Prenatal Exposure to Gabapentin Alters the Development of Ventral Midbrain Dopaminergic Neurons

Abstract

Background: Gabapentin is widely prescribed as an off-label drug for the treatment of various diseases, including drug and alcohol addiction. Approximately 83–95% of the usage of gabapentin is off-label, accounting for more than 90% of its sales in the market, which indicates an alarming situation of drug abuse. Such misuse of gabapentin has serious negative consequences. The safety of the use of gabapentin in pregnant women has always been a serious issue, as gabapentin can cross placental barriers. The impact of gabapentin on brain development in the fetus is not sufficiently investigated, which poses difficulties in clinical decisions regarding prescriptions.Methods: The consequences effect of prenatal gabapentin exposure on the development of ventral midbrain dopaminergic neurons were investigated using three-dimensional neuronal cell cultures. Time-mated Swiss mice were used to isolate embryos. The ventral third of the midbrain was removed and used to enrich the dopaminergic population in 3D cell cultures that were subsequently exposed to gabapentin. The effects of gabapentin on the viability, ATP release, morphogenesis and genes expression of ventral midbrain dopaminergic neurons were investigated.Results: Gabapentin treatment at the therapeutic level interfered with the neurogenesis and morphogenesis of vmDA neurons in the fetal brain by causing changes in morphology and alterations in the expression of key developmental genes, such as Nurr1, Chl1, En1, Bdnf, Drd2, and Pitx3. The TH + total neurite length and dominant neurite length were significantly altered. We also found that gabapentin could halt the metabolic state of these neuronal cells by blocking the generation of ATP.Conclusion: Our findings clearly indicate that gabapentin hampers the morphogenesis and development of dopaminergic neurons. This implies that the use of gabapentin could lead to serious complications in child-bearing women. Therefore, caution must be exercised in clinical decisions regarding the prescription of gabapentin in pregnant women.

The Impact of Mechanical Cues on the Metabolomic and Transcriptomic Profiles of Human Dermal Fibroblasts Cultured in Ultrashort Self-Assembling Peptide 3D Scaffolds

“…This class of peptides can self-assemble to form fiber networks that entrap 99.9% water content, similar to collagen, the most abundant fibrous protein in the extracellular matrix (ECM). The structural organization of these nanofibrous scaffolds creates a 3D microenvironment for the cells that closely mimics the native tissues in vivo . − The characteristics of these biomaterials made them suitable for a range of biomedical applications including wound healing, − cartilage repair, development of 3D neuronal models, − and other cellular models as well as 3D bioprinting. − Despite the increasing interest in developing 3D cellular models that would bridge the translation gap between the 2D in vitro testing and the in vivo systems, less is known about how the mechanical cues of the microenvironment influence cellular processes including its metabolic activity. − In fact, to the best of our knowledge, there are no reports available discussing the influence of ultrashort peptide-based scaffolds on the metabolomics of cells embedded within these scaffolds and correlating this information with the transcriptomic profiles.…”

The Influence of Prenatal Exposure to Methamphetamine on the Development of Dopaminergic Neurons in the Ventral Midbrain

“…The genes Lmx1a/b , Mash1 , and Ngn2 (which regulate early DA destiny), Wnt5a/7a and Netrin1 (which affect axonal plasticity), and Wnt5a , Pitx3 , and Th (which are crucial for neuronal maturation) are important neurogenesis-related genes. However, none of these genes fully accounted for all processes involved in VMDN development [ 31 , 32 , 33 , 34 ]. Lmx1a and b with 64%, 83%, and 100% amino acid sequence identity in the LIM domain, LIM domain, and homeodomain domain, respectively [ 35 ], are involved in the fate and functional activities of mDA progenitors [ 36 ].…”