Maternal exposure to volatile anesthetics induces IL-6 in fetal brains and affects neuronal development
Authors: Yoshimitsu Miyai
Tomonori Matsuyama
Tomoharu Tanaka
Yoshika Iwata
Kenichiro Tatsumi
Akiko Hirotsu
Journal: European Journal of Pharmacology (2019)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: Interleukin-6; Neural precursor cell; Neuroinflammation; Sevoflurane; Volatile anesthetic.
Affiliations: Department of Anesthesia, Kyoto University Hospital, 54 Kawahara-Cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan., Department of Anesthesia, National Hospital Organization Kyoto Medical Center, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto, 612-0861, Japan., Department of Anesthesia, Kyoto University Hospital, 54 Kawahara-Cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. Electronic address: .

Abstract:  Most clinically used general anesthetics have demonstrated neurotoxicity in animal studies, but the related mechanisms remain unknown. Previous studies suggest that anesthetics affect neuronal development through neuroinflammation, and significant effects of neuroinflammation on neurogenesis and neuronal disease have been shown. In the present study, we treated pregnant mice with 2% sevoflurane for 3 h at gestational day 15.5 and analyzed the expression of proinflammatory cytokines, including IL-6 and IL-17, in fetal mice brains. Sevoflurane induced IL-6 mRNA significantly, but did not upregulate IL-17. Other volatile anesthetics, including isoflurane, enflurane, and halothane, induced IL-6 mRNA in fetal brains as well as sevoflurane, but propofol did not. Sevoflurane and isoflurane showed the same effects in cultured microglia and astrocytes, but not in neurons. Because IL-6 induction in fetal brains may affect neuronal precursor cells (NPCs), numbers of NPCs in the subventricular zone were studied, revealing that maternal sevoflurane treatment significantly increases NPCs in offspring at 8 weeks after birth (p8wk). But this effect was absent in IL-6 knockout mice. Finally, behavioral experiments also revealed that maternal sevoflurane exposure causes learning impairments in p8wk offspring. These findings collectively demonstrate that maternal exposure to volatile anesthetics upregulates IL-6 in fetal mice brains, and the effects could result in long-lasting influences on neuronal development. 

Retracted: No

PubPeer comments:
 Figure 4B, P-ERK and p38MAPK are the same blots, and the pattern of blots is very similar between ERK and b-actin.  , 
 P-ERK,ERK, p38 MAPK and actin are immunoblotting from the same membrane using reblotting method, so there is no wonder if the pattern of the blotting is alike. JNK and P-JNK are wb from another membrane. If Mr. Tsanensis is suggesting that caption of ERK and actin is intentionally wrong, that s not true. , 
 #2  If the author means that they used one membrane for blotting p-ERK, ERK, p38MAPK and b-actin (membrane 1: blotted P-ERK, stripped, reblotted ERK, stripped, blotted p38MAPK, stripped, reblotted b-actin), where the P-p38 MAPK came from?? p38MAPK should be the appropriate loading control for the P-p38 MAPK, shouldn t it? , 
 #3 We rechecked the raw data to find that p-p38MAPK were performed first, and reblotted for p38MAPK, p-ERK, ERK and b-actin. So we performed reblotting for 4 times, not twice. u3000We didn t pay much attention to the number of reblottings, but thanks to the suggestions, we noticed the mistake. We have also contacted the journal regarding revisions to the treatise itself.   ,