Narcissus and Daffodil

Pharmacology of Narcissus compounds 341
Early work in animals
Galanthamine reversed the amnesia induced in mice by the injection of the anticholinergic
agent, scopolamine (Chaplygina and Ilyutchenok, 1976). The drug
was also shown to reverse the cholinergic deficit induced in rats by pre-treatment
with the neurotoxin ibotinic acid (Sweeney et al., 1988). In a notable series of
experiments, Sweeney and co-workers produced lesions in the nucleus basalis
magnocellularis of mice; this region is a major site of cholinergic enervation to the
fronto-parietal cortex, and lesions here produce significant deficits in choline
acetyltransferase activity which are linked to deficits in spatial memory. Intraperitoneal
administration of galanthamine attenuated these deficits (Sweeney et al.,
1989), and improved memory in swim tasks (Sweeney et al., 1988) and passive
avoidance tests (Sweeney et al., 1990); repeated doses remained effective, indicating
that tolerance to the drug did not develop. Control animals given sham lesions
showed impaired performance. At relatively high doses (1–4mg/kg) galanthamine
impaired the performance of control animals markedly, although an explanation
for this was not forthcoming (Sweeney et al., 1990).
Other workers confirmed some of this work: for example, Yonkov and
Georgiev (1990) showed that galanthamine enhanced the retention of learned
behaviour in both active and passive avoidance tests in rats. Chopin and Brierly
(1992) showed that galanthamine was capable of reversing scopolamine-induced
poor performance in a passive avoidance test in rats at very similar doses to
tacrine (0.3–10 mg/kg administered intraperitoneally), a measure of the effect on
memory. The doses used in these experiments were far in excess of those used in
man to treat AD. Fishkin et al. (1993) showed that intraperitoneal galanthamine
(1.25–5 mg/kg) significantly attenuated scopolamine-induced learning and memory
deficits in rats, compared to controls as measured by T maze and Morris
water maze experiments.
An interesting hypothesis, relevant to the pathophysiology of AD, is that in addition
to inhibition of acetylcholinesterase, inhibitors of this enzyme may activate
normal processing of the amyloid precursor protein which accumulates in the
disease producing amyloid plaques which are a striking feature of post-mortem
brain samples (Giacobini et al., 1996). Whether or not galanthamine provides such
neuroprotection is unknown, and definitive data will come only from long-term
trials in man, where biopsy or post-mortem samples are available for study.
Early work in man
Early reports from eastern Europe claimed that recovery of consciousness after
surgical anaesthesia was faster if galanthamine was used instead of neostigmine as
a curare antagonist (Paskov, 1986). The mechanism remains obscure; it might be
due to a direct central stimulant action or the ability to antagonise the action of
opiate analgesics. The results from a study in conscious volunteers indicate that
galanthamine may act as a mild central stimulant (Cozanitis and Toivakka, 1991).
Galanthamine crosses the blood-brain barrier readily, and because of this and
the in vitro data discussed above, it was soon proposed as a potential treatment for
brain diseases where cholinergic transmission appeared to be deficient – notably
AD. In this disease, destruction of cholinergic neurones in the brain, notably the