Neurovascular Changes in Acute, sub-Acute and Chronic Mouse Models of Parkinson’s Disease
Sumit Sarkar, James Raymick, Dushyant Mann, John F. Bowyer, Joseph P. Hanig, Larry C Schmued, Merle G. Paule and Srinivasulu Chigurupati
Affiliation: Division of Neurotoxicology, National Center for Toxicological Research/FDA, Bldg. 53D, HFT-32, Jefferson-AR-72079, USA.
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 ±2.91in 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.
Keywords: Blood-brain barrier, Blood vessel, Endothelial cells, FT-gel, GFAP, MPTP, NeuN, Parkinson’s disease, TH.
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