Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson's disease

Abstract

Background It has recently become apparent that neuroinflammation may play a significant role in Parkinson's disease (PD). This is also the case in animal paradigms of the disease. The potential neuroprotective action of the glucagon-like peptide 1 receptor (GLP-1R) agonist exendin-4 (EX-4), which is protective against cytokine mediated apoptosis and may stimulate neurogenesis, was investigated In paradigms of PD. Methods Two rodent 'models' of PD, 6-hydroxydopamine (6-OHDA) and lipopolysaccaride (LPS), were used to test the effects of EX-4. Rats were then investigated in vivo and ex vivo with a wide range of behavioural, neurochemical and histological tests to measure integrity of the nigrostriatal system. Results EX-4 (0.1 and 0.5 μg/kg) was given seven days after intracerebral toxin injection. Seven days later circling behaviour was measured following apomorphine challenge. Circling was significantly lower in rats given EX-4 at both doses compared to animals given 6-OHDA/LPS and vehicle. Consistent with these observations, striatal tissue DA concentrations were markedly higher in 6-OHDA/LPS + EX-4 treated rats versus 6-OHDA/LPS + vehicle groups, whilst assay of L-DOPA production by tyrosine hydroxylase was greatly reduced in the striata of 6-OHDA/LPS + vehicle rats, but this was not the case in rats co-administered EX-4. Furthermore nigral TH staining recorded in 6-OHDA/LPS + vehicle treated animals was markedly lower than in sham-operated or EX-4 treated rats. Finally, EX-4 clearly reversed the loss of extracellular DA in the striata of toxin lesioned freely moving rats. Conclusion The apparent ability of EX-4 to arrest progression of, or even reverse nigral lesions once established, 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.

Semaglutide seems to be more effective the other GLP-1Ras

“…Studies in rodent models of Parkinson's and Alzheimer's diseases and mouse models of ischaemic stroke have suggested that GLP-1 receptor agonist might have neuroprotective effects and prevent memory impairment (16)(17)(18). However, studies in humans have not supported the use of GLP-1 RA in cerebral diseases (19), except for one clinical trial of 48 weeks, which suggested that exenatide once weekly had positive effects in Parkinson's disease, which were sustained beyond the period of exposure (20).…”

GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism

“…Together, the findings of these studies suggest a loss of function in -/-mice and a physiological role for GLP-1R activation in the normal brain, as in the pancreas, that can be augmented by pharmacologic concentrations of agonists and inhibited by antagonists. Recent studies have demonstrated that Ex-4 can induce neurogenesis of neural stem cells both in culture and in the subventricular zone of rat brain after a 6-OHDA insult (38,39) and promote differentiation toward a neuronal phenotype (38), as has been reported for PC12 cells (13). Ex-4's ability to improve dopaminergic markers and function when administered a week or more after 6-OHDA-or cytokine-induced apoptosis, rather than at the time of insult as in our study, is indicative of neuroregenerative action (38,39).…”

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

“…Several recent discoveries have highlighted common cellular pathways that potentially relate neurodegenerative processes with abnormal mitochondrial function and abnormal glucose metabolism [2]. In parallel with these advances, a treatment for insulin resistance (exenatide; a GLP-1 agonist) has been proposed as a disease modifying drug in PD, based on multiple in vitro and in vivo studies [3][4][5][6][7][8][9].…”