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Impact of metformin on neocortical development during pregnancy: Involvement of ERK and p35/CDK5 pathways
Muhammet Oner1, Mei-Chih Chen2, Pang-Ting Cheng1
1Department of Life Sciences, National Chung Hsing University, Taichung, 40227, Taiwan.
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.
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.
Frequently Asked Questions
Based on this study's findings, metformin inhibits neural progenitor cell proliferation within the sub-ventricular zone (SVZ) and ventricular zone (VZ). This suppression is likely mediated by the inactivation of the Extracellular Signal-Regulated Kinase (ERK) signaling pathway during critical stages of neocortical assembly.
The researchers observed that metformin induces a small for gestational age (SGA) phenotype and significantly reduces relative cortical thickness. These morphological changes are accompanied by increased neuronal apoptosis and disrupted cortical lamination within the developing neocortex of the rat model.
The team used in utero electroporation to introduce p35 expression vectors into the developing brain. This technique allowed them to demonstrate that compensating for p35 levels could partially rescue the neuronal migration and maturation defects caused by metformin-induced p35/Cyclin-Dependent Kinase 5 (CDK5) inhibition.
The study's findings indicate that metformin disrupts neuronal migration, cortical layering, and the maturation of cortical neurons. These effects are localized primarily to the sub-ventricular zone (SVZ) and ventricular zone (VZ), where the drug interferes with the p35/Cyclin-Dependent Kinase 5 (CDK5) complex.
The study's authors propose that clinicians should exercise caution when prescribing metformin to pregnant individuals due to potential adverse effects on fetal brain development. They conclude that the drug's interference with essential signaling pathways like ERK and p35/CDK5 poses risks to normal neocortical structural organization.
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