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Progress and Prospects in Parkinson's Research/Therapy/Neuroprotection/Exendin-4 (EX-4)

< Progress and Prospects in Parkinson's Research | Therapy | Neuroprotection

This product (Exenatide) has the merit of being already approved for human use in the treatment of diabetes.


Background

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Exendin-4 (Ex-4), an agonist of a hormone known as Glucagon-like Peptide 1 (GLP-1), is the first of this new class of antihyperglycemia drugs approved to treat Type 2 diabetes. Because of rare, but potentially dangerous side effects – principally pancreatitis - its use is constrained in the UK, through advice from NICE, to patients where 1st and 2nd -line treatments fail to achieve control of blood glucose and either the patient has a high body mass index or insulin treatment is not appropriate[1]. In the US the FDA has issued similar cautionary information[2].

Research

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GLP-1 agonists such as Exendin-4 have been known to have specific effects on neuron growth and function for more than 10 years. A body of in vitro studies and trials in rodents has subsequently established the possibility of various beneficial neurological effects, leading to the first pilot clinical trial in Parkinson's disease patients which began in 2010, with results published in 2013.

Significant papers include:

2002

Perry et al [3] demonstrated promotion of neurite growth and neuron differentiation by Exendin-4

2008

Harkavyi et al [4] showed that EX-4 reversed the loss of extracellular DA in the striata of toxin lesioned freely moving rats.

This suggests that pharmacological manipulation of the GLP-1 receptor system could have substantial therapeutic utility in PD. Critically, in contrast to other peptide agents that have been demonstrated to possess neuroprotective properties in pre-clinical models of PD, EX-4 is in current clinical use in the management of type-II diabetes and freely crosses the blood brain barrier; hence, assessment of the clinical efficacy of EX-4 in patients with PD could be pursued without delay.

2009

Li et al [5] found that Ex-4 treatment protected dopaminergic neurons against degeneration, preserved dopamine levels, and improved motor function in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD).

Our findings demonstrate that Ex-4 can protect neurons against metabolic and oxidative insults, and they provide preclinical support for the therapeutic potential for Ex-4 in the treatment of stroke and PD.

2013

Aviles-Olmos et al [6] carried out a clinical trial with a cohort of 45 PD patients to assess the effect of a year’s injections of Exanatide upon their PD symptoms. This was designed as a pilot study, only single-blinded, as a cost-effective means of gathering preliminary data to determine whether a full double-blind trial might be justified. Comparison of scores in Part 3 (the clinical assessment part) of the standard UPDRS assessment protocol between experimental and control groups was significant at the 5% level, though not at the 1% level.

Exenatide-treated patients had a mean improvement at 12 months on the MDS-UPDRS of 2.7 points, compared with mean decline of 2.2 points in control patients (P = 0.037).

The drug's mechanism of action in Parkinson's disease remains uncertain, but there is considerable evidence that it relates to the creation, operation and maintenance of mitochondria in some way. It may work by any or all of the following mechanisms:

  • promoting neurogenesis[7],
  • influencing mitochondrial development[8],
  • increasing mitochondrial survival

We show here that exendin-4 significantly counter-regulates the reduced abundance of electron transport chain proteins, leading to a reduction of oxidative stress and most likely contributing to the anti-apoptotic action of this drug.

[9], [10], and

  • increasing the efficiency of electron transport in the energy production system through stimulation of a genetic regulator, PGC-1α [11],[12].

Further Reading

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(2009)

Tews et al Anti-apoptotic action of exendin-4 in INS-1 beta cells: comparative protein pattern analysis of isolated mitochondria [9]

(2012)

Hao et al Exenatide prevents high-glucose-induced damage of retinal ganglion cells through a mitochondrial mechanism.[13]

Today

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Therapy > Neuroprotection

Sub Pages:

Neuroprotective agents
Substances with possible neuroprotective properties:
Caffeine,--Celastrol,--Co-Enzyme Q10,--Creatine,--DHA,--Exendin-4 (EX-4),--GDNF,--Glutathione (GSH),--GM1,--Isradipine,--Melatonin,--Minocycline,--Nicotine,--NSAIDs,--Phenylbutyrate,--Phytic Acid,--Probucol,--Quinoxaline,--Rasagiline,--Riboflavin,--Statins,--Tolcapone,--Urate & Uric Acid,--Vitamin D,--Vitamin E,--

References

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  1. ↑ http://publications.nice.org.uk/exenatide-prolonged-release-suspension-for-injection-in-combination-with-oral-antidiabetic-therapy-ta248
  2. ↑ http://www.fda.gov/Drugs/DrugSafety/DrugSafetyNewsletter/ucm119034.htm
  3. ↑ Perry, TracyAnn, Debomoy K. Lahiri, Demao Chen, Jie Zhou, Karen T. Y. Shaw, Josephine M. Egan, and Nigel H. Greig. “A Novel Neurotrophic Property of Glucagon-Like Peptide 1: A Promoter of Nerve Growth Factor-Mediated Differentiation in PC12 Cells.” Journal of Pharmacology and Experimental Therapeutics 300, no. 3 (March 1, 2002): 958–966. doi:10.1124/jpet.300.3.958.
  4. ↑ Harkavyi, A.; Abuirmeileh, A.; Lever, R.; Kingsbury, A. E.; Biggs, C. S. and Whitton, P. S. (2008) Abstract J. Neuroinflammation. 5:19. Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson's disease. http://www.ncbi.nlm.nih.gov/pubmed/18492290
  5. ↑ Li, Y.; Perry, T.; Kindy, M. S.; Harvey, B, K.; Tweedie, D.; Holloway, H. W.; Powers, K.; Shen, H.; Egan, J. M.; Sambamurti, K.; Brossi, A.; Lahiri, D. K.; Mattson, M. P.; Hoffer, B. J.; Wang, Y. and Greig N. H.(2009)Abstract Proc Natl. Acad. Sci. U S A. 106 (4):1285 - 1290. GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. http://www.ncbi.nlm.nih.gov/pubmed/19164583
  6. ↑ Aviles-Olmos, Iciar; Dickson, John; Kefalopoulou, Zinovia; Djamshidian, Atbin; Ell,Peter; soderlund,Therese; Whitton, Peter; Wyse, Richard; Isaacs, tom; Lees,Andrew; Limousin, Thomas and Foltynie (2013) Full Text J. Clin. Invest. doi:10.1172/JCI68295. Exenatide and the treatment of patients with Parkinson’s disease http://www.jci.org/articles/view/68295?key=424690bda975bb0c7d68
  7. ↑ Bertilsson, Göran, Cesare Patrone, Olof Zachrisson, Annica Andersson, Karin Dannaeus, Jessica Heidrich, Jarkko Kortesmaa, et al. “Peptide Hormone Exendin-4 Stimulates Subventricular Zone Neurogenesis in the Adult Rodent Brain and Induces Recovery in an Animal Model of Parkinson’s Disease.” Journal of Neuroscience Research 86, no. 2 (2008): 326–338. doi:10.1002/jnr.21483.
  8. ↑ Fan, R.; X. Li, X. Gu, J. C. N. Chan, G. Xu (2010). "Exendin-4 protects pancreatic beta cells from human islet amyloid polypeptide-induced cell damage: potential involvement of AKT and mitochondria biogenesis". Diabetes, Obesity and Metabolism 12 (9): 815–824. doi:10.1111/j.1463-1326.2010.01238.x. ISSN 1463-1326. http://onlinelibrary.wiley.com/doi/10.1111/j.1463-1326.2010.01238.x/abstract. Retrieved 2013-07-03. 
  9. ↑ 9.0 9.1 Tews, D.; Lehr, S.; Hartwig, S.; Osmersm A.; Paslack, W. and Eckel, J. (2009) Abstract Horm. Metab. Res. 41 (4) 294 – 301 Anti-apoptotic action of exendin-4 in INS-1 beta cells: comparative protein pattern analysis of isolated mitochondria http://www.ncbi.nlm.nih.gov/pubmed/19085810
  10. ↑ Wei, Qian; Yu Qiang Sun, Jin Zhang (2012-09). "Exendin-4, a glucagon-like peptide-1 receptor agonist, inhibits cell apoptosis induced by lipotoxicity in pancreatic β-cell line". Peptides 37 (1): 18-24. doi:10.1016/j.peptides.2012.06.018. ISSN 1873-5169. 
  11. ↑ Zheng, Bin; Zhixiang Liao, Joseph J Locascio, Kristen A Lesniak, Sarah S Roderick, Marla L Watt, Aron C Eklund, Yanli Zhang-James, Peter D Kim, Michael A Hauser, Edna Grünblatt, Linda B Moran, Silvia A Mandel, Peter Riederer, Renee M Miller, Howard J Federoff, Ullrich Wüllner, Spyridon Papapetropoulos, Moussa B Youdim, Ippolita Cantuti-Castelvetri, Anne B Young, Jeffery M Vance, Richard L Davis, John C Hedreen, Charles H Adler, Thomas G Beach, Manuel B Graeber, Frank A Middleton, Jean-Christophe Rochet, Clemens R Scherzer, Global PD Gene Expression (GPEX) Consortium (2010-10-06). "PGC-1α, a potential therapeutic target for early intervention in Parkinson's disease". Science translational medicine 2 (52): 52ra73. doi:10.1126/scitranslmed.3001059. ISSN 1946-6242. 
  12. ↑ Aviles-Olmos, Iciar; Patricia Limousin, Andrew Lees, Thomas Foltynie (2013-02-01). "Parkinson's disease, insulin resistance and novel agents of neuroprotection". Brain 136 (2): 374-384. doi:10.1093/brain/aws009. ISSN 1460-2156 0006-8950, 1460-2156. http://brain.oxfordjournals.org/content/136/2/374. Retrieved 2013-06-28. 
  13. ↑ Hao, M.; Kuang. H.Y.; Fu, Z.; Gao, X.Y.; Liu, . and Deng, W.(2012) AbstractNeurochem. Int> 61 (1): 1-6 Exenatide prevents high-glucose-induced damage of retinal ganglion cells through a mitochondrial mechanism http://www.ncbi.nlm.nih.gov/pubmed/22542771
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