Women do not have to suffer memory loss with this combo …

Estradiol plus galantamine
improve memory

Reverses basal forebrain cholinergic function aging and menopause decline

By Will Block

I’m out of estrogen, and I have a gun.
— Bumpersticker

A s women age, estradiol loses its beneficial effects on cognitive performance, and especially following menopause, due to the progressive decline in basal forebrain cholinergic function. Estradiol (17β-estradiol) is a sex hormone. Compared to the two other estrogens, estrone and estriol, estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect. Estradiol, at high circulating levels, enhances learning and memory in many women, making it a clinical treatment for hormone-related cognitive decline in aging. However, estradiol supplementation is often not enough to overcome memory loss, because it becomes less effective with age.

Treating cognitive impairment

Consequently, in a recent study conducted at the University of Pittsburgh School of Pharmacy, researchers tested whether galantamine—an acetylcholinesterase inhibitor (AChEI) that enhances cholinergic function, and is used to treat memory impairment associated with Alzheimer’s disease—could enhance or restore estradiol effects on cognitive performance in aged rats that had their ovaries removed in middle-age.1 The specific reason for testing the use of galantamine is that basal forebrain cholinergic function declines with age and menopause. The reason for ovary removal in estrogen research is to destroy the endogenous (internal) production of estradiol’s rapidly cycling hormone production. It is then easier to account for the amount of estradiol in play by replacing it exogenously (using external sources). This is done subcutaneously.


Estradiol supplementation is
often not enough to overcome
memory loss, because it becomes
less effective with age.


The measurement of spatial learning in a memory maze

The ovariectomies took place in the rats at 16–17 months of age (the lifespan of the rats used is typically 30 – 36 months). At 21–22 months of age, the rats began receiving daily injections of galantamine (5 mg/day) or a non-active material. The dose of 5 mg/kg was selected based on studies by Geerts et al,2 suggesting that doses in the range of 1.5–5.0 mg/kg in rats produce optimal brain concentrations for the allosteric enhancing effect of galantamine that modulates nicotinic cholinergic receptors (nAChRs). Divided in half after one week, ½ of each group of rats also received estradiol, which was administered by silastic capsules injection beneath their skin.

Succeeding in the maze

Rats were then trained on a delayed-matching-to-position (DMP) T-maze task, followed by an operant stimulus discrimination/reversal learning task. The DMP task is a spatial learning and memory T-maze task. The T-maze consists of an approach alley and two goal arms. The walls of the maze and the doors are constructed of clear Plexiglas, thus allowing animals to view the surrounding room. Sliding doors are positioned midway down the approach alley and at the entrance to each goal arm.

Training and pellets

The rats were first adapted to the maze by placing them in the maze with food for 5 days. Starting on day 6–9, the animals were trained to run to the ends of the goal arms by using a series of forced choices and rewarded with four pellets. Right and left arms were alternated to avoid introducing a side bias. Next, animals began DMP testing, which was performed as 8 trial pairs per day.

The first trial of each pair consisted of a forced choice in which one arm was blocked, forcing the animal to enter the unblocked arm to receive the food reward. The animal was then returned to the approach alley for the second trial in which both goal arms were open.

Forced choices

A choice was defined as the animal placing both front legs and part of both rear legs into a goal arm. Returning to the same arm as the forced choice trial resulted in a food reward, while entering the incorrect arm resulted in no food reward and confinement for 10 seconds. Forced choices were randomized and balanced to avoid introducing a side bias. Animals were run in squads of 4 to 6. After each trial pair, the animal was returned to its home cage for 5–10 min while other animals were tested. Animals received 8 trial pairs per day until they reached the criterion of at least 15/16 correct choices over two consecutive days, or until they received 30 days of training altogether.

Confusing place and response strategies

After reaching criterion, animals received a probe trial during which the T-maze was rotated 180° (relative to extra maze cues) between the forced and open trial. This was done to assess whether rats were using a place strategy (relying on extra maze cues) or a response strategy (independent of extra maze cues). Rats using a place strategy would be impaired by maze rotation, whereas rats using a response strategy would be unaffected. For analysis purposes, rats were given a score of 1 if they entered the same goal arm during the open choice and a score of 0 if they entered the opposite arm. After the probe trial, animals received 8 trial pairs per day for 4 days with increased inter-trial delays (10, 30, 60, 90 seconds on each of the 4 consecutive days).

Enhancing the rate of special memory performance

Treatment with galantamine + estradiol significantly enhanced the rate of DMP acquisition and improved short-term delay-dependent spatial memory performance. Treatment with galantamine or estradiol alone was without significant effect. Effects were task-specific in that galantamine + estradiol treatment did not significantly improve performance on the stimulus discrimination/reversal learning task. In fact, estradiol was associated with a significant increase in incorrect responses on this task after reversal of the stimulus contingency. In addition, treatments did not significantly affect hippocampal choline acetyltransferase activity or acetylcholine release. This may be an effect of age, or possibly is related to compensatory changes associated with long-term AChEI treatment.


Treatment with galantamine or
estradiol alone was without
significant effect.


The data suggest that galantamine can restore the effects of estradiol on enhancing spatial memory by old rats following a long period of hormone deprivation. Thus, galantamine and estradiol could be of particular benefit to older women who have not used hormone therapy for many years and are beginning to show signs of mild cognitive impairment.

A growing conclusion

This is the third of a series of studies by the same researchers showing that combining estradiol treatment with a cholinesterase inhibitor used to treat Alzheimer’s disease can significantly enhance cognitive performance in aged rats and in young rats with partial loss of cholinergic neurons. Each study has progressed to a greater understanding. The data supports the researchers’ hypothesis that the beneficial effects of estradiol on cognitive performance diminish with age and time following loss of ovarian function due to deficits in basal forebrain cholinergic function. Furthermore, the results strongly suggest that beneficial effects can be enhanced or restored by combining estradiol with an appropriate cholinergic such as natural galantamine.


Thus, galantamine and estradiol could
be of particular benefit to
older women who have not used
hormone therapy for many years and
are beginning to show signs of
mild cognitive impairment.


Galantamine may offer added benefits compared to other cholinesterase inhibitors such as donepezil or rivastigmine due to its ability to act as an allosteric (binding with a molecule on a region other than its active site) enhancer at nAChRs. Galantamine also may have added benefit due to its short half-life and the ability to maintain diurnal (during the day) variations in cholinergic activity. Therapies for Alzheimer’s disease that augment the deteriorating cholinergic system are reasonably well tolerated and convenient, given once to several times a day. However, they oppose internal circadian cholinergic rhythms. Cholinergic inhibitors with durations of action longer than a day are at odds with the physiology of the cholinergic system, which is active during the day and quiescent at night. Sleep and the consolidation of daytime experiences into memory may be disturbed.

Even with the development of tolerance, substantial counter-regulatory increases in acetylcholinesterase (AChE) have been measured, and brain AChE inhibition is lower than predicted, which defeats the rationale of the AChEI. Because of galantamine’s short duration, it is thought to avoid disruption of natural cholinergic rhythms, and thus offer added benefit when used with estradiol. This is not the case with other AChEIs.

Estradiol and stress …

Recently, scientists at Kanazawa University, Japan, found that female rats that underwent ovariectomies (ovary removal) and had been harassed with chronic restraint stress lost hippocampal pyramidal cells and experienced cognitive dysfunction.3 However, estrogen replacement, along with Ginkgo biloba extract, prevented induced morphological and behavioral changes. In this study, to clarify the mechanisms underlying the ovarietomized/chronic stress-mediated memory impairment further, the researchers examined the roles of cholinergic systems in similarly-induced memory impairment in female mice.

The mice were randomly divided into two groups: ovarietomized and sham-operated groups. Two weeks after the operation, the mice of each group were further assigned to a chronic stress (6 hours/day) or a non-stress group. Following the 3-week-stress period, all mice were subjected to contextual fear conditioning, (e.g., inducing fear of the dark by electro-shock) and context- and tone-dependent memory tests were conducted 1 or 24 hours after the conditioning.

The ovariectomized/chronic stress mice were found to experience impaired context- and tone-dependent freezing along with the loss of neuron-like cells in the hippocampus, although neither ovary removal nor chronic stress alone caused such behavioral and histological changes.


Galantamine may offer
added benefits compared to
other cholinesterase inhibitors
such as donepezil or rivastigmine
due to its ability to act as
an allosteric enhancer at nAChRs.


Replacement of estradiol for 5 weeks after ovarectomy/chronic stress-induced memory impairment and hippocampal cell loss found that the mice exhibited a significant decrease in choline acetyltransferase in the hippocampus compared with those not receiving estradiol. But, when given the cholinesterase inhibitors donepezil or galantamine, induced memory impairment was reversed. These results suggest that cholinergic dysfunction is involved in ovarectomy/chronic stress-induced conditioned fear memory impairment.

Other supporting studies with rats and women

As early as 2006, Russian researchers found that the combined treatment with galantamine and estradiol on passive avoidance retention in middle-aged ovariectomized female rats could overcome sco­pol­a­mine-induced amnesia.4 Combined treatment with galantamine and estradiol completely restored retrieval of memory traces in middle-aged ovariectomized female rats.

Two years later, essentially the same Russian scientists, investigated the combined efficacy of galantamine and estradiol in low doses used for correcting cognitive disorders in women following total ovariectomies.5 The results showed a pronounced value for the combined therapy, compared to the standard hormonal replacement therapy in women with hypoestrogenic syndrome (the inability to produce enough estrogen). This was confirmed by a significant decrease in the expression of mental impairments found through the use of the mini-mental state exam (MMSE), the Brief Cognitive Rating Scale BCRS, and Cognitive Capacity Screening Examination (CCSE).

Estradiol and galantamine for women’s memory recovery

So if you are a post-menopausal woman suffering from mild cognitive impairment, especially if you once took estradiol, you might want to consider it again, along with galantamine. Please see your doctor and give her (or him) this article. Estradiol is available in a bioidentical form, usually through compounding pharmacies.

References

  1. Gibbs RB, Chipman AM, Hammond R, Nelson D. Galanthamine plus estradiol treatment enhances cognitive performance in aged ovariectomized rats. Horm Behav 2011 Nov;60(5):607-16.
  2. Geerts H, Guillaumat PO, Grantham C, Bode W, Anciaux K, Sachak S. Brain levels and acetylcholinesterase inhibition with galantamine and donepezil in rats, mice, and rabbits. Brain Res 2005;1033:186–93.
  3. Takuma K, Mizoguchi H, Funatsu Y, Hoshina Y, Himeno Y, Fukuzaki E, Kitahara Y, Arai S, Ibi D, Kamei H, Matsuda T, Koike K, Inoue M, Nagai T, Yamada K. Combination of chronic stress and ovariectomy causes conditioned fear memory deficits and hippocampal cholinergic neuronal loss in mice. Neuroscience 2012 Apr 5;207:261-73.
  4. Losev NA, Fedotova YO, Sapronov NS. Antiamnesic effect of combined treatment with galantamine and estradiol in middle-aged ovariectomized female rats. Bull Exp Biol Med 2006 Apr;141(4):427-9.
  5. Sapronov NS, Fedotova IuO, Masalova OO, Losev NA. Combined use of reminyl (galanthamine) and ovestin (oestradiol) for the treatment of cognitive disorders in women with hypoestrogenic syndrome Eksp Klin Farmakol 2008 May-Jun;71(3):36-9.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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