Study Of COG1410 Ameliorate Cognitive Deficits And Provides Neuroprotective Potential By Reduce Aβ Deposition Following Traumatic Brain Injury In Rats

Traumatic brain injuryas a cause of progressive neurodegenerative disorders and display Alzheimer’s disease(AD)-like cognitive impair- ments.There is solid evidence that traumatic brain injury(TBI) is a risk factor for AD and disturbances of the balance between production and degradation of amyloid beta(Aβ) certainly play a crucial role in the disorder.Post mortem analysis of brains of long-term survivors as well as patients surviving only few days after a brain trauma demonstrated a widespread deposition of Aβ peptides. The TBI-induced up-regulation of AβexpressionBy measuring Aβ after experimental TBI in rat, we found that Aβpeaked early after injury(12-48 hours). Although the role of Aβin the injury cascade is unknown, multiple preclinical studies have demonstrated a correlation between reduced Aβ and improved cognitive outcome. Therefore, therapeutic strategies that enhance Aβ clearance may be beneficial after TBI.COG1410, a small, novel Apolipoprotein E(Apo E)peptide derived from the receptor binding region of apo E, has been classified as anti-inflammatory in nature and improves motor, sensorimotor.and cognitive dysfunction following TBI.In order to further examine COG1410’s efficacy on cognitive recovery, the present study evaluated COG1410 relevance to Aβ following TBI. Enhance Aβ clearance through an COG1410-mediated pathwayit appears that the TBI-induced and Aβ related inflammatory cytokines IL-1β and TNF-α can also be reduced after TBI.In this study,It could be speculated that the TBI- induced accumulation of Aβcan be clear by COG1410.Objective: This research was applied with COG1410 to reduce accumulation of Aβ as well as decrease the TBI-induced and Aβ related inflammatory cytokines IL-1β and TNF-αin hippocampus subregion in rats. Toimprove cognitive function in the early days of TBI, and provides a new treatment strategiesfor Clinical.Method: This study included 160 male Sprague-Dawley(SD) rats were randomly divided to four groups: Sham group(n=40), TBI group(n=40), COG1410 group(n=40) and Th group(n=40). Furthermore, each group was divided into 6h, 12 h, 24 h and 48 h. We establishthe TBI model by Marmarou’s falling method. We observe those following indexes: H﹠E stains was used to observe morphological changes in hippocampus subregion. The cellular localization of Aβ was observed by immunofluorescence microscope. The expression of Aβ, IL-1β and TNF-α were evaluated by Western blotting.Morris water maze test can help to detect the other 40 rats ability of cognitive and memory at 7-11 day following TBI by Morris water maze test. The western blot was quantified by using the Gel-Doc analysis software. SPSS 18.0 was used to analysis experimental data. Q-test was selected to determine the significance in two groups. P<0.05 was considered as statistically significant.Result:1 Observed by H﹠E under microscope: The cells in the hippocampus of Sham group,arrangedwell, structure intact, with no significant pathological changes. In TBI group, the hippocampus brain tissue is loose and edema in different degrees. Cells and capillaries gap widened obviously after trauma. The hippocampus neuron number decreased dramatically at the same timestructure suffered severe damage, nuclear Jen part disappears. In COG1410 group, The hippocampus tissue edema is lighter, cells and capillaries gap widened mild. Neuronal structures are contained intact, the number of neurons issignificantly increased compared with TBI group. In Th group, the tissue is similar to TBI group.2 Testing forcognitive learning and memory ability: TBI group compared with the Sham group performed navigation test 7-10 days after trauma, rats escape relatively significant increase in the average latency(P<0.05). Compared with TBI group, COG1410 can significantly improve motor and cognitive learning memory in the MWM.The average escape latency of COG1410 group was significantly shorter in 8-10 days following TBI(P<0.05). The average escape latencyof Th group compared with COG1410 group in 7-10 days following TBI the average escape latencywas significantly longer(P<0.05).3 Expression of TNF-α by western blot:The Sham group has a little expressionof TNF-α,and there were no changes in each point. Compared with the Sham group, the expression of TNF-α was increased 6h after injury(P<0.05), peaked at 12h(P<0.05), continuous high expression at 48h(P<0.05). In COG1410 group, the expression of TNF-α is obviouslylighter than the TBI group in 6-48h(P<0.05).4 Expression of IL-1β by western blot: IL-1βhas a small expression in Sham group, the expression have no difference at all time points. TBI group compared with the Sham group, IL-1β expression was significantly higher from 6h after TBI(P<0.05), and reached its highest point at 12h(P<0.05).In COG1410 group,theexpression of IL-1βis significantly lower than the TBI at all the time points(P<0.05).5 Aβ and Neu N(neuronal marker)double labelling result in immuno- fluorescence in the hippocampus,The green fluorescent of Neu N accumu- lated in neuronal nucleus labeled by FICT, the red fluorescent of Aβ was accumulated around neuronal cell labeled by TRITC.At 12 h after TBI, Neu N(green) and Aβ(red) werecollocated in hippocampus.6 Expression of Aβ by western blot: In Sham group, we could not see the change of Aβ in all points. Compared with the Sham group,the value of Aβis gradually raising from 6h and peaked at 12 h in TBI group(P<0.05). Aβ gathering togetherdid not ease over time, it is still higher than the Sham group at 24 h post trauma(P<0.05). The changes of Aβ expression in COG1410 group is significantly lower than the TBI group in 6-24h(P<0.05). The changes of Aβ expression in Th group is significantly higher than the COG1410 group in 6-24h(P<0.05).Conclusion:We have shown that TBI increases Aβ. Treatmentwith an COG1410 reduces the TBI-induced A β peak at 12-48 hours.At the same time Aβ related inflammatory cytokines IL-1β and TNF-α can also be reduced.These biochemical changes are accompanied by improvements in congnitive functional outcome and a reduction in brain lesion volume. These data suggest that COG1410 is neuroprotective in TBI models of central nervus system(CNS) dysfunction.