Modulation of Sox10, HIF-1α, Survivin, and YAP by Minocycline in the Treatment of Neurodevelopmental Handicaps following Hypoxic Insult

Abstract

Premature infants are at an increased risk of developing cognitive and motor handicaps due to chronic hypoxia. Although the current therapies have reduced the incidence of these handicaps, untoward side effects abound. Using a murine model of sublethal hypoxia, we demonstrated reduction in several transcription factors that modulate expression of genes known to be involved in several neural functions. We demonstrate the induction of these genes by minocycline, a tetracycline antibiotic with noncanonical functions, in both in vitro and in vivo studies. Specifically, there was induction of genes, including Sox10, Hif1a, Hif2a, Birc5, Yap1, Epo, Bdnf, Notch1 (cleaved), Pcna, Mag, Mobp, Plp1, synapsin, Adgra2, Pecam1, and reduction in activation of caspase 3, all known to affect proliferation, apoptosis, synaptic transmission, and nerve transmission. Minocycline treatment of mouse pups reared under sublethal hypoxic conditions resulted in improvement in open field testing parameters. These studies demonstrate beneficial effects of minocycline treatment following hypoxic insult, document up-regulation of several genes associated with improved cognitive function, and support the possibility of minocycline as a potential therapeutic target in the treatment of neurodevelopmental handicaps observed in the very premature newborn population. Additionally, these studies may aid in further interpretation of the effects of minocycline in the treatment trials and animal model studies of fragile X syndrome and multiple sclerosis.

Minocycline mitigates the effect of neonatal hypoxic insult on human brain organoids

“…Interestingly, the expression levels of Yap and Sox10, two transcription factors that modulate expression of multiple genes with neural functions similar to findings in mice 29 , were also significantly decreased in the organoids under hypoxic stress and rescued by minocycline (Supplementary Fig. 11B, C).…”

“…In prior work in the mouse, we have found that minocycline prevents the downregulation by hypoxia of a transcriptional program of neurogenesis controlled by YAP and Sox10 29 . In particular, these transcription factors regulate genes involved in proliferation, apoptosis, and neural development 26 .…”

“…7) were evaluated. Because minocycline has been shown to prevent damage due to lack of oxygen in mouse models 29 , we tested it using this human brain organoid model under normoxic and hypoxic conditions. After a dose curve was performed, 2 μM was chosen as the dose for subsequent experiments.…”

“…In both mouse and human studies minocycline has been shown to be effective in many brain diseases 24,25 . Mouse studies have shown efficacy in using minocycline for treating the effects of chronic neonatal hypoxia, but it has not yet been tested in humans 1,26–29 . In this study, we used brain organoids in a hypoxia chamber as a means to model human neonatal hypoxic stress.…”

PD-L1 confers resistance to EGFR mutation-independent tyrosine kinase inhibitors in non-small cell lung cancer via upregulation of YAP1 expression

“…Hypoxia modulates SIAH2 ubiquitin E3 ligase, which enhances the formation of a complex between YAP1 and HIF-1α, which increases HIF-1α stability [ 33 ]. Hypoxia also increases YAP1 gene expression [ 34 ]. The evidence provided here demonstrates that upregulation of YAP1 expression by PD-L1 may confer TKI resistance by increasing ROS generation and therefore promoting HIF-1α expression.…”