Abstract
Each year, 1 million children die due to perinatal asphyxia; however, there are no effective drugs to protect the neonatal brain against hypoxic/ischemic damage. In this study, we demonstrated for the first time the neuroprotective capacity of 3,3’-diindolylmethane (DIM) in an in vivo model of rat perinatal asphyxia, which has translational value and corresponds to hypoxic/ischemic episodes in human newborns. Posttreatment with DIM restored the weight of the ipsilateral hemisphere and normalized cell number in the brain structures of rats exposed to perinatal asphyxia. DIM also downregulated the mRNA expression of HIF1A-regulated Bnip3 and Hif1a which is a hypoxic marker, and the expression of miR-181b which is an indicator of perinatal asphyxia. In addition, DIM inhibited apoptosis and oxidative stress accompanying perinatal asphyxia through: downregulation of FAS, CASP-3, CAPN1, GPx3 and SOD-1, attenuation of caspase-9 activity, and upregulation of anti-apoptotic Bcl2 mRNA. The protective effects of DIM were accompanied by the inhibition of the AhR and NMDA signaling pathways, as indicated by the reduced expression levels of AhR, ARNT, CYP1A1, GluN1 and GluN2B, which was correlated with enhanced global DNA methylation and the methylation of the Ahr and Grin2b genes. Because our study provided evidence that in rat brain undergoing perinatal asphyxia, DIM predominantly targets AhR and NMDA, we postulate that compounds that possess the ability to inhibit their signaling are promising therapeutic tools to prevent stroke.
Highlights
IntroductionBratek are first authors and contributed
We demonstrated for the first time the strong neuroprotective capacity of DIM in an in vivo model of birth asphyxia, as evidenced by the restoration of the weight of the ipsilateral brain hemisphere, the normalization of the number of neurons in rat brains exposed to hypoxia/ischemia and the inhibition of mRNA expression of Hif1a and HIF1Aregulated Bnip3 after postreatment with DIM
The rat model of perinatal asphyxia used in our study is clinically relevant because it corresponds to hypoxic/ischemic episodes in human newborns
Summary
Bratek are first authors and contributed . Perinatal asphyxia affects 2–4 newborns per 1000 births. 1 million children die due to hypoxia [1]. Oxygen deprivation in the perinatal period can lead to permanent brain damage and result in the onset of hypoxic-ischemic encephalopathy (HIE). HIE is the most serious consequence of perinatal asphyxia and has a wide spectrum of symptoms, such as cerebral palsy, convulsions, mental and motor impairment, and speech, hearing or visual disturbances. The gold standard for reducing brain damage induced by asphyxia is oxygen therapy and moderate hypothermia [2]. There is still a lack of effective and
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