Diabetes increases the risk and worsens the progression of cognitive impairment. The hippocampus is an important domain for learning and memory. We previously showed that endothelin-1 (ET-1) reduced diabetes-induced inflammation in hippocampal neurons, suggesting a neuroprotective effect. Given that neurons and endothelial cells within the neurovascular unit depend on each other for proper function, we investigated the effect of ET-1 on brain-derived neurotrophic factor (BDNF) synthesis, a key neurotrophin and prosurvival factor, in neuronal (HT22 hippocampal neurons) and brain microvascular endothelial (BMEC-5i) cells under normal and diabetes-mimicking (high glucose plus palmitate) conditions. Cells were treated with exogenous ET-1 or ET receptor antagonists including ETB receptor selective antagonist BQ788 (1 μM) or dual-receptor antagonist bosentan (10 μM). Mature (m)BDNF, proBDNF and caspase-3 levels were measured by Western blotting. Diabetic conditions reduced the prosurvival mBDNF/proBDNF ratio in both HT22 and BMEC-5i cells. Addition of exogenous ET-1 had no effect on the BDNF system in HT22 cells in diabetic conditions. Both HT22 and BMEC-5i cells had an increase in the mBDNF/proBDNF ratio when grown in diabetes-simulating conditions in the presence of endothelin receptor inhibition. These data suggest that blockade of ET-1 may provide neuroprotection to hippocampal cells through the modulation of the BDNF system., R. Ward, Y. Abdul, A. Ergul., and Seznam literatury
In the developing brain, mature brain derived neurotrophic factor (mBDNF) and its precursor (proBDNF) exhibit prosurvival and proapoptotic functions, respectively. However, it is still unknown whether mBDNF or proBDNF is a major form of neurotrophin expressed in the immature brain, as well as if the level of active caspase -3 correlates with the levels of BDNF forms during normal brain development. Here we found that both proBDNF and mBDNF were expressed abundantly in the rat brainstem, hippocampus and cerebellum between embryonic day 20 and postnatal day 8. The levels of mature neurotrophin as well as mBDNF to proBDNF ratios negatively correlated with the expression of active caspase -3 across brain regions. The immature cortex was the only structure, in which proBDNF was the major product of bdnf gene, especially in the cortical layers 2-3. And only in the cortex, the expression of BDNF precursor positive ly correlated with the levels of active caspase -3. These findings suggest that proBDNF alone may play an important role in the regulation of naturally occurring cell death during cortical development., P. N. Menshanov, D. A. Lanshakov, N. N. Dygalo., and Obsahuje bibliografii