title: The corticotrophin-releasing factor-like peptide urocortin reverses key deficits in two rodent models of Parkinson's disease.
abstract: The potential neuroprotective action of the corticotrophin-releasing factor-related peptide urocortin (UCN) was investigated in the rat 6-hydroxydopamine (6-OHDA) and lipopolysaccharide (LPS) paradigms of Parkinson's disease. UCN (20 fmol) was either given at the same time as (T = 0) or 7 days after (T = +7) intracerebral 6-OHDA or LPS injection. At 14 days after 6-OHDA or LPS injection, circling behaviour was measured following apomorphine challenge. Circling was significantly lower in rats given UCN at either T = 0 or T = +7 compared with animals given 6-OHDA or LPS and vehicle. Sham-treated rats showed no circling. Consistent with these observations, striatal dopamine concentrations were markedly higher in 6-OHDA/LPS + UCN rats vs. 6-OHDA/LPS + vehicle groups. Additionally, L-dihydroxyphenylalanine production by tyrosine hydroxylase was greatly reduced in the striata of 6-OHDA/LPS + vehicle rats, whereas this was not the case in rats coadministered UCN. Finally, the numbers of tyrosine hydroxylase-positive cells recorded in the substantia nigra of 6-OHDA/LPS + vehicle-treated animals were markedly lower than those of sham-operated or 6-OHDA/LPS + UCN rats. Critically, UCN was effective in reversing lesion-induced deficits when given either at the same time as or 7 days after the neurotoxic insult. To our knowledge, this is the first time that such an effect has been demonstrated in vivo. The apparent ability of UCN to arrest the progression of or even reverse nigral lesions once established suggests that pharmacological manipulation of this system could have substantial therapeutic utility.
authors.affiliation: Department of Pharmacology, The School of Pharmacy, 29-39 Brunswick Square, London, UK.
authors.forename: Amjad
authors.initials: A
authors.lastname: Abuirmeileh
authors.forename: Rebecca
authors.initials: R
authors.lastname: Lever
authors.forename: Ann E
authors.initials: AE
authors.lastname: Kingsbury
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lees
authors.forename: Ian C
authors.initials: IC
authors.lastname: Locke
authors.forename: Richard A
authors.initials: RA
authors.lastname: Knight
authors.forename: Hardial S
authors.initials: HS
authors.lastname: Chowdrey
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Biggs
authors.forename: Peter S
authors.initials: PS
authors.lastname: Whitton
mesh_terms: D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D015153:Blotting, Western; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D003627:Data Interpretation, Statistical; D004298:Dopamine / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D017072:Neostriatum / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar; D013239:Stereotyped Behavior / Q000187:drug effects; D013378:Substantia Nigra / Q000502:physiology; D013565:Sympatholytics; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D054832:Urocortins
chemical_list: D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D013565:Sympatholytics; D054832:Urocortins; D016627:Oxidopamine; D003346:Corticotropin-Releasing Hormone; D014446:Tyrosine 3-Monooxygenase; D001058:Apomorphine; D004298:Dopamine