Spontaneous partial recovery of striatal dopaminergic uptake despite nigral cell loss in asymptomatic MPTP-lesioned female minipigs

Abstract

The Göttingen minipig is a large animal with a gyrencephalic brain that expresses -complex behavior, making it an attractive model for Parkinson's disease research. Here, we investigate the temporal evolution of presynaptic dopaminergic function for 14 months after injections of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the minipig using a multi-tracer longitudinal positron emission tomography (PET) design. We injected seven sedated minipigs with 1-2 mg/kg of MPTP, and two with saline, three times a week over four weeks. We monitored behavioral deficits using a validated motor scale and walking mat. Brains were imaged with (+)-⍺-[¹¹C]-dihydrotetrabenazine ([¹¹C]-DTBZ) and [¹⁸F]-dihydroxyphenylalanine ([¹⁸F]-FDOPA) PET at baseline and 1, 3, 10 and 14 months after MPTP injection, and immunohistochemistry was used to assess nigral cell loss. The minipigs showed mild bradykinesia and impaired coordination at early timepoints after MPTP. PET revealed decreases of striatal [¹¹C]-DTBZ and [¹⁸F]-FDOPA uptake post-MPTP with partial spontaneous recovery of [¹⁸F]-FDOPA after 10 months. Postmortem analysis estimated an MPTP-induced nigral loss of 57% tyrosine hydroxylase+ and 43% Nissl-stained cells. Normal motor function despite substantial damage to the dopaminergic system is consistent with prodromal Parkinson's disease, and offers an opportunity for testing disease-modifying therapies. However, partial spontaneous recovery of dopamine terminal function must be taken into account in future studies.

Keywords: Dopamine; MPTP; Minipig; Parkinson’s disease; Positron emission tomography; Vesicular monoamine transporter 2.