By Silvia Petrova (See Member Profile)

Posted 5 December 2002

Abstract
There is a theoretical basis for thinking that the combination of nicotine with the cholinesterase inhibitor galantamine may have enhanced therapeutic effects in patients with Alzheimer's disease. One of the hallmarks of the AD brain is a reduced density of nicotinic receptors in specific brain regions. Scientific studies find that nicotine induces an upregulation of nAChR sites in human brains, including brains of AD patients. Nicotine has a neuroprotective effect against Ab deposition and increases the expression of high-affinity nerve growth factor (NGF). Experimental and preliminary clinical findings confirm that nicotine has cognitive and memory-enhancing effects. Rediscovery of galantamine ("the gift from the gods") and its therapeutic efficacy on cognitive impairment and mild and moderate forms of AD is accepted with great optimism. With its dual mode of action as a cholinesterase inhibitor and allosteric modulator of nAChRs, galantamine covers many aspects of cholinergic dysfunction and deficiency in these pathologic conditions.What can be expected if nicotine and galantamine are applied in combination, but consecutively? This review will describe the theoretical premise and discuss the hypothesis.

Age-related disorders such as Alzheimer's are going to be one of the biggest medical and social problems in civilized countries. According to the World Health Organization, around 35 million people in industrialized countries will suffer from Alzheimer's disease by 2010. The number of patients with AD in the U.S. is about four million, and the expenses for medication and social care are increasing drastically.

Treatment of AD is difficult, complex, and yet unresolved all over the world. Several groups of drugs are considered to be relatively effective. The only drugs labeled to date for the treatment of cognitive symptoms in patients with AD are cholinesterase inhibitors like tacrine, donepezil, rivastigmin and recently galantamine (Reminyl). Vitamin E, gingko biloba, selegeline, estrogens, a mixture of ergoloid mesylates and NSAIDs have also being studied.

In "Present and future of Alzheimer therapy," E. Jacobini of Switzerland suggests that the combination of cholinesterase inhibitors with estrogens, antioxidants, and antiinflammation drugs may represent a further improvement of current therapy. He emphasized that, from an economic perspective, treatment with cholinesterase inhibitors is not cost-neutral.¹

Nicotine is also being studied for its effect as a neurotransmitter enhancer. "Nicotine—long the whipping boy of doctors everywhere—may prove to be beneficial for people with Alzheimer's disease," said Canadian researcher Verner Knott of Royal Ottawa Hospital at the March 2001 Conference on Dementia organized by Toronto's Rotman Research Institute. A significant body of evidence exists on nicotine's positive effect on cognitive function. Of course, because of other known health risks, no one will recommend that people smoke in order to avoid AD, but, Knott said, "a drug that has properties like nicotine might be a way of looking at treatment."

In the past years, several studies were conducted on the application of nicotine patches or the use of nicotine-laced gum for treatment of AD. But the available literature contains no single study on the combination of nicotine and ChEIs (especially galantamine) for treatment of cognitive decline or AD.

The hypothesis that the combination of nicotine with galantamine may produce broader therapeutic effects on cognitive decline and AD patients will be discussed below:

Why nicotine plus galantamine? What can we expect? Consider these three main points:

1. The involvement of CNS neuronal nicotinic acetylcholine receptors in the pathological process of AD

2. Nicotine, its effect on nAChRs in brain and its therapeutic benefits for AD

3. Galantamine, a cholinesterase inhibitor with a dual mode of action as allosteric activator of nAChRs

1. Neuronal nicotinic receptors (nAChRs): Structure and function
Neuronal nAChRs are a family of ligand-gated ion channels that are widely distributed in human brain. They have a pentameric structure and consist of various complements of a2-a9 and b2-b4 subunits. Unlike their muscle counterparts, they occur not only in postsynaptic, but also in pre-, peri-, and extrasynaptic sites, where they may modulate neuronal function by a variety of actions.² In general, nAChRs consist of a large, hydrophilic amino-terminal domain; a compact hydrophobic domain; a small, highly variable hydrophilic domain; and a hydrophobic C-terminal domain of approximately 20 amino acids.

It is thought that the large hydrophilic domain containing the amino terminal contains phosphorylation sites and is exposed to the synaptic cleft, where it plays a role in ligand binding. The small hydrophilic domain exposed to the cytoplasm contains glycosylation sites, and the four hydrophobic domains comprise the transmembrane segments of the receptors, some of which line the ion channel.^3,4

Neuronal nAChRs contain ACh binding sites, which are thought to exist at the interface between the a- and b subunit, as well as allosteric binding sites. The latter are structurally distinct receptor sites that are insensitive to Ach, but are subject to modulation by a variety of compounds, including physostigmine, steroids, ethanol and Ca2+ ion channel blockers.

Several subtypes of allosteric binding sites exist: a) Noncompetitive allosteric activator site. Compounds that bind to this site are termed channel activators, as they enhance channel opening and ion conductance. They include cholinesterase inhibitors such as physostigmine, galantamine, etc. It is suggested that this class of receptor primarily functions to enhance nAChR activity induced by the binding of ACh at the classical site.⁵ b) Noncompetitive allosteric inhibitor site. Ligands binding here inhibit ion channel function and include chlorpromazine, ethanol, local anesthetics, barbiturates etc. Ethanol produces a dose-related decrease in nAChR number, and chronic ethanol treatment also partly attenuated nAChR upregulation produced by nicotine treatment of the cells. c) Steroid-binding sites. Steroids desensitize nAChRs and produce tolerance to nicotine d) Dihydropyridine site. e) Additional allosteric modulation of nicotinic receptors. Desensitization of the nAChR ion channel via phosphorylation by protein kinase A, protein kinase C, or tyrosine kinase.

It was established that the majority of high-affinity nAChRs in the brain are of the a4b2 subtypes and are found mostly in cortex, hippocampus, and thalamus. Marked reductions of high-affinity nACHRs, predominantly a4b2 subtype, have been observed in the brains of AD patients compared to age-matched controls.⁶ Neuronal nAChRs mediate the effect of nicotine and are involved in a number of functional processes including cognition, learning and memory, arousal, cerebral blood flow and metabolism, and a growing list of pathological conditions. NAChR activation modulates the release of a number of neurotransmitters such as ACh, dopamine (DA), GABA, and glutamate. There is evidence to suggest that nAChR activation (especially the a4b2 subtype) provides protection against b-amyloid neurotoxicity.^7,8 PET studies of AD patients revealed significantly reduced uptake of (¹¹C) nicotine in the frontal and temporal cortices in comparison to healthy, age-matched volunteers, and this observation confirmed earlier postmortem findings.⁹

Neuronal nAChRs are also potential therapeutic targets in a number of CNS disorders, and nicotine was observed to be beneficial in Parkinson's disease, Tourette's syndrome, and others.¹⁰ Despite the significant body of knowledge available about nAChRs, much remains to be elucidated.

2. Nicotine
Nicotine is a potent modulator of CNS function. Nicotinic receptors go against the generally accepted paradigm in that overexposure to agonists produces receptor downregulation, and overexposure to antagonist produces receptor upregulation. In particular, long-term exposure to nicotine results in an increased number of nAChRs in the brains of humans. Postmortem studies have revealed increased (3H) nicotine and (3H)ACh binding sites in the brains of smokers compared to nonsmokers, with a dose-dependent correlation observed between increased binding sites and the number of cigarettes smoked.¹¹ Furthermore, the number of binding sites observed in the brains of ex-smokers was lower than that of nonsmokers. Interestingly, the NIDA reported that nicotine receptor levels fell to normal in lifetime smokers who had quit at least two months prior to death, suggesting that nicotine produces changes in the brain that may be reversible with time.¹² A recent study of the effect of nicotine on the expression of nicotinic receptors in the brains of patients with AD showed significantly increased number of nAChRs, especially a4, in smoking AD (SAD) compared to nonsmoking AD (NSAD). This may be relevant to the neuroprotective effect of nicotine.¹³ In rats, subchronic treatment (0,45 mg/kg daily) with nicotine results in an increase in the number of high-affinity nAChR sites in the cortex.

Upregulation, desensitization, and the eventual inactivation of nAChRs appear to be dependent upon the nature of the agonist itself. a4b2 and a7 nAChRs are more sensitive to upregulation and desensitization than are other subtypes. Nicotine induces upregulation of nAChR sites, and the mechanism by which this happens is thought to involve reduced turnover of cell surface receptors as a result of posttranscriptional mechanisms.¹⁴ The desensitization of nAChRs is thought to involve phosphorylation of the receptor mediated by protein kinase A and protein kinase C. Nicotine can partially prevent the neurotoxicity of Ab in vivo and in vitro.¹⁵ One study showed that normal people who smoke have fewer amyloid plaques in their brain than do nonsmokers. There are clearly protective roles for nicotine; however, the mechanism is not fully understood.^13,16

High-affinity NGF receptor (TrkA) levels are decreased in AD brains as compared to age-matched control brains. Nicotine increases the expression of high-affinity nerve growth factor receptors both in vitro and in vivo. Rats with chronic indwelling intravenous catheters were continuously infused with nicotine to a total dose of 12 mg/kg over 24 hours. This treatment resulted in a 44 percent increase in TrkA receptor expression in the hippocampus. The increase in TrkA expression produced by nicotine was shown to be related to its cytoprotective actions. These results suggest that nicotine's neuroprotective actions might also be mediated through its interaction with central a7 nAChRs and a subsequent increase in TrkA receptor expression.¹⁷

A specific CNS effect of nicotine includes EEG desynchronization, increased cerebral blood flow, and increased cerebral glucose utilization through stimulation of nAChRs. In humans, nicotine increases arousal, visual attention, and perception. It improves the speed and accuracy of motor function, as well as performance in complex psychomotor tasks such as driving a car.¹⁸ Despite the complex effect elicited by nicotine, the exact role of brain nAChRs remains unclear. A significant body of evidence suggests that presynaptic nAChRs exist in cortical, hippocampal, and cerebellar brain regions. Nicotine interacts with a variety of presynaptic nAChRs to facilitate the release of a number of neurotransmitters, including ACh, DA, noradrenaline (NA), serotonin, GABA, and glutamate. Nicotine and nicotinic agonists have cognitive and memory-enhancing properties. Short-term nicotine treatment has been shown to improve working memory performance in rats. Long-term nicotine treatment has also been shown to improve memory in animal studies, surprisingly without development of tolerance.^19,20 Interestingly, improvement of memory persisted for up to two weeks after drug withdrawal, although the mechanism by which this effect could occur are unclear.²¹

Results of a small pilot study on learning and memory suggest that nicotine can improve cognition in some patients with AD. White and Levin studied a chronic nicotine effect in patients with mild to moderate AD by applying nicotine patches (Nicotrol) 16 hours a day for two four-week periods separated by a two-week washout period at the increasing doses of 5 mg./day for one week, 10 mg./day during weeks two and three, and 15 mg./day during week four. Nicotine significantly improved attentional performance as measured by the Conners'continuous performance test (CPT), but did not improve performance on other tests measuring motor and memory function. The small size of the study (eight patients) limited statistical power. It is suggested that higher doses of nicotine, other nicotinic ligands, or a combination treatment of nicotine with other therapies may be efficacious for producing broader therapeutic effects.²² Despite a large number of studies, the cognitive effects of nicotine on humans remain to be fully elucidated. Different means of administration, varying doses, and the participation of smoking and nonsmoking subjects in studies have resulted in difficulties in interpretation of results.

3. Galantamine
This is a specific, competitive, and reversible acetylcholinesterase inhibitor (AChEI) with a dual mode of action.

The history of galantamine use goes back at least 3,200 years. Some scholars believe that in the Greek epic, Odysseus used galantamine in the form of a snowdrops extract as an antidote to protect himself from the goddess Circe's mind-altering drugs. (Hermes shows Odysseus the nature of the medicine, which has "a black root, but milk-like flower. The gods call it holy and it is difficult for men to dig up.") Circe had used a potion believed to have been made from jimsonweed, which contains atropine, to induce amnesia and a delusional state in Odysseus's crew. With the help of galantamine, Odysseus was able to retrieve the lost memories of his crew and protect his own memory.^23,24

The first data on the anticholinesterase activity of galantamine were reported by Mashkovsky and Kruglikova-Lvova (1951), and Paskov (1957, 1958, 1959). Scientifically, galantamine was first isolated by Proskurnina and Yakovleva (1952) from Galanthus woronowi, family Amaryllidaceae.They determined its physicochemical characteristics and identified it as an alkaloid with a tertiary atom in its molecule.²⁵

Galantamine is a natural plant-derived product that has been used in Bulgaria for more than 40 years. In 1956 in Sofia, upon D. Paskov's suggestion, L. Ivanova extracted an alkaloid base from the leaves of the plant Galanthus nivalis L. In the form of hydrobromide salt, it is commercially available as a registered trademark of Sopharma AD under the trade name NIVALIN®. It is a plant preparation produced with original technology for extraction of the alkaloid galantamine from the bulbs of the plant snowdrops (Leucojum aestivum, family Amaryllidaceae). NIVALIN is offered in ampules containing 1.5, 2.5, 5 and 10 mg., and tablets of 5 and 10 mg. Clinical applications of NIVALIN include a wide spectrum of disorders ranging from pathology of the neuromuscular system, numerous diseases of peripheral and central nervous system including poliomyelitis, neuritis, polyneuritis and neuropathia, myasthenia, cerebral palsy, residual paresis following haemorrhagic stroke, enuresis nocturna, some forms of impotence, poisoning with morphine and analogues, etc.^25,26 Kilimov (1961) and Cechini (1966) observed a positive effect in patients with motor disorders due to brain vascular lesions. Daskalov and Atanassov (1980) found its positive effect in aphasia owing to cerebrovascular processes.²⁵ Recommended daily doses are 20-30 mg., while duration of therapeutic courses is 30-60 days, followed by medication-free intervals of four to six weeks.^25,27

Although in use for several thousand years, with about 50 years of scientific studies, galantamine has only recently been studied for its ability to alleviate Alzheimer's symptoms. The Austrian company Sanochemia Pharmazeutika AG, involved in the field of the active pharmaceutical ingredient (API) research for many years, was among the first to recognize the immense potential of galantamine. The group attempted to breed its own Caucasian snowdrops, but cultivation of the wild plant produced a dramatic loss of the active substance. By 1995, galantamine was approved by Austrian authorities as a treatment for Alzheimer's. Sanochemia succeeded in 1996 in chemically synthesizing galantamine when it obtained the first patent on the process, ensuring the group exclusive global rights until the year 2014 at the earliest.²⁸

In February 2001, the U.S. Food and Drug Administration (FDA) approved Reminyl® (galantamine hydrobromide) for the treatment of mild to moderate Alzheimer's disease. Developed by the Janssen Research Foundation, a wholly owned subsidary of Johnson &Johnson and under a codevelopment and licensing agreement with the UK-based Shire Pharmaceuticals Group plc., Reminyl has been approved in many other countries. The drug is available by prescription in 4-mg., 8-mg., or 12-mg. tablets. Global demand for this remarkable chemical—which can perhaps be compared with penicillin in terms of its impact—could rise sharply in the future.

What does galantamine do to improve the symptoms of AD patients? Gordon Wilcock has said that "to halt the disease, you have to stop the brain cells from being killed." Galantamine rescues brain cells from death. It was found that a few cholinesterase inhibitors, including galantamine, produce beneficial effects even after drug treatment has been terminated.²⁹ These effects assume modes of action other than mere esterase inhibition and are capable of inducing systemic changes. Allosterically potentiating ligands sensitize nicotinic receptors by increasing the probability of channel opening induced by acetylcholine and nicotinic agonists and by slowing down receptor desensitization.³⁰ Allosteric modulation of nAChR is a novel approach which circumvents the development of tolerance.

Allosteric modulators bind to a site on nAChR that is different from the binding site of ACh. This allosteric interaction amplifies the actions of ACh at post- and presynaptic nAChR. In particular, presynaptic nAChR are capable of modulating the release of ACh and other neurotransmitters, such as glutamate, serotonin, and GABA, which may contribute to symptoms of the illness. Allosteric modulation of nAChR could, therefore, produce significant therapeutic benefit in AD. As well as modulating nAChR, galantamine inhibits AchE. The extent to which the clinical benefits of galantamine are attributable specifically to its nicotinic effects is uncertain and requires further investigation. However, galantamine maintains the patients' level of cognitive and daily function for at least one year, a finding which has not been reported for other AChE inhibitors. Galantamine's modulatory effects on nAChR may influence transcriptional regulation, resulting in an increased synthesis of nAChR. This may account for galantamine's sustained efficacy.³¹ Data from placebo-controlled, double-blind clinical trials in the U.S. and Europe involving more than 2,650 patients with mild to moderate AD show that Reminyl (galantamine) was found to improve cognition and global function significantly.³² Similar results were observed in a Bulgarian study with NIVALIN.³³ Unlike with synthetic AchEIs such as tacrine, Reminyl side effects, primarily gastrointestinal, were minor and diminished over the months of the study. There was no evidence of liver toxicity.

If the studies are what they appear to be, galantamine is perhaps the best treatment yet discovered for age-related memory impairment, decline, and dementia progressing to Alzheimer's disease.

Conclusions
There is a theoretical basis for thinking that a combination of nicotine and the cholinesterase inhibitor galantamine may have an enhanced therapeutic effect on patients with cognitive decline or Alzheimer's. If one of the hallmarks of AD brains is reduction in density of nicotinic receptors in specific brain regions, then any effort to increase the number of nAChRs has to be considered an important step in therapeutic approaches. It is established that nicotine induces upregulation of nAChR sites in human brains, including brains of AD patients. Observations that nicotine is neuroprotective against b-amyloid deposition and increases the expression of high-affinity nerve growth factor magnify its therapeutic value. Experimental and preliminary clinical findings confirm that nicotine has cognitive and memory-enhancing effects. It can be supposed that some kind of periodical or cyclic way of application will be appropriate in order to obtain optimal therapeutic effect.

The rediscovery of galantamine is greeted with great optimism in scientific circles and makes it one of the best—if not the best—treatment yet discovered in this field. Galantamine, with its dual mode of action as cholinesterase inhibitor and allosteric modulator of nAChRs, covers many aspects of cholinergic dysfunction and deficiency in these pathologic conditions. It is supposed that galantamine's modulatory effects on nAChRs may influence transcriptional regulation that results in an increased synthesis of AChRs. But the extent to which the clinical benefits of galantamine may be attributable specifically to its nicotinic effects requires further investigation. Allosteric modulation of nAChRs is the novel approach that circumvents the development of tolerance.

What could be expected if nicotine and galantamine were applied in combination, but in a consecutive, periodical or cyclic way, similar to contraceptive hormones? At the beginning, application of nicotine (as patches, gums, vaporization, or maybe, in the future, tablets) for a three-to-four-week period is expected to increase the density of nAChRs. Consecutive application of galantamine for about 30-60 days (as applied in Bulgaria for more than 40 years) is expected to have an enhanced effect by its dual mode of action on the cholinergic system, and that effect will be facilitated by an increased number of AChERs, induced by nicotine. Consecutive application of both substances will avoid cumulative cholinergic side effects. Such a therapeutic cycle probably has to be repeated several times, and the necessity of medication-free intervals of four to six weeks between therapeutic courses may prove to be of interest.

Of course, all suggestions that a combination treatment of nicotine with galantamine may be efficacious for producing broader therapeutic effects in cognitive impairment and AD patients needs experimental and clinical approval. Any investments in such a project would be cost-effective and may reveal new horizons. Could nicotine advance from the current health nightmare of tobacco addiction to becoming an important new therapeutic in combination with the "gift from the gods," galantamine? The answer is for scientists to find.—Silvia Petrova , Psychiatrist, Sophia, Bulgaria.

Email: silmax@yahoo.com

Address:
Dr. Silvia Petrova
j.k Chr. Smirnenski bl 62- A,
Sofia 1574
Bulgaria

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