Abstract:
Background In recent years, studies have found that aluminum is closely related to the occurrence and development of various neurological diseases. The neurotoxic effects of aluminum include affectng the content of central neurotransmiters, causing nerve cell death, and promotng abnormal phosphorylaton and aggregaton of Tau protein. Current studies use cell models to investgate the mechanism of necroptosis induced by aluminum.
Objective This experiment is designed to investigate the role of tumor necrosis factor receptor 1 (TNFR1)-receptor interacting protein 1 (RIP1)/receptor interacting protein 3 (RIP3) signaling pathway in aluminum Al(mal)3-induced learning and memory impairment in rats.
Methods Forty healthy adult male SD rats were randomly divided into surgical control group, solvent control group, necrostain-1 (Nec-1) group, Nec-1+Al(mal)3 group, and Al(mal)3 group, with eight rats in each group. By intracerebroventricular injecton, the Nec-1 group was given 1.258 4 mmol/L Nec-1 at 5 μL, the Al(mal)3 group was given 50 mmol/L Al(mal)3 at 5 μL, the Nec-1+Al(mal)3 group was injected 5 μL 1.258 4 mmol/L Nec-1 1 hour before being given 5 μL 50 mmol/L Al(mal)3, the solvent control group was given an equal volume of normal saline, and the surgical control group was treated with the same lateral ventricle cannula without any reagent treatment. They were treated every two days and contnuously for 10 days. The spontaneous learning reacton rate of each group of rats was determined by Y maze to detect spatal learning and memory ability of rats; the pathological changes of hippocampus were observed afer HE staining under light microscope; the ultrastructure of hippocampus was observed under electron microscope; the expression levels of TNFR1, RIP1, and RIP3 in hippocampus were measured by Western blot.
Results There was no significant difference in the rate of spontaneous reaction alternation among the surgical control group(35.88±2.44)%, the solvent control group(34.38±3.06)%, the Nec-1 group(35.65±4.48)%, and the Nec-1+Al(mal)3 group(32.01±6.93)%. Compared with the other four groups, the spontaneous reacton alternaton rate of rats in the Al(mal)3 group decreased to (21.96±2.05)% (Ps < 0.05). The light microscope observaton showed that the hippocampal neurons of the Al(mal)3 group had different degrees of cytoplasmic acidophilia enhancement, shrunk cell body, dark red cytoplasm, disorderly distributed cells, and reduced neurons; by contrast, the hippocampal neurons of the other four groups had intact and clear structure, clear nuclei, large nucleoplasm ratio, obvious nucleolus, even color, and neatly distributed cells. The electron microscope observaton showed that the Al(mal)3 group had ruptured hippocampal neurons, greatly reduced organelles, vacuolated cytoplasm, pyknotc nucleus, perinuclear cavitaton, expanded cell volume, and invisible synapses between neurons; by contrast, the hippocampal neurons in the other four groups had clear structure, intact membrane, full cytoplasm, clear organelles such as perinuclear mitochondria, endoplasmic retculum, and Golgi bodies, large and clear nucleus, obvious nucleolus, and complete and clearly visible synapses between neurons. There was no signifcant difference in the expression of TNFR1, RIP1, and RIP3 among the surgical control group, the solvent control group, the Nec-1 group, and the Nec-1+Al(mal)3 group. Compared with the other four groups, the expression levels of TNFR1, RIP1, and RIP3 of rats in the Al(mal)3 group decreased signifcantly (Ps < 0.05).
Conclusion Aluminium may cause necroptosis by triggering TNFR1-RIP1/RIP3 signaling pathway, thereby producing neurotoxicity and impairing learning and memory ability.
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