AICAR (5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside) increases the production of toxic molecules and affects the profile of cytokines release in LPS-stimulated rat primary microglial cultures.
AICAR (5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside, Acadesine, AICA riboside) is an activator of AMP-activated protein kinase (AMPK). The results of recent studies suggest that AICAR, in addition to its application for treating metabolic disorders, may also have therapeutic potential for treating neuroinflammatory diseases where reactive microglia play an etiological role. However, the molecular mechanisms of action by which AICAR exerts its anti-inflammatory effects still remain unclear or controversial. In this paper we attempt to evaluate the effects of AICAR on non-stimulated and LPS-activated rat primary microglial cell cultures. The presented evidence supports the conclusion that AMPK activated by AICAR is involved in regulation of ROS and cytokine production (IL-1 beta, TNF-alpha (6h), IL-10 and TGF-beta) as well as arginase I and PGC-1alpha expression. Furthermore, we found that the effects of AICAR on IL-6 and TNF-alpha (12, 24h) release and on the expression of iNOS and NF-kappaB p65 are not AMPK-dependent because the pre-treatment of LPS-activated microglia with compound C (a pharmacological inhibitor of AMPK) did not reverse the effect of AICAR. The results of the presented study provide additional data about AMPK-dependent and -independent mechanisms whereby AICAR may modulate inflammatory response of microglia.
Department of Clinical Pharmacology, Medical University of Silesia, Katowice, Poland. labuzek@rubikon.pl
Krzysztof
K
Łabuzek
Sebastian
S
Liber
Bozena
B
Gabryel
Bogusław
B
Okopień
D000091162:AMP-Activated Protein Kinase Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001119:Arginase / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011494:Protein Kinases / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism
D016207:Cytokines; D007004:Hypoglycemic Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D012265:Ribonucleotides; D014157:Transcription Factors; D009569:Nitric Oxide; D000620:Aminoimidazole Carboxamide; D052247:Nitric Oxide Synthase Type II; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D001119:Arginase; C542908:arginase I, rat; C031143:AICA ribonucleotide; D001973:Bromodeoxyuridine