Host: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
Name : WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
Location : Kyoto
Date : July 01, 2018 - July 06, 2018
Alzheimer's disease (AD) is a neurodegenerative disorder that presents in patients as a progressive cognitive decline and dementia. Effective therapies for AD have not been identified yet. Neuronal loss in AD brain is accompanied with a state of chronic neuroinflammation characterized by adverse activation of microglia, which are representatives of the mononuclear phagocyte system. Compounds that reduce harmful secretions of microglia have been suggested as potential therapeutic agents for slowing down AD. For example, microglial cytotoxicity can be reduced by non-steroidal anti-inflammatory drugs inhibiting cyclooxygenases (COX), but the significant adverse effects caused by chronic use of these drugs limit their clinical application. Hence, identification of anti-inflammatory agents capable of normalizing microglial functions without inhibiting COX enzymes has been proposed as one of the strategies for developing effective and safe AD medications. Since microglia express receptors for kainic acid (KA), we tested the ability of novel kainoid derivatives, to inhibit microglial adverse activation.
Overall, six structurally different KA derivatives were synthesized and their ability to inhibit select functions of immune-stimulated microglia was tested in vitro by using three different microglial models. Human monocytic THP-1 cells were used to study secretions of cytotoxins and the pro-inflammatory cytokine monocyte chemoattractant protein (MCP)-1. Human myelomonocytic HL-60 cells were used to model the respiratory burst response. Murine BV-2 microglia were used to induce secretion of nitric oxide (NO).
Two of the kainoid analogs tested at 1 - 20 μM inhibited all of the microglial functions studied without adversely affecting cell viability. By testing their derivatives, we gained insights into structure-function relationships for these compounds. Since KA did not inhibit microglial functions studied, these kainoids likely were not interacting with kainate receptors. The selective inhibitor zopolrestat was used to study aldose reductase as the candidate molecular target of kainoids.
We have identified two novel kainoid-based compounds, which effectively inhibit adverse activation of microglia in vitro, and have ruled out kainate receptors as their molecular targets. These compounds should be considered as potential therapeutic agents for AD, but further studies are needed to confirm their anti-neuroinflammatory activity in vivo and identify their molecular mechanisms of action.
