Allopregnanolone Reinstates Tyrosine Hydroxylase Immunoreactive Neurons and Motor Performance in an MPTP-Lesioned Mouse Model of Parkinson's Disease

Abstract

Restorative/protective therapies to restore dopamine neurons in the substantia nigra pars compacta (SNpc) are greatly needed to effectively change the debilitating course of Parkinson's disease. In this study, we tested the therapeutic potential of a neurogenic neurosteroid, allopregnanolone, in the restoration of the components of the nigrostriatal pathway in MPTP-lesioned mice by measuring striatal dopamine levels, total and tyrosine hydroxylase immunoreactive neuron numbers and BrdU-positive cells in the SNpc. An acute treatment (once/week for two weeks) with allopregnanolone restored the number of tyrosine hydroxylase-positive and total cell numbers in the SNpc of MPTP-lesioned mice, even though this did not increase striatal dopamine. It was also noted that MPTP treated mice to which allopregnanolone was administered had an increase in BrdU-positive cells in the SNpc. The effects of allopregnanolone in MPTP-lesioned mice were more apparent in mice that underwent behavioral tests. Interestingly, mice treated with allopregnanolone after MPTP lesion were able to perform at levels similar to that of non-lesioned control mice in a rotarod test. These data demonstrate that allopregnanolone promotes the restoration of tyrosine hydroxylase immunoreactive neurons and total cells in the nigrostriatal tract, improves the motor performance in MPTP-treated mice, and may serve as a therapeutic strategy for Parkinson's disease.

Neuroprotective Effect of Progesterone in MPTP-Treated Male Mice

“…In support of the role of PROG metabolites in neuroprotection, several in vitro and in vivo studies have shown that blockage of 5α-reductase, the first enzyme involved in the conversion of PROG into DHP, abolishes the neuroprotective effect of PROG in various models [50,51,52]. Furthermore, administration of THP once weekly for 2 weeks to MPTP-treated mice is reported to restore positive cells for tyrosine hydroxylase in the substantia nigra as well as motor behavior, and to induce the generation of new positive neurons for tyrosine hydroxylase in the substantia nigra [53]. In this study, THP was administered at a time when the damage induced by MPTP is stable, that is after 7 days [54].…”

“…Moreover, an alteration in PROG metabolism has also been reported in a different animal model of PD [58]. Further work is needed to investigate how the decrease in PROG metabolites contributes to the degenerative process, but current data suggest that PROG could be an interesting therapeutic compound, since THP is known to modulate dopaminergic systems, to act as a positive neuromodulator of GABA A receptors, and to have neuroprotective effects [53,59]. Future studies that compare the neuroprotective effect of PROG and THP on dopaminergic neurons could also be very informative, as THP could potentially be used instead of PROG when 5α-reductase activity is impaired, as has been observed to occur in PD patients.…”

Cognitive Deficits and Disruption of Neurogenesis in a Mouse Model of Apolipoprotein E4 Domain Interaction

“…Unbiased Stereology-The stereology was performed as described previously (26). Briefly, montage images of all sections that contain the hippocampus were captured using a 3i microscope with Slidebook 5.5 software (Intelligent Imaging Innovations, Inc, Denver, CO).…”

Regulation of the Neurodegenerative Process Associated to Parkinson’s Disease by CD4+ T-cells

“…Allopregnanolone, a metabolite of progesterone produced by astrocytes within the CNS, is selectively enriched in the SN of post-mortem brains of healthy individuals (Bixo et al 1997), and has been shown dramatically reduced not only in brains of PD patients, but also in 6-OHDA lesioned rats (Luchetti et al 2010;Melcangi et al 2012). Interestingly, systemic administration of allopregnanolone into MPTPintoxicated mice promotes restoration of dopaminergic neurons in the SN and improves motor performance of these mice (Adeosun et al 2012). Considering this data, it is possible to speculate that increased GABA detected during PD might work initially counteracting inflammatory function mediated by pathogenic encephalitogenic CD4+ T-cells and M1-like microglia, nevertheless, this beneficial effect might be lost once the concentration of positive regulators of GABA signalling is significantly reduced upon PD (Fig.…”