Ramakrishna Kakarla, Krishnamurthy Sairam
Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University (IIT BHU), Varanasi, India.
Department of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram, India.
Int J Dev Neurosci. 2023 Feb;83(1):31-43. doi: 10.1002/jdn.10234. Epub 2022 Nov 3.
Neonatal anoxia is linked to long-lasting neurodevelopmental deficits. Due to the lack of pharmacological intervention to treat neonatal anoxia, there is interest in finding new molecules for its treatment. Indole-3-carbinol (I3C) has shown neuroprotective effects in some disease conditions. However, the neuroprotective role of I3C in neonatal anoxia has not been explored. Consequently, we have investigated the effect of I3C on neonatal anoxia-induced brain injury and neurodevelopmental deficits. Rat pups after 30 h of birth were subjected to two episodes of anoxia (10 min in each) at a time interval of 24 h by flowing 100% nitrogen. I3C was administered within 30 min of the second episode of anoxia on a postnatal day (PND) 3 and continued for PND 9. Neurodevelopmental deficits, cortical mitochondrial membrane potential (MMP), opening of mitochondrial permeability transition pore (MPTP), electron transport chain (ETC) enzyme activities, oxidative stress, hypoxia-inducible factor-1α (HIF-1α) levels, histopathological changes, and apoptosis were measured. I3C treatment dose-dependently ameliorated the neurodevelopmental deficits and somatic growth in anoxic pups. I3C improved mitochondrial function by enhancing the MMP, mitochondrial ETC enzymes, and antioxidants. It blocked the MPTP opening and release of cytochrome C in anoxic pups. Further, I3C reduced the elevated cortical HIF-1α in neonatal anoxic pups. Furthermore, I3C ameliorated histopathological abnormalities and mitochondrial-mediated apoptotic indicators Cyt C, caspase-9, and caspase-3. Our study concludes that I3C improved neuronal development in anoxic pups by enhancing mitochondrial function, reducing HIF-1α, and mitigating apoptosis.
新生儿缺氧与长期的神经发育缺陷有关。由于缺乏治疗新生儿缺氧的药物干预措施，人们对寻找新的治疗分子很感兴趣。吲哚 - 3 - 甲醇（I3C）在某些疾病状态下已显示出神经保护作用。然而，I3C在新生儿缺氧中的神经保护作用尚未得到探索。因此，我们研究了I3C对新生儿缺氧诱导的脑损伤和神经发育缺陷的影响。出生30小时后的大鼠幼崽通过通入100%氮气，在24小时的时间间隔内经历两次缺氧发作（每次10分钟）。I3C在出生后第3天第二次缺氧发作后30分钟内给药，并持续到出生后第9天。测量神经发育缺陷、皮质线粒体膜电位（MMP）、线粒体通透性转换孔（MPTP）的开放、电子传递链（ETC）酶活性、氧化应激、缺氧诱导因子 - 1α（HIF - 1α）水平、组织病理学变化和细胞凋亡。I3C治疗剂量依赖性地改善了缺氧幼崽的神经发育缺陷和身体生长。I3C通过增强MMP、线粒体ETC酶和抗氧化剂来改善线粒体功能。它阻断了缺氧幼崽中MPTP的开放和细胞色素C的释放。此外，I3C降低了新生儿缺氧幼崽皮质中升高的HIF - 1α。此外，I3C改善了组织病理学异常以及线粒体介导的凋亡指标细胞色素C、半胱天冬酶 - 9和半胱天冬酶 - 3。我们的研究得出结论，I3C通过增强线粒体功能、降低HIF - 1α和减轻细胞凋亡来改善缺氧幼崽的神经元发育。
