Demographic and clinical studies imply that female sex may be protective for Parkinson's disease (PD), but pathophysiological evidence to support these observations is missing. In early PD, functional changes may be detected in the primary motor cortex using transcranial magnetic stimulation (TMS). We hypothesised that if pathophysiology differs between sexes in PD, this will be reflected in differences of motor cortex measurements. On the other hand, female sex is associated with worse levodopa- induced dyskinesia (LID) in more advanced stages of PD. 17-β-estradiol (E2) is known to influence dopamine metabolism. Our aim was to define the influence of E2 on LID in the female hemiparkinsonian rat model of PD directly and indirectly via the expression of markers for postsynaptic plasticity changes that are associated with LID.
Forty-one newly diagnosed PD patients were clinically assessed with MDS-UPDRS part III and accelerometry. Various measures of cortical excitability and sensorimotor cortex plasticity were measured over both hemispheres in PD patients and 23 healthy participants. 6-hydroxydopamine was injected stereotactically into female rats' right median forebundle and afterwards animals received levodopa or saline solution subcutaneously for two weeks. All rats were ovariectomized, half of them received empty and the other half implants filled with E2 subcutaneously.
We found no sex or interhemispheric differences in healthy participants. Female patients had preserved interhemispheric balance of motor thresholds, more efficient short-interval intracortical inhibition and a physiological focal response to sensorimotor plasticity protocol PAS25 compared to male patients. E2 worsened LID when female hemiparkinsonian rats received a larger dose of levodopa. In rats that received a saline solution, E2 lowered the expression of biomarkers for LID (ΔFosB) and postsynaptic denervation hypersensitivity (c-Fos). However, E2 increased the expression of ΔFosB in rats, that received levodopa.
The study provides one of the first neurophysiological evidence of sex differences in early PD. Female patients have a more favourable profile of TMS measures, possibly reflecting a more successful cortical compensation or delayed maladaptive changes in the sensorimotor cortex. We concluded that E2 potentiates the effects of dopamine in the female sex. In the dopamine denervated striatum, E2 can lower the maladaptive activation of the indirect pathway at first. However, when treated with levodopa, E2 potentiates the hyperactivation of the direct pathway and worsens LID.
|
