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.