Dietary alpha‐Lipoic Acid Impacts Brain Development of the Young Pig
Authors: Mudd Austin T , Waworuntu Rosaline , Berg Brian M , Dilger Ryan N 
Published: November 2023

Alpha‐lipoic acid (a‐LA) is an antioxidant that has been shown to ameliorate age‐associated impairments of brain and cardiovascular functions as well as diabetic neuropathy in rodents and humans. While the developing brain is highly metabolic and therefore potentially subject to periods of oxidative stress, relatively little is known about the extent to which antioxidants influence the developing brain. Using the preclinical piglet model, this exploratory study was designed to examine dose response effects of a‐LA on growth, cognition and brain development. Beginning at 2 d of age, 31 male pigs received one of three diets formulated to contain: control (CONT) [0 mg a‐LA/100g], low a‐LA (LOW) [120 mg a‐LA/100g], or high a‐LA (HIGH) [240 mg a‐LA/100g]. From 14 to 28 d of age, pigs were subjected to a spatial T‐maze behavioral assessment and neuroimaging procedures were performed upon study completion at 31 d of age. No differences due to diets were observed in measures of small intestine weight or length, or brain volumes. Additionally, there was no observed interactive effect of diet x day for bodyweight measures. Spatial T‐maze assessment did not reveal learning differences due to diet, however HIGH‐fed piglets exhibited faster (P = 0.02) latency to choice compared with CONT and LOW‐fed pigs on d 2 of the reversal phase. Neuroimaging analysis of microstructure using diffusion tensor imaging (DTI) revealed decreased (P = 0.01) fractional anisotropy (FA) in the internal capsule of HIGH‐fed pigs, compared with CONT‐ and LOW‐fed pigs. Moreover, internal capsule axial diffusivity values in HIGH‐fed pigs were smaller (P < 0.01) than CONT pigs, but were not different from LOW‐fed pigs. Tract‐based spatial statistics (TBSS), which provide a voxel‐wise comparison of FA values along pre‐determined fiber tracts, revealed 4,116 voxels in which HIGH‐fed pigs exhibited lower (P < 0.05) FA values compared with CONT pigs. Furthermore, TBSS revealed 7,105 voxels with lower (P < 0.05) FA values in HIGH‐fed pigs compared with LOW‐fed pigs. In both comparisons, the largest voxel‐wise FA value differences were localized to areas of the internal capsule, further corroborating DTI observations. No TBSS differences were observed between CONT and LOW‐fed pigs. Taken together, the DTI and TBSS data suggest an altered trajectory of brain white matter maturation in HIGH‐fed piglets. In conclusion, lack of difference in growth, behavioral assessment, and neuroimaging outcomes between LOW and CONT pigs, indicate low concentrations of a‐LA support normal development. Future research is warranted to determine if supplementation of low concentrations of a‐LA may confer specific neurodevelopmental benefits to piglets exposed to hypoxia, oxidative or inflammatory stress during development. However, since supplementation at high concentrations may delay brain myelination future research should explore immunohistochemistry staining and/or electron microscopy in conjunction with longitudinal follow‐up to better understand the implications of these findings.Support or Funding InformationSupported by Mead Johnson Nutrition.