Characterization of novel kainic acid analogs as inhibitors of select microglial functions

Abstract

Alzheimer's disease (AD) is characterized by abnormal accumulation of extracellular amyloid beta protein (Aβ) plaques and intracellular neurofibrillary tangles, as well as by a state of chronic inflammation in the central nervous system (CNS). Adverse activation of microglia, the brain immune cells, is believed to contribute to AD pathology including excessive neuronal death. Thus, normalizing immune functions of microglia could slow neurodegeneration, and identification of novel compounds capable of modifying microglial functions is an important goal. Since kainic acid (KA) has been shown to modulate microglial morphology and immune functions, we synthesized six new KA analogs (KAAs) and tested their effects on select microglial functions by using three different cell types as microglia models. Four of the KAAs at low micromolar concentrations inhibited secretion of cytotoxins, monocyte chemoattractant protein (MCP)-1, reactive oxygen species and nitric oxide (NO) by immune-stimulated microglia-like cells. We hypothesize that the effects of the novel KAAs on microglia-like cells are not mediated by KA receptors since their biological activity was distinct from that of KA in all assays performed. A structural similarity search identified aldose reductase (AR) as a potential target for the novel KAAs. This hypothesis was supported by use of AR inhibitor zopolrestat, which abolished the inhibitory effects of two KAAs on microglial secretion of NO. Since the newly developed KAAs inhibited pro-inflammatory and cytotoxic functions of microglia, they should be further investigated for their potential beneficial effect on neuroinflammation and neurodegeneration in AD animal models.

Keywords: Aldose reductase; Anti-inflammatory drugs; Neurodegenerative disease; Neuroinflammation; Neuroprotection; Zopolrestat.