Abstract
BackgroundNeuroinflammation often results in enduring cognitive impairment and is a risk factor for postoperative cognitive dysfunction. There are currently no effective treatments for infection-induced cognitive impairment. Previous studies have shown that the iron chelator deferoxamine (DFO) can increase the resistance of neurons to injury and disease by stimulating adaptive cellular stress responses. However, the impact of DFO on the cognitive sequelae of neuroinflammation is unknown.MethodsA mouse model of lipopolysaccharide (LPS)-induced cognitive impairment was established to evaluate the neuroprotective effects of DFO against LPS-induced memory deficits and neuroinflammation. Adult C57BL/6 mice were treated with 0.5 μg of DFO 3 days prior to intracerebroventricular microinjection of 2 μg of LPS. Cognitive function was assessed using a Morris water maze from post-injection days 1 to 3. Animal behavioral tests, as well as pathological and biochemical assays were performed to evaluate the LPS-induced hippocampal damage and the neuroprotective effect of DFO.ResultsTreatment of mice with LPS resulted in deficits in cognitive performance in the Morris water maze without changing locomotor activity, which were ameliorated by pretreatment with DFO. DFO prevented LPS-induced microglial activation and elevations of IL-1β and TNF-α levels in the hippocampus. Moreover, DFO attenuated elevated expression of caspase-3, modulated GSK3β activity, and prevented LPS-induced increases of MDA and SOD levels in the hippocampus. DFO also significantly blocked LPS-induced iron accumulation and altered expression of proteins related to iron metabolism in the hippocampus.ConclusionsOur results suggest that DFO may possess a neuroprotective effect against LPS-induced neuroinflammation and cognitive deficits via mechanisms involving maintenance of less brain iron, prevention of neuroinflammation, and alleviation of oxidative stress and apoptosis.
Highlights
Neuroinflammation often results in enduring cognitive impairment and is a risk factor for postoperative cognitive dysfunction
Activation of microglia by LPS has been linked to the pathogenesis of neuronal death, neurogenesis failure, and hippocampus-dependent memory and synaptic plasticity impairments; the mechanisms responsible for these effects are not well understood [18], brain tissue oxidative damage has been considered an important contributor to memory impairment induced by LPS [19]
In the preliminary experiment designed for determining the optimal dose of LPS, intracerebroventricular administration of 2 μg of LPS induced memory impairment but no swimming speed change in the Morris water maze (MWM)
Summary
Neuroinflammation often results in enduring cognitive impairment and is a risk factor for postoperative cognitive dysfunction. The elderly are vulnerable to the adverse effects of infections on cognitive function, and the aging process itself is associated with enhanced neuroinflammatory processes involving microglial activation and production of pro-inflammatory cytokines [2,3]. It is known that pro-inflammatory mediators disrupt hippocampal neuronal functions, including longterm potentiation and working memory consolidation [15,16]. Cytokines such as TNF-α and IL-1β are involved in hippocampal long-term potentiation and dendritic branching, which are processes involved in memory formation and maintenance [17]. Activation of microglia by LPS has been linked to the pathogenesis of neuronal death, neurogenesis failure, and hippocampus-dependent memory and synaptic plasticity impairments; the mechanisms responsible for these effects are not well understood [18], brain tissue oxidative damage has been considered an important contributor to memory impairment induced by LPS [19]
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