| 【Research Background】With the development of the aging society,the number of the elderly increases,and more and more elderly patients undergo anesthesia and surgery,which increases the risk of potential postoperative cognitive dysfunction（POCD）.According to the relevant survey results,more than25.8%of the elderly aged 60 years developed POCD within one week after surgery,and nearly 9.9%of the elderly patients developed POCD within three months after surgery.Among them,there is a stronger correlation between age and POCD,and aging is an important factor.So.Prevention and treatment of POCD is imminent.Neuroinflammation is currently recognized as one of its target mechanisms,but another target is ER stress（ERS）.Currently,studies mainly focus on inflammation,oxidative stress,mitochondrial disorders,synaptic plasticity,etc.,and there are few studies on ER stress.ERS is a self-protective response of eukaryotic cells.Appropriate ERS can maintain cell homeostasis by activating relevant signaling pathways,but excessive ERS can cause the accumulation of unfolded proteins or faulty proteins beyond the limits of cell processing,and the apoptosis process is initiated in the cell,resulting in apoptosis.Therefore,harmful factors affecting the brain will cause excessive ERS in neuron cells,causing apoptosis of nerve cells,and then developing into POCD.【Objective】To explore the effect of galantamine on isoflurane-induced cognitive dysfunction in aged mice,elucidate its relevant mechanism,and provide a new strategy for the prevention and treatment of POCD.【Methods】1.In our experiment,75 20-month-old C57BL/6J aged mice were randomly divided into five groups with 15 animals in each group.Control group was CON group,isoflurane anesthesia group was ISO group,galanthamine,The low,middle and high concentrations of ISO+Gal-L,ISO+Gal-M and ISO+Gal-H were treated with GAL,and the concentrations of the three groups of GAL were 1 mg·kg-1,3 mg·kg-1and5 mg·kg-1GAL,respectively.2.Experimental treatment was carried out.CON group:inhaled air for 6 hours;ISO group:isoflurane anesthesia for 6 h;ISO+GAL-L group:Aged mice were given intraperitoneal injection of 1 mg·kg-1galantamine for 1 h and then anesthetized with isoflurane for 6 h;In ISO+GAL-M group:aged mice were given intraperitoneal injection of 3 mg·kg-1galantamine for 1 h and then anesthetized with isoflurane for 6 h.ISO+GAL-H group:Aged mice were given intraperitoneal injection of 5mg·kg-1 galantamine for 1 h and then anesthetized with isoflurane for 6h.3.12 hours after the completion of anesthesia,spatial learning and memory abilities of aged mice were determined by Y maze and open field4.Neuron apoptosis in hippocampal CA1 region were measured by TUNEL5.m RNA expression levels of GRP78,ATF4 and CHOP in hippocampus of aged mice in each group were determined by q RT-PCR.6.GRP78,ATF4,and CHOP proteins in hippocampus of aged mice in each group were determined by Western-blot.【Result】1.In the Y maze experiment,compared with the CON group,the residence time and shuttle times of the old mice in the ISO group were significantly shortened（P<0.01）.Compared with ISO group,the residence time and shuttle times of aged mice in ISO+GAL-L,ISO+GAL-M and ISO+GAL-H groups were significantly prolonged（P<0.01）.In particular,older mice in ISO+GAL-H group showed better residence time and shuttle times than those in ISO+GAL-L and ISO+GAL-M groups（P<0.05）.2.In open field experiment,compared with CON group,the residence time in the center of the aged mice in ISO group was significantly longer（P<0.01）,and the total exploration distance had no statistical difference（P>0.05）.Compared with ISO group,the central residence time of aged mice in ISO+GAL-L,ISO+GAL-M and ISO+GAL-H groups was significantly shortened（P<0.01）,and there was no statistical difference in the total exploration distance（P>0.05）.It is worth noting that,Compared with ISO+GAL-H and ISO+GAL-M groups,the residence time in the center of the aged mice in ISO+GAL-L and ISO+Gal-M groups was shorter（P<0.05）,and there was no statistical difference in the total exploration distance（P>0.05）.3.TUNEL results showed that compared with CON group,the apoptosis of hippocampal CA1 neuronal cells in the ISO group was significant（P<0.05）.Compared with ISO group,the apoptosis of neurons in hippocampal CA1 region of aged mice in ISO+GAL-L,ISO+GAL-M and ISO+GAL-H groups was significantly decreased（P<0.01）.The apoptosis of neurons in ISO+GAL-H group was less than that in ISO+GAL-L and ISO+GAL-M groups（P<0.05）.4.q RT-PCR results showed that compared with CON group,m RNA expression levels of GRP78,ATF4 and CHOP in ISO group were significantly higher（P<0.01）;Compared with ISO group,m RNA expression levels of GRP78,ATF4 and CHOP in ISO+GAL-L,ISO+GAL-M and ISO+GAL-H groups were significantly decreased（P<0.05）.In particular,the expression levels of GRP78,ATF4 and CHOP in ISO+GAL-H group were significantly lower than those in ISO+GAL-L and ISO+GAL-M group（P<0.05）.5.Western-blot showed that compared with CON group,the protein expressions of GRP78,ATF4 and CHOP in ISO group were significantly higher（P<0.01）.Compared with ISO group,the protein expressions of GRP78,ATF4 and CHOP in ISO+GAL-L,ISO+GAL-M and ISO+GAL-H groups were significantly decreased（P<0.05）.In particular,the protein expressions of GRP78,ATF4 and CHOP in ISO+GAL-H group were significantly decreased compared with those in ISO+GAL-L and ISO+GAL-M group（P<0.05）.【Conclusion】1.Galantamine can alleviate cognitive dysfunction in elderly mice induced by isoflurane anesthesia.2.Galantamine can downregulate the m RNA and protein expressions of GRP78,ATF4,and CHOP,inhibit endoplasmic reticulum stress,reduce neuronal apoptosis,and exert neuroprotective effects. |
