title: Methodology and effects of repeated intranasal delivery of DNSP-11 in a rat model of Parkinson's disease.
abstract: BACKGROUND
  To circumvent the challenges associated with delivering large compounds directly to the brain for the treatment of Parkinson's disease (PD), non-invasive procedures utilizing smaller molecules with protective and/or restorative actions on dopaminergic neurons are needed.
  
  
  METHODS
  We developed a methodology for evaluating the effects of a synthetic neuroactive peptide, DNSP-11, on the nigrostriatal system using repeated intranasal delivery in both normal and a unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of PD.
  
  
  RESULTS
  Normal rats repeatedly administered varying doses of DNSP-11 intranasally for 3 weeks exhibited a significant increase in dopamine (DA) turnover in both the striatum and substantia nigra (SN) at 300μg, suggestive of a stimulative effect of the dopaminergic system. Additionally, a protective effect was observed following repeated intranasal administration in 6-OHDA lesioned rats, as suggested by: a significant decrease in d-amphetamine-induced rotation at 2 weeks; a decrease in DA turnover in the lesioned striatum; and an increased sparing of tyrosine hydroxylase (TH) positive (+) neurons in a specific sub-region of the lesioned substantia nigra pars compacta (SNpc). Finally, tracer studies showed (125)I-DNSP-11 distributed diffusely throughout the brain, including the striatum and SN, as quickly as 30min after a single intranasal dose.
  
  
  METHODS
  The results of bilateral intranasal administration of DNSP-11 are compared to our unilateral single infusion studies to the brain in rats.
  
  
  CONCLUSIONS
  These studies support that DNSP-11 can be delivered intranasally and maintain its neuroactive properties in both normal rats and in a unilateral 6-OHDA rat model of PD.
authors.affiliation: Department of Anatomy & Neurobiology, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Mallory J
authors.initials: MJ
authors.lastname: Stenslik
authors.affiliation: Department of Anatomy & Neurobiology, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Potts
authors.affiliation: Department of Anatomy & Neurobiology, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: James W H
authors.initials: JW
authors.lastname: Sonne
authors.affiliation: Department of Anatomy & Neurobiology, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Cass
authors.affiliation: Department of Anatomy & Neurobiology, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Turchan-Cholewo
authors.affiliation: Department of Anatomy & Neurobiology, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Francois
authors.initials: F
authors.lastname: Pomerleau
authors.affiliation: Department of Anatomy & Neurobiology, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Huettl
authors.affiliation: Department of Anatomy & Neurobiology, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ai
authors.affiliation: Department of Anatomy & Neurobiology, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Don M
authors.initials: DM
authors.lastname: Gash
authors.affiliation: Department of Anatomy & Neurobiology, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Greg A
authors.initials: GA
authors.lastname: Gerhardt
authors.affiliation: Department of Anatomy & Neurobiology, University of Kentucky College of Medicine, Lexington, KY, USA; Department of Molecular & Cellular Biochemistry and Center of Structural Biology, University of Kentucky College of Medicine, Lexington, KY, USA. Electronic address: lhbradley@uky.edu.
authors.forename: Luke H
authors.initials: LH
authors.lastname: Bradley
mesh_terms: D000281:Administration, Intranasal; D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001345:Autoradiography; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003913:Dextroamphetamine / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007839:Functional Laterality / Q000187:drug effects; D008297:Male; D009842:Oligopeptides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D009842:Oligopeptides; C000597541:prolyl-prolyl-glutamyl-alanyl-prolyl-alanyl-glutamyl-aspartyl-arginyl-seryl-leucinamide; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D003913:Dextroamphetamine; D004298:Dopamine
keywords: 6-Hydroxydopamine; Intranasal administration; Neurochemistry; Neuroprotection; Nigrostriatal pathway; Peptide