Dhruv R. Patel, Avik Roy, S. Raha
Apr 21, 2020
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Influential Citations
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Quality indicators
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JCI insight
Abstract
Discovery strategies commonly focus on the identification of chemical libraries or natural products, but the modulation of endogenous ligands offers a much better therapeutic strategy due to their low adverse potential. Recently, we have seen that hexadecanamide (Hex) is present in hippocampal nuclei of normal mice as an endogenous ligand of peroxisome proliferator-activated receptor alpha (PPARα). This study underlines the importance of Hex in inducing the expression of brain-derived neurotrophic factor (BDNF) from hippocampal neurons via PPARα. The level of Hex was less in the hippocampus of 5xFAD mice as compared to non-Tg mice. Oral administration of Hex increased the level of this molecule in the hippocampus to stimulate BDNF and its downstream plasticity-associated molecules, promote synaptic functions in the hippocampus and improve memory and learning in 5xFAD mice. However, oral Hex remained unable to stimulate hippocampal plasticity and improve cognitive behaviors in 5xFADPparα-null (5x with global PPARα-/-) and 5xFADPparα-ΔHippo (5x with hippocampus-specific PPARα-/-) mice, indicating an essential role of hippocampal PPARα in Hex-mediated improvement in hippocampal functions. This is the first demonstration of protection of hippocampal functions by oral administration of a hippocampus-based drug, suggesting that hexadecanamide may be explored for therapeutic intervention in AD.