SLR - July 2012 - Paul Peterson
Reference: Navaratna, Deepti, et al. Decreased Cerebrovascular Brain-Derived Neurotrophic Factor-Mediated Neuroprotection in the Diabetic Brain. Diabetes. 2011; 60:1789-1796
Scientific Literature Review
Reviewed by: Paul Peterson, DPM
Residency Program: Mercy Hospital, Coon Rapids, MN
Podiatric Relevance:
Many podiatric patients are diabetic, and there are a number of illnesses that are associated with diabetes. Advanced glycolsylation end-products (AGE) can lead to both peripheral and central nervous system damage. Diminished cognitive abilities are found in patients with Type 1 diabetes, and Type 2 diabetes is known to also affect learning and memory. In this study, the authors hypothesized that the diabetic brain was not as well protected against neuronal injury as a non-diabetic brain. Because of this, the diabetic patient is more likely to develop Alzheimer’s disease and vascular dementia. Diabetics are also at a greatly increased risk for severe stroke. Specifically, they studied the neuroprotective factor brain-derived neurotrophic factor (BDNF).
Methods:
Rats were utilized for this study design, and they induced diabetes with injections of streptozotocin. They then treated them with insulin to mimic a treated diabetic patient. The rat brains were examined and probed for anti-BDNF antibodies. Human brain specimens were also used. They examined microvessel endothelial cells from rapidly autopsied brains. The human brains were treated with (AGE)-BSA, and the MEK/extracellular signal-related kinase (ERK) (one of the major mechanisms that allow endothelial cells to respond to extracellular stimuli), and then also treated with U0126 (the inhibitor of MEK/ERK ). They then tested the different treatment groups to hypoxic conditions and monitored neuroprotection during hypoxia.
Results:
In rats, BDNF expression was reduced in diabetic rat brain endothelium in vivo. In humans, AGE-BSA treatment decreased BDNF levels in brain endothelial cells. This treatment caused a change in cell morphology, with changes in cell shape and loss of cell-to-cell contact. AGE-BSA-induced reduction of BDNF was dependent on ERK/MAP kinase signaling. Levels of phospho-ERK were significantly elevated in AGE BSA-treated cells. Blockade of ERK signaling with U0126 decreased phospho-ERK levels, and significantly prevented this AGE-BSA-induced suppression of BDNF. Blockade of ERK signaling also interfered with the ability of AGE-BSA to decrease the secretion of BDNF into conditioned media. Taken together, these data suggested that the ability of AGE-BSA to suppress endothelial BDNF requires ERK/MAP kinase signaling. BDNF-mediated neuroprotection was lost after AGE-BSA treatment in brain endothelial cells. Addition of exogenous BDNF back into the culture media restored protection and decreased neuronal death. Finally, the role of ERK signaling in the pathway was confirmed by U0126 experiments. Blockade of ERK with U0126 not only prevented endothelial BDNF suppression but also restored neuroprotection.
Conclusions:
AGEs lead to reduced cerebrovascular secretion of BDNF, which is a major mediator of neuroprotection. The treatment of primary brain microvascular cells with AGE-BSA significantly suppressed the production of BDNF via ERK/MAP kinase signaling pathways, whereas treatment with high glucose alone did not. Because of the loss of BDNF, endothelial cells exposed to AGE-BSA were no longer able to protect neuronal cultures against hypoxic injury. Their data provide a potential mechanism that may underlie the increased neuronal vulnerability of diabetic brains. The diabetes-induced decrease of BDNF in cerebral microvessels seems to be mediated by AGEs via activation of the ERK signaling pathway. These findings are consistent with known receptor-mediated effects of AGEs; however, nonreceptor-mediated effects of AGEs cannot be ruled out, and more investigation is required to demonstrate a direct involvement of RAGE in this pathway. Although our in vitro model of AGE-BSA treatment cannot be equated to in vivo diabetic conditions, it is useful in assessing the direct contribution of AGEs to neurotrophic reduction observed in vivo. In conclusion, this study identified a vascular mechanism that may explain why diabetes increases risk for neurologic injury such as stroke. Strategies to preserve neurovascular trophic coupling mechanisms may lead to the development of novel preventive neuroprotective therapy in diabetes.