Abstract
BackgroundIt 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.MethodsTwo 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.ResultsEX-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.ConclusionThe 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.
Highlights
It has recently become apparent that neuroinflammation may play a significant role in Parkinson's disease (PD)
Apomorphine (APO) induced circling is regarded as a quantitative index of NS lesion severity [21] and an attenuation is predictive of potential anti-parkinsonian activity
Our findings reveal that tight contralateral circling was clearly evident in 6-OHDA and LPS treated rats, but this was dose-dependently attenuated by EX-4
Summary
It has recently become apparent that neuroinflammation may play a significant role in Parkinson's disease (PD). A positive therapeutic effect could be produced by molecules with neurotrophic properties or the ability to stimulate neurogenesis of cells with a dopaminergic phenotype. For such an approach to have an improved beneficial effect it would be desirable to stabilize the destructive elements which favour neurodegeneration within the nigra. It has recently been observed that the glucagonlike peptide-1 receptor (GLP-1R) agonist exendin-4 (EX4) shows neurotrophic [10] and 'neuroprotective' [11] properties in cultured PC12 cells subjected to excitotoxic stress. Very recently it has been observed that EX-4 reverses indicators of NS damage in 6-hydroxydopamine (6-OHDA)
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