Progesterone and the striatal 6-hydroxydopamine model of Parkinson’s disease
Degree GrantorUniversity of Canterbury
Degree NameDoctor of Philosophy
Parkinson’s disease (PD) is a common neurodegenerative disorder that is characterised by akinesia, muscular rigidity, and postural instability, due primarily to the loss of dopaminergic neurons in the substantia nigra and depletion of upstream dopamine in the striatum. Current dopaminergic treatments reduce motor symptoms, but have diminishing benefits as the disease progresses. Treatment with the neuroactive steroid natural progesterone (PROG) improves outcomes in many experimental models of brain injury due to its pleiotropic mechanisms of neuroprotection, many of which may also benefit PD. This thesis investigated the influence of PROG on motor impairments in the unilateral intrastriatal 6-hydroxydopamine (6-OHDA) lesion model of PD in rats. We established a PD-like impairment with a d-amphetamine induced rotation test at day 7 after large lesions and then administered PROG (4 mg/kg or 8 mg/kg) once daily for 7 days starting at day 8. Both PROG doses markedly improved the primary outcome measure, forelimb akinesia on the adjusting steps test, with improvement sustained for six weeks after treatment had stopped. In a second study the beneficial influence of PROG (8 mg/kg) on akinesia was replicated for rats with large lesions and was extended to rats with small lesions so that the latter rats were now similar to sham operated controls. We also found that PROG modestly improved postural instability of the ipsilateral forelimb on the postural instability test, and sensorimotor integration on the whisker test, but did not improve skilled reaching accuracy on a single-pellet reaching task, forelimb use asymmetry on the cylinder test, sensory neglect on the corridor test, or rotation bias after apomorphine. Furthermore, PROG did not change striatal tyrosine hydroxylase density when assessed in rats with large lesions. This study has provided the most thorough examination to date regarding PROG’s influence on motor skills in an animal model of PD. Furthermore, this study has produced novel evidence of the beneficial effects of PROG treatment on forelimb akinesia. These initial promising findings suggest that PROG is an effective therapy for akinesia and thus provides an impetus to further investigate PROG’s efficacy for the treatment of PD.