Background: To further the exploration of the pathogenesis of mild cognitive impairment (MCI), we aimed to determine the appropriate dose for a rapidly established MCI rat model using D-galactose (D-gal), with lasting cognitive effects. Methods:In Experiment 1, we evaluated various D-gal concentrations (100-2,000 mg/kg/day), and determined that, compared with saline injections of the same volume. In Experiment 2, we evaluated the duration of the effect of 1,000 mg/kg/day D-gal injections for 1 week, with MWM testing initiated at 1 day, 1 month, and 3 months after completion of the injection regime in three model groups, respectively. Results:In Experiment 1, D-gal injections at a concentration of 1,000 mg/kg/day for 1 week was adequate to induce a significantly worse Morris water maze (MWM) test performance and pathomorphologic changes in the hippocampus, with MWM testing initiated 1 day after completion of the injection regime. In Experiment 2, Before modeling, the overall condition (fur, mental state, foraging behavior, and activity level), body weight, swimming speed, and swimming time did not significantly differ between the control (saline injections) and model groups (D-gal injections). After modeling, MWM test performance was considerably worse (longer escape latencies and fewer platform crossings within 90 seconds) in the model groups than in the control group, without significant differences among model groups. Furthermore, movement trajectories were similar among model groups.Conclusions: These results demonstrate that subcutaneous injections of D-gal 1,000 mg/kg/day for 1 week produce changes consistent with the characteristics and pathological processes of MCI. Thus, highdose D-gal injection allows the rapid establishment of an MCI model that is effective and sustainable.

Background: The development of novel treatment strategies to reverse or impede cognitive dysfunction associated with mild cognitive impairment (MCI) has gained attention in recent times. Meanwhile, hyperbaric oxygen (HBO) has been widely used as a neuroprotective therapy that can promote recovery of damaged neurons. The aim of this study was to investigate the effects of HBO on cognitive function in rats with MCI and to clarify the associated mechanisms. Methods:We established a D-galactose-induced MCI rat model and evaluated the role of extracellularregulated kinase (ERK) signaling in HBO therapy for cognitive function using a specific inhibitor, U0126.All Rats were randomly assigned to four groups with 12 rats per group: normal control group; D-gal model group (group MCI); D-gal + HBO group (group HBO); D-gal + HBO + U0126 group (group U0126). We evaluated cognitive function by Morris water maze and pathological changes by hematoxylin and eosin (HE) staining of hippocampal slices. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of caspase 3, while total ERK1/2 and phospho-ERK1/2 were assessed by Western blotting.Results: Shorter escape latency was observed in the HBO group as compared to the MCI group, which was to some extent reversed by U0126. Similarly, the HBO group showed the highest number of platform crossings as compared to the MCI and U0126 groups. Pathological analysis also showed less apoptosis and better hippocampal cell morphology in the HBO group. Caspase 3 levels also differed significantly, with lowest expression in the HBO group as compared to the MCI and U0126 groups. The levels of total ERK1/2 and p-ERK1/2 were more elevated in the HBO group as compared to the MCI group.Conclusions: This study found that HBO treatment has a protective effect on early cognitive dysfunction in rats with MCI. HBO therapy may act through ERK signaling, which inhibits apoptosis and protects cognitive function.

Background: Mild cognitive impairment (MCI) as a prestage of dementia shares the most risk factors with dementia. In the present study, we explored the effect of flurbiprofen axetil on reducing the response of the central nervous system to inflammatory factors and anti-inhibiting apoptosis with the aim of developing a formalin-induced inflammatory pain model using MCI rats.Methods: Rats were subjected to sham operation (Sham group) or formalin-induced inflammatory pain, with or without flurbiprofen axetil (10 mg/kg). MCI rats were administered D-galactose (1,000 mg/kg) for 7 days subcutaneously. Thereafter, formalin was injected subcutaneously into the hind paws of rats, while sham group was injected with only normal saline. In the formalin/flurbiprofen group (F/F group), flurbiprofen axetil was injected into the tail vein 15 min before formalin was given, and the formalin/saline group (F/S group) used normal saline instead of the drug for injection. The pain score was recorded, and the time-score curve was drawn. The escape latency time and the number of times crossing the platform were recorded. The expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), AMP-activated protein kinase-α (AMPKα), and nuclear factor-κB p65 (NF-κB p65) in hippocampal tissue was determined. Varying degrees of pathological changes in the hippocampal CA1 region were observed. Results:The II phase pain score of rats in the F/F group was lower than that of the F/S group rats (P<0.05).The evasion incubation period and the number of platform crossings increased in both the F/F group and the F/S group (P<0.05), and were more significant in the F/S group. The relative content of AMPKα increased sequentially in the 3 groups, and the difference between the two comparisons of each group was statistically significant (P<0.05). The relative content of IL-6, TNF-α and NF-κB in the F/S group was greater than that of the F/F group, and the difference was statistically significant (P<0.001). Pathological morphological observations can be seen that the phenomena of nuclear consolidation, deep staining, and neuronal apoptosis occur, and the F/S group is more obvious. Conclusions:Flurbiprofen axetil can reduce the inflammatory response and cognitive function of an inflammatory pain model using MCI rats through the AMPKα/NF-κB signaling pathway.