Progesterone Exerts a Neuromodulatory Effect on Turning Behavior of Hemiparkinsonian Male Rats: Expression of 3 α -Hydroxysteroid Oxidoreductase and Allopregnanolone as Suggestive of GABAA Receptors Involvement

Roberto Yunes, Sebastián Casas, Eliana Gaglio, Ricardo Cabrera, Roberto Yunes, Sebastián Casas, Eliana Gaglio, Ricardo Cabrera

Abstract

There is a growing amount of evidence for a neuroprotective role of progesterone and its neuroactive metabolite, allopregnanolone, in animal models of neurodegenerative diseases. By using a model of hemiparkinsonism in male rats, injection of the neurotoxic 6-OHDA in left striatum, we studied progesterone's effects on rotational behavior induced by amphetamine or apomorphine. Also, in order to find potential explanatory mechanisms, we studied expression and activity of nigrostriatal 3α-hydroxysteroid oxidoreductase, the enzyme that catalyzes progesterone to its active metabolite allopregnanolone. Coherently, we tested allopregnanolone for a possible neuromodulatory effect on rotational behavior. Also, since allopregnanolone is known as a GABAA modulator, we finally examined the action of GABAA antagonist bicuculline. We found that progesterone, in addition to an apparent neuroprotective effect, also increased ipsilateral expression and activity of 3α-hydroxysteroid oxidoreductase. It was interesting to note that ipsilateral administration of allopregnanolone reversed a clear sign of motor neurodegeneration, that is, contralateral rotational behavior. A possible GABAA involvement modulated by allopregnanolone was shown by the blocking effect of bicuculline. Our results suggest that early administration of progesterone possibly activates genomic mechanisms that promote neuroprotection subchronically. This, in turn, could be partially mediated by fast, nongenomic, actions of allopregnanolone acting as an acute modulator of GABAergic transmission.

Figures

Figure 1
Figure 1
Schematic representation of a brain coronary section showing the corpus striatum and the place where microinjections were performed. Coordinates: Anterior-Posterior, +1.2 mm; Mediolateral, +2.5 mm; Dorsoventral, −6.5 mm relative to bregma. CC, corpus callosum; CPu, caudate putamen (modified from Paxinos G. and Watson C, 1997; The Rat Brain in Stereotaxic Coordinates, third edition).
Figure 2
Figure 2
(a) Experimental procedure I: performed to evaluate the effects of progesterone on turning behavior and effects on nigrostriatal expression and enzymatic activity of 3α-HSOR of hemiparkinsonian rats. (b) Experimental procedure II: performed to study the effects of allopregnanolone on turning behavior of hemiparkinsonian rats. HP group (hemiparkinsonian group), P4-treated HP group (progesterone-treated hemiparkinsonian group). Time 0: surgery-day.
Figure 3
Figure 3
Effect of progesterone treatment on turning behavior induced by amphetamine (a) and apomorphine (b) at eight weeks after 6-OHDA lesion. Results are expressed as turns/hour (mean ± SEM); ∗∗P < 0.01 and ∗∗∗P < 0.001 (one-way ANOVA).
Figure 4
Figure 4
Gene expression of 3α-HSOR in left (a) and right striatum (b). Results are expressed as mean ± SEM of relative units cDNA of sham, HP, and P4-treated HP groups; ∗P < 0.05 and ∗∗∗P < 0.001 (one-way ANOVA). Ethidium bromide fluorescence photograph of the gel electrophoresis of the amplification products, of sham, HP, and P4-treated HP. The gel photographs were quantified using ImageJ software (National Institutes of Health, USA) and expressed as arbitrary units relative to cyclophilin A. HP group (hemiparkinsonian group), P4-treated HP group (progesterone-treated hemiparkinsonian group).
Figure 5
Figure 5
Enzymatic activity of 3α-HSOR in left (a) and right (b) striatum of sham, HP, and P4-treated HP groups. Results are expressed as a mean ± SEM of nmol/mg/min; ∗∗P < 0.01 (one-way ANOVA). HP group (hemiparkinsonian group), P4-treated HP group (progesterone-treated hemiparkinsonian group).
Figure 6
Figure 6
Effect of intraventricular vehicle, ALLO [2 μM], and bicuculline [4.9 μM] + ALLO on turning behavior induced by apomorphine at eight weeks after 6-OHDA lesion. Results are expressed as turns/hour; ∗∗∗P < 0.001 (two-way ANOVA). ALLO: allopregnanolone, Bic: bicuculline, HP group: hemiparkinsonian group, and P4-treated HP group: progesterone-treated hemiparkinsonian group.

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