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

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

Background
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. In the US the FDA has issued similar cautionary information.

Research
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 demonstrated promotion of neurite growth and neuron differentiation by Exendin-4

2008

Harkavyi et al 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 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 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 ,
 * influencing mitochondrial development ,
 * 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."

,, and
 * increasing the efficiency of electron transport in the energy production system through stimulation of a genetic regulator, PGC-1α,.