title: Neurovascular changes in acute, sub-acute and chronic mouse models of Parkinson's disease.
abstract: Although selective neurodegeneration of nigro-striatal dopaminergic neurons is widely accepted as a cause of Parkinson's disease (PD), the role of vascular components in the brain in PD pathology is not well understood. However, the neurodegeneration seen in PD is known to be associated with neuroinflammatory-like changes that can affect or be associated with brain vascular function. Thus, dysfunction of the capillary endothelial cell component of neurovascular units present in the brain may contribute to the damage to dopaminergic neurons that occurs in PD. An animal model of PD employing acute, sub-acute and chronic exposures of mice to methyl-phenyl-tetrahydropyridine (MPTP) was used to determine the extent to which brain vasculature may be damaged in PD. Fluoro-Turquoise gelatin labeling of microvessels and endothelial cells was used to determine the extent of vascular damage produced by MPTP. In addition, tyrosine hydroxylase (TH) and NeuN were employed to detect and quantify dopaminergic neuron damage in the striatum (CPu) and substantia nigra (SNc). Gliosis was evaluated through GFAP immunohistochemistry. MPTP treatment drastically reduced TH immunoreactive neurons in the SNc (20.68 ± 2.83 in acute; 22.98 ± 2.14 in sub-acute; 10.20 ± 2.24 in chronic vs 34.88 ± 2.91 in controls; p<0.001). Similarly, TH immunoreactive terminals were dramatically reduced in the CPu of MPTP treated mice. Additionally, all three MPTP exposures resulted in a decrease in the intensity, length, and number of vessels in both CPu and SNc. Degenerative vascular changes such as endothelial cell 'clusters' were also observed after MPTP suggesting that vasculature damage may be modifying the availability of nutrients and exposing blood cells and/or toxic substances to neurons and glia. In summary, vascular damage and degeneration could be an additional exacerbating factor in the progression of PD, and therapeutics that protect and insure vascular integrity may be novel treatments for PD.
authors.forename: Sumit
authors.initials: S
authors.lastname: Sarkar
authors.forename: James
authors.initials: J
authors.lastname: Raymick
authors.forename: Dushyant
authors.initials: D
authors.lastname: Mann
authors.forename: John F
authors.initials: JF
authors.lastname: Bowyer
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Hanig
authors.forename: Larry C
authors.initials: LC
authors.lastname: Schmued
authors.forename: Merle G
authors.initials: MG
authors.lastname: Paule
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research/FDA, Bldg. 53D, HFT-32, Jefferson-AR-72079, USA. Sumit.Sarkar@FDA.hhs.gov.
authors.forename: Srinivasulu
authors.initials: S
authors.lastname: Chigurupati
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000473:pathology*; D002552:Cerebral Ventricles / Q000473:pathology*; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000473:pathology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D013266:Stilbamidines; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D005904:Glial Fibrillary Acidic Protein; D013266:Stilbamidines; D014446:Tyrosine 3-Monooxygenase; D010751:Phosphopyruvate Hydratase