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. 2022 Jul 22:13:923113.
doi: 10.3389/fphar.2022.923113. eCollection 2022.

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

Walaa F Alsanie  1   2 , Sherin Abdelrahman  3   4 , Majid Alhomrani  1   2 , Ahmed Gaber  2   5 , Hamza Habeeballah  6 , Heba A Alkhatabi  7   8   9 , Raed I Felimban  7   10 , Charlotte A E Hauser  3   4 , Hossam H Tayeb  7   11 , Abdulhakeem S Alamri  1   2 , Bassem M Raafat  12 , Sirajudheen Anwar  13 , Khaled A Alswat  14 , Yusuf S Althobaiti  15   16 , Yousif A Asiri  17
Affiliations

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

Walaa F Alsanie et al. Front Pharmacol. .

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.

Keywords: development; gabapentin; morphogenesis; neurons; pregnancy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The experimental design of the present study.
FIGURE 2
FIGURE 2
Viability (A) and ATP release (B) in gabapentin-treated and control cultures.
FIGURE 3
FIGURE 3
Gabapentin-induced elongation observed in total neurite length (A) and dominant neurite length (B) of TH + vmDA neurons. TH + vmDA neurons showing no significant changes in the number of branches (C) and neurites (D) of in response to gabapentin treatment. Representative images and illustration for vmDA neurons immunolabeled with TH in both groups; control (E,E’) and gabapentin-treated (F,F’) show the increase in neurites elongation in response to gabapentin exposure. (G,H) images show large field of view (20x) for both groups; control and gabapentin treated cultures, respectively. Scale bar = 50 um (E,F). Scale bar = 10 um (G,H). Data are represented as mean ± SEM, n = 4 experiments. *p < 0.05.
FIGURE 4
FIGURE 4
VM nondopaminergic neurons (TUJ1+/TH-) subjected to gabapentin exposure having no changes in the total neurite length (A), the dominant neurite length (B) or the number of neurites (D), while having significant increases in the number of branches (C). Representative images and illustration for VM neurons immunolabeled with TUJ1 in both groups; control (E,E’) and gabapentin-treated (F,F’) show the increase in the numbers of branches in response to gabapentin exposure. (G,H) images show large field of view (20x) for both groups; control and gabapentin treated cultures, respectively. Scale bar = 50 um (E,F). Scale bar = 10 um (G,H). Data are represented as mean ± SEM, n = 4 experiments. *p < 0.05.
FIGURE 5
FIGURE 5
Gabapentin exposure inducing a significant upregulation in the expression of Nurr1 (B), En1 (C), Pitx3 (D), Chl1 (F), Dat (G) and Drd2 (H), significant downregulation the expression of Bdnf (I), and no significant change in the expression of Lmx1a (A) and Th (E) in vmDA neurons.
See this image and copyright information in PMC

References

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