Maternal dietary docosahexanoic acid content affects the rat pup auditory system.

Previous studies of the effects of dietary docosahexanoic acid (DHA), 22:6n3, on neurodevelopment have focused mainly on visual-evoked potentials and indices of visual activity, measures that may be confounded by effects on the retina rather than on neural pathways. We investigated the effect of pre- and postnatal maternal dietary DHA content on auditory brainstem conduction times (ABCTs), the appearance of the auditory startle reflex (ASR), and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) activity in brainstem homogenates. Timed pregnant dams were fed, beginning on day 2 of gestation and throughout lactation, a purified diet containing one of three levels of DHA (0, 1, or 3% of total fatty acids, or 0, 0.4 or 1.2% of total energy). On postnatal day (PND) 3, pups were randomly crossfostered within diet groups to minimize litter effects and culled to 10 per litter. Cerebrums and milk from culled pups stomachs were collected for lipid analysis. The timing of appearance of the ASR was determined between PND 10 through 14 and ABCTs were measured in pups on PND 24 and 31. Pups were sacrificed on PND 31 and cerebrums were removed. In each of two replicated studies, pups in the 1% DHA group weighed significantly less on PND 3 and they gained significantly less weight from PND 3 to 31 compared with pups in the 0 or 3% groups (p<0.01). The auditory studies were not conducted on the 1% DHA group since measures of auditory function are in part a function of somatic growth. The tissue fatty acid data for the 1% DHA group did not show unexpected findings. Higher dietary DHA was reflected in milk and pup cerebrums, and levels of arachidonic acid were inversely related to levels of DHA. In the pups of dams fed diets containing 3% versus 0% DHA, the ASR appeared significantly later (p<0.001) and the ABCTs were longer (p<0.05) on PND 31. CNPase activity levels were not different between the 0 and 3% DHA groups. This study demonstrated that the auditory brainstem response is sensitive for identifying effects of diet on neurodevelopment, and that diets supplemented with high levels of DHA may exert a negative influence on central nervous system development, potentially through effects on myelin. This study suggests the need for further studies of pre- and postnatal long chain polyunsaturated fatty acid dietary supplementation.

Role and mechanisms of interleukin-1 in the modulation of neurotoxicity.

OBJECTIVE: Recent studies on cerebral ischemia in the rat have demonstrated that administration of interleukin-1 receptor antagonist (IL-1ra) markedly reduces the volumes of infarcts which are associated with N-methyl-D-aspartate (NMDA)-mediated neurotoxicity. These observations suggested that endogenous interleukin-1 (IL-1) may be involved in the mediation of excitotoxic neuronal injury following ischemia. METHOD: In the present studies, we examined the role of interleukin-1beta (IL-1beta) in NMDA-related and microglia-induced excitotoxicity in cocultures of mixed neurons and microglia. RESULTS: Our observations in these mixed cultures indicated that addition of IL-1beta exaggerated NMDA and glutamate-evoked hippocampal neuron death. Addition of microglia, activated by lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma), to cocultures of cortical neurons and glia induced significantly greater neurotoxicity when compared with cocultures of cortical neurons and untreated microglia. This neurotoxicity did not require that activated glia be in cell-to-cell contact with neurons. Addition of either IL-1ra or the NMDA receptor antagonist MK-801 to cocultures of cortical neurons and activated glia partially reversed the neuronal damage mediated by activated microglia. Finally, IL-1beta concentrations in the supernatant of cocultures of cortical neurons and microglia treated by LPS and IFN-gamma were markedly increased when compared with coculture of neurons with untreated microglia. CONCLUSION: These results suggest that both the NMDA receptor and the IL-1 receptor are involved in microglia-mediated neurotoxicity.