Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson's disease.
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 mug/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.
Harkavyi
Alexander
A
Department of Pharmacology, The School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK. alexander.harkavyi@pharmacy.ac.uk
Abuirmeileh
Amjad
A
Lever
Rebecca
R
Kingsbury
Ann E
AE
Biggs
Christopher S
CS
Whitton
Peter S
PS
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001058:Apomorphine / Q000633:toxicity; D001522:Behavior, Animal / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000032:analysis; D004353:Drug Evaluation, Preclinical; D004731:Endotoxins / Q000633:toxicity*; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D007980:Levodopa / Q000096:biosynthesis; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000819:agonists* / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology / Q000627:therapeutic use*
D000978:Antiparkinson Agents; D004731:Endotoxins; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D009419:Nerve Tissue Proteins; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D007980:Levodopa; C044101:endotoxin, Escherichia coli; D016627:Oxidopamine; D000077270:Exenatide; D014446:Tyrosine 3-Monooxygenase; D001058:Apomorphine; D004298:Dopamine