03 Feb Some Blood Pressure Medications May Be Protective Against Alzheimer’s Disease
MedicalResearch.com Interview with:
Dr. Juan M. Saavedra, MD and
Dr. Abdel Elkahloun PhD
Comparative genomics and Cancer Genetics Branch
National Human Genome Research Institute,
National Institutes of Health, Bethesda, MD
MedicalResearch: What is the background for this study? What are the main findings?
Response: Alzheimer’s disease is the most frequent age-related dementia, a progressing, devastating illness without effective treatment. By the time it is diagnosed, major and irreversible cell injury has already occurred. It is therefore imperative to identify therapeutic agents effective against early, pre-symptomatic injury mechanisms and risk factors increasing vulnerability the disease.
We focused on a class of compounds blocking receptors for Angiotensin II, the Angiotensin Receptor Blockers (ARBs). These compounds are commonly used for the treatment of hypertension, a major risk factor for Alzheimer’s disease.
We and others have found that in addition to their cardiovascular benefits, ARBs are strongly neuroprotective. The present study was designed to explore in depth the neuroprotective effects of one member of the ARB class, candesartan. To this effect we cultured neurons extracted from the rat brain. These neurons were exposed to high concentrations of glutamate, a recently identified early injury mechanism in Alzheimer’s disease. We found that candesartan prevented glutamate-induced neuronal injury.
We conducted in-depth examination of our results by genome-wide expression profile analysis. We found that candesartan normalized glutamate-induced alterations in expression of hundreds of genes, including many involved in neuronal inflammation, cardiovascular disease, diabetes and alterations in amyloid metabolism a hallmark for Alzheimer’s disease. This was evidence of direct neuroprotective effects of relevance for this disorder.
When we compared our results with published databases obtained from autopsy samples from Alzheimer’s disease patients, we found impressive correlations. The expression of more than 400 genes altered by glutamate and normalized by candesartan in our cultures was similarly changed in the Alzheimer’s databases.
The conclusion was that our cell culture results represented alterations found in the human condition. Our observations provide novel evidence of neuroprotection from early mechanisms of injury in Alzheimer’s disease and support testing candesartan in controlled clinical studies including individuals at the early stages of the illness, to unequivocally demonstrate their therapeutic effect.
MedicalResearch: What should clinicians and patients take away from your report?
Response: Our report demonstrates that a drug used for the treatment of cardiovascular and metabolic disorders is in addition strongly neuroprotective. The impressive association of gene expression normalized in our cultures by candesartan and hundreds of genes with similar alterations in the brain of Alzheimer’s patients strongly indicates that ARBs such as candesartan are excellent candidate therapeutics for this illness.
Patients may learn that there is hope for the treatment of Alzheimer’s disease. There are compounds available which may be useful to delay or even eventually prevent Alzheimer’s disease. It is essential to initiate definite clinical studies to firmly establish the therapeutic efficacy ARBs in the early or pre-clinical stages of the disease. This is a necessary step to request FDA approval to repurpose these compounds for the treatment of Alzheimer’s disease.
Considering the present evidence, it will be logical for clinicians to consider choosing ARBs for the treatment of conditions such as cardiovascular, renal and metabolic disorders which make patients very vulnerable to the disease. Clinicians may also help their Institutions, Government and private foundations to support long-term controlled clinical studies to demonstrate the efficacy of ARBs for the treatment of Alzheimer’s disease.
MedicalResearch: What recommendations do you have for future research as a result of this study?
Response: Retrospective studies suggest that, when hypertension is treated with ARBs instead of other unrelated anti-hypertensive medicines, the development of Alzheimer’s disease is substantially delayed. However, final convincing evidence requires long-term clinical controlled studies on subjects not yet experiencing signs of the disease. Such studies may include individuals at high risk of developing the disease, such as those carrying gene mutations making them vulnerable to the illness, patients at the initial stages of cardiovascular, renal and metabolic disease or exposed to traumatic brain injury.
Substantial efforts must continue to find validated biomarkers for Alzheimer’s disease. This would allow to identify individuals at risk many years before the disease is firmly established and impossible to treat.
MedicalResearch: Is there anything else you would like to add?
Response: Alzheimer’s disease does not start by sudden loss of cognition and brain function. The process begins many years earlier, with early and progressive cell injury. After many years of treatment failures, it is now clear that in order to prevent or delay the development of Alzheimer’s disease, treatments must start at the very early stages of the disease, preferably many years before the clinical diagnosis is reached, and must include young individuals with medical or genetic risk factors for the disease. There is hope that ARBs may represent a novel therapeutic approach to be first tested in these populations. Development of validated biomarkers may permit extending the clinical studies to the general population.
Citation:
Alzheimers Res Ther. 2016 Jan 28;8(1):5. doi: 10.1186/s13195-015-0167-5.
Elkahloun AG1, Hafko R2, Saavedra JM3,4.
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Dr. Juan M. Saavedra, MD and, Dr. Abdel Elkahloun PhD, & Dr. Kenneth L. Dretchen PHD (2016). Some Blood Pressure Medications May Be Protective Against Alzheimer’s Disease
Last Updated on February 3, 2016 by Marie Benz MD FAAD