Change in brain plasmalogen composition by exposure to prenatal undernutrition leads to behavioral impairment of rats.

Hino K, Kaneko S, Harasawa T, Kimura T, Takei S, Shinohara M, Yamazaki F, Morita S, Sato S, Kubo Y, Kono T, Setou M, Yochioka M, Fujino J, Sugohara H, Kojima H, Yamada N, and Udagawa J. (2019) Change in brain plasmalogen composition by exposure to prenatal undernutrition leads to behavioral impairment of rats. The Journal of Neuroscience, 39(39): 7689-7702

Maternal stress during pregnancy has been associated with the presence of psychological, developmental, and behavioral disorders in the offspring. These stressors can include infection, typical life stresses, traumatic events, and malnutrition. There is evidence suggesting that these stressors can result in alterations in fetal programming through epigenetic changes in neurotransmission systems, resulting in this link between prenatal stress and neurobehavioral disorders. Hino et al were interested in the effects of maternal stress on neurotransmitter systems and any resultant behavioral defects and studied this through comparing different diets in pregnant rats. The pregnant rats were either allowed to eat ad libitum (AL) or a restricted diet that was 40% (40F) of what the AL group consumed from gestational day 5.5 to 10.5 (blastocyst implantation to closure of the neural tube). As lipid composition is often altered in psychological and behavioral disorders, this study focused on phospholipid levels and whether treatments with different types of phospholipids including plasmalogens, a class of lipids containing a vinyl-ether bond at sn-1, could recover any effects caused by malnutrition during fetal development.

To analyze changes in the phospholipid composition of the prefrontal cortex, (PFC) matrix-assisted laser desorption/ionization (MALDI)-tandem mass spectrometry was utilized. The intensity of the 18:0/22:6 species (m/z 774.5) was found to be 6.6-fold greater in the offspring of the 40F group compared to the offspring from the AL group, but there were no other significant differences between the groups for the other phospholipids studied. In addition, 20:1/22:6, lyso-PE 20:4, and lyso-PE 22:6 in the nucleus accumbens and lyso-PE 20:4 and lyso-PE 22:6 in the caudate putamen were reduced in the 40F offspring compared to the AL offspring.

Hino et al also wanted to examine the effect of the 18:0/22:6 plasmalogen species and supplemented the offspring with different phospholipid mixtures through either phosphatidylethanolamine liposomes (PEL) that contained phosphatidylcholine (PC) and plasmalogens, 16:0/18:1 diacyl PE and PC (POPEL), or control liposomes (CL) made out of PCs. The open-field test and elevated maze test were used to examine behavior in the rats after they were administered the treatments intravenously. It was found that the age-related decline in the frequency of crossing and the time spent in the center of the open-field arena was reduced in the rats treated with PEL compared to the CL-treated group. Four days after treatment, the amount of PE 18:0/22:6 is still greater in the PFC in the PEL group compared to the CL group, however many other phospholipid species were lower in the PEL group.

Hino et al found that prenatal malnutrition from gestational day 5.5 to 10.5 in rats can change the phospholipid composition of the brain of the offspring and alter their behavior. As prenatal stress has been associated with behavioral changes for many years, more interesting is their finding that treatment with plasmalogens can recover these effects. Although it has been shown a number of times that internal plasmalogen levels increases with plasmalogen treatment, there are fewer papers that demonstrate the ability of plasmalogens to directly recover a behavioral effect, indicating the importance of these findings. This paper also supports the work that we have completed where our PPI-1040 drug recovered a behavioral effect. The treatment that provided plasmalogens was able to reduce the hyperactive behavior seen in the CL group through lowering the frequency of field crosses and time spent in the middle of the arena. Plasmalogens constitute 20% of the rat cortex and the human brain and due to the vinyl-bond, they provide membranes with increased structure, decrease fluidity, and are involved in vesicular fusion. These results suggest that supplementing plasmalogen levels in a deficient system could improve neurotransmission and normalize neurobehavioral disorders.