Dietary Alpha-Lipoic Acid Alters Piglet Neurodevelopment

Abstract

Introduction: Alpha-lipoic acid (a-LA) is an antioxidant shown to ameliorate age-associated impairments of brain and cardiovascular function. Human milk is known to have high antioxidant capacity; however, the role of antioxidants in the developing brain is largely uncharacterized. This exploratory study aimed to examine the dose-response effects of a-LA on piglet growth and neurodevelopment.

Methods: Beginning at 2 days of age, 31 male pigs received 1 of 3 diets: control (CONT) (0 mg a-LA/100 g), low a-LA (LOW) (120 mg a-LA/100 g), or high a-LA (HIGH) (240 mg a-LA/100 g). From 14 to 28 days of age, pigs were subjected to spatial T-maze assessment, and macrostructural and microstructural neuroimaging procedures were performed at 31 days of age.

Results: No differences due to diet were observed for bodyweight gain or intestinal weight and length. Spatial T-maze assessment did not reveal learning differences due to diet in proportion of correct choices or latency to choice measures. Diffusion tensor imaging revealed decreased (P = 0.01) fractional anisotropy (FA) in the internal capsule of HIGH-fed pigs compared with both the CONT (P < 0.01)- and LOW (P = 0.03)-fed pigs, which were not different from one another. Analysis of axial diffusivity (AD) within the internal capsule revealed a main effect of diet (P < 0.01) in which HIGH-fed piglets exhibited smaller (P < 0.01) rates of diffusion compared with CONT piglets, but HIGH-fed piglets were not different (P = 0.12) than LOW-fed piglets. Tract-based spatial statistics, a comparison of FA values along white matter tracts, revealed 1,650 voxels where CONT piglets exhibited higher (P < 0.05) values compared with HIGH-fed piglets.

Conclusion: The lack of differences in intestinal and bodyweight measures among piglets indicate a-LA supplementation does not impact overall growth, regardless of concentration. Additionally, no observed differences between CONT- and LOW-fed piglets in behavior and neuroimaging measures indicate a low concentration of a-LA does not affect normal brain development. Supplementation of a-LA at a high concentration appeared to alter white matter maturation in the internal capsule, which may indicate delayed neurodevelopment in these piglets.

Keywords: alpha-lipoic acid; antioxidant; internal capsule; neonatal; neurodevelopment; nutrition; piglet.

Figure 1

Piglet daily bodyweight. Average body weight of each dietary treatment group over 28-day trial period (n = 10–11 per treatment); there was no observed interactive effect of treatment × day for daily bodyweight and no main effect of treatment, only a main effect of day was observed (P < 0.001).

Figure 2

Spatial T-maze assessment. (A) No diet × day interaction or main effect of diet was observed in proportion of correct choices on each day. Only a main effect of day (P < 0.05) was observed for proportion of correct choice. (B) No diet × day interaction or main effect of diet was observed in latency to choice on each day. Only a main effect of day (P < 0.05) was observed for latency to choice. CONT, LOW, and HIGH treatments were formulated to contain 0, 240, and 480 mg alpha-lipoic acid per liter of reconstituted milk replacer, respectively. (A = acquisition, 8-day phase; R = reversal, 6-day phase).

Figure 3

Internal capsule axial diffusivity and fractional anisotropy. (A) A main effect (P < 0.01) of dietary treatment was observed for internal capsule axial diffusivity (AD). (B) A main effect (P = 0.01) of dietary treatment was observed for internal capsule fractional anisotropy (FA). CONT, LOW, and HIGH treatments were formulated to contain 0, 240, and 480 mg alpha-lipoic acid per liter of reconstituted milk replacer, respectively. ^abMeans without a common superscript letter differ (P < 0.05).

Figure 4

White matter tract fractional anisotropy differences. Fractional anisotropy differences along predetermined white matter tracts in which CONT piglets exhibited higher (P < 0.05) FA values compared with HIGH piglets. The images generated are an average of all piglet brains from this study, green lines signify regions in which all piglets exhibited white matter voxels. Representative slices were chosen to highlight areas in which FA values in CONT piglets were significantly different when compared with HIGH piglets, noted as red–yellow voxels. (A) Axial slices, with varying X-coordinates and static Y = 103 and Z = 110 coordinates, determined using the Piglet Brain Atlas (23). (B) Coronal slices, with varying Y-coordinates and static X = 68 and Z = 78 coordinates, determined using the Piglet Brain Atlas. Red and yellow colors indicate degree of statistical difference from P = 0.05 to P = 0.0001, respectively (23).