Cognitive enhancement
therapy for Alzheimer's disease. The way forward.
Parnetti L, Senin U, Mecocci P.
Perugia University, Italy.
parnetti@unipg.it
Drugs 1997 May;53(5):752-68
ABSTRACT
Although at present there is no
definitive treatment or cure for Alzheimer's disease, different
pharmacological strategies are being actively investigated. At present,
cholinergic therapy and nootropics and some neuronotrophic agents represent
the available approaches to symptomatic treatment of Alzheimer's disease.
The
use of cholinesterase inhibitors (ChEI) constitutes the best cholinergic
approach to increase acetylcholine levels. Available data suggest that about
15 to 40% of Alzheimer's disease patients show a varying degree of cognitive
improvement while taking these medications; however, haematological
complications (neutropenia or agranulocytosis), together with hepatotoxicity,
need to be considered carefully. Recent data suggest that long term
administration of nootropics may lead to a significant improvement of
cognitive functions in Alzheimer's disease patients compared with untreated
individuals, having excellent tolerability. Protocols for the
intracerebroventricular administration of neuronotrophic substances are also
ongoing. The most promising approaches for the future currently undergoing
investigation involve attempts to slow the production of beta-amyloid and/or
to inhibit beta-amyloid aggregation. Another rational therapeutic approach
would be to inhibit the formation of paired helical filaments (PHF) by
increasing and/or modulating the activities of protein phosphatases and
kinases. Antioxidant therapy should disrupt or prevent the free radical/beta-amyloid
recirculating cascade and the progressive neurodegeneration. Idebenone, a
synthetic compound acting as an 'electron trapper' and free radical scavenger,
has shown some efficacy in degenerative and vascular dementia; at present,
other different molecules having antioxidative properties [lazaroids
(21-aminosteroids), pyrrolopyrimidines, nitric oxide blockers, selegiline,
some vitamins] are under investigation. Lowering absorption or brain tissue
concentrations of aluminium also offers possible therapeutic opportunities for
slowing the rate of clinical progression of the disease; in this sense, some
evidence exists using the aluminium chelating agent deferoxamine (desferrioxamine).
Inflammation also may play a significant pathogenetic role in Alzheimer's
disease. As shown by several retrospective analyses, there is an inverse
association of anti-inflammatory drug use with the frequency of Alzheimer's
disease diagnosis. Consequently, clinical trials using both nonsteroidal and
steroidal molecules have been proposed. These lines of pharmacological
intervention represent an important premise for future therapeutic strategies
capable of counteracting the pathogenesis of Alzheimer's disease.
