| Objective:To explore the intervention mechanism of Sodium Para-aminosalicylic Acid on learning, memory and expression of neuro filament protein in hippocampus of manganese-exposed rats.Methods:144 healthy male Sprague-Dawley rats were randomly divided into blank control group (control group),manganese-exposed group and PAS-Na preventive intervention group (prevention group), total of three groups were builded. The rats in the manganese-exposed group were intraperitoneally (ip) MnCl2·4H2O 15mg/kg, and the control group were ip the same capacity of saline water 1 time/day,5 days/week for 12 weeks; the PAS-Na prevention group were daily treated with PAS-Na 200mg/kg by subcutaneous injection (sc)on back when exposed to manganese, for 12 weeks. After exposed to manganese for 12 weeks, the manganese-exposed group were randomly subdivide into manganese-exposed group and PAS-Na treatment group (treatment group), altogether three groups, the treatment group were daily treated with PAS-Na 200mg/kg by sc on back when the manganese-exposed group were sc on back the same capacity of saline water 1 time/day,3 days/week, for 6 weeks.The whole experiment lasted 18 weeks. Before rats were killed, the ability of learning and memory was tested by Morris Water Maze (MWM) which lasted five days, from Monday to Friday respectively in the sixth week, twelfth week, eighteenth week. Each group animals were randomly divided into two parts when rats were disserted:One part of rats in each group were fixed with 4% Para formaldehyde for the perfusion fixation by heart, then took brain tissues quickly, frozen section, using immunohistochemical method to count the number of Choline Acetyltransferase(ChAT) postive cells of the vertical limb of the diagonal band, the horizontal limb of the diagonal band, nucleus basalis of Meynert in the basal forebrain nucleus and the number of Neurofilament protein (NF) positive cells in Subgrandular Zone of Dentate Gyrus (SGZ). The second part of rats in each group were cervically dislocated, and rapidly craniotomy for fresh brain tissues to determine the activation of Choline Acetylcholine transferase (ChAT), the activation of Acetylcholine Esterase (AChE)and also the brain protein content in basal forebrains.Results:1.Manganese exposure for 6 weeks, PAS-Na prevention intervention for 6 weeks.①The MWM test showed that the escape latency of the third day, the fourth day, the fifth day's training and the swimming distance of the fifth day's training were obviously prolonged in the manganese-exposed group as compared with that of the control group (P<0.05); and the escape latency of the fifth day's training and the swimming distance of the fifth day's training of the rats in the PAS-Na preventive group were significantly shorter than that in the manganese-exposed group (P<0.05).②ChAT positive cells of basal forebrain hDB significantly decreased in the manganese-exposed group as compared with that of the control group (P< 0.01),and the number of ChAT was evidently increased in the PAS-Na preventive group (P<0.05).③The activation of ChAT of basal forebrain in the manganese-exposed group was distinctly lower than the control group (P<0.01), those of PAS-Na preventive group was a little higher than the manganese-exposed group, but the difference between them was no statistically significant (P> 0.05); the activation of AChE of basal forebrain among the groups was no significant difference (P>0.05)④The NF positive cells of Subgrandular Zone of Dentate Gyrus(SGZ) among the groups showed no significant difference (P>0.05)2.Manganese exposure for 12 weeks, PAS-Na prevention interventions for 12 weeks.①The MWM test showed that the escape latency and swimming distance of the fifth day's training were obviously prolonged in the manganese-exposed group as compared with that of the control group (P<0.05);and the escape latency and swimming distance of the fifth day's training of the rats in the PAS-Na preventive group were significantly shorter than that in the manganese-exposed group (P<0.05).②ChAT positive cells of basal forebrain vDB, hBD, NBM region significantly decreased in the manganese-exposed group as compared with that of the control group (P<0.05),and the number of ChAT of these region were evidently increased in the PAS-Na preventive group (P<0.05)③The activation of ChAT of basal forebrain in the manganese-exposed group was significantly lower than the control group (P<0.01),when the activation of AChE of basal forebrain significantly higher than the control group(P<0.01);at the some time the activation of ChAT in PAS-Na preventive group higher than the manganese-exposed group (P<0.05), when the activation of AChE of basal forebrain lower than the manganese-exposed group (P<0.05)④The NF positive cells of Subgrandular Zone of Dentate Gyrus(SGZ) among the groups showed no significant difference (P> 0.05)3. Manganese exposure for 12 weeks, PAS-Na treatment for 6 weeks①The MWM test showed that the escape latency and swimming distance of the first day, the fifth day's training were obviously prolonged in the manganese-exposed group as compared with that of the control group (P< 0.05),and the swimming distance of the first day, fifth day's training of the rats in the PAS-Na treatment group were significantly shorter than that in the manganese-exposed group (P<0.05).②ChAT positive cells of basal forebrain vDB,hDB region significantly decreased in the manganese-exposed group as compared with that of the control group (P<0.05),and the number of ChAT of these region were evidently increased in the PAS-Na treatment group(P<0.05).③The activation of ChAT of basal forebrain in the manganese-exposed group was significantly lower than the control group (P<0.01),when the activation of AchE of basal forebrain significantly higher than the control group (P<0.01);at the some time the activation of AChE of basal forebrain in the PAS-Na treatment group lower than the manganese-exposed group(P<0.05).④The NF positive cells of Subgrandular Zone of Dentate Gyrus(SGZ) in the manganese-exposed group were distinctly less than that in the control group (P <0.01),after the treatment of PAS-Na for 6 weeks, the number of NF was evidently increased in the PAS-Na treatment(P<0.05).Conclusion:①Manganese exposure can cause learning and memory dysfunction in rats, both PAS-Na preventive intervention and treatment are antagonist to manganese exposure by showing reduce the adverse effects on learning and memory. The mechanism may be through protecting the function of choline acetyl neurons.②PAS-Na treatment can significantly increase the number of NF positive cell in hippocampus SGZ, this may be one of the protective mechanisms that PAS-Na treatment do to hippocampal neurons.
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