| First Author | Hasegawa M | Year | 2024 |
| Journal | Biochem Biophys Res Commun | Volume | 737 |
| Pages | 150922 | PubMed ID | 39486137 |
| Mgi Jnum | J:359117 | Mgi Id | MGI:7782312 |
| Doi | 10.1016/j.bbrc.2024.150922 | Citation | Hasegawa M, et al. (2024) Maternal immune activation induces neurodevelopmental impairments of adult offspring through alterations in tryptophane-kynurenine pathway in the placenta. Biochem Biophys Res Commun 737:150922 |
| abstractText | Maternal immune activation (MIA) is recognized as one of the significant environmental risk factors for neuropsychiatric disorders such as schizophrenia in adult offspring. However, the pathophysiological mechanisms remain unknown. The tryptophan (TRP)-kynurenine (KYN) pathway, influenced by inflammation, may be implicated in the pathophysiology of neuropsychiatric disorders. We investigated whether abnormal behaviors in adult offspring could be induced by MIA through alterations in the TRP-KYN pathway. MIA increased not only IL-6 expression in the placenta but also reactive oxygen species (ROS) levels in both the placenta and fetal brain and disrupted cortical layering in the fetal brain. We observed increased levels of 3-hydroxykynurenine (3-HK), a metabolite with oxidative stress properties, in both the placenta and fetal brain. In the knockout mice of kynurenine 3-monooxygenase (KMO), the enzyme responsible for 3-HK production, MIA failed to induce the abnormal behaviors in adult offspring. Notably, RO-618048, a KMO inhibitor that does not cross the blood-brain barrier (BBB), also blocked MIA-induced abnormal behaviors in adult offspring, reduced not only increased IL-6 expression in the placenta but also ROS levels in both the placenta and fetal brain, and prevented abnormal cortical development in the fetal brain. These findings suggest that MIA-induced abnormal behaviors in adult offspring may result from the increase in 3-HK levels through activation of KMO. Therefore, KMO is an attractive target for the prevention of neuropsychiatric disorders associated with MIA. |
