Flavonoids, a prenatal prophylaxis via targeting JAK2/STAT3 signaling to oppose IL-6/MIA associated autism
Received 29 May 2009; received in revised form 15 July 2009; accepted 24 August 2009. published online 22 September 2009.
Abstract
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.
aRashid Laboratory for Developmental Neurobiology, Silver Child Development Center, University of South Florida, Tampa, FL 33613, USA
bNeuroimmunology Laboratory, Department of Psychiatry & Behavioral Medicine; College of Medicine, University of South Florida, Tampa, FL 33613, USA
cDepartment of Neurosurgery and Brain Repair, College of Medicine, University of South Florida, Tampa, FL 33613, USA
dRothman Center for Neuropsychiatry, Department of Pediatrics, College of Medicine, University of South Florida, All Children's Hospital, St. Petersburg, FL 33701, USA
eDepartment of Pathology and Cell Biology, College of Medicine, University of South Florida, Tampa, FL 33620, USA
Corresponding author. Silver Child Development Center, Department of Psychiatry, University of South Florida, 3515 E Fletcher Ave. Tampa, Florida 33613, USA. Tel.: +1 813 0974 9326; fax: +1 813 974 3223.
ABSTRACT