Motor and Cognitive Advantages Persist 12 Months After Exenatide Exposure in Parkinson’s Disease

Abstract

Abstract. Background:Data from an open label randomised controlled trial have suggested possible advantages on both motor and non-motor measures in patients with Parkinson's disease following 12 months exposure to exenatide. Objective: Continued follow up of these same patients was performed to investigate whether these possible advantages persisted in the prolonged absence of this medication. Methods: All participants from an open label, randomised controlled trial of exenatide as a treatment for Parkinson's disease, were invited for a further follow up assessment at the UCL Institute of Neurology. This visit included all 20 individuals who had previously completed twelve months exposure to exenatide 10ug bd and the 24 individuals who had acted as randomised controls. Motor severity of PD was compared after overnight withdrawal of conventional PD medication using blinded video assessment of the MDS-UPDRS, together with several non-motor tests. This assessment was thus 24 months after their original baseline visit, i.e. 12 months after cessation of exenatide. Results: Compared to the control group of patients, patients previously exposed to exenatide had an advantage of 5.6 points (95% CI, 2.2-9.0; p = 0.002) using blinded video rating of the MDS-UPDRS part 3 motor subscale. There was also a difference of 5.3 points; (95% CI, 9.3-1.4; p = 0.006) between the 2 groups on the Mattis Dementia Rating scale.

Isolation of Positive Modulator of Glucagon-like Peptide-1 Signaling from Trigonella foenum-graecum (Fenugreek) Seed

“…In addition to hypoglycemic effect, extract of fenugreek seed also displays neuroprotective properties (21) and anti-inflammatory effects (22,23) in disease animal models. These mechanisms of effects are consistent with the current trials of GLP-1 analogs in treatment of psoriasis (5) and Parkinson disease (2).…”

“…Mice with GLP-1R gene knock-out or with functionally deficient GLP-1R signaling exhibit impaired glucose homeostasis, learning, and memory (1). Clinical trials have also targeted GLP-1 signaling in other conditions, including psoriasis, heart disease, and neurodegenerative disease (2)(3)(4)(5). As such, GLP-1R signaling might be an ideal research target for the discovery and development of drugs for the treatment of various conditions from metabolic disorders to neurodegeneration.…”

Modulation of Glucagon-like Peptide-1 (GLP-1) Potency by Endocannabinoid-like Lipids Represents a Novel Mode of Regulating GLP-1 Receptor Signaling

“…However, neurons expressing GLP-1Rs in notable areas, such as caudal hippocampus and the dopaminergic neurons in the substantia nigra, have no apparent innervations from GLP-1-producing neurons (1,3,14). Both areas are anatomic sites of deficient functions in disease that are ameliorable by GLP-1 analog therapy, which improves memory/learning in an Alzheimer mouse model and Parkinson symptoms in humans (5,6,41). It has been suggested that GLP1Rs in these areas might be activated by the circulating GLP-1 in cerebrospinal fluid and blood (40), which is normally at a level that is probably below the threshold concentration for GLP-1R activation (42).…”

“…Mice deficient in GLP-1R expression or with blunted GLP-1R function show impairment of physiologic features not limited to glucose homeostasis but also including learning and memory (4). Clinical trials targeting GLP-1 signaling to treat non-metabolic diseases include those for psoriasis, heart disease, and neurodegenerative diseases (5)(6)(7). Despite encouraging outcomes with GLP-1 analogs in reducing myocardial infarct size in acute coronary occlusion (7) and improving clinical symptoms in patients with Parkinson disease (5), the mechanisms of physiological regulation of GLP-1R signaling beyond energy homeostasis remain largely unknown.…”

Is Parkinson's disease the new cancer?

“…Nevertheless, the data provide 'strong encouragement' for assessing exenatide 'as a potential disease modifying agent in Parkinson's disease'. 10 'This is the first time in the 20 years I have lived with PD that I have witnessed such robust data that support the view that we can permanently alter the degenerative nature of Parkinson's,' Isaacs notes. 'The really exciting thing about exenatide is that it is approved for type 2 diabetes, and that means that, unlike other new medicines, it won't have to go through the same time-consuming and expensive safety procedures before it is able to be prescribed to people with PD.'…”