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Nicotinic modulation in
an animal model of a form of associative learning impaired in Alzheimer's
disease.
Woodruff-Pak DS, Santos IS.
Department of Psychology
Temple University,
Philadelphia, PA 19122, USA.
pak@astro.temple.edu
Abstract
Eyeblink classical conditioning is a widely used associative learning paradigm
that has striking behavioral and neurobiological parallels between humans and
other mammals. Eyeblink conditioning is impaired in older organisms, and
patients with Alzheimer's disease (AD) are impaired beyond the normal aging
deficit. The cholinergic system is of demonstrated involvement in eyeblink
conditioning. Blockade of nicotinic cholinergic receptors with mecamylamine
prolonged acquisition of conditioned responses (CRs) in young adult rabbits, and
the nicotinic agonist, GTS-21 ameliorated conditioning deficits in older
rabbits. Galantamine induces allosteric modulation of nicotinic cholinergic
receptors to increase acetylcholine release as well as acting as an
acetylcholinesterase inhibitor. Galantamine doses of 0.0, 1.0, 2.0, 3.0, and 4.0
mg/kg were tested in ten daily sessions in 40 retired breeder rabbits (mean age
= 29 months) in the 750 ms delay conditioning paradigm. A dose of 3 mg/kg
galantamine was effective in improving conditioning in older rabbits, enabling
them to achieve learning criterion rapidly and to produce a very high percentage
of CRs. Control tests of rabbits in explicitly unpaired conditions
demonstrated that non-associative factors could not account for the results. The
efficacy of galantamine in a learning paradigm that shows severe impairment in
AD indicates that the drug may be effective as a cognition-enhancer in AD.
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Allosteric sensitization of nicotinic receptors by galantamine,
a new treatment strategy for Alzheimer's disease.
Maelicke A, Samochocki M, Jostock R,
Fehrenbacher A, Ludwig J, Albuquerque E
Laboratory of Molecular Neurobiology,
Institute of Physiological Chemistry and
Pathobiochemistry,
Johannes-Gutenberg University Medical School, Mainz, Germany
Abstract
Cholinesterase inhibitors are the only approved drug
treatment for patients with mild to moderately severe Alzheimer's disease.
Interestingly, the clinical potency of these drugs does not correlate well with
their activity as cholinesterase inhibitors, nor is their action as short lived
as would be expected from purely symptomatic treatment. A few cholinesterase
inhibitors, including galantamine, produce beneficial effects even after drug
treatment has been terminated. These effects assume modes of action other than
mere esterase inhibition and are capable of inducing systemic changes. We have
recently discovered a mechanism that could account, at least in part, for the
above-mentioned unexpected properties of some cholinesterase inhibitors. We have
found that a subgroup of cholinesterase inhibitors, including galantamine but
excluding tacrine, directly interacts with nicotinic acetylcholine receptors.
These compounds, named 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. The allosterically potentiating ligand action, which is not
necessarily associated with cholinesterase inhibition, has been demonstrated by
whole-cell patch-clamp recordings to occur in natural murine and human neurons
and in murine and human cell lines expressing various subtypes of neuronal
nicotinic acetylcholine receptors.
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Articles
Galantamine boosts memory
Galantamine
rescues brain cells
Galantamine
and memory
enhancement
Galantamine
fights Alzheimer's
Galantamine
the old become young
www.AlzheimersTreatments.com
Research
abstracts
Galantamine:
its use in Alzheimer's
Galantamine:
in Alzheimer's patients
Galantamine:
acetylcholinesterase
inhibition
Galantamine:
therapeutic effects beyond cognition
Galantamine:
benefits to Alzheimer's patients
Galantamine:
modulation of nicotinic receptors in Alzheimer's
Galantamine:
a study in Alzheimer's
Galantamine:
its effects on Alzheimer's
Galantamine:
a new treatment for Alzheimer's
Galantamine:
effect on nicotinic receptor binding
Galantamine:
an allosterically potentiating ligant
Galantamine:
nicotinic modulation in older rabbits
Galantamine: effect on memory &
nicotinic receptors in rats
Galantamine:
a 6 month study
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