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.

Equine pituitary pars intermedia dysfunction: a spontaneous model of synucleinopathy

“…Equine PPID exhibits neurochemical perturbations including oxidative stress and antioxidant deficiency that may provide a favorable environment for protein aggregation 38 . Previous work demonstrated reduced dopamine content in pars intermedia of PPID-afflicted horses 17 , 33 , 38 , 39 . The cell bodies of the dopaminergic neurons that innervate the pars intermedia originate from the periventricular nuclei 39 – 41 .…”

“…Previous work demonstrated reduced dopamine content in pars intermedia of PPID-afflicted horses 17 , 33 , 38 , 39 . The cell bodies of the dopaminergic neurons that innervate the pars intermedia originate from the periventricular nuclei 39 – 41 . In PD, damaged dopaminergic neurons arise in the substantia nigra compacta which degenerate and cause dopamine loss in the basal ganglia, crucial for coordination of fine motor movements 42 .…”

Senolytic and senomorphic secondary metabolites as therapeutic agents in Drosophila melanogaster models of Parkinson’s disease

“…Pergolide improves symptoms in PD patients, either as a standalone treatment or in combination with levodopa ( 219 , 220 ). The symptomatic improvement of pergolide is attributed to its action on both dopamine D1 and D2 receptors, whereas other drugs, like bromocriptine, primarily target only dopamine D2 receptors ( 219 ). However, the use of pergolide has also raised concerns regarding its potential side effects.…”

Pituitary Pars Intermedia Dysfunction (PPID) in Horses

“…Activation of the D2 receptor reduces POMC production by the pars intermedia within hours, resulting in reduced severity of clinical signs and limiting sequelae that accompany PPID [ 17 , 142 , 143 ]. Pergolide provides an exogenous supply of dopamine that would usually be provided by the hypothalamus and restores pituitary pars intermedia function through the provision of dopaminergic inhibition [ 121 , 142 , 144 ]. Restoration of dopamine has been observed to reduce ACTH concentrations to within reference intervals in 28–74% of cases [ 118 ].…”