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Glucagon-like peptide 1 receptor stimulation by exendin-4 reverses key deficits in distinct rodent models of Parkinson's disease

Harkavyi, Alexander and Abuirmeileh, Amjad and Lever, Rebecca and Kingsbury, Ann E. and Biggs, Christopher S. and Whitton, Peter S. (2008) Glucagon-like peptide 1 receptor stimulation by exendin-4 reverses key deficits in distinct rodent models of Parkinson's disease. Journal of Neuroinflammation, 5 (1). p. 19. ISSN 1742-2094

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Official URL: http://dx.doi.org/10.1186/1742-2094-5-19

Abstract

Abstract (provisional). 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 0.5ug/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. Conclusions: 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.

Item Type:Article
Research Community:University of Westminster > Life Sciences, School of
ID Code:4954
Deposited On:02 Jun 2008 12:06
Last Modified:11 Dec 2009 11:19

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