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Sharma et al. Zinc supplementation prevents against LPS induced neurotoxicity in rats

as it is present suspended in the air as a component neural tube defects, may also reduce mental health
[25]
of the air pollutant PM2.5 or as part of house dust problems in children. Iodine deficiency in the pregnant
and aerosols generated from contaminated water. [2,3] mother subsequently causes hypothyroxinemia i.e.
These PM2.5 i.e. particulate matter less than 2.5 μm low maternal free thyroxine (T ) and results in damage
4
originate from several sources like oil refineries, metal to the developing brain, which is further aggravated by
processing facilities, tailpipe and brake emissions, cretinism in the fetus.
residential fuel combustion, power plants, and wild
fires. Furthermore, occupational exposure to LPS is Zinc is also one of an essential element in diet of
common for people in agricultural settings or in textile pregnant females as maternal zinc deficiency affects
mills as suggested by previous reports. It has also fetal growth and development, complications of
[4]
been reported that gastrointestinal distress and excess pregnancy, labor and delivery and maternal and infant
alcohol intake are known to increase uptake of LPS health. Zinc is a structural constituent essential
[26]
[27]
from gastrointestinal tract into blood. [5,6] for cell growth, development, and differentiation.
Increasing evidence demonstrates that zinc has an
Further, high levels of LPS have also been detected anti-inflammatory effect. A recent study found that
[28]
in women with bacterial vaginosis. In humans, gram- subcutaneous injection with zinc sulfate alleviated LPS-
[7]
negative bacterial infections are a recognized cause of induced neurodevelopmental damage in fetal brain. [29,30]
embryo loss and preterm labor. Mimicking maternal Zinc is capable of inhibiting LPS or IL-1β-induced nitric
[8]
infection by exposing the pregnant rodents to LPS oxide (NO) formation as well as NO formation by NO
[31]
at early gestational stages resulted in embryonic synthase (NOS). Many studies reported that Zn
2+
resorption and fetal death. [9,10] LPS exposure at middle inhibits LPS-induced TNF-α production by inactivating
gestational stages caused teratogenesis, fetal death nuclear factor-κB (NF-κB) genes which is mediated by
and preterm delivery. [11-13] In addition, several studies protein kinase A. [32,33] Another mechanism reported that
showed that maternal LPS exposure at late gestational Zn increased the intracellular levels of cGMP due
2+
stages led to fetal death, growth restriction, skeletal to reduced enzyme activity of phosphodiestrase-1
development retardation, and preterm labor. [14-18] (PDE-1), PDE-3, PDE-4 in cellular lysate and inhibits
the LPS-induced TNF-α and IL-1β. The development
[34]
Numerous reports demonstrate that inflammatory of anxiety has been previously reported in zinc-deficient
cytokines, such as tumor necrosis factor alpha (TNF-α), rats. [35,36] Zinc can act as a critical neural messenger
have been associated with LPS-induced adverse in healthy and diseased states of the brain through
developmental outcomes. Indeed, several studies its ability to regulate N-methyl-D-aspartate receptor
showed that maternal LPS exposure during pregnancy activity which have central importance in cognitive
significantly increased the level of proinflammatory functions (learning and memory). Recent studies
[37]
cytokines in maternal serum, amniotic fluid, fetal showed that ZnSO supplementation during pregnancy
4
liver, and fetal brain. [19,20] Another study found that protects against LPS-induced fetal growth restriction
the expression of TNF-α, IL-1β and IL-6 is also much and demise through its anti-inflammatory effect. [28]
higher in brains with periventricular leukomalacia (PVL)
than in those without PVL. Mimicking intrauterine Nevertheless, the molecular mechanism of
[21]
infection and inflammation by LPS exposure during zinc-mediated protection against LPS induced
pregnancy significantly increased the levels of TNF-α, developmental toxicity remains elusive. Present study
interleukin-1β (IL-1β) and IL-6 in maternal serum, fetal was designed to investigate the gender biased effects
liver and amniotic fluid, TNF-α and IL-10 in fetal brain of LPS injection during d14-17 of pregnancy on the
in rodents. Several studies showed that maternal neurobehavioral, biochemical and histopathological
[18]
exposure of LPS (120 µg/kg) intraperitoneal in mouse parameters in off-springs. Also, the neuroprotective
at late gestational stages markedly impaired the potentials of zinc supplementation in ameliorating
learning abilities and social behavioral performance in these LPS induced alterations have been established.
adulthood. [22-24]
METHODS
Nutritional deficits may also cause neurodevelopmental
disorders, such as spina bifida, which is common, and Animals
anencephaly, which is rare. Both disorders are neural Healthy Sprague-Dawley rats between 5-7 weeks age
tube defects with malformation and dysfunction of the were procured at the central animal house of Panjab
nervous system and its supporting structures, leading University, Chandigarh, India. They were acclimatized
to serious physical disability. Folic acid (vitamin B) in the department animal house for two weeks in
supplementation in early pregnancy, aimed to prevent polypropylene cages in hygienic conditions. They were
34 Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ March 21, 2017