ToxSci Advance Access published online on June 5, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp126
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Diabetes impairs hippocampal function via advanced-glycation-end product–mediated new neuron generation in animals with diabetes-related depression
Shao-hua Wang, Ph.D, The Department of Endocrinology, affiliated ZhongDa Hospital of Southeast University, No.87 DingJiaQiao Road, Nanjing, PR China, 210009 E-mail: wshgyj{at}yahoo.com.cn tel:0086-25-83285148; fax: 0086-25-83285132 Zi-lin Sun (Corresponding author), Ph.D, M.D. The Department of Endocrinology, affiliated ZhongDa Hospital of Southeast University, No.87 DingJiaQiao Road, Nanjing, PR China, 210009 E-mail: sunzilin1963{at}yahoo.com.cn tel:0086-25-83285148; fax: 0086-25-83285132 Yi-jing Guo, Master, Ph.D student .The Department of Neurology, affiliated ZhongDa Hospital of Southeast University, No.87 DingJiaQiao Road, Nanjing, PR China, 210009 E-mail: janegyj{at}yahoo.com.cn tel:0086-25-83272027; fax: 0086-25-83285132 Yang Yuan, Ph.D student, The Department of Endocrinology, affiliated ZhongDa Hospital of Southeast University, No.87 DingJiaQiao Road, Nanjing, PR China, 210009 E-mail: yang_yuan000{at}sina.com.cn tel:0086-25-83285148; fax: 0086-25-83285132 Bing-quan Yang, Master, The Department of Endocrinology, affiliated ZhongDa Hospital of Southeast University, No.87 DingJiaQiao Road, Nanjing, PR China, 210009 E-mail: bqyung{at}163.com tel:0086-25-83285148; fax: 0086-25-83285132
Zi-lin Sun, Ph.D, M.D. The Department of Endocrinology, affiliated ZhongDa Hospital of Southeast University, No.87 DingJiaQiao Road, Nanjing, PR China, 210009 E-mail: sunzilin1963{at}yahoo.com.cn tel:0086-25-83285148; fax: 0086-25-83285132
Received March 30, 2009; revision received May 6, 2009; accepted May 21, 2009
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Abstract |
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The diabetes-induced reduction of neurogenesis in hippocampal dentate and its reversal with antidepressant medications implies a potential mechanism for diabetes-related depression and cognitive decline. In the following article, the role of advanced glycation end products (AGEs) in hippocampal neurogenesis deficits in diabetic animals with depression has been further explained in the light of an in vitro study. Diabetes was induced in animals with the use of streptozotocin (55 mg/kg, i.p.), and the animals then divided into those with and those without depression-like behaviors as analyzed by behavioral tests. The AGE formation inhibitor aminoguanidine (10 mg/kg) was administrated for an additional 4 weeks. Proliferating cells, their survival, and their phenotype fate were monitored with bromodeoxyuridine labeling and confocal laser microscopy. The presence of AGE peptides was determined with the use of a flow injection assay. Animals with diabetes and depressive symptoms displayed a reduction in hippocampal neurogenesis and an elevated serum level of AGE peptides, both of which were reversed by a 4-week regimen of aminoguanidine (10 mg/kg, i.p.), which inhibits AGE formation; in addition, the depressive behaviors were improved. These findings provided in vivo evidence that diabetes impairs hippocampal function via the AGE-mediated generation of new neurons. This likely represents a putative mechanism that is responsible for diabetes-related depression and cognitive decline, and it suggests a potential approach for future research.
Key Words: Diabetes mellitus; Hippocampus; Neurogenesis; Advanced glycation end products, Neural stem cells; Depression.