reperfusion injury in diabetic rats. Naunyn-Schmiedeberg's Archives of Pharmacology, 391(7), 705–717.

2.Airaksinen, M. S., & Saarma, M. (2002). The GDNF family: Signalling, biological functions, and therapeutic value. Nature Reviews Neuroscience, 3(5), 383–394.

3.Aisen, P. S. (2002). The potential of anti-inflammatory drugs for the treatment of Alzheimer's disease. Lancet Neurology, 1(5), 279–284.

4. Akimoto, H., Negishi, A., Oshima, S., Wakiyama, H., Okita, M., Horii, N., Inoue, N., Ohshima, S., & Kobayashi, D. (2020). Antidiabetic drugs for the risk of Alzheimer's disease in patients with type 2 DM using FAERS. American Journal of Alzheimer's Disease and Other Dementias, 35, 1533317519899546.

5.Akiyama, H., Barger, S., Barnum, S., Bradt, B., Bauer, J., Cole, G. M., Cooper, N. R., Eikelenboom, P., Emmerling, M., Fiebich, B. L., Finch, C. E., Frautschy, S., Griffin, W. S., Hampel, H., Hull, M., Landreth, G., Lue, L., Mrak, R., Mackenzie, I. R., … Wyss-Coray, T. (2000). Inflammation and Alzheimer's disease. Neurobiology of Aging, 21(3), 383–421.

6.Aksoy, D., Solmaz, V., Cavusoglu, T., Meral, A., Ates, U., & Erbas, O. (2017). Neuroprotective effects of exenatide in a rotenone-induced rat model of Parkinson's disease. The American Journal of the Medical Sciences, 354(3), 319–324.
7. Alexander, S. P. H., Christopoulos, A., Davenport, A. P., Kelly, E., Mathie, A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Pawson, A. J., Sharman, J. L., Southan, C., Davies, J. A., & CGTP collaborators. (2019). THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein-coupled receptors. British Journal of Pharmacology, 176(Suppl 1), S21–S141.

8. Alexander, S. P. H., Fabbro, D., Kelly, E., Mathie, A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Pawson, A. J., Sharman, J. L., Southan, C., Davies, J. A., & CGTP collaborators. (2019). THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Catalytic receptors. British Journal of Pharmacology, 176(Suppl 1), S247–S296.

9. Alexander, S. P. H., Mathie, A., Peters, J. A., Veale, E. L., Striessnig, J., Kelly, E., Armstrong, J. F., Faccenda, E., Harding, S. D., Pawson, A. J., Sharman, J. L., Southan, C., Davies, J. A., & CGTP collaborators. (2019). THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels. British Journal of Pharmacology, 176(Suppl 1), S142–S228.

10. Allen, S. J., Watson, J. J., Shoemark, D. K., Barua, N. U., & Patel, N. K. (2013). GDNF, NGF, and BDNF as therapeutic options for neurodegeneration. Pharmacology & Therapeutics, 138(2), 155–175.

For more information:1950477648nn@gmail.com