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Betaine in the Brain: Characterization of Betaine Uptake, its Influence on Other Osmolytes and its Potential Role in Neuroprotection from Osmotic Stress

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Abstract

Betaine (N-trimethylglycine), a common osmolyte, has received attention because of the number of clinical reports associating betaine supplementation with improved cognition, neuroprotection and exercise physiology. However, tissue analyses report little accumulation of betaine in brain tissue despite the presence of betaine/GABA transporters (BGT1) at the blood brain barrier and in nervous tissue, calling into question whether betaine influences neuronal function directly or indirectly. Therefore, the focus of this study was to determine what capacity nervous tissue has to accumulate betaine, specifically in the hippocampus, a region of the brain associated with learning and memory and one that is particularly susceptible to damage (e.g., seizure activity). Here we report that hippocampal slices actively accumulate betaine in a time, dose and osmolality dependent manner, resulting in peak intracellular concentrations four times extracellular concentrations within 8 h. Our data also indicate that betaine uptake differentially influences the accumulation of other osmolytes. Under isosmotic conditions, betaine uptake minimally impacted some osmolytes (e.g., glycerylphosphorylcholine and glutamate) while significantly reducing others (taurine, creatine, and myo-inositol). Under osmotic stress (hyperosmotic) conditions, we observed dramatic changes in osmolytes like glycine and glutamine—key players in inhibitory neurotransmission—and little change in osmolytes such as taurine, creatine and myo-inositol when betaine was available. These data suggest that betaine may influence pathways of inhibitory neurotransmitter production/recycling in addition to serving as an osmolyte and metabolic intermediate. In sum, our data provide detailed characterization of betaine uptake in the hippocampus that implicates betaine in the modulation of hippocampal neurophysiology and neuroprotection.

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Acknowledgements

We are grateful for financial support from Whitman College and Danisco Sweeteners Oy, particularly for their support of the undergraduate student researchers on this project. We would like to thank Drs. Kirsti Tiihonen and Stuart AS Craig for their contributions to experimental design and data analysis. This research was partially funded by Danisco USA, Inc., a commercial supplier of betaine, and intellectually supported by employees of Danisco, Drs. Tiihonen and Craig. The authors declare that they have no competing interests to disclose and that the findings reported in this study do not constitute an endorsement for betaine as a product.

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  1. Biology Department, Whitman College, 345 Boyer Ave., Walla Walla, WA, 99362, USA

    Leena S. Knight, Quinn Piibe, Ian Lambie, Christopher Perkins & Paul H. Yancey

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  1. Leena S. Knight
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Knight, L.S., Piibe, Q., Lambie, I. et al. Betaine in the Brain: Characterization of Betaine Uptake, its Influence on Other Osmolytes and its Potential Role in Neuroprotection from Osmotic Stress. Neurochem Res 42, 3490–3503 (2017). https://doi.org/10.1007/s11064-017-2397-3

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