Topographical Distribution of Morphological Changes in a Partial Model of Parkinson's Disease--Effects of Nanoencapsulated Neurotrophic Factors Administration

Mol Neurobiol. 2015 Oct;52(2):846-58. doi: 10.1007/s12035-015-9234-y. Epub 2015 Jun 4.

Abstract

Administration of various neurotrophic factors is a promising strategy against Parkinson's disease (PD). An intrastriatal infusion of 6-hydroxidopamine (6-OHDA) in rats is a suitable model to study PD. This work aims to describe stereological parameters regarding rostro-caudal gradient, in order to characterize the model and verify its suitability for elucidating the benefits of therapeutic strategies. Administration of 6-OHDA induced a reduction in tyrosine hidroxylase (TH) reactivity in the dorsolateral part of the striatum, being higher in the caudal section than in the rostral one. Loss of TH-positive neurons and axodendritic network was highly significant in the external third of substantia nigra (e-SN) in the 6-OHDA group versus the saline one. After the administration of nanospheres loaded with neurotrophic factors (NTF: vascular endothelial growth factor (VEGF) + glial cell line-derived neurotrophic factor (GDNF)), parkinsonized rats showed more TH-positive fibers than those of control groups; this recovery taking place chiefly in the rostral sections. Neuronal density and axodendritic network in e-SN was more significant than in the entire SN; the topographical analysis showed that the highest difference between NTF versus control group was attained in the middle section. A high number of bromodeoxyuridine (BrdU)-positive cells were found in sub- and periventricular areas in the group receiving NTF, where most of them co-expressed doublecortin. Measurements on the e-SN achieved more specific and significant results than in the entire SN. This difference in rostro-caudal gradients underpins the usefulness of a topological approach to the assessment of the lesion and therapeutic strategies. Findings confirmed the neurorestorative, neurogenic, and synergistic effects of VEGF+GDNF administration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Corpus Striatum / drug effects
  • Corpus Striatum / enzymology
  • DNA Replication
  • Doublecortin Domain Proteins
  • Doublecortin Protein
  • Drug Synergism
  • Drug Therapy, Combination
  • Glial Cell Line-Derived Neurotrophic Factor / administration & dosage
  • Glial Cell Line-Derived Neurotrophic Factor / pharmacokinetics
  • Glial Cell Line-Derived Neurotrophic Factor / therapeutic use*
  • Glial Fibrillary Acidic Protein / analysis
  • Injections, Intralesional
  • Male
  • Microtubule-Associated Proteins / analysis
  • Nanocapsules
  • Nerve Tissue Proteins / analysis
  • Neuroglia / chemistry
  • Neuroglia / drug effects
  • Neuroglia / ultrastructure
  • Neurons / chemistry
  • Neurons / drug effects
  • Neurons / ultrastructure
  • Neuropeptides / analysis
  • Oxidopamine / toxicity
  • Parkinsonian Disorders / drug therapy*
  • Parkinsonian Disorders / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Tissue Distribution
  • Tyrosine 3-Monooxygenase / analysis
  • Vascular Endothelial Growth Factor A / administration & dosage
  • Vascular Endothelial Growth Factor A / pharmacokinetics
  • Vascular Endothelial Growth Factor A / therapeutic use*

Substances

  • Dcx protein, rat
  • Doublecortin Domain Proteins
  • Doublecortin Protein
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Fibrillary Acidic Protein
  • Microtubule-Associated Proteins
  • Nanocapsules
  • Nerve Tissue Proteins
  • Neuropeptides
  • Vascular Endothelial Growth Factor A
  • Oxidopamine
  • Tyrosine 3-Monooxygenase