Levothyroxine mitigates autism-related behaviours in the maternally separated male mice possibly through manipulating hippocampal nitrite imbalance and neuroinflammation

Objectives Autism spectrum disorder (ASD) is one of the progressively occurring neuro­developmental condition. There is a link between low concentrations of thyroid hormones during neonatal stage with ASD susceptibility. Neuroprotective effects have been reported for levothyroxine. We aimed to evaluate the effect of levothyroxine on autism-like behaviours in mice subjected to MS paradigm, focusing on its possible effects on hippocampal nitrite imbalance and neuroinflammation.Methods Thirty-two mice were randomly allocated into four groups: including control group (normal saline (10 ml/kg)) and MS groups respectively treated with normal saline (10 ml/kg) or levothyroxine at doses of 0.625 or 1.25 µg/g BW orally for 2 weeks. Shuttle box, marble burying (MB), elevated plus maze (EPM) and three-chamber tests were performed. Nitrite levels and expression of genes related to neuroinflammation, including Tlr4, Inos, Il-1β and Nlrp3, were measured in the hippocampus.Results Levothyroxine increased social interaction indexes in the three-chamber, enhanced passive avoidance memory in the shuttle box, increased time spent in open arms of EPM and reduced repetitive behaviours in the MB tests. Levothyroxine reduced the hippocampal nitrite level and expression of neuroinflammatory markers.Conclusions Levothyroxine, maybe through attenuating of the hippocampal nitrite imbalance and neuroinflammation, mitigates autism-related behaviours in MS mice.