title: Colchicine induced intraneuronal free zinc accumulation and dentate granule cell degeneration.
abstract: Colchicine has been discovered to inhibit many inflammatory processes such as gout, familial Mediterranean fever, pericarditis and Behcet disease. Other than these beneficial anti-inflammatory effects, colchicine blocks microtubule-assisted axonal transport, which results in the selective loss of dentate granule cells of the hippocampus. The mechanism of the colchicine-induced dentate granule cell death and depletion of mossy fiber terminals still remains unclear. In the present study, we hypothesized that colchicine-induced dentate granule cell death may be caused by accumulation of labile intracellular zinc. 10 μg kg(-1) of colchicine was injected into the adult rat hippocampus and then brain sections were evaluated at 1 day or 1 week later. Neuronal cell death was evaluated by H&E staining or Fluoro-Jade B. Zinc accumulation and vesicular zinc were detected by N-(6-methoxy-8-quinolyl)-para-toluene sulfonamide (TSQ) staining. To test whether an extracellular zinc chelator can prevent this process, CaEDTA was injected into the hippocampus over a 5 min period with colchicine. To test whether other microtubule toxins also produce similar effects as colchicine, vincristine was injected into the hippocampus. The present study found that colchicine injection induced intracellular zinc accumulation in the dentate granule cells and depleted vesicular zinc from mossy fiber terminals. Injection of a zinc chelator, CaEDTA, did not block the zinc accumulation and neuronal death. Vincristine also produced intracellular zinc accumulation and neuronal death. These results suggest that colchicine-induced dentate granule cell death is caused by blocking axonal zinc flow and accumulation of intracellular labile zinc.
authors.affiliation: Department of Physiology, College of Medicine, Hallym University, 1-Okcheon Dong, Chuncheon, Korea 200-702. swsuh@hallym.ac.kr.
authors.forename: Bo Young
authors.initials: BY
authors.lastname: Choi
authors.forename: Bo Eun
authors.initials: BE
authors.lastname: Lee
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Kim
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Min
authors.initials: M
authors.lastname: Sohn
authors.forename: Hong Ki
authors.initials: HK
authors.lastname: Song
authors.forename: Tae Nyoung
authors.initials: TN
authors.lastname: Chung
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Suh
mesh_terms: D002614:Chelating Agents / Q000494:pharmacology*; D003078:Colchicine / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D008870:Microtubules / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology; D015032:Zinc / Q000378:metabolism*
chemical_list: D002614:Chelating Agents; D014750:Vincristine; D015032:Zinc; D003078:Colchicine