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NMDA-receptor antagonists havebeen tested therapeutically in strokebut failed to decrease the initialcalcium overload and the subsequentneuronal damage. In addition, themultiple side-effects of theseantagonists, possibly caused by theirinterference with normal synaptictransmission, limit their use. Gao andcolleagues present ASICs as animportant functional link betweenNMDA receptor-mediated toxicity andischaemic neuronal damage. Incultures of hippocampal neurons,

inhibitors of either NMDA receptor orCaMKII prevented activation of ASICsafter ischaemia and stopped cell death,demonstrating that ASICs could begood targets for the development ofnew neuroprotective drugs.

Both NMDA receptors and ASICshave been implicated in the neuraldamage caused by seizures and inpain modulation, where a similar co-functioning of the two channels mightalso take place. Krishtal explained toThe Lancet Neurology that a recentlydiscovered ion blocker, which inhibits

ASICs in sensory neurons, is showingpromising results in reducing post-operative and inflammatory pain.“Why not test this inhibitor in brainischaemia models?”, he comments. “Itis unfortunate that Zn2+, which blockssome ASICs in nanomolar concentra-tions, is neurotoxic. The moststraightforward way of testing therelevance of this hypothesis willdepend on the discovery of effectiveinhibitors.”

Elena Becker-Barroso

http://neurology.thelancet.com Vol 5 January 2006 27

Inhibiting the action of butyryl-cholinesterase in the brain raisescerebral acetylcholine concentrations,reduces amyloid � load, and improveslearning in rats, reports an internationalteam of scientists (Proc Natl Acad SciUSA 2005; 102: 17213–18). Thesefindings could translate into newtreatments for Alzheimer’s disease(AD).

AD is associated with a progressivedecline in the production of theneurotransmitter acetylcholine in theforebrain cholinergic neurons, and withthe eventual loss of these cells.Cholinergic treatments for the diseaseattempt to reduce the effects of theselosses by inhibiting acetyl-cholinesterase, the enzyme that breaksdown acetylcholine. “However,acetylcholinesterase production alsofalls in AD, and when this happensbutyrylcholinesterase may act as aback-up, continuing to break downacetylcholine”, explains Nigel Greig(National Institute on Aging,Baltimore, MD, USA). “Butyryl-cholinesterase is normally made in glialcells, but there is evidence that innormal brains it can step in when theregular acetylcholinesterase system isoverworked. If it also steps in whenacetylcholinesterase levels fall in AD—and we know its levels are higher in thebrains of AD patients—currenttreatments based largely on

acetylcholine esterase inhibition wouldbe sidestepped.”

Grieg’s group set out to establishthe effects of inhibiting butyryl-cholinesterase by producing specific,cymserine analogue inhibitors of theenzyme, which they injected into rats.“Inhibiting this enzyme led to verysignificant increases in cerebralacetylcholine levels compared withcontrols—in fact up to 300% at doseswell below the toxic level of the drug”,explains Greig. “We also saw significantimprovements in long-termpotentiation in the hippocampus,suggesting that the memory-formingsystem of these animals had beenstimulated. Although this relies onglutamatergic transmission, it’s alsotrue that cholinergic nerves enter thisarea and almost certainly have amodulatory effect on theseglutamatergic systems. Indeed, the ratsthat received the inhibitors learnedtheir way around mazes much morequickly.”

The researchers also showed that theinhibitors significantly reduced theformation of amyloid precursor proteinas well as the beta-amyloid A�40

and A�42 isoforms in humanneuroblastoma cells and transgenicmice respectively. “The brains of peoplewith AD always show a positive relationbetween the butyrylcholinesteraselevel and A� plaque load”, explains

Greig. “This also ties in with the resultswe obtained on hippocampal long-term potentiation since there is someevidence to suggest that soluble A�oligomers inhibit this.”

“It’s interesting that these inhibitorsare quickly cleared from the plasma andenter the brain”, remarks AdolfoToledano (Ramón y Cajal Institute,Madrid, Spain). “This suggests theycould have fewer systemic side-effectsthan acetylcholine inhibitors. It wouldbe interesting to see the effects of long-term administration of these drugs inanimals expressing human A� and incholinergic-impaired nucleus basalis ofMeynert models.”

Adrian Burton

Inhibition of butyrylcholinesterase could ease AD

Phenethylcymserine in its butyrylcholinesterase binding site

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