Abstract
This study examined the ameliorating effect of alpha-glycosyl isoquercitrin (AGIQ), an antioxidant, on disrupted hippocampal neurogenesis in the dentate gyrus (DG) in a rat model of autism spectrum disorder induced by prenatal valproic acid (VPA) exposure. Dams were intraperitoneally injected with 500 mg/kg VPA on gestational day 12. AGIQ was administered in the diet at 0.25 or 0.5% to dams from gestational day 13 until weaning at postnatal day (PND) 21 and then to pups until PND 63. At PND 21, VPA-exposed offspring showed decreased numbers of type-2a and type-3 neural progenitor cells (NPCs) among granule cell lineage subpopulations. AGIQ treatment at both doses rescued the reduction in type-3 NPCs. AGIQ upregulated Reln and Vldlr transcript levels in the DG at 0.5% and ≥ 0.25%, respectively, and increased the number of reelin+ interneurons in the DG hilus at 0.5%. AGIQ at 0.25% and/or 0.5% also upregulated Ntrk2, Cntf, Igf1, and Chrnb2. At PND 63, there were no changes in the granule cell lineage subpopulations in response to VPA or AGIQ. AGIQ at 0.25% increased the number of FOS+ granule cells, accompanied by Gria2 and Gria3 upregulation and increasing trend in the number of FOS+ granule cells at 0.5%. There was no definitive evidence of VPA-induced oxidative stress in the hippocampus throughout postnatal life. These results indicate that AGIQ ameliorates the VPA-induced disruption of hippocampal neurogenesis at weaning involving reelin, BDNF-TrkB, CNTF, and IGF1 signaling, and enhances FOS-mediated synaptic plasticity in adulthood, potentially through AMPA-receptor upregulation. The ameliorating effects of AGIQ may involve direct interactions with neural signaling cascades rather than antioxidant capacity.
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Acknowledgements
The authors thank Yayoi Kohno for her technical assistance in preparing the histological specimens. We also thank Jeremy Allen, Ph.D., from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
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This work was supported by San-Ei Gen F.F.I., Inc. and by a research fund from the Institute of Global Innovation Research, Tokyo University of Agriculture and Technology.
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Kazumi Takashima: Methodology, formal analysis, investigation, data curation, writing—original draft, and visualization. Hiromu Okano: Methodology, formal analysis, investigation, data curation, and writing—review and editing. Ryota Ojiro: Investigation and writing—review and editing. Qian Tang: Investigation and writing—review and editing. Yasunori Takahashi: Investigation and writing—review and editing. Shunsuke Ozawa: Investigation and writing—review and editing. Xinyu Zou: Investigation and writing—review and editing. Mihoko Koyanagi: Resources, writing—review and editing, and project administration. Robert R. Maronpot: Validation and writing—review and editing. Toshinori Yoshida: Investigation and writing—review and editing. Makoto Shibutani: Conceptualization, writing—review and editing, visualization, supervision, and funding acquisition.
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Animal experiments in the present study were conducted in accordance with the National Institutes of Health guide for the care and use of laboratory animals (NIH Publications No. 8023, revised 1978), and all efforts were made to minimize animal suffering. The experimental procedures were approved by the Animal Care and Use Committee of the Tokyo University of Agriculture and Technology (Approved No.: R2-05 for main study; R03-162 for satellite study).
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Mihoko Koyanagi is employed by a food additive manufacturer whose product lines include AGIQ. Robert R. Maronpot is a scientific consultant at the aforementioned food additive manufacturer. The views and opinions expressed in this article are those of the authors and not necessarily those of their respective employers. Kazumi Takashima, Hiromu Okano, Ryota Ojiro, Qian Tang, Yasunori Takahashi, Shunsuke Ozawa, Xinyu Zou, Toshinori Yoshida, and Makoto Shibutani declare that no conflicts of interest exist.
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Takashima, K., Okano, H., Ojiro, R. et al. Continuous Exposure to Alpha-Glycosyl Isoquercitrin from Gestation Ameliorates Disrupted Hippocampal Neurogenesis in Rats Induced by Gestational Injection of Valproic Acid. Neurotox Res 40, 2278–2296 (2022). https://doi.org/10.1007/s12640-022-00574-8
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DOI: https://doi.org/10.1007/s12640-022-00574-8