Allopregnanolone, a neuroactive steroid derived from progesterone, is synthesized within the nervous tissue, by means of specific enzymes. Contrary to progesterone and its first metabolite dihydroprogesterone, allopregnanolone is able to interact with GABA-A receptor and not with the classical progesterone receptor. This suggests that the effect of progesterone administration may be due to activation of progesteronereceptor, or of GABA-A receptor, or both. However, this is rarely considered in the experimental studies. Here we summarize and discuss the hot topics involving the actions of allopregnanolone within the nervous tissue. One major role of this neuroactive steroid is neuroprotection in case of lesion, ischemia or peripheral neuropathies (i.e., diabetes). In addition, allopregnanolone may reduce the symptoms of neurodegenerative diseases (e.g., Alzheimer, Parkinson, Niemann-Pick type C, multiple sclerosis) in animal models and now translational studies are developed for its therapeutic use. Allopregnanolone may exert a beneficial effect also in case of neuropathic pain and it is also a potential candidate for the treatment of mood and anxiety disorders. Finally, this neuroactive steroid seems to have important physiological roles in the early differentiation of some neural circuits (in particular at hippocampal level), and to reduce stress during pregnancy. In conclusion, it appears that allopregnanolone is a key regulator of physiological functions and may have interesting therapeutic perspectives for neurodegenerative and psychiatric disorders.

Copyright © 2013 Elsevier Ltd. All rights reserved.

OBJECTIVES:

Progesterone has been reported to have a neuroprotective role in depression-like rats in a hemiparkinsonian model of the disease. In this work, we investigate if this hormone affects the three principal neurochemicals striatal systems (dopaminergic, glutamatergic, and GABAergic) that are involved in the physiopathology of the disease in a hemiparkinsonim male rat model at 8 weeks post-chemical injury.

METHODS:

For this purpose, we design three experimental groups: (1) sham group; (2) hemiparkinsonian group; and (3) hemiparkinsonian group subcutaneously injected with progesterone at 7 days post-chemical injury. Animals were tested in an automated rotational device at 8 weeks post-chemical injury. After behavioral test, K(+)-evoked [(3)H]-dopamine, [(3)H]-glutamate, and [(3)H]-gamma aminobutyric acid release from striatum slices were analyzed by superfusion experiments.

RESULTS:

The hemiparkinsonian group showed distinctive alterations that are produced by neurodegeneration of left nigrostriatal dopaminergic pathway by 6-hydroxydopamine hydrobromide (6-OHDA). On the other hand, the administration of progesterone 7 days after the injection of the neurotoxin was able to (1) improve the K(+)-evoked [(3)H]-dopamine release from the damaged striata (left); (2) avoid significant increase in the K(+)-evoked [(3)H]-glutamate release from the left striata; and (3) progesteronedoes not modify the K(+)-evoked [(3)H]-gamma aminobutyric acid release from the left striata.

DISCUSSION:

These results suggest that progesterone does have neuroprotective and neuromodulatory effects on striatal neurotransmission systems in the hemiparkinsonian male rats. The possible mechanisms would involve genomic and non-genomic actions of this neuroactive steroid which would modulate the activity of dopaminergic, glutamatergic, and GABAergic pathways.

Hemiparkinsonism induced by 6-hydroxydopamine (6-OHDA) injected in left corpus striatum is a recognized model of motor deficits in rats. Some reports concerning motor deficits indicate a favorable response to steroid administration in hemiparkinsonian animals. However, there is no much information regardingprogesterone administration in relation to cognitive and affective dysfunctions. Here we could confirm earlier reports regarding a mild deficit of memory and a noticeable depressive-like behavior 4 weeks after injecting 6-OHDA. We also present some evidence that progesterone could be – when administered 7 days after the injection of 6-OHDA – a possible neuroprotector concerning both motor deficits as well as cognitive – memory- and depression-like behaviors. The affective deficit was reverted by administering the tricyclic antidepressant imipramine. Since Parkinson‘s disease is a conspicuous cause of psycho-organic decline in human beings, it would be important to be able of dealing early with non-motor indicators in order to use prospective neuroprotectors to prevent the progression of the disease.

Copyright © 2011 Elsevier Inc. All rights reserved.

The sex difference in Parkinson‘s disease, with a higher susceptibility in men, suggests a modulatory effect of sex steroids in the brain. Numerous studies highlight that sex steroids have neuroprotective properties against various brain injuries. This paper reviews the protective effects of sex hormones, particularly estradiol, progesterone and androgens, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of Parkinson‘s disease as compared to methamphetamine toxicity. The molecular mechanisms underlying beneficial actions of sex steroids on the brain have been investigated showing steroid, dose, timing and duration specificities and presently focus is on the dopamine signaling pathways, the next frontier. Both genomic and non-genomic actions of estrogen converge to promote survival factors and show sex differences. Neuroprotection by estrogen involves activation of signaling molecules such as the phosphatidylinositol-3 kinase/Akt and the mitogen-activated protein kinase pathways. Interaction with growth factors, such as insulin-like growth factor 1, also contributes to protective actions of estrogen.

A higher prevalence and incidence of Parkinson disease (PD) is observed in men and beneficial motor effects of estrogens are observed in parkinsonian women. Lesion of the dopamine (DA) nigrostriatal pathway in animals with 1-methyl 4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) provides a model of PD and this is based on its use in humans as side-product of a drug abuse. Presently treatment of PD is mainly symptomatic. The MPTP mouse is used to study the neuroprotective roles of estrogenic drugs on the DA system. Estrogens, but not androgens, are active neuroprotectants as well as progesterone and dehydroepiandrosterone. An estrogen receptor agonist PPT and the selective estrogen receptor modulator raloxifene are also neuroprotective. Striatal DA neurons of estrogen receptor alpha knockout mice are more susceptible to MPTP toxicity than wild-type mice and neuroprotection by estradiol is associated with the activation of the PI3-K pathway involving Akt, GSK3beta, Bcl2 and BAD.

The objective of this experiment was to measure blood progesterone concentrations during early gestation to determine if the apparent reproductive failure in ewes bred out-of-season is due to a failure to conceive or embryonic loss. Blood samples were collected from spring- (n=61) and autumn-bred ewes (n=29) from Days 8 to 39 post-oestrus. Serum progesterone concentrations were analysed to ascertain whether ewes were ovulating and failing to maintain pregnancy, or conception was failing. Following pregnancy diagnosis 62 days after ram introduction, ewes were categorised as; no display of oestrus, mated but then identified as non-pregnant, or pregnant. A majority of spring-bred ewes that failed to display oestrus had silent oestrus (86%) and 66% of those ewes had abnormally short-lived corpora lutea. Circulating progesteroneconcentrations during dioestrus in ewes that had ovulated and displayed oestrus were unaffected by season. Similarly, progesterone concentrations during dioestrus did not differ between pregnant and mated non-pregnant ewes. The results indicated that while early luteylosis, low progesterone secretion from corpora lutea and embryo mortality did occur, these were in only a small proportion of ewes. Progesteroneconcentrations indicated that a majority of mated non-pregnant ewes had elevated progesteroneconcentrations necessary for the production of at least one viable embryo/foetus. This may be indicative to the failure of maternal recognition of pregnancy, and it is recommended that events surrounding this stage of pregnancy (Days 12-14) be examined more closely in ewes during the non-breeding season.

Eleven postmenopausal women with Parkinson disease and levodopa-induced peak-dose dyskinesias underwent a double-blind, placebo-controlled, crossover study. The active treatment consisted of estrogen replacement therapy for 12 weeks, followed by medroxyprogesterone acetate for 2 weeks. Estrogen replacement therapy-medroxyprogesterone acetate administration significantly improved peak-dose dyskinesia without worsening motor disability, thus suggesting a possible benefit on dyskinesias in postmenopausal women with Parkinson disease.

Neurosteroids are a group of steroid hormones synthesized by the brain in the presence of steroidogenic enzymes. Specific neurosteroids modulate function of several receptors, and also regulate growth of neurons, myelinization and synaptogenesis in the central nervous system. Some neurosteroids have been shown to display neuroprotective properties, which may have important implications for their potential use in the treatment of various neuropathologies such as: age-dependent dementia, stroke, epilepsy, spinal cord injury, Alzheimer’s disease (AD), Parkinson‘s disease (PD) and Niemann-Pick type C disease (NP-C). This paper focuses on neuroprotection afforded by neurosteroids.