It has been suggested that maternal immune activation (MIA) by a range of infections can affect fetal brain development and thus behavior of young and adult offspring. Most recently, Smith and colleagues (2007) reported that increased IL-6 in the maternal serum plays a key role in altering fetal brain development and impairing behaviors in social interactions in the offspring, all the way into adulthood. Interestingly, these effects could be attenuated by blocking IL-6, using anti-IL-6 antibody and/or mice deficient in IL-6. Our preliminary studies showed that the citrus bioflavonoid, luteolin, inhibits neuronal JAK2/STAT3 phosphorylation in both murine neuron-like (N2a) cells and primary cultured neuronal cells challenged with mouse recombinant IL-6 protein. As a validation of these findings, we next examined the effects of a STAT3 inhibitor (S31-201) and diosmin, a flavanoid structurally similar to luteolin, on JAK2/STAT3 signaling in vivo. When either agent was applied to pregnant mice with an injection of IL-6, JAK2/STAT3 phosphorylation and pro-inflammatory cytokines were both significantly reduced in brain homogenates from newborn mice. We further showed that diosmin administered orally in chow [10 mg/kg/day (0.005% diosmin in NIH31 control chow)] significantly changes behavioral deficits in social interaction and reduces pro-inflammatory cytokines in brain tissues of IL-6/MIA adult offspring. We also found that diosmin reduces the CNS levels in pro- inflammatory cytokines consistent with JAK2/STAT3 signal pathway inhibition. It's well known that the risk of altering fetal brain development is associated with prenatal maternal infection, specifically, with cytokine- related inflammatory events in the CNS. Presumably, diosmin molecular inhibition of JAK2/STAT3 pathway could be involved in improving abnormal social interaction in IL-6/MIA adulthood offspring. In this proposal, we will examine whether or not JAK2/STAT3 signal pathway activation could be specifically involved in brain histological abnormalities in IL-6-induced MIA (presumably resulting in development of abnormal behavior in adult offspring that mimics features of autism). In addition, we intend to fully characterize and qualify diosmin's potential effect on improving abnormal, autistic like social behaviors in IL-6/MIA offspring in adulthood via its attenuation of the JAK2/STAT3 signal pathway. These studies could lay the foundation for autism clinical trials with diosmin diet supplementation in the near future.
It has been suggested that activation of pregnant mother's immune system by infections can affect the brain of the developing fetus and thus behavior of young and adult offspring. Most recently, it was reported that increased IL-6 (a chemical messenger of the immune system) in the mother's blood plays a key role in altering fetal brain development and impairing behaviors in social interactions in the offspring. Interestingly, these effects could be avoided by blocking IL-6 chemically with an antibody or by genetically altering mice so they are deficient in IL-6. Our preliminary studies showed that the natural citrus molecule, luteolin, inhibits the signaling mechanism (JAK2/STAT3) in neurons which carries IL-6's signal to the nucleus. This occurred in neuron-like (N2a) cells and neurons removed and cultured from mouse brains and then challenged with mouse IL-6 protein. As a validation of these findings, we next examined the effects of an artificial STAT3 inhibitor and diosmin, a structurally similar natural citrus molecule to luteolin, on JAK2/STAT3 signaling in mice. When either agent was applied to pregnant mice with an injection of IL-6 to activate the mother's immune system JAK2/STAT3 activation and inflammatory cytokines were both significantly reduced in the brains of the newborn mice. We further showed that diosmin given orally mixed in mouse food significantly improves behavioral problems in social interaction and reduces inflammatory cytokines in brain tissues of the offspring of the IL-6 injected mothers. Further, diosmin specifically reduces the brain inflammatory cytokines triggered by JAK2/STAT3 signaling. Presumably, diosmin inhibition of JAK2/STAT3 pathway could be involved in improving abnormal social interaction in offspring of IL-6 injected mothers. In this proposal, we will examine whether or not JAK2/STAT3 signal pathway activation could be specifically involved in brain structural abnormalities in IL-6-induced activation of the maternal immune system (presumably resulting in development of abnormal behavior in adult offspring that mimics features of autism). In addition, we intend to fully test diosmin's potential effect on improving abnormal, autistic like behaviors of offspring of IL-6 immune activated mothers by the JAK2/STAT3 signal pathway blocking with diosmin. These studies could lay the foundation for diosmin as a prenatal supplement in at-risk mothers to avoid autism development in their children, much like folate is currently in use to avoid neural tube defects.
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