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.
Highlights
Parkinson’s disease (PD), a neurodegenerative disorder originally described in 1817 [1], affects more than 1% of the population above 55 years old, and prevalence increases to 3.1% between 75 and 84 years old [2]
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
Since allopregnanolone is known as a GABAA modulator, we examined the action of GABAA antagonist bicuculline
Summary
Parkinson’s disease (PD), a neurodegenerative disorder originally described in 1817 [1], affects more than 1% of the population above 55 years old, and prevalence increases to 3.1% between 75 and 84 years old [2]. We have previously demonstrated that the neuroactive steroids progesterone and ALLO modulate striatal dopaminergic activity of rats under different gonadal hormonal conditions [19, 20] and that systemic administration of progesterone to hemiparkinsonian rats prevents depressionlike behavior [21]. These beneficial premotor effects led us to inquire whether or not the neuroprotective effects of progesterone and/or its metabolite ALLO on premotor conditions could be extended to motor manifestations in a model of hemiparkinsonism in rats. By using such a model of hemiparkinsonism in male rats, our objectives were to study (1) the effect of progesterone on turning behavior; (2) the potential actions of progesterone on expression and activity of nigrostriatal 3α-HSOR; (3) the eventual modulatory effect of intrastriatal-administered ALLO on turning behavior; and (4) the existence of some evidence regarding GABAergic transmission involvement since ALLO is a potent GABAA modulatory neurosteroid
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