Metallothionein prevents neurodegeneration and central nervous system cell death after treatment with gliotoxin 6‐aminonicotinamide

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Abstract
Transgenic expression of interleukin-6 (IL-6) in the CNS under the control of the glial fibrillary acidic protein (GFAP) gene promoter (GFAP-IL6 mice) induces significant inflammation and neurodegeneration but also affords neuroprotection against acute traumatic brain injury. This neuroprotection is likely mediated by the IL-6-induced protective factors metallothioneins-I and -II (MT-I+II). Here we evaluate the neuroprotective roles of IL-6 vs. MT-I+II during 6-aminonicotinamide (6-AN)-induced neurotoxicity, by using GFAP-IL6 mice and transgenic mice overexpressing MT-I (TgMT) as well as GFAP-IL6 mice crossed with TgMT mice (GFAP-IL6 × TgMT). 6-AN caused acute damage of brainstem gray matter areas identified by necrosis of astrocytes, followed by inflammatory responses. After 6-AN-induced toxicity, secondary damage was observed, consisting of oxidative stress, neurodegeneration, and apoptotic cell death. We hereby show that the primary injury caused by 6-AN was comparable in wild-type and GFAP-IL6 mice, but MT-I overexpression could significantly protect the brain tissue. As expected, GFAP-IL6 mice showed increased CNS inflammation with more gliosis, macrophages, and lymphocytes, including increased cytokine expression, relative to the other mice. However, GFAP-IL6 mice showed reduced oxidative stress (judged from nitrotyrosine, malondialdehyde, and 8-oxoguanine stainings), neurodegeneration (accumulation of neurofibrillary tangles), and apoptosis (determined from TUNEL and caspase-3). MT-I+II expression was significantly higher in GFAP-IL6 mice than in wild types, which may contribute to the IL-6-induced neuroprotection. In support of this, overexpression of MT-I in GFAP-IL6 × TgMT as well as TgMT mice protected the brainstem tissue significantly from 6-AN-induced toxicity and secondary brain tissue damage. Overall, the results demonstrate that brain MT-I+II proteins are fundamental neuroprotective factors, which in the future may become therapeutic agents.