Impact of metformin on neocortical development during pregnancy: Involvement of ERK and p35/CDK5 pathways

Muhammet Oner; Mei-Chih Chen; Pang-Ting Cheng; Yu-Hsuan Li; Yu-Chiao Cheng; Ayse Celik; Shiuan-Woei Soong; Li-Wen Hsu; Din-You Lin; G M Shazzad Hossain Prince; Trayee Dhar; Hsu-Chen Cheng; Pin-Chi Tang; Ho Lin

doi:10.1016/j.chemosphere.2024.142124

Impact of metformin on neocortical development during pregnancy: Involvement of ERK and p35/CDK5 pathways

Chemosphere. 2024 Apr 25:358:142124. doi: 10.1016/j.chemosphere.2024.142124. Online ahead of print.

Authors

Affiliations

¹ Department of Life Sciences, National Chung Hsing University, Taichung, 40227, Taiwan.
² Translational Cell Therapy Center, Department of Medical Research, China Medical University Hospital, Taichung, 40447, Taiwan.
³ Department of Animal Science, National Chung Hsing University, Taichung, 40227, Taiwan.
⁴ Department of Life Sciences, National Chung Hsing University, Taichung, 40227, Taiwan. Electronic address: hlin@dragon.nchu.edu.tw.

PMID: 38677614
DOI: 10.1016/j.chemosphere.2024.142124

Abstract

Metformin, the most commonly prescribed drug for the treatment of diabetes, is increasingly used during pregnancy to address various disorders such as diabetes, obesity, preeclampsia, and metabolic diseases. However, its impact on neocortex development remains unclear. Here, we investigated the direct effects of metformin on neocortex development, focusing on ERK and p35/CDK5 regulation. Using a pregnant rat model, we found that metformin treatment during pregnancy induces small for gestational age (SGA) and reduces relative cortical thickness in embryos and neonates. Additionally, we discovered that metformin inhibits neural progenitor cell proliferation in the sub-ventricular zone (SVZ)/ventricular zone (VZ) of the developing neocortex, a process possibly mediated by ERK inactivation. Furthermore, metformin induces neuronal apoptosis in the SVZ/VZ area of the developing neocortex. Moreover, metformin retards neuronal migration, cortical lamination, and differentiation, potentially through p35/CDK5 inhibition in the developing neocortex. Remarkably, compensating for p35 through in utero electroporation partially rescues metformin-impaired neuronal migration and development. In summary, our study reveals that metformin disrupts neocortex development by inhibiting neuronal progenitor proliferation, neuronal migration, cortical layering, and cortical neuron maturation, likely via ERK and p35/CDK5 inhibition. Consequently, our findings advocate for caution in metformin usage during pregnancy, given its potential adverse effects on fetal brain development.

Keywords: Cortical lamination; ERK; Metformin; Neural progenitor cell proliferation; Neuronal apoptosis; Neuronal differentiation; Neuronal migration; Small for gestational age (SGA); p35/Cyclin-dependent kinase 5 (CDK5).