Drug Combo Slows Alzheimer's Memory Loss

Researchers have found that by combining the experimental memory-enhancing drug SGS742 with donepezil, a drug used to treat memory loss in Alzheimer's disease, it was possible to enhance memory in laboratory rats to a greater extent than was seen when either of the drugs was used separately.

Donepezil inhibits acetylcholinesterase, an enzyme responsible for the destruction of one neurotransmitter, acetylcholine. This leads to increased concentrations of acetylcholine in the brain, and the increased concentrations are believed to be responsible for the improvement seen during treatment. Donepezil improves the symptoms but does not slow down the progression of Alzheimer's disease. SGS742 is a GABA(B) receptor antagonist. It is an orally active drug and possesses neurochemical and psychopharmacologic features that suggest it could improve memory and cognition in humans.

Investigators at Johns Hopkins University (Baltimore, MD, USA) worked with 60 normal young male rats that were not memory-impaired. Each rat was given at various times SGS742, donepezil, a combination of the two drugs, or no drugs at all, and was tested on its skill navigating a series of mazes that placed increasing demands on its memory.

Results of the study published in the June 2005 issue of Neuropharmacology revealed that the drug combination allowed the animals to acquire and retain information more quickly and for a longer period of time than if they had not received this treatment.

At the molecular level it was found that rats treated with SGS742 expressed reduced amounts of CREB2 (cyclic-AMP response element binding). CREB proteins are transcription factors that bind to certain sequences called CRE elements in DNA and thereby increase or decrease the transcription of certain genes. CREB proteins in neurons have been shown to be involved in the formation of long-term memories

"The findings in laboratory animals--improved memory in our tests and evidence that SGS742 targets the biology for making memories in the brain--places this drug on solid footing as a candidate therapeutic agent,” said senior author, Dr. Michela Gallagher, professor of psychologic and brain sciences at Johns Hopkins University. "Memory impairment occurs early in Alzheimer's disease and worsens as the disease progresses. However, until the later stages of the disease, memory is impaired but not entirely gone. By augmenting the brain's memory-making ability, drugs could be used to treat this symptom and to improve the quality of life for patients who have a disease that has a slow progression over years.”



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