Lovastatin’s impact on brain cholesterol levels is found to produce neuroprotective effects.
Statins are known to reduce cholesterol synthesis in the liver, easily cross the blood-brain barrier, and have various additional effects on brain cells.
Lovastatin, aka Mevinolin, is commonly used as a medication to slow the production of cholesterol in the body, leading to reduced concentration of cholesterol in the blood, and thereby preventing buildup on artery walls.
Interestingly, in the average healthy adult, 25% of total cholesterol is in the brain.
This cholesterol in the brain is necessary to maintain the nicotinic acetylcholine receptors (nAChRs) at the cell membranes and for moving ions across the membranes.
There are different kinds of nAChRs present in the central nervous system, with both homomeric and dimeric species. The most abundant of the homomeric species in the central nervous system is α7 nAChR, while the most abundant dimeric species is the combination of α4 and β2 subunits.
These nAChR species play roles in a variety of cognitive functions, including learning, memory, and involvement in the development of Alzheimer’s disease. At the same time, the nAChRs all seem to be quite sensitive to membrane cholesterol levels. As has been demonstrated, the levels of nAChRs may be altered by manipulating the cholesterol level.
Cholesterol is known to have a big impact on muscle-type nAChR, however, its impact on neuronal-type nAChR is less studied.
Consequently, a study was formed to evaluate the impact of ongoing lovastatin treatment on cholesterol levels and the α7 and α4-containing nAChRs.
When cultured hippocampal neurons were incubated with varying levels of lovastatin for up to 14 days the total and surface cholesterol levels were significantly reduced, in a dose-dependent manner. No signs of neuronal damage were observed at the concentrations used, 0, 10, 50, 100, and 1000 nM.
The levels of α7 nAChR found in the cultured hippocampal nerves were monitored and found to be increased with the lovastatin treatments.
Previous studies have suggested that individuals with long-term statin treatment are less susceptible to developing Alzheimer’s disease. The nAChR species in the central nervous system are potentially a key to this phenomenon.
The lingering question remains: is it the impact on cholesterol biosynthesis, which occurs in the liver, and the resulting decreased level of cholesterol interacting with the nAChRs in the brain, or is it the statin itself entering the brain, that is responsible for the neuroprotective effect? It is quite possibly a combination of both factors and more research may be able to tease this information apart.
Borroni V, Kamerbeek C, Pediconi M, et al. Lovastatin differentially regulates α7 and α4 neuronal nicotinic acetylcholine receptor levels in rat hippocampal neurons. Molecules. 2020 Oct 20;25(20):4838. doi: 10.3390/molecules25204838. PMID: 33092257.