Abstract
BackgroundPerinatal maternal malnutrition is related to altered growth of tissues and organs. The nervous system development is very sensitive to environmental insults, being the hippocampus a vulnerable structure, in which altered number of neurons and granular cells has been observed. Moreover, glial cells are also affected, and increased expression of proinflammatory mediators has been observed. We studied the effect of Glucagon-like peptide-1 receptor (GLP-1R) agonists, liraglutide, which have very potent metabolic and neuroprotective effects, in order to ameliorate/prevent the glial alterations present in the hippocampus of the pups from mothers with food restriction during pregnancy and lactation (maternal perinatal food restriction—MPFR).MethodsPregnant Sprague-Dawley rats were randomly assigned to 50% food restriction (FR; n = 12) or ad libitum controls (CT, n = 12) groups at day of pregnancy 12 (GD12). From GD14 to parturition, pregnant FR and CT rats were treated with liraglutide (100 μg/kg) or vehicle. At postnatal day 21 and before weaning, 48 males and 45 females (CT and MPFR) were sacrificed. mRNA expression levels of interleukin-1β (IL1β), interleukin-6 (IL-6), nuclear factor-κβ, major histocompatibility complex-II (MHCII), interleukin 10 (IL10), arginase 1 (Arg1), and transforming growth factor (TGFβ) were assessed in the hippocampus by quantitative real-time polymerase chain reaction. Iba1 and GFAP-immunoreactivity were assessed by immunocytochemistry.ResultsThe mRNA expression IL1β, IL6, NF-κB, and MHCII increased in the hippocampus of male but not in female pups from MPFR. In addition, there was an increase in the percentage of GFAP and Iba1-immupositive cells in the dentate gyrus compared to controls, indicating an inflammatory response in the brain. On the other hand, liraglutide treatment prevented the neuroinflammatory process, promoting the production of anti-inflammatory molecules such as IL10, TGFβ, and arginase 1, and decreasing the number and reactivity of microglial cells and astrocytes in the hippocampus of male pups.ConclusionTherefore, the GLP-1 analog, liraglutide, emerges as neuroprotective drug that minimizes the harmful effects of maternal food restriction, decreasing neuroinflammation in the hippocampus in a very early stage.
Highlights
IntroductionThe nervous system development is very sensitive to environmental insults, being the hippocampus a vulnerable structure, in which altered number of neurons and granular cells has been observed
Perinatal maternal malnutrition is related to altered growth of tissues and organs
Food restriction during pregnancy decreased body weight gain of the dams independently of liraglutide After beginning on day 12 of gestation the food restriction protocol (50% of daily intake of control dams), a significantly decrease in the body weight gain was observed from day 14 of pregnancy in food-restricted dams compared to controls fed ad libitum (MPFR/VEH, n = 6; control groups (CT)/VEH; n = 6)
Summary
The nervous system development is very sensitive to environmental insults, being the hippocampus a vulnerable structure, in which altered number of neurons and granular cells has been observed. The development of the nervous system is very sensitive to environmental insults, which influence the temporal and regional arising of critical developmental processes (i.e., proliferation, migration, differentiation, synaptogenesis, myelination, and apoptosis) [3]. In this regard, undernutrition during early life causes deficits and distortions of brain structure and function. The hippocampus is highly affected, altering its morphology, causing a deficit in the total number of dentate gyrus granule cells and neurons, and since a vulnerable structure to undernutrition. Malnutrition of the mother attenuates the field excitatory postsynaptic potentials, reduces dendritic spine density, and affects morphology of hippocampus, and so it alters learning and memory-based behaviors [7, 8]
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