Deferoxamine Attenuates Lipopolysaccharide- Induced Central Neuroinflammation And Memory Impairment In Mice

Part I Establishment of a mouse model of LPS-induced cognitive impairmentObjective To establish a mouse model of LPS-induced cognitive impairment. Methods Forty C57 mice were randomly assigned into five groups and administered with 0,0.01, 0.1,2 and 5μg of LPS by stereotactic intracerebroventricular injection 5 days after acquisition training in a Morris water maze (MWM). The probe test for reference memory was conducted 1 day after LPS administration, and working memory was tested on days 1 to 3 after LPS administration. Results The Morris water maze indicated cognitive decline in all LPS groups, while 2000 ng LPS group showed decrease of platform-site crossovers, distance around platform, percentage of distance and time traveled in the target quadrant during probe testing, latency to the platform during the working memory test in Morris water maze (P< 0.05). Discussions Intracerebroventri-cular administration of lipopolysaccharide at dose of 2μg induces cognitive decline in C57 mice, suggesting that LPS-induced CNS inflammation could contribute to establish a cognitive dysfunction model in mice.Part II Effect of DFO on LPS-induced cognitive impairment in miceObjective To investigate effects of DFO on LPS-induced cognitive impairment in mice. Methods To optimize the dose of DFO to alter LPS-induced cognitive impairment, six randomly assigned groups of mice were intracerebroventricularly administrated with 0, 0,0.1,0.5,2.5 and 5μg of DFO 3 days prior to micro injection of LPS and all groups received intracerebroventricular administration of LPS, except the first group that served as a control group. Then one hundred mice were randomly assigned into four groups:control, DFO, LPS, and LPS+DFO (n= 25 for each). Intracerebroventricular administration of 0.5μg DFO was commenced 3 days prior to microinjection of 2μg LPS, while the control group received equal volume of aCSF (artificial cerebrospinal fluid). Body weights were determined daily. The MWM and open field test were carried out and the status of microglia, levels of IL-1β and TNF-α,expression of caspase-3 and GSK3-beta,the activities of malondialdehyde (MDA) and superoxide dismutase (SOD), as well as iron metabolic changes in the hippocampus were observed to evaluate the LPS-induced hippocampal damage and the neuroprotective effect of DFO. Results Treatment 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 0.5μg 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 GSK3P 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. Discussion Our results suggest that DFO reduces LPS-induced hippocampal inflammation and consequently the pathological progression by blocking iron accumulation in neurons, eventually improving memory performance.Conclusions:LPS triggers a transient neurocognitive decline in a mouse model that is associated with brain iron accumulation and a series of inflammatory cascade response; 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.