الفهرس 
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Abstract
IONPs have attracted widespread interest due to their superparamagnetic properties and their potential applications in many fields. Industrially, they are used in wastewater treatment, gas sensing, semiconductors, sorbents, lubrications, cosmetics, coatings, paints. In biomedicine such as drug targeting, gene delivery, cell labeling, a contrast agent in magnetic resonance imaging and hyperthermia therapy.
Due to their unique physico chemical properties, IONPs can potentially cause adverse effects on organs such as brain in our study, also liver, spleen, lung can be affected. Therefore, Safety issues of these nanoparticles in any clinical applications are a major concern. The main toxicological concern of IONPs is that via fenton reaction they produce ROS that cause brain damage and dysfunction.
Qurecetin , a natural flavonoid and strong antioxidant and free radical scavenger and iron chelator, has potential therapeutic for several neuronal injuries and neurodegenerative diseases, consequently they could counteract toxicological effects of these nanoparticles.
The aim of our study to explore possible mechanism of IONPs-induced brain toxicity and dysfunction and possible protective effects of quercetin administration at different doses through measuring changes in body weight, MDA and iron levels, glutathione redox, enzymatic biomarkers, neurotransmitter hormones, mitochondrial biogenesis, histological findings and immunohistochemistry.
Twenty five male adult rats, weighing 150 ± 30 B.W., were allocated equally into five groups: control received normal basal diet and water adlibitum, IONPs group intraperitoneally injected with IONPs 50 mg/kg b.w. three times a week, IONPs+QT 25 mg group was administrated with the same dose of IONPs and gavaged with QT 25 mg QT/kg b.w. daily, IONPs+QT 50 mg group was administrated with the same dose of IONPs and gavaged with QT 50 mg QT/kg b.w. daily, and IONPs+QT 100 mg group was administrated with the same dose of IONPs and gavaged with QT 100 mg QT/kg b.w. daily.
At the end of experiment, final body weight were measured, the rats were fasted for 12 hrs and anesthetized using ketamine/xylazine (100 mg/kg, 10 mg/kg i.p.) then euthanized, The brain were immediately dissected, rinsed with chilled normal saline 0.9% and divided into three parts; first one was used for histopathological examination (fixed in neutralbuffered formalin10%), second one for gene expression of PGC-1α and mtTFA (snap frozen in liquid nitrogen and stored at -80 oC) and the third part was used for estimation of iron level, enzymatic biomarkers, neurotransmitter hormones and oxidative and antioxidant indices (weight and stored at -80 oC).
The obtained results can be summarized as following:
1- IONPs induced a significant increment in body weight.
2- IONPs induced a significant increment in Fe level.
3- Our histopathological findings confirmed damage induced by penetration of iron nanoparticles into brain tissue induce histopathological changes included congestion of submeningeal blood vessels, satellosis, neurophagia, gliosis and spongiosis, congestion of Choroid plexus and severe depletion of purkinji cell. our histological findings linked with alterations which occurred in our study in brain enzymatic biomarkers, neurotransmitter hormones, mitochondrial biogenesis gene expression , antioxidant and oxidant indices. As following:
3.1- IONPs induced a significant increase in ACHE and CK activity compared to control.
3.2- IONPs induced a significant decrease in Serotonin, Melatonin and Epinephrine levels.
3.3- IONPs induced a significant down regulation of PGC-1 and mtTFA genes compared to control rats.
3.4- IONPs induced a significant reduction in Total GSH level, GSH level and GSH/GSSG ratio alongside with a significant increment in GSSG level compared to control values. on the other hand, IONPs induced a significant increment in MDA.
3.5- Immunohistochemical findings confirmed oxidative damage induced by IONPs through apoptosis as Immunohistochemical evaluation of brain tissue showed that Brain of a rat of control group showing caspase3 negative immunostained neurons and negative and strong bcl-2 positive brown immunostained neurons. In IONPs treated rats, cerebrum showing strong, moderate and weak caspase3 positive brown immunostained neurons, brain showing negative, few strong and weak bcl-2 positive brown immunostained neurons.
4- Compared to IONPs group, QT 25, 50 and 100 mg/kg b.w. + IONPs induced a non-significant difference in body weight in all weeks.
5- Compared to IONPs group, QT 25, 50 and 100 mg/kg b.w. +IONPs induced a non-significant reduction in Fe level these results were confirmed by Prussian blue stain by moderate, few and very few blue spots representing Fe contents respectively. therefore, it was noticeable that QT 100 mg/kg b.w. was the best one.
6- our histopathological results cofirmed role of QT in chelating iron and inhibiting oxidative stress protecting neural tissue through restoring these histopathological changes in IONPs-treated rats by maintaining normal histological structure of brain tissue especially by in IONPs-treated rats QT 100 mg/kg b.w. in which only there was mild depletion of purkinji cell and this linked with improvement as following:
6.1- Compared to IONPS group, Co-treatment with QT 25, 50, 100 mg/kg b.w. induced a significant (P<0.05) decrease in ACHE level and CK level, Obviously, QT 100 mg/kg b.w. was better than QT 50 mg/kg b.w. and QT 25 mg/kg b.w. has lowest effect in modulating brain enzymatic biomarkers.
6.2- Compared to IONPs group, Co-administration of QT 25, 50 and 100 mg/kg b.w. induced a significant (P<0.05) increase in Melatonin, Epinephrine and Serotonin levels except QT 25 mg/kg b.w. induced a non significant increase in Serotonin. Clearly, QT 100 mg/kg b.w. was better than QT 50 mg/kg b.w. and QT 25 mg/kg b.w. was the lowest one in moderating neurotransmitter hormones.
6.3- The co-supplementation with QT 25, 50 mg/kg b.w. results in a non significant up regulation of PGC1 and mtTFA genes, The co-supplementation with QT 100 mg/kg b.w. results in a significant (P<0.05) up regulation of PGC1) and mtTFA genes compared to IONPs treated rats. Evidently, QT 50 mg/kg b.w. was better than QT 25 mg/kg b.w. and QT 100 mg/kg b.w. was the best one in up regulation of the two genes.
6.4- Compared to IONPs group, Co-supplementation with QT 25 and 50 mg/kg b.w. induced a non-significant increment in Total GSH level, GSH level and GSH/GSSG ratio alongside with a non significant reduction in GSSG level, Co-administration with QT 100 mg/kg b.w. induced a significant (P<0.05) increment in Total GSH level, GSH level and GSH/GSSG ratio alongside with a non significant reduction in GSSG level. On the other hand, Compared to IONPs group, Co-administration of QT 25, 50 and 100 mg/kg b.w. induced a significant (P<0.05) reduction in MDA level. Noticeably, QT 50 mg/kg b.w. was better than QT 25 mg/kg b.w. and QT 100 mg/kg b.w. was the best one.
6.5- antiapoptosis properity of QT appeared through Brain of rat treated with IONPs and QT 25 mg/kg b.w. showing strong, moderate , weak caspase3 positive brown immunostained neurons and negative bcl-2 brown immunostained neurons. In rat treated with IONPs and QT 50 mg/kg b.w., Cerebrum showing strong, moderate and weak caspase3 positive brown immunostained neurons, brain showing moderate and weak bcl-2 positive brown immunostained neurons. In rat treated with IONPs and QT 100 mg/kg b.w., Brain showing negative , weak caspase3 positive brown immunostained neurons and strong bcl-2 positive brown immunostained neurons.