title: Indomethacin reverses decreased hippocampal cell proliferation in streptozotocin-induced diabetic mice.
abstract: Diabetes in humans and animals is accompanied by chronic low-grade inflammation, which could be a possible mediator of developing neuropathology and neurobehavioral deficits. The objective of the present study determined if decreasing inflammation could reverse diabetes-induced decreases in hippocampal cell proliferation, one aspect of hippocampal neurogenesis. C57BL/6J mice were made diabetic by administering streptozotocin (STZ; 195 mg/kg). STZ mice or vehicle controls received chronic treatment with the non-steroidal anti-inflammatory drug indomethacin (2 mg/kg for 14 days). Levels of glucose, corticosterone and cytokines were measured from plasma, cell proliferation was measured using BrdU incorporation in the hippocampus and TNF-αR1 and TNF-αR2 mRNA was measured using real-time PCR. STZ-induced diabetes increased plasma levels of glucose and corticosterone and decreased body weight. Cell proliferation in the hippocampus was reduced in diabetic mice by 50 %. The decreased level of cell proliferation was reversed by chronic treatment with indomethacin without changes to corticosterone and glucose levels. Plasma TNF-α levels increased in diabetic mice and were normalized by indomethacin treatment whereas IL-1 and IL-6 levels were unchanged by diabetes or indomethacin. In contrast, plasma levels of the cytokines IL-10 and IFN-gamma decreased in diabetic mice and were not affected by indomethacin treatment. STZ-induced diabetes decreased hippocampal expression of TNF-αR2 but not TNF-αR1 mRNA. Indomethacin ameliorated the effects of STZ on hippocampal neurogenesis independent of corticosterone and glycemic control, possibly by mediating the proinflammatory cytokine TNF-α. Inflammation is a potential novel pharmacological target for alleviating neurobehavioral complications arising from diabetes.
authors.affiliation: School of Nursing, University of Pennsylvania, 418 Curie Boulevard, Philadelphia, PA, 19104, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Ho
authors.forename: Bethany R
authors.initials: BR
authors.lastname: Brookshire
authors.forename: Janet E
authors.initials: JE
authors.lastname: Clark
authors.forename: Irwin
authors.initials: I
authors.lastname: Lucki
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003345:Corticosterone / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D006624:Hippocampus / Q000473:pathology*; D007213:Indomethacin / Q000494:pharmacology*; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001786:Blood Glucose; D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D003345:Corticosterone; D007213:Indomethacin