A team of scientists at Indiana University, Bloomington, has identified 24 compounds — including caffeine, retinoic acid, and rolipram — with the potential to boost an enzyme in the brain shown to protect against dementia.
The enzyme in question is called nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2).
Its protective effect was discovered last year through research conducted by Indiana University Professor Hui-Chen Lu and co-authors.
According to the researchers, NMNAT2 plays two roles in the brain:
(i) a protective function to guard neurons from stress;
(ii) and a ‘chaperone function’ to combat misfolded proteins called tau, which accumulate in the brain as ‘plaques’ due to aging.
Misfolded proteins have been linked to neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Huntington’s diseases, as well as amyotrophic lateral sclerosis.
To identify substances with the potential to affect the production of the NMNAT2 enzyme in the brain, Prof. Lu and her colleagues 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.
The team’s earlier research found that mice altered to produce misfolded tau also produced lower levels of NMNAT2.
To confirm the effect of caffeine, the authors 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 the 1990s.
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,” Prof. Lu said.
An additional 13 compounds were identified as having potential to lower the production of NMNAT2.
“These compounds are also important because understanding their role in the body could lead to new insights into how they may contribute to dementia,” Prof. Lu explained.
“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.”
The team’s findings were published online March 7 in the journal Scientific Reports.
Yousuf O. Ali et al. 2017. Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons. Scientific Reports 7, article number: 43846; doi: 10.1038/srep43846
This article is based on a press-release from Indiana University.