Decoding the Interplay of Cholinesterase Inhibitors, Energy Metabolism, Cognitive Decline, and Hepatotoxicity: Insights from Animal Models (NW24J-04-00140)
Basic information
Investigator: RNDr. David Kolář, Ph.D.
Main recipient: University of Hradec Kralove
Co-recipient: National Institute of Mental Health (NIMH)
Research period: 1/5/2024 – 31/12/2027
Total budget: 6,998,000 CZK
NIMH budget: 4,275,000 CZK
Supported by: Czech Health Research Council (AZV ČR)
Annotation
Alzheimer's disease (AD) is classified as a neurodegenerative disease. Patients suffering from AD progressively lose a large number of nerve cells, which gradually leads to the loss of certain cognitive functions – thinking, memory, and judgment. In addition to the pathophysiological aggregation of proteins (amyloid-beta, phosphorylated tau protein), changes in brain energy metabolism appear in the early stages of the disease. The major manifestations include decreased glucose turnover, dysregulated insulin signaling, mitochondrial senescence, and changes in the mitochondrial respiratory chain. The medication currently used to combat AD (including acetylcholinesterase inhibitors and NMDA receptor antagonists) only alleviates the symptoms of the disease. One of the first drugs used was tacrine, whose primary mechanism of action was the reversible inhibition of acetylcholinesterase in the brain. In 2013, the use of tacrine was discontinued due to strong adverse effects on liver function. The induced hepatotoxicity is caused by the formation of toxic metabolites (via cytochrome P450; CYP1A2) affecting the redox balance of hepatocytes, destabilizing mitochondrial membranes, and leading to the depletion of liver glutathione reserves. Previous studies have shown that hybrid molecules combining tacrine and an antioxidant pharmacophore can reduce hepatotoxicity and even act hepatoprotectively. Based on this knowledge, a series of tacrine-trolox derivatives was designed and prepared, aiming not only to inhibit acetylcholinesterase but also to act hepatoprotectively. In 2015, this series was characterized in vitro. Pilot studies showed that selected derivatives exhibit lower cytotoxicity towards liver cells compared to the parent drug, tacrine. However, little is known about their in vivo effects on cognitive functions, brain energy metabolism, or potentially induced hepatotoxicity.