Flavonoids, a prenatal prophylaxis via targeting JAK2/STAT3 signaling to oppose IL-6/MIA associated autism.
Maternal immune activation (MIA) can affect fetal brain development and thus behavior of young and adult offspring. Reports have shown that increased Interleukin-6 (IL-6) in the maternal serum plays a key role in altering fetal brain development, and may impair social behaviors in the offspring. Interestingly, these effects could be attenuated by blocking IL-6. The current study investigated the effects of luteolin, a citrus bioflavonoid, and its structural analog, diosmin, on IL-6 induced JAK2/STAT3 (Janus tyrosine kinase-2/signal transducer and activator of transcription-3) phosphorylation and signaling as well as behavioral phenotypes of MIA offspring. Luteolin and diosmin inhibited neuronal JAK2/STAT3 phosphorylation both in vitro and in vivo following IL-6 challenge as well as significantly diminishing behavioral deficits in social interaction. Importantly, our results showed that diosmin (10mg/kgday) was able to block the STAT3 signal pathway; significantly opposing MIA-induced abnormal behavior and neuropathological abnormalities in MIA/adult offspring. Diosmin's molecular inhibition of JAK2/STAT3 pathway may underlie the attenuation of abnormal social interaction in IL-6/MIA adult offspring.
Parker-Athill
Ellisa
E
Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, University of South Florida, Tampa, FL 33613, USA.
Luo
Deyan
D
Bailey
Antoinette
A
Giunta
Brian
B
Tian
Jun
J
Shytle
R Douglas
RD
Murphy
Tanya
T
Legradi
Gabor
G
Tan
Jun
J
D000704:Analysis of Variance; D000818:Animals; D001321:Autistic Disorder / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D016207:Cytokines / Q000378:metabolism; D004145:Diosmin / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D015850:Interleukin-6 / Q000009:adverse effects*; D053614:Janus Kinase 2 / Q000378:metabolism*; D047311:Luteolin / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
D016207:Cytokines; D005419:Flavonoids; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D012694:Serine; D004145:Diosmin; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D047311:Luteolin