Claudia Mattern

Revisiting the roles of progesterone and allopregnanolone in the nervous system: Resurgence of the progesterone receptors

Progesterone is commonly considered as a female reproductive hormone and is well-known for its role in pregnancy. It is less well appreciated that progesterone and its metabolite allopregnanolone are also male hormones, as they are produced in both sexes by the adrenal glands. In addition, they are synthesized within the nervous system. Progesterone and allopregnanolone are associated with adaptation to stress, and increased production of progesterone within the brain may be part of the response of neural cells to injury. Progesterone receptors (PR) are widely distributed throughout the brain, but their study has been mainly limited to the hypothalamus and reproductive functions, and the extra-hypothalamic receptors have been neglected. This lack of information about brain functions of PR is unexpected, as the protective and trophic effects of progesterone are much investigated, and as the therapeutic potential of progesterone as a neuroprotective and promyelinating agent is currently being assessed in clinical trials. The little attention devoted to the brain functions of PR may relate to the widely accepted assumption that non-reproductive actions of progesterone may be mainly mediated by allopregnanolone, which does not bind to PR, but acts as a potent positive modulator of γ-aminobutyric acid type A (GABA(A) receptors. The aim of this review is to critically discuss effects of progesterone on the nervous system via PR, and of allopregnanolone via its modulation of GABA(A) receptors, with main focus on the brain.

Progesterone Synthesis in the Nervous System: Implications for Myelination and Myelin Repair

Progesterone is well known as a female reproductive hormone and in particular for its role in uterine receptivity, implantation, and the maintenance of pregnancy. However, neuroendocrine research over the past decades has established that progesterone has multiple functions beyond reproduction. Within the nervous system, its neuromodulatory and neuroprotective effects are much studied. Although progesterone has been shown to also promote myelin repair, its influence and that of other steroids on myelination and remyelination is relatively neglected. Reasons for this are that hormonal influences are still not considered as a central problem by most myelin biologists, and that neuroendocrinologists are not sufficiently concerned with the importance of myelin in neuron functions and viability. The effects of progesterone in the nervous system involve a variety of signaling mechanisms. The identification of the classical intracellular progesterone receptors as therapeutic targets for myelin repair suggests new health benefits for synthetic progestins, specifically designed for contraceptive use and hormone replacement therapies. There are also major advantages to use natural progesterone in neuroprotective and myelin repair strategies, because progesterone is converted to biologically active metabolites in nervous tissues and interacts with multiple target proteins. The delivery of progesterone however represents a challenge because of its first-pass metabolism in digestive tract and liver. Recently, the intranasal route of progesterone administration has received attention for easy and efficient targeting of the brain. Progesterone in the brain is derived from the steroidogenic endocrine glands or from local synthesis by neural cells. Stimulating the formation of endogenous progesterone is currently explored as an alternative strategy for neuroprotection, axonal regeneration, and myelin repair.

Dopaminergic and serotonergic activity in neostriatum and nucleus accumbens enhanced by intranasal administration of testosterone

Testosterone was administered intranasally in anesthetized male rats, and its effects on the activity of dopaminergic and serotonergic neurons in the neostriatum and nucleus accumbens were assessed by means of microdialysis and HPLC. The treatment (0.5, 1.0 or 2.0 mg/kg of testosterone or vehicle, 10 microl volume) was applied in both nostrils, half (5 microl) into each. Subcutaneous injections of testosterone (2.0, 4.0 or 8.0 mg/kg) or vehicle were tested in other subjects. Samples were collected for 5 h. In the neostriatum, an increase of dopamine occurred after 2.0 mg/kg. Serotonin levels increased after 1.0 mg/kg dose. In the nucleus accumbens, dopamine and serotonin increased after 1.0 mg/kg and 2.0 mg/kg doses. Subcutaneous administration of 8.0 mg/kg testosterone increased dopamine and serotonin in the neostriatum only. We conclude that intranasal administration of testosterone is a more efficacious way for targeting the brain than the subcutaneous route, and may be considered as a means to activate central dopaminergic and serotonergic systems.

Progesterone receptors: a key for neuroprotection in experimental stroke.

Progesterone receptors (PR) are expressed throughout the brain. However, their functional significance remains understudied. Here we report a novel role of PR as crucial mediators of neuroprotection using a model of transient middle cerebral artery occlusion and PR knockout mice. Six hours after ischemia, we observed a rapid increase in progesterone and 5α-dihydroprogesterone, the endogenous PR ligands, a process that may be a part of the natural neuroprotective mechanisms. PR deficiency, and even haploinsufficiency, increases the susceptibility of the brain to stroke damage. Within a time window of 24 h, PR-dependent signaling of endogenous brain progesterone limits the extent of tissue damage and the impairment of motor functions. Longer-term improvement requires additional treatment with exogenous progesterone and is also PR dependent. The potent and selective PR agonist Nestorone is also effective. In contrast to progesterone, levels of the neurosteroid allopregnanolone, which modulates γ-aminobutyric acid type A receptors, did not increase after stroke, but its administration protected both wild-type and PR-deficient mice against ischemic damage. These results show that 1) PR are linked to signaling pathways that influence susceptibility to stroke, and 2) PR are direct key targets for both endogenous neuroprotection and for therapeutic strategies after stroke, and they suggest a novel indication for synthetic progestins already validated for contraception. Although allopregnanolone may not be an endogenous neuroprotective agent, its administration protects the brain against ischemic damage by signaling mechanisms not involving PR. Collectively, our data clarify the relative roles of PR and allopregnanolone in neuroprotection after stroke.

Intranasal Administration of the Dopaminergic Agonists l‐DOPA, Amphetamine, and Cocaine Increases Dopamine Activity in the Neostriatum: A Microdialysis Study in the Rat

Abstract: The effectiveness of intranasal drug administration to stimulate central neuronal systems is well known from drug addiction and has also been considered as an alternative pharmacokinetic approach to treat brain disorders such as Parkinsons disease. In the present study, the possible neurochemical effects of intranasal administration of the psychostimulants cocaine and amphetamine and of the antiparkinsonian drug l‐DOPA were analyzed. By using in vivo microdialysis in the urethane‐anesthetized rat, it was found that unilateral intranasal administration of either of the psychostimulants led to huge and rapid increases of extracellular dopamine levels in the neostriatum followed by decreases of its metabolites dihydroxyphenylacetic acid and homovanillic acid. Furthermore, intranasal administration of l‐DOPA, but not of the saline vehicle, also led to increased extracellular levels of neostriatal dopamine and to increases of its metabolites. Because the effect of intranasal l‐DOPA on neostriatal dopamine was observed only ipsilaterally but not contralaterally to the side of intranasal drug administration, it can be hypothesized that l‐DOPA was not effective via passage through the circulation but may have acted through a neuronal or an extraneuronal route. These data provide neurochemical evidence that the intranasal route may not only be efficient in drug abuse, but may also be useful to target the brain therapeutically, as in the case of neurodegenerative brain disorders.

Anxiolytic-like effect of combined extracts of Zingiber officinale and Ginkgo biloba in the elevated plus-maze

The effects of the known anxiolytic compound diazepam (DZ) on the behavior of rats in the elevated plus-maze were compared with those of zingicomb (ZC) (registered trademark of Mattern et Partner), a combination preparation of standardized extracts of Ginkgo biloba and Zingiber officinale. DZ was administered intraperitoneally (IP) in a reference dosage of 1 mg/kg 30 min before the rats were tested on the elevated plus-maze for 5 min. The treatment with DZ elevated the time spent on the open arms and excursions into the end of the open arms, increased scanning over the edge of an open arm, and decreased risk-assessment from an enclosed arm. ZC was administered intragastrically (IG) in four doses ranging between 0.5 and 100 mg/kg 60 min prior to plus-maze testing. The treatment with 0.5 mg/kg ZC elevated the time spent on the open arms and excursions into the end of the open arms; at the high dosage of 100 mg/kg, ZC led to fewer excursions to and less scanning of the open arms. Injection of 1 or 10 mg/kg ZC had no significant effect on the behavior in the maze. These data provide evidence that ZC has anxiolytic effects in the elevated plus-maze comparable to those of DZ, but that in high dosage the phytopharmacon may also have anxiogenic properties. The anxiolytic-like effects of ZC are discussed with regard to the known antiserotonergic action of ginger and Ginkgo biloba.

Increased neostriatal dopamine activity after intraperitoneal or intranasal administration of L-DOPA: on the role of benserazide pretreatment.

L‐DOPA provides the most potent medication to treat Parkinsons disease, and such systemic treatment is usually combined with a peripheral amino acid decarboxylase inhibitor to amplify its central effectiveness. Since L‐DOPA can lose its efficacy or can lead to adverse effects with prolonged application, current pharmacokinetic and dynamic research is aimed at improving the drugs applicability. In a previous study, performed with in vivo microdialysis in the anesthetized rat, we have shown that intranasal L‐DOPA administration (without prior decarboxylase inhibition) can increase extracellular dopamine levels in the neostriatum. Using similar experimental conditions in the present experiment, we tested the neurochemical effects of L‐DOPA treatment in combination with the peripheral amino acid decarboxylase inhibitor benserazide. In accordance with other data, it was found that the combination of i.p. benserazide and i.p. L‐DOPA led to pronounced increases of extracellular levels of dopamine, dihydroxyplenylacetic acid and homovanillic acid in the neostriatum, whereas i.p. L‐DOPA alone only moderately increased dopamine, but strongly increased the metabolite levels. Furthermore, increased dopamine levels, and weaker increases of dihydroxyplenylacetic acid and homovanillic acid were observed after i.p. benserazide followed by intranasal L‐DOPA. Finally, we found that i.p. benserazide alone can lead to pronounced increases in neostriatal dopamine and moderate increases of dihydroxyplenylacetic acid levels, whereas it did not affect homovanillic acid. Thus, not only the combination of L‐DOPA (i.p. or intranasal) with the presumed peripheral L‐DOPA decarboxylase inhibitor benserazide, but also each component alone can affect dopamine activity in the brain. Especially the findings with benserazide treatment might be of relevance for understanding the mechanisms of current L‐DOPA therapy, since they indicate that part of the treatments actions may possibly be determined by central dopaminergic effects of the accompanying amino acid decarboxylase inhibitor. Synapse 27:294–302, 1997.

Blockade of lithium chloride-induced conditioned place aversion as a test for antiemetic agents: Comparison of metoclopramide with combined extracts of Zingiber officinale and Ginkgo biloba

The present study tests the hypothesis that the blockade of lithium chloride-induced conditioned place aversion might be a suitable model to assess antiemetic properties of drugs, especially in species that do not vomit, like rats. The effects of the known antiemetic compound metoclopramide were compared with those of zingicomb, a combination preparation of extracts of Ginkgo biloba and Zingiber officinale, also presumed to have antiemetic properties. Place conditioning was performed using a conventional three-compartment test procedure. On three successive conditioning trials, rats received an intraperitoneal (i.p.) injection of lithium chloride (125 mg/kg) and were placed into the compartment that they had preferred over three baseline trials. During the test, rats treated with lithium chloride (LiCl) spent less time in the treatment compartment, indicative of a conditioned place aversion (CPA). In the first experiment, metoclopramide (MCP) was administered intragastrically (IG) in doses of 2 or 10 mg/kg 60 min prior to LiCl injection. The pretreatment with 50 and 100 mg/kg zingicomb attenuated the LiCl-produced CPA, whereas a dosage of 10 mg/kg had no effect. These findings suggest that LiCl-induced CPA is a viable procedure with which to assess the antiemetic properties of metoclopramide. Furthermore, the data confirm the hypothesis that the phytopharmacon zingicomb might have antiemetic properties that are comparable to those of metoclopramide.

Behavioral Actions of Intranasal Application of Dopamine: Effects on Forced Swimming, Elevated Plus-Maze and Open Field Parameters

Background: Recently, we found evidence that intra-nasally administered dopamine (DA), can enter the brain, leading to an immediate increase in extracellular DA levels in striatal subregions. This offers a potential alternative approach to target the brain with exogenous DA, which otherwise cannot cross the blood-brain barrier. Here, we examined whether intra-nasally applied DA also exerts behavioral activity on mesocortical and nigrostriatal dopaminergic functions. Method: Male Wistar rats (3–4 months) were tested for potential behavioral effects of intra-nasally applied DA (0.03, 0.3 or 3.0 mg/kg) in the forced swimming test (FST) for antidepressant-like activity, elevated plus-maze for anxiety-related behavior, and on motor activity in a novel and familiar environment. Results: Intra-nasally administered dopamine in a dose of 0.3 mg/kg exerted antidepressant-like activity in the FST, but had neither anxiolytic-like nor anxiogenic-like effects in the elevated plus-maze. Furthermore, intra-nasal dopamine stimulated locomotor activity in a familiar, but not novel, open field. Conclusions: These results support the view that intra-nasally applied DA can act on the central nervous system by entering the brain via the nose-brain pathway, making this kind of application procedure a promising alternative for targeting the brain, and thus treating disorders involving mesocortical and/or nigrostriatal dopaminergic disturbances.

Intranasal application of dopamine reduces activity and improves attention in Naples High Excitability rats that feature the mesocortical variant of ADHD.

Based on findings of a profound action of intranasally applied dopamine (DA) on dopamine release in the striatum, we examined the possibility that intranasal application of DA would influence indices of attention and activity in juvenile male rats of the Naples High Excitability line. This rat model features the main aspects of Attention Deficit/Hyperactivity Disorder (ADHD). Juvenile NHE rats received an intranasal application of either DA (0.075 mg/kg, 0.15 mg/kg and 0.3 mg/kg) or vehicle into both nostrils daily for 15 days. On day 14, 1 h after treatment, they were tested in the Làt maze, and one day later, in the eight arm radial maze. Activity in the Làt maze: The highest dose of DA (0.3 mg/kg) decreased horizontal (HA) and vertical (VA) activity during the first 10 min of the test. No effect was found for rearing duration (RD), which indexes non-selective attention (NSA). Activity in the radial maze: No treatment effects were found for HA and VA components, and for RD. Attention indices: The intermediate dose of DA (0.15 mg/kg) significantly improved the number of arms visited before the first repetitive arm entry in the radial maze, an index of selective spatial attention (SSA). In conclusion, intranasal application of DA reduced hyperactivity at the highest dose used, whereas the intermediate dose improved attention in an animal model of ADHD. These results suggest the potential of employing intranasal DA for therapeutic purposes.