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Abstract Prenatal brain development is particularly sensitive to chemicals that can disrupt synapse formation and cause neurodevelopmental disorders. In most cases, such chemicals increase cellular oxidative stress. For example, prenatal exposure to the anti-epileptic drug valproic acid (VPA), induces oxidative stress and synaptic alterations, promoting autism spectrum disorders (ASD) in humans and autism-like behaviors in rodents. Using VPA to model chemically induced ASD, we tested whether activation of cellular mechanisms that increase antioxidant gene expression would be sufficient to prevent VPA-induced synaptic alterations. As a master regulator of cellular defense pathways, the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) promotes expression of detoxification enzymes and antioxidant gene products. To increase NRF2 activity, we used the phytochemical and potent NRF2 activator, sulforaphane (SFN). In our models of human neurodevelopment, SFN activated NRF2, increasing expression of antioxidant genes and preventing oxidative stress. SFN also enhanced expression of genes associated with synapse formation. Consistent with these gene expression profiles, SFN protected developing neural networks from VPA-induced reductions in synapse formation. Furthermore, in mouse cortical neurons, SFN rescued VPA-induced reductions in neural activity. These results demonstrate the ability of SFN to protect developing neural networks during the vulnerable period of synapse formation, while also identifying molecular signatures of SFN-mediated neuroprotection that could be relevant for combatting other environmental toxicants.
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Inhibiting the Keap1/Nrf2 Protein‐Protein Interaction with Protein‐Like Polymers
Abstract Successful and selective inhibition of the cytosolic protein‐protein interaction (PPI) between nuclear factor erythroid 2‐related factor 2 (Nrf2) and Kelch‐like ECH‐associating protein 1 (Keap1) can enhance the antioxidant response, with the potential for a therapeutic effect in a range of settings including in neurodegenerative disease (ND). Small molecule inhibitors have been developed, yet many have off‐target effects, or are otherwise limited by poor cellular permeability. Peptide‐based strategies have also been attempted to enhance specificity, yet face challenges due to susceptibility to degradation and lack of cellular penetration. Herein, these barriers are overcome utilizing a polymer‐based proteomimetics. The protein‐like polymer (PLP) consists of a synthetic, lipophilic polymer backbone displaying water soluble Keap1‐binding peptides on each monomer unit forming a brush polymer architecture. The PLPs are capable of engaging Keap1 and displacing the cellular protective transcription factor Nrf2, which then translocates to the nucleus, activating the antioxidant response element (ARE). PLPs exhibit increased Keap1 binding affinity by several orders of magnitude compared to free peptides, maintain serum stability, are cell‐penetrant, and selectively activate the ARE pathway in cells, including in primary cortical neuronal cultures. Keap1/Nrf2‐inhibitory PLPs have the potential to impact the treatment of disease states associated with dysregulation of oxidative stress, such as NDs.
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- PAR ID:
- 10491088
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Advanced Materials
- Volume:
- 36
- Issue:
- 21
- ISSN:
- 0935-9648
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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