Restoring pars intermedia dopamine concentrations and tyrosine hydroxylase expression levels with pergolide: evidence from horses with pituitary pars intermedia dysfunction

Abstract

Background: Pituitary pars intermedia dysfunction (PPID) develops slowly in aged horses as degeneration of hypothalamic dopaminergic neurons leads to proliferation of pars intermedia (PI) melanotropes through hyperplasia and adenoma formation. Dopamine (DA) concentrations and tyrosine hydroxylase (TH) immunoreactivity are markedly reduced in PI tissue of PPID-affected equids and treatment with the DA receptor agonist pergolide results in notable clinical improvement. Thus, we hypothesized that pergolide treatment of PPID-affected horses would result in greater DA and TH levels in PI tissue collected from PPID-affected horses versus untreated PPID-affected horses. To test this hypothesis, pituitary glands were removed from 18 horses: four untreated PPID-affected horses, four aged and four young horses without signs of PPID, and six PPID-affected horses that had been treated with pergolide at 2 µg/kg orally once daily for 6 months. DA concentrations and TH expression levels in PI tissues were determined by high performance liquid chromatography with electrochemical detection and Western blot analyses, respectively.

Results: DA and TH levels were lowest in PI collected from untreated PPID-affected horses while levels in the pergolide treated horses were similar to those of aged horses without signs of PPID.

Conclusions: These findings provide evidence of restoration of DA and TH levels following treatment with pergolide. Equine PPID is a potential animal model of dopaminergic neurodegeneration, which could provide insight into human neurodegenerative diseases.

Keywords: Dopamine agonist; Equine; Parkinson disease animal model; Pituitary pars intermedia adenoma.

Fig. 1

A 6-month treatment with pergolide restores the concentration of DA in the pars intermedia of PPID horses to the level of comparably aged horses without PPID. DA concentrations were measured in the pars intermedia of pituitary glands using HPLC-ED. Pituitary glands were collected from horse controls (young and old normal control horses), PPID untreated horses, and PPID afflicted horses that had received treatment with pergolide (DA agonist) at 2 µg/kg per os for 6 months. Columns represent mean DA concentrations + S.E.M. * Values that are significantly different from the young control group (p < 0.05)

Fig. 2

TH expression levels are re-established in the pars intermedia of PPID horses on a 6-month pergolide regimen. TH expression levels were determined in the pars intermedia of pituitary glands using western blot. Pituitary glands were collected from horse controls (young and old normal control horses), PPID untreated horses, and PPID afflicted horses that had received treatment with pergolide (DA agonist) at 2 µg/kg per os for 6 months. Columns represent mean TH concentrations normalized to β-actin + S.E.M. * The PPID-untreated value is significantly different from the young and old control groups as well as the PPID-treated group (p < 0.05)