March 11, 2017 – This is very good news for a heavy coffee drinker like myself: scientists have identified 24 compounds that increase the brain’s production of the enzyme NMNAT2, which helps prevent the formation of these tangles associated with neurodegenerative disorders such as Alzheimer’s disease. And yes, one of these compounds is caffeine, of which I consume tons every day. And upon self examination, I would say that I am not suffering from Alzheimer’s at all, except I have forgotten my 66th birthday a couple of days ago.
“This latest work could help advance efforts to develop drugs that increase levels of this enzyme in the brain, creating a chemical ‘blockade’ against the debilitating effects of neurodegenerative disorders,” said Hui-Chen Lu, who led the study and is a Gill Professor in the Linda and Jack Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences, a part of the IU Bloomington College of Arts and Sciences. To identify substances with the potential to affect the production of the NMNAT2 enzyme in the brain, Lu’s team screened over 1,280 compounds, including existing drugs, using a method developed in her lab. A total of 24 compounds were identified as having potential to increase the production of NMNAT2 in the brain.
One of the substances shown to increase production of the enzyme was caffeine, which also has been shown to improve memory function in mice genetically modified to produce high levels of misfolded tau proteins. Lu’s earlier research found that mice altered to produce misfolded tau also produced lower levels of NMNAT2. To confirm the effect of caffeine, IU researchers administered caffeine to mice modified to produce lower levels of NMNAT2. As a result, the mice began to produce the same levels of the enzyme as normal mice.
Another compound found to strongly boost NMNAT2 production in the brain was rolipram, an “orphaned drug” whose development as an antidepressant was discontinued in clinical development in the mid-1990s, primarily for clinical safety reasons. The compound remains of interest to brain researchers due to several other studies also showing evidence it could reduce the impact of tangled proteins in the brain. Other compounds shown by the study to increase the production of NMNAT2 in the brain, although not as strongly as caffeine or rolipram, were ziprasidone, cantharidin, wortmannin and retinoic acid. The effect of retinoic acid could be significant since the compound derives from vitamin A. At this point in time however, it remains totally unknown if any of these compounds could clinically be “repurposed” for a protective treatment of dementia, taking into account in vivo efficacy and safety issues.
An additional 13 compounds were identified as having potential to lower the production of NMNAT2. Lu said these compounds are also important because understanding their role in the body could lead to new insights into how they may contribute to dementia. “Increasing our knowledge about the pathways in the brain that appear to naturally cause the decline of this necessary protein is equally as important as identifying compounds that could play a role in future treatment of these debilitating mental disorders,” Prof. Lu said.
Journal Reference: Yousuf O. Ali, Gillian Bradley, Hui-Chen Lu. Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons. Scientific Reports, 2017; 7: 43846 DOI: 10.1038/srep43846