A Role for Hippocampal Tumor Necrosis Factor-α (TNF) Production in Streptozotocin (STZ)-Induced Diabetic Neuropathy
Re, Ashley Christina
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In the central nervous system, the pro-inflammatory cytokine and protein mediator, Tumor Necrosis Factor (TNF), plays an important role in development of neuropathic pain. Studies have shown that suppression of TNF in the brain dramatically reduces chronic constriction injury-induced neuropathic pain. For this study, it is hypothesized that TNF, specifically in the hippocampus, a brain region implicated in perception of pain and pain memory formation, plays a role in the development of diabetic neuropathy. The aims to test this hypothesis are: (1) preventing TNF production in hippocampi alone will alleviate diabetic neuropathy in streptozotocin (STZ)-injected Sprague-Dawley rats, a type 1 diabetes model; and (2) peritoneal macrophages from diabetic rats will produce more TNF when stimulated with lipopolysaccharide (LPS), and inhibiting hippocampal TNF production will prevent the aforementioned from occurring. At the time of neuropathy development (assessed via behavioral measurements of pain: thermal hyperalgesia and mechanical allodynia) bilateral intra-hippocampal injection of either small inhibitory RNA (siRNA) targeting TNF (preventing TNF production) or a non-targeting control siRNA will be performed. In a separate group of rats at day-28 post-STZ/saline injection, the tricyclic antidepressant desipramine will be administered to alleviate pain, thereby serving as a positive control. At either day-28 or day-60 post-STZ/saline injection, rats are euthanized and blood, brain regions, sciatic nerves, and peritoneal macrophages are harvested. TNF levels are assessed via bioassay. It is predicted that by preventing TNF production in the hippocampus, (1) neuropathic pain will be alleviated post-STZ, and (2) peritoneal macrophages will change from acting as pro-inflammatory to anti-inflammatory immune effector cells.