Streptozotocin produces oxidative stress, inflammation and decreases BDNF concentrations to induce apoptosis of RIN5F cells and type 2 diabetes mellitus in Wistar rats

• Streptozotocin (STZ) altered antioxidant and reduced BDNF content of RIN5F cells.
• STZ (65 mg/kg)-induced type 2 diabetes mellitus significantly reduced plasma BDNF (P < 0.001) and increased TNF-α and IL-6 (P < 0.001) levels in vivo.
• Brain, pancreas and liver of STZ-induced type 2 diabetes animals showed a significant reduction in their BDNF levels (P < 0.001) compared to control.
• Brain of STZ-induced type 2 diabetes animals showed enhanced neuronal apoptosis in hippocampus (CA1,2,3 along with DG) regions and hypothalamus (PVN regions).
• These results suggest that STZ induces apoptosis of pancreatic β cells and hippocampal and hypothalamic neurons by reducing BDNF secretion, a neurotrophic factor that is essential for their survival.

BackgroundNeurodegenerative disorders, such as deficits in learning, memory and cognition and Alzheimer's disease are associated with diabetes mellitus. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor and is known to possess anti-obesity, anti-diabetic actions and is believed to have a role in memory and Alzheimer's disease.ObjectiveTo investigate whether STZ can reduce BDNF production by rat insulinoma (RIN5F) cells in vitro and decrease BDNF levels in the pancreas, liver and brain in vivo.MethodsStreptozotocin (STZ)-induced cytotoxicity to RIN5F cells in vitro and type 2 DM in Wistar rats was employed in the present study. Cell viability, activities of various anti-oxidants and secretion of BDNF by RIN5F cells in vitro were measured using MTT assay, biochemical methods and ELISA respectively. In STZ-induced type 2 DM rats: plasma glucose, interleukin-6 and tumor necrosis factor-α levels and BDNF protein expression in the pancreas, liver and brain tissues were measured. In addition, neuronal count and morphology in the hippocampus and hypothalamus areas was assessed.ResultsSTZ-induced suppression of RIN5F cell viability was abrogated by BDNF. STZ suppressed BDNF secretion by RIN5F cells in vitro. STZ-induced type 2 DM rats showed hyperglycemia, enhanced plasma IL-6 and TNF-αlevels and reduced plasma and pancreas, liver and brain tissues (P < 0.001) and increased oxidative stress compared to untreated control. Hypothalamic and hippocampal neuron in STZ-treated animals showed a decrease in the number of neurons and morphological changes suggesting of STZ cytotoxicity.ConclusionsThe results of the present study suggest that STZ is not only cytotoxic to pancreatic beta cells but also to hypothalamic and hippocampal neurons by inducing oxidative stress. STZ ability to suppress BDNF production by pancreas, liver and brain tissues suggests that impaired memory, learning, and cognitive dysfunction seen in diabetes mellitus could be due to BDNF deficiency.