Current and future treatments of memory complaints and Alzheimer'a[euro][TM]s disease

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Date: Sept. 2011
From: Therapy(Vol. 8, Issue 5)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 7,982 words
Lexile Measure: 1120L

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Author(s): William K Summers 1

KEYWORDS

:

Alzheimer'âs; amyloid; cerebral hypoperfusion; neurodegeneration; neuronal atrophy; oxidative stress; tau protein

In the early 1980s, my colleagues and I developed tacrine as the first pragmatic treatment for Alzheimer'âs disease (AD) [1] . Tacrine was synthesized by Adrian Albert as part of the Australian World War II effort to find an intravenous antiseptic [2] . Use of tacrine to treat AD was unanticipated by the scientific community and there was considerable controversy [3-5] . Yet 7 years later, in 1993, tacrine (Cognex® ) was the first US FDA-approved treatment for AD.

The theory behind tacrine was the cholinergic hypothesis [6] . According to this theory, drugs that enhanced cholinergic neuronal function would improve memory. This might be by cholinesterase inhibition (CI), stimulation of the nicotinic receptor or enhancement of acetylcholine production.

The intent of tacrine was to assist failing cholinergic neurons. Symptomatic treatment. Prevention or reversal of the disease process was never intended with CI therapy. It was understood that the deficits of the cholinergic system seen in AD were the result of the disease, not the cause.

Current therapies

* Pharmacotherapies

At present there are three other cholinesterase inhibitors - donepezil (Aricept® ), rivastigmine (Exelon® ) and galantamine (Reminyl® ) [6] . The latter has nicotinic receptor agonist effects. Benefits of CI for each patient results from the potency and dose of the pharmaceutical agent, and the severity of the cholinergic deficit, and the ability of the cholinergic system to respond to stimuli. In end-stage AD, when the cholinergic system is largely destroyed, these agents have little value. A defective cholinergic neuron can be stimulated to work more efficiently, but a dead neuron cannot.

Memantine (Namenda) is the first in a novel class of AD medications acting on the glutamatergic system by reversibly blocking NMDA glutamate receptors [101] . The NMDA receptor (NMDAR), a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function [7] . Calcium flux through NMDARs is thought to play a critical role in synaptic plasticity, a cellular mechanism for learning and memory. At normal levels, glutamate aids in memory and learning, but if levels are too high, glutamate appears to overstimulate nerve cells, triggering the signal for apoptosis, hence killing key brain cells [8] . The common wisdom is that memantine helps Alzheimer'âs patients by downmodulation of calcium influx, thus enabling more efficient memory plasticity.

If AD is a progressive disease characterized by the diffuse death of neurons, it seems probable that memantine'âs benefit may also be due to blocking both caspase-dependent and/or capsase-independent apoptosis [9,10] . By preserving AD neurons and permitting repair and recovery, memantine may actually be a disease-modifying agent. In what may prove to be flawed work, the first meta-analysis of memantine'âs value in mild Alzheimer'âs did not show promise [11] . The study examined a battery of memory tests over a short period of time, not progression of the illness over years.

* Available current alternatives

Memory calisthenics became quite popular in the early 2000s in both academia and alternative medicine [12] . This was not...

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Gale Document Number: GALE|A268609821