胎生期のヒストン脱アセチル化酵素阻害は脊髄ミクログリアの活性化と機械的アロディニアを引き起こす

抄録

Valproic acid (VPA) is an anticonvulsant drug that is approved for use in epilepsy and bipolar disorder, but it also acts as a histone deacetylase (HDAC) inhibitor. We have previously demonstrated that prenatal exposure to VPA at embryonic day 12.5 (E12.5) causes autism-like behavioral abnormalities in mouse offspring. We have also found that prenatal VPA exposure causes long-lasting mechanical allodynia and spinal microglial activation. In the present study, we examined the effects of prenatal exposure to trichostatin A (TSA), a potent and specific inhibitor of HDAC class I/II, on tactile sensitivity and microglial morphology in the spinal cord. Pregnant ICR mice were intraperitoneally injected with either TSA (1 mg/kg) or vehicle on E12.5. Both male and female offspring of TSA-treated mothers (defined as TSA-treated mice) showed a significant decrease in withdrawal threshold in the von Frey test. The numbers of microglia in laminae I-IV and V-VI of the spinal cord dorsal horn in TSA-treated mice were increased compared with those in control mice. Increases in average intensity and cell area per microglia in laminae I-IV and V-VI were also observed in TSA-treated mice. These findings suggest that inhibition of HDAC during pregnancy causes mechanical allodynia associated with spinal microglial activation.