Alzheimer's disease, according to a new study.
"We hypothesize that candesartan, or other members of the ARB group, may not only slow progression of Alzheimer's but also prevent or delay its development."
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In laboratory neuronal cultures, an FDA-approved drug used to treat high blood pressure reduced cell damage often linked to Alzheimer's disease, say researchers at Georgetown University Medical Center (GUMC) and the National Institutes of Health.
What is Atacand?
Atacand (Candesartan) belongs to a class of drugs called angiotensin receptor blockers (ARBs). It works by relaxing blood vessels so blood can flow more easily. Candesartan keeps blood vessels from narrowing, which lowers blood pressure and improves blood flow.
Atacand is used to treat high blood pressure (hypertension).
Resarechers say their work, published online in the journal Alzheimer's Research and Therapy, provides information supporting the potential effect of the drug candesartan -- as well as other Angiotensin receptor blockers (ARBs) for the early treatment of Alzheimer's disease.
"Our findings make sense in many ways." Hypertension reduces blood flow throughout the body and brain and is a risk factor of Alzheimer's disease. Previous epidemiological studies found that Alzheimer's progression is delayed in hypertensive patients treated with ARBs," says senior author Juan M. Saavedra, MD, from GUMC's Department of Pharmacology and Physiology.Using neuronal cultures, the researchers explored the action of candesartan on the neurotoxic effects of exposure to excessive glutamate, a demonstrated injury factor in the early stages of Alzheimer's disease.
The scientists found that candesartan prevented glutamate-induced neuronal death. They conducted in-depth gene analyses of the laboratory results, demonstrating that candesartan prevented neuronal inflammation and many other pathological processes, including alterations in amyloid metabolism, a hallmark of Alzheimer's disease.
"The correlations were impressive -- the expression of 471 genes that were altered by excess glutamate in our cultures were also altered in brain autopsy samples from patients who suffered from Alzheimer's disease. Candesartan normalized expression of these genes in our cultures," Elkahloun says."We hypothesize that candesartan, or other members of the ARB group, may not only slow progression of Alzheimer's but also prevent or delay its development," Saavedra says.
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The researchers say this work has immediate translational value, supporting testing candesartan, or other ARBs, in controlled clinical studies on patients at early stages of Alzheimer's disease.
Candesartan prevented glutamate upregulation or downregulation of several hundred genes in cultures. Ingenuity pathway analysis and gene set enrichment analysis revealed that inflammation, cardiovascular disease and diabetes signal transduction pathways and amyloid β metabolism were major components of the neuronal response to glutamate excitotoxicity.
Further analysis showed associations of glutamate-induced changes in the expression of several hundred genes, normalized by candesartan, with similar alterations observed in hippocampus from Alzheimer’s disease patients. Gene analysis of neurons and cerebrovascular endothelial cells obtained by laser capture microdissection revealed that genes up- and downregulated by glutamate were preferentially expressed in endothelial cells and neurons, respectively.
Data may be interpreted as evidence of direct candesartan neuroprotection beyond its effects on blood pressure, revealing common and novel disease mechanisms that may underlie the in vitro gene alterations reported here and glutamate-induced cell injury in Alzheimer’s disease.
Observations provide novel evidence for candesartan neuroprotection through early molecular mechanisms of injury in Alzheimer’s disease, supporting testing this compound in controlled clinical studies in the early stages of the illness.
An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimer’s disease
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The work was supported by grants from the National Institutes of Health including the National Human Genome Research Institute (MD 20892) and the National Institute of Mental Health (MH 002762-16). The authors report having no personal financial interests related to the study.
About Georgetown University Medical Center
Georgetown University Medical Center is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health).