PMID- 30790558 OWN - NLM STAT- MEDLINE DCOM- 20190722 LR - 20190722 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 851 DP - 2019 May 15 TI - Characterization of novel kainic acid analogs as inhibitors of select microglial functions. PG - 25-35 LID - S0014-2999(19)30122-0 [pii] LID - 10.1016/j.ejphar.2019.02.025 [doi] AB - Alzheimer's disease (AD) is characterized by abnormal accumulation of extracellular amyloid beta protein (Abeta) 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. CI - Copyright (c) 2019 Elsevier B.V. All rights reserved. FAU - Alford, Morgan A AU - Alford MA AD - Department of Biology, University of British Columbia Okanagan Campus, 3187 University Way, Kelowna, BC, Canada V1V 1V7. FAU - Tian, Zhenlin AU - Tian Z AD - Department of Chemistry, University of British Columbia Okanagan Campus, Kelowna, BC, Canada. FAU - Menard, Frederic AU - Menard F AD - Department of Chemistry, University of British Columbia Okanagan Campus, Kelowna, BC, Canada. FAU - Klegeris, Andis AU - Klegeris A AD - Department of Biology, University of British Columbia Okanagan Campus, 3187 University Way, Kelowna, BC, Canada V1V 1V7. Electronic address: andis.klegeris@ubc.ca. LA - eng PT - Journal Article DEP - 20190218 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Benzothiazoles) RN - 0 (Phthalazines) RN - 0 (Reactive Oxygen Species) RN - 1PV3S9WP3D (zopolrestat) RN - 31C4KY9ESH (Nitric Oxide) RN - SIV03811UC (Kainic Acid) SB - IM MH - Benzothiazoles/pharmacology MH - HL-60 Cells MH - Humans MH - Kainic Acid/*analogs & derivatives/*pharmacology MH - Microglia/*drug effects/metabolism MH - Neurons/drug effects/metabolism MH - Nitric Oxide/metabolism MH - Phthalazines/pharmacology MH - Reactive Oxygen Species/metabolism OTO - NOTNLM OT - Aldose reductase OT - Anti-inflammatory drugs OT - Neurodegenerative disease OT - Neuroinflammation OT - Neuroprotection OT - Zopolrestat EDAT- 2019/02/23 06:00 MHDA- 2019/07/23 06:00 CRDT- 2019/02/22 06:00 PHST- 2018/10/24 00:00 [received] PHST- 2019/02/13 00:00 [revised] PHST- 2019/02/14 00:00 [accepted] PHST- 2019/02/23 06:00 [pubmed] PHST- 2019/07/23 06:00 [medline] PHST- 2019/02/22 06:00 [entrez] AID - S0014-2999(19)30122-0 [pii] AID - 10.1016/j.ejphar.2019.02.025 [doi] PST - ppublish SO - Eur J Pharmacol. 2019 May 15;851:25-35. doi: 10.1016/j.ejphar.2019.02.025. Epub 2019 Feb 18.