title: Characterization of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, in rat partial and full nigral 6-hydroxydopamine lesion models of Parkinson's disease.
abstract: Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, have been demonstrated to promote neuroprotection in the rat 6-hydroxydopamine (6-OHDA) neurotoxin model of Parkinson's disease (PD), a neurodegenerative disorder characterized by progressive nigrostriatal dopaminergic neuron loss. In this report, we characterized the effect of a long-acting GLP-1 receptor agonist, liraglutide (500µg/kg/day, s.c.) in the context of a partial or advanced (full) 6-OHDA induced nigral lesion in the rat. Rats received a low (3µg, partial lesion) or high (13.5µg, full lesion) 6-OHDA dose stereotaxically injected into the right medial forebrain bundle (n=17-20 rats per experimental group). Six weeks after induction of a partial nigral dopaminergic lesion, vehicle or liraglutide was administered for four weeks. In the full lesion model, vehicle dosing or liraglutide treatment was applied for a total of six weeks starting three weeks pre-lesion, or administered for three weeks starting on the lesion day. Quantitative stereology was applied to assess the total number of midbrain tyrosine hydroxylase (TH) positive dopaminergic neurons. As compared to vehicle controls, liraglutide had no effect on the rotational responsiveness to d-amphetamine or apomorphine, respectively. In correspondence, while numbers of TH-positive nigral neurons were significantly reduced in the lesion side (partial lesion ≈55%; full lesion ≈90%) liraglutide administration had no influence dopaminergic neuronal loss in either PD model setting. In conclusion, liraglutide showed no neuroprotective effects in the context of moderate or substantial midbrain dopaminergic neuronal loss and associated functional motor deficits in the rat 6-OHDA lesion model of PD.
authors.affiliation: Gubra, Agern Allé1, DK-2970 Hoersholm, Denmark. Electronic address: hbh@gubra.dk.
authors.forename: Henrik H
authors.initials: HH
authors.lastname: Hansen
authors.affiliation: Gubra, Agern Allé1, DK-2970 Hoersholm, Denmark.
authors.forename: Katrine
authors.initials: K
authors.lastname: Fabricius
authors.affiliation: Gubra, Agern Allé1, DK-2970 Hoersholm, Denmark.
authors.forename: Pernille
authors.initials: P
authors.lastname: Barkholt
authors.affiliation: Neurobiology Research Unit, Rigshospitalet, Juliane Maries Vej 28, DK-2100 Copenhagen, Denmark.
authors.forename: Jens D
authors.initials: JD
authors.lastname: Mikkelsen
authors.affiliation: Gubra, Agern Allé1, DK-2970 Hoersholm, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Jelsing
authors.affiliation: Diabetes Research, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark.
authors.forename: Charles
authors.initials: C
authors.lastname: Pyke
authors.affiliation: Diabetes Research, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark.
authors.forename: Lotte Bjerre
authors.initials: LB
authors.lastname: Knudsen
authors.affiliation: Gubra, Agern Allé1, DK-2970 Hoersholm, Denmark. Electronic address: niels@gubra.dk.
authors.forename: Niels
authors.initials: N
authors.lastname: Vrang
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage*; D001058:Apomorphine / Q000008:administration & dosage; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000008:administration & dosage; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000069450:Liraglutide / Q000008:administration & dosage*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D018696:Neuroprotective Agents; D000069450:Liraglutide; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D001058:Apomorphine; D004298:Dopamine; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: 6-Hydroxydopamine; Dopaminergic neuron; GLP-1 receptor agonist; Liraglutide; Parkinson's disease; Tyrosine hydroxylase