Harkavyi, Alexander; (2009) Neuroprotective effect of GLP-1 receptor agonist exendin-4 in rat models of Parkinson's disease. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder with no current cure and therapies that are directed towards symptomatic relief but have potentially disabling side effect profiles. The need for an alternative therapeutic approach is crucial. Not so long ago it has been demonstrated that the glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (EX-4) originally isolated from saliva of Heloderma suspectum lizard (Eng et al., 1992) is neurotrophic and neuroprotective in vitro leading to the suggestion that stimulation of central GLP-1 receptors could have therapeutic value in neurodegenerative disorders such as PD (Perry et al., 2002b). Here we have investigated the effects of EX-4 treatment in rats with nigrostriatal lesions following central 6-hydroxydopamine (6-OHDA) or lipopolysaccharide (LPS) injection. Both toxins were delivered stereotactically and animals were then investigated in vivo and ex vivo with a wide range of behavioural, neurochemical and histological tests to assess the integrity of the nigrostriatal dopamine (DA) system. EX-4 was administered twice daily at two different doses seven days after intracerebral toxin injection for the duration of one week. Another week thereafter the lesion severity was quantified based on contralateral circling behaviour following apomorphine injection. Circling was very pronounced in toxin only treated animals and significantly lower in rats co-treated with EX-4 at both doses (0.1 and 0.5μg/kg) while it was increased again in groups co-treated with either GLP-1R antagonist EX-9-39 or the DA D3-receptor antagonist nafadotride. This suggested that the neuroprotective effect of EX-4 involved activation of both GLP-1R and DA D3-receptors. Animals were then implanted with microdialysis probes and extracellular DA was measured using in vivo microdialysis. Both basal and potassium evoked levels of DA were markedly reduced in toxin treated animals but were comparable to control levels in EX-4 treated groups. Groups co-treated with either of the two antagonists resulted in DA levels being comparable to 6-OHDA or LPS only treated animals, which again shows the involvement of both GLP-1Rs and D3-receptors. In addition to these findings, striatal tissue DA, tyrosine hydroxylase (TH) activity and TH immunolabelling were also measured in these groups and all confirmed the behavioural and in vivo data. In conclusion, EX-4 clearly reverses the loss of extracellular DA and the integrity of the nigrostriatal system in toxin lesioned rats. The mechanism involves both the GLP-1R and D3-receptors. EX-4 readily enters the brain on peripheral administration and is already in use for type 2 diabetes for which it was FDA approved in 2005 and in our view should be clinically tested in human PD patients without further delay.

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