Upregulation of p­Akt by glial cell line­derived neurotrophic factor ameliorates cell apoptosis in the hippocampus of rats with streptozotocin­induced diabetic encephalopathy.

ABSTRACT

The loss of neurotrophic factor support has been shown to contribute to the development of the central nervous system. Glial cell line­derived neurotrophic factor (GDNF), a potent neurotrophic factor, is closely associated with apoptosis and exerts neuroprotective effects on numerous populations of cells. However, the underlying mechanisms of these protective effects remain unknown. In the present study, a significant increase in Bax levels and DNA fragmentation was observed in the hippocampus obtained from the brains of diabetic rats 60 days after diabetes had been induced. The apoptotic changes were correlated with the loss of GDNF/Akt signaling. GDNF administration was found to reverse the diabetes­induced Bax and DNA fragmentation changes. This was associated with an improvement in the level of p­Akt/Akt. In addition, combination of GDNF with a specific inhibitor of the phosphoinositide 3­kinase (PI3K)/Akt pathway, Wortmannin, significantly abrogated the effects of GDNF on the levels of p­Akt/Akt, Bax and DNA fragmentation. However, a p38 mitogen­activated proten kinase (MAPK) inhibitor, SB203580, had no effect on the expression of p­Akt/Akt, Bax or DNA fragmentation. These results demonstrate the pivotal role of GDNF as well as the PI3K/Akt pathway, but not the MAPK pathway, in the prevention of diabetes­induced neuronal apoptosis in the hippocampus.