Role of pregnenolone, dehydroepiandrosterone and their sulfate esters on learning and memory in cognitive aging

Brain Research Reviews 37 (2001) 301–312 www.elsevier.com / locate / bres

Review

Role of pregnenolone, dehydroepiandrosterone and their sulfate esters on learning and memory in cognitive aging ´ *, Willy Mayo, Michel Le Moal Monique Vallee ¨ , 33077 Bordeaux, Cedex, France Institut F. Magendie — INSERM U259, Domaine de Carreire, Rue Camille Saint Saens Accepted 25 July 2001

Abstract Aging is a general process of functional decline which involves in particular a decline of cognitive abilities. However, the severity of this decline differs from one subject to another and inter-individual differences have been reported in humans and animals. These differences are of great interest especially as concerns investigation of the neurobiological factors involved in cognitive aging. Intensive pharmacological studies suggest that neurosteroids, which are steroids synthesized in the brain in an independent manner from peripheral steroid sources, could be involved in learning and memory processes. This review summarizes data in animals and humans in favor of a role of neurosteroids in cognitive aging. Studies in animals demonstrated that the neurosteroids pregnenolone (PREG) and dehydroepiandrosterone (DHEA), as sulfate derivatives (PREGS and DHEAS, respectively), display memory-enhancing properties in aged rodents. Moreover, it was recently shown that memory performance was correlated with PREGS levels in the hippocampus of 24-month-old rats. Human studies, however, have reported contradictory results. First, improvement of learning and memory dysfunction was found after DHEA administration to individuals with low DHEAS levels, but other studies failed to detect significant cognitive effects after DHEA administration. Second, cognitive dysfunctions have been associated with low DHEAS levels, high DHEAS levels, or high DHEA levels; while in other studies, no relationship was found. As future research perspectives, we propose the use of new methods of quantification of neurosteroids as a useful tool for understanding their respective role in improving learning and memory impairments associated with normal aging and / or with pathological aging, such as Alzheimer’s disease.  2001 Published by Elsevier Science B.V. Theme: Disorders of the nervous system and aging Topic: Learning and memory: physiology Keywords: Neurosteroids; Learning; Memory; Aging; Rodent; Human.

Contents 1. Introduction ............................................................................................................................................................................................ 1.1. Learning and memory in cognitive aging .......................................................................................................................................... 1.2. Neuroactive steroids as potential factors underlying the individual’s age-related cognitive decline ........................................................ 1.3. Purpose .......................................................................................................................................................................................... 2. Animal studies ........................................................................................................................................................................................ 2.1. Behavioral tasks used to study cognitive aging in rodents................................................................................................................... 2.1.1. Spatial learning tasks ............................................................................................................................................................. 2.1.2. Conditioned learning tasks ..................................................................................................................................................... 2.2. Neurosteroids as pharmacological agents in studies of age-related cognitive deficits............................................................................. 2.2.1. Effects of the administration of neurosteroids in spatial learning tasks ....................................................................................... 2.2.2. Effects of the administration of neurosteroids in conditioned learning tasks................................................................................ 2.3. Neurosteroids as physiological agents in cognitive aging.................................................................................................................... 3. Human studies......................................................................................................................................................................................... *Corresponding author. Tel.: 133-5-5757-3660; fax: 133-5-5696-6893. ´ E-mail address: [email protected] (M. Vallee). 0165-0173 / 01 / $ – see front matter  2001 Published by Elsevier Science B.V. PII: S0165-0173( 01 )00135-7

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3.1. DHEA and DHEAS as biomarkers of healthy aging........................................................................................................................... 3.2. Association between DHEA or DHEAS plasma levels and cognitive performance ............................................................................... 3.2.1. Healthy elderly population ..................................................................................................................................................... 3.2.2. Residential care population..................................................................................................................................................... 3.2.3. Alzheimer’s disease patients ................................................................................................................................................... 3.3. Effects of DHEA treatment on cognitive performance........................................................................................................................ 3.4. Conclusion ..................................................................................................................................................................................... 4. Conclusions and future perspectives.......................................................................................................................................................... 4.1. Which neurosteroids for which behavioral effects? ............................................................................................................................ 4.2. Stable analogs of neurosteroids ........................................................................................................................................................ 4.3. New method of quantification of neurosteroid levels .......................................................................................................................... 4.4. Application to clinical studies .......................................................................................................................................................... References...................................................................................................................................................................................................

1. Introduction

1.1. Learning and memory in cognitive aging Human aging is a concern of our modern society due to its socioeconomical and medical consequences. Aging can be characterized as a general process of alterations of biological functions. The decline of neuronal abilities in particular involves a decline of cognitive and memory abilities. In humans, the age-related functional decline can evolve in neurological pathologies such as Alzheimer’s disease. A recent study in an elderly subjects population reported a prevalence of 16 and 4% of the subjects exhibiting cognitive deficits and dementia, respectively [36]. Moreover, the risk of dementia is known to increase with age. There is general agreement in the literature on cognitive aging that humans display memory losses with age, but that not all types of memory are affected equally [35]. One of the types of memory that show a greater age-related alteration is that of spatial information [22,60,77]. Agerelated deficits in spatial memory are not exclusively restricted to humans: aged rats often show impaired performance in spatial learning tests [3,20,34,82] and pathological changes can be detected in a number of selected neural regions involved in spatial memory performance [24]. However, learning and memory decline is not a common process for all the subjects. Intensive literature reported the existence of inter-individual differences in humans [52] and in animals as well [17,68]. For example, the spatial performance of aged rats shows a high variability: some rats display abilities similar to young ones, whereas others are severely impaired (see Fig. 1). The heterogeneity as to the severity of the age-related cognitive deficits is of great interest for investigating the neurobiological factors underlying cognitive function, especially the neurobiological processes at the origin of age-related cognitive decline (for review see [9]). Moreover, aged rats might serve as a useful model of human aging, especially of age-related memory dysfunctions [4,76]. Besides showing variability in age-related impairments of cognitive functioning, small rodents also possess

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other advantages for aging research: they have a relatively short lifespan (2–3 years) and their environment can be strictly controlled. Thus, the aged rat model has two main advantages. First, it can enhance our understanding of the underlying substrates and mechanisms, i.e. the brain–behavior relation (for example, the relation between steroids content in brain and learning and memory performance). Secondly, this model can be used to assess the effects of putative neuroprotective and / or cognition-enhancing compounds or treatments [1].

1.2. Neuroactive steroids as potential factors underlying the individual’ s age-related cognitive decline Steroids have been proposed as one of the neurobiological factors involved in age-related cognitive decline. Indeed, the observation that steroids alter with age and can

Fig. 1. Distance (m) traveled to find the hidden platform in the water maze task in 3-month-old and 23-month-old rats. Lower distances traveled indicate better spatial learning. The lines represent the median of each population.

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be involved in learning and memory processes has led to the hypothesis that varying concentrations of steroids may affect both physical and cognitive aging. For example, support for this hypothesis is provided by studies in humans and animals showing that plasma levels of cortisol or corticosterone, respectively, increase with age and are related to memory abilities in old subjects [42,51]. Accordingly, the maintaining of elevated or low plasma corticosterone levels throughout the life of rats, induced by early environmental manipulations, is related to poor and elevated memory performance, respectively, when the animals become old [82]. Moreover, it has been reported that concentrations of dehydroepiandrosterone in unsulfated (DHEA) or sulfated forms (DHEAS) in blood are markedly decreased with age in humans [65,66,86], especially in subjects diagnosed with Alzheimer’s disease [63,80]. Apart from being synthesized in adrenals, DHEA and DHEAS belong to the class of neurosteroids, which are both synthesized and accumulated in the nervous system to levels at least in part independent of peripheral steroidogenesis [6,18]. Neurosteroids, defined in this way, include mainly pregnenolone (PREG), dehydroepiandrosterone (DHEA), their sulfate derivatives, PREGS and DHEAS and progesterone (PROG), which is metabolized to 5a-dihydroprogesterone (5a-DH PROG) and 3a,5a-tetrahydroprogesterone (3a,5a-TH PROG), also named allopregnanolone. Distinct neurotransmitter-mediated effects have been reported, mainly through g-aminobutyric acidA (GABAA ) receptors, N-methyl-D-aspartate (NMDA)-type of glutamatergic receptors and sigma receptors [53,54,67,95]. According to their interactions with these brain neurotransmitters, PREG, DHEA and their sulfate derivatives are hypothesized to display excitatory cellular actions, while PROG and their metabolites 5a-DH PROG and 3a,5a-TH PROG have inhibitory cellular properties. As a consequence, neurosteroids have been hypothesized to exhibit a broad spectrum of biological actions, from interactions with development to complex processes such as learning and memory. Although there is abundant data describing memory-enhancing effects following administration of PREG, DHEA or their sulfate esters in adult male and female rodents [19,27–29,31,32,40,41,55,56,72], the physiological relevance of these effects is open to discussion for several reasons. First, the range of doses used in the pharmacological studies is varies greatly from one study to another. Second, a direct relationship between brain levels and performance has not yet been established. Finally, the effects of administration of steroids as regards cerebral concentrations have seldom been evaluated [15,74].

1.3. Purpose The present review summarizes animal and human studies concerned with the role of PREG, DHEA and their sulfate esters in relation to learning and memory in

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cognitive aging. Animal studies have mainly reported (1) the beneficial effects of PREGS and DHEAS upon agerelated memory deficit and (2) the direct relationship between the memory performance and PREGS concentrations in the hippocampus of old rodents. These data strongly suggest that PREG and DHEA, as sulfate derivatives, are partly involved in mediating the regulation of cognitive function, especially during aging. In humans, however, epidemiological studies reported divergent results concerning firstly the beneficial effect of DHEA replacement, and secondly the link between plasma DHEA and DHEAS content and cognitive performance. Finally, in the last section of this review we propose new methods of research in order to further explore the physiological action of neurosteroids in cognitive aging and to find potential therapeutics for the age-related cognitive deficits.

2. Animal studies

2.1. Behavioral tasks used to study cognitive aging in rodents Two major learning paradigms are commonly used in behavioral rodent studies. Spatial learning tasks are among the most frequently used tests for detecting potential cognition enhancers [57] and serve as valuable experimental paradigms for studying the cognitive changes that accompany aging [2,33]. Beside spatial learning paradigms, conditioned learning paradigms are also frequently used in rodents because of ease of control of the conditioned stimulus. Although a great number of tasks have been developed for these two paradigms, the tasks presented below are restricted to the main behavioral procedures used to examine the role of neurosteroids in cognitive aging.

2.1.1. Spatial learning tasks In the spatial learning tasks, the animal’s behavior can be driven either by an aversive stimulus where the goal is to find a refuge (platform in the water maze task), by an appetitive stimulus, or by spontaneous choice exploration (novel arm versus familiar arms in the Y-maze task). A variety of behaviors that cover different information processing are needed to characterize cognitive impairments in animal models of behavioral deficiency. The age-associated spatial deficit is usually seen in cross-sectional studies, in which the performance of naive young animals is compared with that of naive aged animals. However, as Ingram [39] pointed out, no distinction can be made between age and cohort differences when a cross-sectional approach is used. Therefore, it is better to investigate the effects of aging by using longitudinal design, where animals are tested at regular intervals throughout their entire lifespan. Longitudinal studies have

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shown that spatial learning performance is sometimes preserved in the aged animal, if the animal has acquired the task at a younger age. This beneficial effect of a previous experience has been shown for example in the water maze task [20,82]. In contrast, although the Y-maze task is sensitive to age-related decreases, this test is not influenced by previous experience and can be used to examine age-related cognitive deficits using longitudinal approaches [20,82].

2.1.2. Conditioned learning tasks Conditioned learning tasks can involve aversive or reinforcement learning. The animals avoid (do not enter or else leave quickly) a location where they previously received an aversive stimulus (footshock). An avoidance task can require either an active (moving) or passive (resting) position. Passive and active avoidance tasks measure memory of an aversive experience, through simple avoidance of a location in which the aversive experience occurred. When the aversive stimulus is made predictable (conditioned stimulus), the animal can actively respond (active avoidance). The learning performance is measured by the ability of the animal to avoid (in a passive or active way) the compartment where a shock has occurred during the training phase. In reinforcement paradigms, animals can learn an operant lever-press, e.g. to gain access to an appetitive stimulus (water or food). 2.2. Neurosteroids as pharmacological agents in studies of age-related cognitive deficits 2.2.1. Effects of the administration of neurosteroids in spatial learning tasks We investigated the effects of systemic PREGS administration in 24-month-old rats in a Y-maze arm discrimination task. Pretraining administration of PREGS (47.5 mg / kg, i.p.) was able to restore 6-h delay retention deficits in old rats and interestingly, this beneficial effect lasted for 10 days [83]. One study recently reported a lack of memory-enhancing effect of neurosteroids in old mice. Indeed, Shi et al. [78] found that DHEA (20 mg / kg, s.c.) did not affect the retention deficits observed in aged mice in the water maze task. The procedure used by the authors was not the procedure commonly used in this task, since the test consisted of six trials of training and one retention session performed 1, 2, 4 or 5 weeks later. Thus, the lack of effect of post-training injection of DHEA in improving the performance could be due to the long delay used between training and retention. Moreover, because DHEA was injected after training, no conclusion can be drawn regarding the effect of DHEA on the learning impairment usually observed in aged rodents in the water-maze task. The authors also tested the effect of 7-oxo-DHEA, an endogenous DHEA metabolite found in human urine and rabbit liver slices [30]. Given that 7-oxo-DHEA was able to

increase the retention performance at 1, 2 and 4 weeks delay, the authors suggested that 7-oxo-DHEA was more effective than its parent steroid DHEA in increasing memory performance in old mice.

2.2.2. Effects of the administration of neurosteroids in conditioned learning tasks The effects of the administration of DHEAS were first analyzed in a footshock active avoidance task in middleaged (18 months old) and old (24 months old) mice [26]. The injection immediately post-training of DHEAS (20 mg / kg, s.c.) improved, 1 week later, the retention performance in middle-aged and old mice up to the high level observed in 2-month-old mice. The ability of PREGS and DHEAS to modulate the age-induced learning impairment was also tested in 16month-old mice using the step-down type of passive avoidance [71]. Decreased step-down latency was observed in the passive avoidance task in 16-month-old mice compared to 3-month-old mice, revealing retention deficits in old mice. Pretraining injections of PREGS or DHEAS (1–20 mg / kg, s.c.) dose-dependently improved the 24 h delay retention performances in this task in old mice. The maximal effects were obtained with 5 mg / kg dose for PREGS and with 10 mg / kg dose for DHEAS. Together, the above data suggest learning- and memoryenhancing effects following the administration of PREG, DHEA and their sulfate esters in middle-aged and old rodents. 2.3. Neurosteroids as physiological agents in cognitive aging Given that the animal studies described in the previous sections used a pharmacological approach, the physiological relevance of such studies may be questioned [87]. To assess the role of endogenous neurosteroids in learning and memory processes, we measured PREGS levels in different brain areas in old rats previously tested for their learning and memory abilities [83,85]. We tested PREGS, since it was the most potent memory-enhancing neurosteroid described in pharmacological studies in adult rodents [27,28,70]. Rats (24-month-old) were tested in a Y-maze discrimination arm task and 1 week later in the spatial learning water-maze task. Then, the brain areas and blood samples were collected and PREGS concentrations were assessed using a radioimmunoassay technique. First, as expected, we observed a great variability within the learning performance in the water maze test in old rats. Moreover, the distance traveled to reach the hidden platform in the water maze correlated with the arm discrimination performance in the Y-maze (Spearman’s, r 520.67, P,0.001). These results suggested that the performance ability of the population of old rats was consistent in two spatial memory paradigms. On this basis, we were confident as concerns the appropriateness of

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studying the relationship between individual performance and PREGS levels. We first found that PREGS levels in the hippocampus were decreased and displayed a higher variability in 24-month-old rats compared to 2-month-old ones (see Fig. 2). Moreover, learning performance in the water maze was positively correlated with the concentrations of PREGS in the hippocampus (see Fig. 3). This correlation seemed to be specific of the hippocampus, since no correlation was found with PREGS levels either in other brain areas, such as the amygdala, frontal cortex, cortex and striatum, or in plasma. Moreover this brain area specificity was in favor of a role for PREGS in cognitive aging since the hippocampus is one of the cerebral areas selectively affected during aging and involved in mediating spatial learning and memory functions [21]. Overall, the above data are in support of a potential physiological role of hippocampal PREGS in the agerelated learning and memory alterations. Nevertheless, some drawbacks can be outlined from the previous correlation study. First, the correlation found does not necessarily entail a cause–effect relationship. We attempted to demonstrate this relationship by injecting PREGS in memorydeficient old rats. Fig. 4 shows that PREGS (5 ng / 0.5 ml) administered in the hippocampus immediately after training was able to restore the retention performance in a

Fig. 2. PREGS levels in the hippocampus of 3- and 24-month-old rats. Average PREGS concentrations were decreased but their variance was increased in old animals compared to young animals. The lines represent the median of each population.

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Fig. 3. Correlation between the levels of endogenous PREGS in the hippocampus and the learning performance in the water-maze task of individuals 24-month-old rats. PREGS concentrations are expressed in log (ng / g). The performance was assessed by measuring the distance to reach the hidden platform during the last 3 days of learning in the water maze. Animals that swam for the longest distance (thus exhibiting worse performance) had the lowest level of PREGS in the hippocampus [y 5 (27.0162.18) x 1 12.61].

Y-maze arm discrimination task at levels similar to those of young rats. The second drawback concerns the specific role of PREGS regarding the other neurosteroids. Indeed, the radioimmunoassay method only allowed measurement of PREGS in one biological sample, and did not allow measurement of the other memory-related neurosteroids,

Fig. 4. Bilateral injection of PREGS (5 ng / 0.5 ml) into the dorsal hippocampus restored memory-deficits of 22-month-old rats in the Ymaze discrimination arm task. The retention performance is expressed as the percentage of number of visits to the novel arm. The animals that were not previously able to discriminate between the novel and familiar arms of the maze could perform this discrimination after the injection of PREGS, while vehicle-treated animals still displayed impaired performance. **, P,0.01, compared to chance level. The dotted line expresses the level of equivalent exploration of the three arms (chance level, 33%).

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which might be physiologically involved in the regulation of learning and memory processes. To this end, the use of other methods of quantification of neurosteroids (as described in Section 4) could be helpful to determine the specific role of PREGS.

cross-sectional or longitudinal design are summarized in Table 1. The findings of these studies are contradictory (see for review [88]). Cognitive dysfunctions have been associated with low DHEAS levels [97], high DHEAS levels [61,62], or high DHEA levels [58,62]. In other studies, no relationship was found [5,10,13,14,47,59,62,69].

3. Human studies

3.1. DHEA and DHEAS as biomarkers of healthy aging Most of the studies concerning the role of neurosteroids in human learning and memory focused on DHEA and DHEAS, which are the neurosteroids found most abundantly in plasma and cerebrospinal fluid in humans [37,65]. These two neurosteroids appeared to be of great interest for elderly populations for two major reasons. The first is that circulating levels of these steroids decline progressively and markedly with age reaching levels at age 80 that are about 20% of those at age 20 [65,66,86]. Secondly, numerous animal studies have convincingly demonstrated the beneficial effect of DHEA and DHEAS in preventing age-related memory deficits. Collectively, these observations have led investigators to speculate that some of the degenerative changes associated with human aging may be related to a progressive deficit in circulating DHEA or DHEAS. The idea of DHEA as a possible ‘fountain of youth’ [7] was derived from these speculations. However, given that most of the experimental studies in animals have been conducted in rodents, which have little, if any, circulating DHEA, the extrapolation from animal models to humans is not immediately obvious. We describe here studies that investigated, first, whether DHEA and / or DHEAS levels in plasma are associated with cognitive performance and, second, whether DHEA and / or DHEAS administration can improve performance. These studies were conducted in different elderly populations, either healthy or in residential care, or in Alzheimer’s disease patients presenting cognitive deficits. Different aspects of cognitive performance have been assessed in human studies. In elderly populations, a neuropsychological test battery has mostly been used including visual memory (short- and long-term memory), verbal memory (immediate and delayed recall), spatial memory and attention / concentration test. In Alzheimer’s disease patients, the diagnosis was based on DSM-III or DSM-IV criteria of the American Psychiatric Association and cognitive performance was often assessed using the Mini-Mental State Examination test.

3.2. Association between DHEA or DHEAS plasma levels and cognitive performance Studies attempting to relate DHEA and DHEAS plasma levels and cognitive functioning in elderly humans in a

3.2.1. Healthy elderly population Prospective studies have measured DHEAS plasma levels and the risk of cognitive decline in the elderly but DHEAS levels, measured many years before the cognitive testing, were not associated with cognitive function [5]. Similarly, a 4-year longitudinal study in a population of elderly women (aged from 65 to 80 years) showed that change in cognitive performance over time was not associated with plasma DHEAS levels [96]. Moreover, a cross-sectional study and a longitudinal study over an 18-month period in healthy aged men and women (mean, 72 years) reported no association between plasma DHEAS levels and cognitive performance [13,14]. Moreover, a recent 12-year longitudinal study reported that decline in endogenous DHEAS concentration was independent of cognitive status and cognitive decline in healthy aging men [59]. Indeed, neither the rate of decline in serum DHEAS concentrations in men nor the mean DHEAS concentrations within individuals were related to memory status or memory decline. A comparison between the highest and lower DHEAS quartiles revealed no memory performance differences, despite the fact that these groups differed in endogenous DHEAS concentrations by more than a factor of 4 for a mean duration of 12 years [59]. A tendency towards an inverse association between plasma DHEAS levels and cognitive impairment and decline has also been reported in a 2-year prospective study in 189 healthy participants aged 55–80 years [44]. Overall, the studies described above suggest that plasma DHEAS levels are not associated with the memory performance of healthy elderly. 3.2.2. Residential care population In a frail elderly residential care population (aged from 78 to 95 years), Morrison et al. [62] found that DHEA and DHEAS plasma levels increased with the level of cognitive dysfunction in women, while no association was found in men. The finding in women corresponds to an unexpected inverse correlation between DHEA or DHEAS and cognitive impairment, which the authors believe could be due to the unusual population tested. These data confirm previous findings of Morrison’s group, showing that cognitive dysfunction in another sample of women residents from the same nursing home correlated with increased rather than decreased plasma DHEAS levels [61]. Another study conducted in men and women (91–104 years) in longterm-care facilities for the elderly reported, in contrast, no

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Table 1 Associations between plasma DHEA, DHEAS levels and cognitive performance in humans Population types

Study design

Main findings

References

Healthy elderly men and women

Prospective study (16-year delay)

DHEAS levels did not predict the cognitive change over time

Barret-Connor and Edelstein, [5]

Elderly women population (65–80 years)

Prospective study (4-year delay)

Baseline DHEAS levels were not associated with cognitive decline

Yaffe et al. [96]

Healthy men and women (72 years)

Cross sectional and longitudinal studies

DHEAS levels were not related to cognitive decline

Carlson and Sherwin, [13,14]

Healthy men (50–91 years)

12-year longitudinal study

Decline in DHEAS levels independent from cognitive decline

Moffat et al. [59]

Healthy men and women (67 years)

Cross sectional and prospective (2-year delay) studies

Inverse, but not significant, association between DHEAS and cognitive impairment

Kalmijn et al. [44]

Frail elderly residential care women (78–95 years)

Cross-sectional study

Inverse correlation between DHEA or DHEAS and cognitive impairment

Morrison et al. [61,62]

Old men and women (91–104 years) in long-stay facilities

Cross-sectional study

No association between DHEAS levels and cognitive performance

Ravaglia et al. [69]

Alzheimer’s patients

Cross-sectional study (comparison to ageand gender-comparable elderly control individuals)

Decrease in DHEAS levels, no change of DHEA level

Yanase et al. [97]

Decrease in DHEAS levels

¨ Nasman et al. [63]; Schneider et al. [75]; Sunderland et al. [80]; Leblhuber et al. [46]

3-year longitudinal study

Decrease in DHEAS levels

Hillen et al. [38]

6-month longitudinal study

DHEA levels did not predict cognitive impairment

Miller et al. [58]

Alzheimer’s patients (70–104 years) Alzheimer’s men and women patients (moderate cognitive impairments)

association between plasma DHEAS levels and cognitive testing scores in men or women [69].

3.3. Effects of DHEA treatment on cognitive performance

3.2.3. Alzheimer’ s disease patients It has been shown that plasma DHEAS levels in men and women patients (mean, 73 years) with Alzheimer’s disease exhibited a decrease of 54% in men and 50% in women, compared to age- and gender-comparable elderly control individuals [97]. However, no change was found in plasma DHEA levels. The decreased plasma DHEAS levels in Alzheimer’s disease patients was also found in several other studies [46,63,75,80], and has recently been confirmed in a 3-year longitudinal study (70–104 years) [38]. These findings suggest that low DHEAS plasma levels might be associated with the cognitive impairment observed in patients with Alzheimer’s disease. In contrast, a 6-month longitudinal study, conducted in men and women patients with Alzheimer’s disease and showing moderate cognitive impairment, unexpectedly found that lower plasma DHEA levels were associated with better memory performance at the beginning of the study [58]. However, the initial DHEA plasma levels did not predict decline in cognitive function over time.

Human studies have reported improvement of learning and memory dysfunction after DHEA administration to individuals with low DHEAS levels [12,94], but other studies failed to detect significant cognitive effects of DHEA administration [11,90–93]. Table 2 summarizes the findings concerning DHEA replacement studies in humans. A first single-case study reported that a 47-year-old woman showing a life-long history of specific learning disabilities and deficient circulating DHEA and DHEAS levels was able to recover from some memory dysfunctions following chronic DHEA treatment, which normalized the plasma levels of DHEA and DHEAS [12]. Similarly, a clinical trial in six depressed elderly patients with low DHEA levels reported an improvement in memory after subchronic DHEA treatment [94]. Studies carried out by Wolf’s group did not support the previous findings. Indeed, a single administration of DHEA (300 mg) in young healthy subjects (25 years old) had no effect on performance in several tests covering different aspects of memory, such as visual, verbal or declarative memory [90]. Moreover, 2 weeks of DHEA

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Table 2 Effects of DHEA treatment on cognitive performance in humans Population types

Study design

Main findings

References

47-year-old woman (long history of learning disabilities, low DHEA and DHEAS levels)

Single case study

Chronic DHEA treatment normalized DHEA and DHEAS levels and reverse some memory dysfunctions

Bonnet and Brown [12]

Elderly patients with low DHEA levels

Clinical trial (n56)

Chronic DHEA treatment improved memory

Wolkowitz et al. [94]

Single administration of DHEA (300 mg) had no effect on memory performance

Wolf et al. [90]

Young healthy subjects (25-year-old) Elderly healthy men and women (70-year-old)

2 weeks of DHEA substitution (50 mg / day) or placebo

No improvement of attention and declarative memory

Wolf et al. [91–93]

Old men and women (45–63 years) with midlife-onset dysthymia

Double-blind crossover treatment (3 weeks on 90 mg DHEA, 3 weeks on 450 mg DHEA, and 6 weeks on placebo)

No specific effect on cognitive performance

Bloch et al. [11]

substitution (50 mg / day) in healthy elderly men and women (mean age, 70 years) failed to improve cognitive abilities, such as attention and declarative memory [91– 93]. Similarly, a double-blind crossover treatment with DHEA did not specifically alter the cognitive performance in men and women aged 45–63 years with midlife-onset dysthymia [11]. In this study the treatment consisted of 3 weeks on 90 mg DHEA, 3 weeks on 450 mg DHEA or 6 weeks on placebo.

3.4. Conclusion Presently available human experimental studies regarding, first, the relationships between DHEA or DHEAS plasma levels and learning and memory abilities and, second, the effects of DHEA replacement on cognition have not led to a clear picture. Thus, human cross-sectional and longitudinal studies suggest that plasma DHEAS might be associated with global measures of well being and functioning; however, a consistent relationship with cognition has not been detected to date. The lack of relationship between the plasma levels of neurosteroids and cognitive function corroborates our findings in aged rodents [83,85]. These data could suggest a central action of neurosteroids synthesized in the brain, independent of the peripheral steroidogenesis. It has also been proposed that due to the wide interindividual variability of the DHEAS secretion changes, the determination of DHEAS levels might not be a sensitive predictor of cognitive performances of elderly subjects, whereas the evaluation of the cortisol:DHEAS ratio could shed more light on the neuroendocrine features of the subjects [23]. Second, given that non-beneficial effects of DHEA treatment have been reported, the hypothesis that positive long-term effects occur after DHEA replacement awaits future experimental demonstration [87,89]. This is in sharp

contrast to the media ‘hype’ concerning DHEA in certain countries. Thus, the therapeutic use of neurosteroids for cognitive dysfunctions is to date of uncertain value. Indeed, the beneficial effects of neurosteroids on cognitive functions have still to be demonstrated; moreover, the possible negative side effects of a long-term DHEA replacement have been poorly explored. Taking these facts into account there are expectations as concerns long-term experimental studies, such as the recent 1-year longitudinal study of Baulieu et al. [8], that should shed light on the role of neurosteroids in improving age-related neurodegenerative changes, such as learning and memory process alterations.

4. Conclusions and future perspectives

4.1. Which neurosteroids for which behavioral effects? Given that all neurosteroids are derived from PREG and given the existence of some reverse metabolic pathways (for example the reverse pathways between the non-sulfated and sulfated forms of PREG and DHEA), the possibility that several neurosteroids might contribute to the effect observed following the administration of a single neurosteroid could not be ruled out. In this regard, several studies suggest that the effect of PREG or PREGS could be attributed to its conversion to allopregnanolone (3a,5a-TH PROG). This suggestion emerged from observations that administration of PREG and / or PREGS induced an increase of 3a,5a-TH PROG levels, and that the inhibition of 3a,5a-TH PROG synthesis abolishes the memory-enhancing effects of PREG or PREGS. For example, the administration of PREGS (20 mg / kg. i.v.), which reversed the amnesia induced by the

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NMDA receptor antagonist dizolcipine in a passive avoidance test, increased the whole brain content of PREG by 50-fold and PROG, 5a-DH PROG and 3a,5a-TH PROG by 5–6 fold in adrenalectomized and castrated (Adx / CX) rats, i.e. without peripheral sources of steroids [15]. The increase of 5a-DH PROG and 3a,5a-TH PROG levels and the antagonism of dizolcipine amnesia observed after the injection of PREGS were reversed by inhibiting the conversion of PROG to 5a-DH PROG with the 5a-reductase blocker SKF 105111 [15]. Similarly, Romeo et al. [74] reported that PREGS administration (48 mmol / kg, i.p.) increased the whole brain content of PREGS by 10-fold, of PREG and 3a,5a-TH PROG by 7-fold and PROG by 2-fold. In the study of Cheney et al. [15], the administration of SKF 105111 eliminated the protective action of PREGS, but not 3a,5a-TH PROG, on the passive avoidance retention disruption elicited by dizolcipine. Together, these results suggest that PREGS prevents dizolcipine-induced memory deficit via an increase of brain 5a-DH PROG and / or 3a,5a-TH PROG content. However, given that PREGS and 3a,5a-TH PROG are negative and positive modulators of GABAA receptors, respectively, a common GABA-related memory-enhancing property is unexpected and suggests distinct mechanisms of action for the two neurosteroids. It has further been suggested that the sulfated form of DHEA might be the active agent for memory enhancement. This hypothesis was assumed when some authors reported that steroid sulfatase inhibitors could potentiate the memory-enhancing effect of DHEAS [25,43,48,49,73]. The two sulfatase inhibitors used, the estrone-3-O-sulfamate (EMATE) and ( p-O-sulfamoyl)-N-tetracanoyl tyramine (DU-14), blocked the conversion of DHEAS to DHEA, resulting in an increase of the endogenous levels of DHEAS in the blood and brain of rats and a decrease of DHEA levels [43,73]. The inhibitor EMATE has been shown to potentiate the enhancement of performance of mice induced by DHEAS, but not PREGS, in an active avoidance T-maze memory paradigm [25]. EMATE could also block by itself the scopolamine-induced amnesia in a passive avoidance task in rats [49]. However, given that EMATE has oestrogenic properties, the memory-enhancing effects observed could be mediated through oestrogenic effects. To control for the possible oestrogenic effects, the non-oestrogenic steroid sulfatase inhibitor DU14 has been used. It has been shown that DU-14 could reverse scopolamine-induced amnesia in a passive avoidance task in rats [49,73]. Similarly, DU-14 reversed the scopolamine-induced impairment and by itself increased performance in learning and spatial memory in the Morris water-maze in rats [43]. However, since no comparison between the effects of DHEA alone and DHEA1sulfate inhibitor has been examined, and since DHEAS displays dose-dependent memory-enhancing properties, the conclusion that the memory-enhancing effect of DHEA is due to its conversion into DHEAS needs further confirmation.

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4.2. Stable analogs of neurosteroids In addition to the use of steroidogenesis enzyme inhibitors, the synthesis of stable analogs of neurosteroids could be helpful to determine the relative effect of one neurosteroid versus its metabolites. For example, Chu et al. [16] synthesized the stable analog of DHEAS, 17-oxoandrosta-3,5-dien-3-methyl sulfonate, which is not metabolized in DHEA. Thus, this compound could be used to examine the specific effect of DHEAS versus DHEA on learning and memory processes. Accordingly, the stable analog of PREGS, such as its (2) enantiomer, has been synthesized by Covey’s group, and identical modulatory properties on GABAA receptors have been reported for both enantiomers [64].

4.3. New method of quantification of neurosteroid levels One of the best approaches to determine which neurosteroids are involved in learning and memory processes might be to study the relation between the memory-related steroid effect and the content of the entire spectrum of neurosteroids in brain areas involved in these processes. To this end, given that the commonly used radioimmunoassay method allows measurement of only one neurosteroid at a time, a new method of quantification of neurosteroids levels is needed. Several groups recently proposed new methods for the simultaneous quantification of traces of neurosteroids using a mass spectrometry technique [45,50,79,81,84]. Thus, these methods should allow exploration of variations of neurosteroid levels in specific brain areas during alterations of learning and memory processes, such as those which occur during aging.

4.4. Application to clinical studies Although clinical studies have not yet succeeded in finding a beneficial effect of DHEA replacement upon age-related memory impairments, neurosteroids may provide an alternative for clinically effective therapeutics for learning and memory impairments associated with normal aging and / or with pathological aging, such as Alzheimer’s disease.

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