A new study raises hope for prevention of Alzheimer's disease by the sexual enhancer sildenafil
The role of blood supply in the aging brain and in neuronal degeneration has often been underestimated. We know that circulatory disturbances significantly correlate with the development of memory deficits. Mild cognitive deficit is most often caused by inadequate blood flow to brain tissue.
As described in my book 'Parkinson's and Alzheimer's Today', blood supply to the more than 80 billion neurons in the brain is provided by a 650 km network of blood vessels. Not surprisingly, the capillary system of the central nervous system is very prominent, since one-fifth of the energy we take in is consumed here.
The changes in the vascular walls known as arteriosclerosis lead to reduced blood flow and are often detected in Alzheimer's patients long before the cognitive impairment sets in. Blood vessels in brain are normally dilated by a gaseous neuromodulator released from synapses which is nitric oxide (NO) produced by neuronal NO synthase (nNOS). It rapidly diffuses into the pericytes surrounding capillaries, causing them to relax and allowing the capillaries to dilate, thus improving blood supply (as shown in the following figure).
Neurons and glial cells (especially astrocytes) are in close contact with blood vessels and together form the so-called neurovascular unit. Astrocyte processes lie close together around the small blood vessels and capillaries, with the cerebrospinal fluid flowing between them (the processes are only indicated here for the sake of clarity). The perivascular area delimited by astrocytes is also called the glymphatic space (in reference to the glia and lymph in the body; however, there is no lymph in the brain). Thus, an active exchange of substances takes place between astrocytes and neurons involving the blood vessels. The microglia, which are comparable to the monocytes in the blood, release inflammatory mediators (cytokines) in old age. They play an important role in Alzheimer's disease pathogenesis. In addition, the pericytes sitting on the vessel wall are important because the NO released from synaptic contacts leads to their relaxation and dilation of the vessels, particularly in the area of activated neurons (Fig. 2.4 from Klimaschewski L.P. Aging and neurodegenerative diseases - why are neurons lost? In: Parkinson and Alzheimer today. Springer, 2021)
A team led by Jiansong Fang of the Lerner Research Institute of the Cleveland Clinic in Ohio (USA) has now published a study in which 1,600 already approved drugs were tested to determine whether they are effective against Alzheimer's dementia. Taking into account age, gender, and co-morbidities (i.e. other diseases such as high blood pressure, diabetes, or arteriosclerosis), they made a surprising discovery: the Viagra active ingredient sildenafil, which is taken to treat pulmonary hypertension and potency disorders, reduces the risk of Alzheimer's dementia by about 70 percent (the study was based on the health data of seven million people).
In the journal "Nature Aging," the researchers further report that sildenafil can also directly promote the growth of neurons derived from stem cells of Alzheimer's patients. It also reduces the amount of disease-associated tau proteins, especially in its phosphorylated form. The data remain to be confirmed in a prospective follow-up study, but suggest that inhibition of phosphodiesterase-5 (PDE-5) by Viagra not only dilates blood vessels but also exerts protective effects directly on degenerating neurons. A clinical (phase II) trial in Alzheimer's disease patients is planned to confirm the causality and clinical effects of sildenafil on the brain.
A capillary in the brain with typical glial processes of the astrocytes attached (iStock_Dr_Microbe).
Reference:
Fang J, Zhang P, Zhou Y, Chiang C-W, Tan J, Hou Y, Stauffer S, Li L, Pieper AA, Cummings J, Cheng F (2021) Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer’s disease. Nature Aging 1:1175-1188