Dual action of galantamine in Alzheimer’s disease

PP De Deyn
Professor
Middelheim Hospital
University of Antwerp
Belgium

Alzheimer’s disease is a chronic, progressive illness accompanied by impaired neurotransmission in the brain. Decline in cognition and activities of daily life, distressing behavioural changes and alterations in personality are key symptoms of the disease.(1) As the proportion of elderly people increases, the burden of Alzheimer’s disease on individuals, families and society escalates.

So far, improving cholinergic neurotransmission using cholinesterase (ChE) inhibitors has produced the best evidence of clinical efficacy in Alzheimer’s disease.

Importance of the cholinergic system in Alzheimer’s disease
Central cholinergic pathways play a major role in cognition and memory, with the degeneration of these pathways viewed as central to the disease process.(2–7) Acetylcholine modulates both pre- and postsynaptic nicotinic acetylcholine receptors (nAChRs). nAChRs are ligand-gated ion channels composed of varied combinations of five membrane- spanning protein subunits. When ACh binds to a-subunits, it induces a conformational change in the ion channel proteins, causing the channel to open. This allows an ionic current (eg, K(+) and Ca(2+) ions) to flow into the cholinergic neurone, causing cell excitation.(8) nAChRs are thought to be particularly important in brain areas such as the hippocampus and neocortex, which are involved in memory and learning.(9–11) A large body of evidence supports a central role of nAChRs in Alzheimer’s disease (see Table 1).

[[HPE06_table1_85]]

Cholinergic strategies for treatment
The correlation of cholinergic deficits and cognitive impairment provides the rationale for targeted therapies that reduce symptoms and improve function in patients with Alzheimer’s disease via the enhancement of cholinergic function. Two potential strategies exist for enhancing cholinergic function:

1. Preventing the degradation of ACh by inhibiting AChE, the enzyme responsible for the breakdown of ACh in the synaptic cleft, results in increased availability of ACh. This partially offsets the reduction in cholinergic function caused by degeneration of cholinergic neurones. However, in the long run this agonistic stimulation could induce desensitisation of nAChRs, leading to tolerance and loss of efficacy.(27,28)

Because drugs acting solely as ChE inhibitors appear to delay the progression of the disease for a limited period of time, there is growing interest in drugs that act on additional targets. Drugs capable of slowing or halting neurodegenerative changes could provide more sustained therapeutic effects.

2. Allosteric modulation of nAChRs is a process whereby synaptic transmission is increased or decreased indirectly by a chemical mediator.(29) Similar to other neuroreceptors, nAChRs can be modulated via a second (allosteric) binding site, distinct from that of the agonist (see Figure 1).

[[HPE06_fig1_86]]

↓Article continues below this sponsored advert↓

Explore the latest advances in respiratory care at events delivered by renowned experts from CofE

AboutTickets

↑Advertisement↑

The allosteric modulator is not capable of activating nAChRs by itself. However, when the modulator and natural agonist bind simultaneously to their respective binding sites on the same receptor, the modulator helps the natural agonist to induce an electrical response. A modulator with such activity is called an allosterically potentiating ligand (APL).

Cholinergic and noncholinergic neurones are known to be subject to allosteric control via nAChRs.(29) APL binding makes nAChRs more sensitive to ACh, enhancing the response of nAChRs to available ACh and increasing the amount of ion flux across the cell membrane. In this way, APLs for nAChRs can enhance the neuronal response to ACh, even when ACh levels are decreased.

Compounds acting as APLs on nAChRs such as galantamine could therefore have the capacity to reduce the nicotinic cholinergic deficit in Alzheimer’s disease. The allosteric nature of galantamine’s effect on nAChRs has been confirmed by experiments with a monoclonal antibody (FK1) that competes with galantamine for the allosteric binding site of nAChRs.(8) In the presence of FK1 antibodies, the positive action of galantamine on nAChRs activity was blocked.(8,30)

Galantamine is the only cholinergic drug approved for the treatment of Alzheimer’s disease that has been proven to act as both a positive allosteric modulator of nAChRs and to have inhibitory activity for AChE (see Figure 2).

[[HPE06_fig2_86]]

Possible impact on other neurological symptoms and dementia types
Modulation of nAChRs by galantamine may improve the release of other neurotransmitters that play a role in emotional and behavioural disturbances.(14)

Trials are currently underway to determine whether the sustained, broad spectrum of efficacy that galantamine shows in Alzheimer’s disease extends to patients with other types of dementia, such as vascular dementia.(31)

Conclusion
Today’s practitioners will have to improve their awareness of possible Alzheimer’s disease in elderly patients. Since actual therapy is essentially symptomatic, early diagnosis is of great value for successful treatment. Also, the choice of drug could have an effect on the outcome. The unique dual mode of action of galantamine may have important clinical benefits in addition to those seen with conventional agents that simply inhibit ACh degradation.

References

1. Feldman H, Gracon S. Alzheimer’s disease: symptomatic drugs under development. In: Gauthier S, editor. Clinical diagnosis and management of Alzheimer’s disease. London: Martin Dunitz; 1996.
2. Bartus RT, Dean RL 3rd, Beer B, et al. Science 1982;217:408-14.
3. Whitehouse PJ, Price DL, Struble RG, et al. Science 1982;215:1237-9.
4. Davies P, Maloney AJ. Lancet 1976;2:1403.
5. Gallagher M, Colombo PJ. Curr Opin Neurobiol 1995;5:161-8.
6. Kasa P, Rakonczay Z, Gulya K. Prog Neurobiol 1997;52:511-35.
7. Schroder H, Giacobini E, Struble RG, et al. Neurobiol Aging 1991;12:259-62.
8. Albuquerque EX, Santos MD, Alkondon M, et al. Alzheimer Dis Assoc Disord 2001;15:S19-25.
9. Nordberg A, Alafuzoff I, Winblad B. J Neurosci Res 1992;31:103-11.
10. Nordberg A, Lundqvist H, Hartvig P, et al. Alzheimer Dis Assoc Disord 1995;9:21-7.
11. Perry E, Morris CM, Court JA, et al. Neuroscience 195;64:385-95.
12. Nordberg A, Winblad B. Neurosci Lett 1986;72:115-9.
13. Martin-Ruiz CM, Court JA, Molnar E, et al. J Neurochem 1999;73:1635-40.
14. Maelicke A. Dement Geriatr Cogn Disord 2000; 11 Suppl:11-8.
15. Paterson D, Nordberg A. Prog Neurobiol 2000;61:75-111.
16. Nordberg A. Behav Brain Res 1993;57:215-24.
17. Nordberg A. Rev Neurol (Paris) 1999;155 Suppl 4:S53-63.
18. Guan ZZ, Zhang X, Ravid R, et al. J Neurochem 2000;74:237-43.
19. Samochocki M, Zerlin M, Jostock R, et al. Acta Neurol Scand 2000;102 Suppl 176:68-73.
20. Marks MJ, Stitzel JA, Collins AC. Pharmacol Biochem Behav 1987;27:505-12.
21. Rowell PP, Winkler DL. J Neurochem 1984;43:1593-8.
22. Kerr JS, Sherwood N, Hindmarch I. Psychopharmacology (Berl) 1991;104:113-9.
23. Wilson AL, Langley LK, Monley J, et al. Pharmacol Biochem Behav 1995;51:509-14.
24. Sahakian BJ, Jones GMM. The effects of nicotine on attention, information processing, and working memory in patients with dementia of the Alzheimer type. In: Adlkofer F, Thruau K, editors. Effects of nicotine on biological systems. Basel: Birkhauser Verlag; 1991.
25. White HK, Levin ED. Psychopharmacology 1999;143:158-65.
26. Parks RW, Becker RE, Rippey RF, et al. Neuropsychol Rev 1996;6:61-79.
27. Wonnacott S, Marks MJ. Drug Discov Today 1999;4:490-2.
28. Maelicke A, Albuquerque EX. Drug Discov Today 1996;1:53-9.
29. Maelicke A, Schrattenholz A, Samochocki M, et al. Behav Brain Res 2000;113:199-206.
30.  Maelicke A, Samochocki M, Jostock R, et al. Biol Psychiatry 2001;49:279-88.
31. Maelicke A. Int J Clin Pract 2001;Suppl 120:24-8.