Abstract
Background: To date it is proved that Alzheimer’s disease (AD) is characterized by a multifactorial etiology which comprises mitochondrial dysfunction, energy depletion, inflammation, and oxidative stress associated with glutathione depletion. All these factors are known to be impacted by beta amyloid protein (Aβ), which is responsible for the activation of amyloidogenic cascade. In the present work a rat intracerebroventricular Aβ(1-40) infusion model of early AD was employed to investigate the effects of Ibuprofen-Glutathione (IBU-GSH) conjugate on morphological modifications, Aβ plaque formation, apoptosis, learning, and memory performance. Methods: Water maze test was used to evaluate drug administration effects on spatial reference memory, immunohistochemistry was carried out to determine Aβ 1-40, iNOS and caspase-3 expression; semithin sections and ultrastructural analyses, by means of light and transmission electron microscopy, respectively, were realized to evaluate samples morphology; TUNEL analysis to identify apoptotic cells. Results and Conclusion: Results showed that in the Aβ+IBU-GSH conjugate treated group, long-term memory consolidation at day 12 was improved, while learning appeared slower respect to control. In Aβ-infused rats, a higher number of Aβ plaques, disorganized pyramidal pyknotic cells, apoptotic cells containing fragmented or swollen mitochondria, dilated blood vessels, and a low number of oligodendrocytes along with the high expression of inducible Nitric Oxide Synthase (iNOS) and caspase-3 were put in evidence. The inflammatory state seemed to be reversed by IBU-GSH treatment, as evidenced by a lower number of Aβ plaques and pyknotic cells, and reorganized neurons containing normal mitochondria; despite this, persistent dilated blood vessels, decreased iNOS expression, lower percentage of apoptosis, and weak caspase-3 levels were observed. Thus mitochondria involvement in the AD inflammatory state is here strongly suggested and neuro-protective and anti-apoptotic IBU-GSH conjugate effect could be useful to reduce the AD inflammatory state.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia, associated with cardinal symptoms such as progressive memory loss due to the degeneration of neurons and synapses in the cerebral cortex and subcortical regions of the brain [1,2]
It was found that the time spent to reach the platform by beta amyloid protein (Aβ)+IBU-GSH treated group was lower at the second and third day of training respect to the time spent by the Aβ treated group
This report describes the in vivo effects exerted by IBU-GSH conjugate on morphological modifications, Aβ plaque formation, inducible Nitric Oxide Synthase (iNOS) protein expression, and apoptosis rate occurrence in parallel to learning and memory performance in Aβ(1-40)-infused rat cerebral cortex, which represents a model of AD
Summary
Alzheimer’s disease (AD) is the most common form of dementia, associated with cardinal symptoms such as progressive memory loss due to the degeneration of neurons and synapses in the cerebral cortex and subcortical regions of the brain [1,2]. The pathogenic cascade that leads to neurodegeneration in AD brain results in the production of Aβassociated free radicals, oxidative stress, and alterations to Glutathione (GSH) metabolism [4]. A significant decrease in Cu and significant increases in Zn and Fe were found in AD hippocampus and amygdala, while Cu, Fe, and Zn are elevated in senile plaques of AD These metal ions can catalyze free radical reactions and contribute to oxidative damage observed in AD brain [8]. To date it is proved that Alzheimer’s disease (AD) is characterized by a multifactorial etiology which comprises mitochondrial dysfunction, energy depletion, inflammation, and oxidative stress associated with glutathione depletion All these factors are known to be impacted by beta amyloid protein (Aβ), which is responsible for the activation of amyloidogenic cascade. In the present work a rat intracerebroventricular Aβ(1-40) infusion model of early AD was employed to investigate the effects of Ibuprofen-Glutathione (IBU-GSH) conjugate on morphological modifications, Aβ plaque formation, apoptosis, learning, and memory performance
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