The pathophysiology of equine pituitary pars intermedia dysfunction: The role of dopaminergic neurodegeneration, oxidative stress and alpha-synuclein

Equine pituitary pars intermedia dysfunction (PPID) is a common disease of aged horses. The pathogenesis of PPID is poorly understood, but a loss of dopaminergic inhibition of the pituitary pars intermedia is suggested. The goal of this thesis was to gain a better understanding of the pathologic mechanisms that result in PPID and to define factors that predispose horses to developing this condition. We hypothesized that PPID results from dopaminergic neurodegeneration of the periventricular dopaminergic neurons in response to accumulation of oxidatively damaged nerve terminal protein, α-synuclein; the same mechanism proposed in nigrostriatal dopaminergic neurodegeneration with Parkinson's disease. Immunohistochemical examination of pituitary and hypothalamic tissue demonstrated a loss of dopaminergic neurons in PPID affected horses compared to age-matched controls. In addition, 3-nitrotyrosine (an oxidative stress marker) and α-synuclein were increased and co-localized in the pars intermedia of horses with disease. These findings suggest a role for nitration of overexpressed α-synuclein in the pathogenesis of neurodegeneration in PPID. To assess whether horses developed PPID due to poor antioxidant defense mechanisms, biochemical assays were used to compare accumulation of oxidative damage to systemic and local (pituitary) antioxidant capacity. Accumulation of markers of oxidative stress was not associated with a deficiency in antioxidant capacity. However, we did observe an age-associated decrease in manganese superoxide dismutase (MnSOD) activity and a failure of MnSOD activity to increase in response to oxidative stress. These findings suggest MnSOD may contribute to disease susceptibility. In summary, evidence from our laboratory is consistent with earlier published data indicating PPID is due to a loss of dopaminergic inhibition and furthermore suggests that PPID is a dopaminergic neurodegenerative disease. The role of oxidative stress and α-synclein expression in the pathophysiology of PPID is a new finding. These results suggest the pathogenesis of PPID may be mechanistically similar to that of Parkinson's disease.