Metallothionein reduces central nervous system inflammation, neurodegeneration, and cell death following kainic acid‐induced epileptic seizures

Abstract

We examined metallothionein (MT)-induced neuroprotection during kainic acid (KA)-induced excitotoxicity by studying transgenic mice with MT-I overexpression (TgMT mice). KA induces epileptic seizures and hippocampal excitotoxicity, followed by inflammation and delayed brain damage. We show for the first time that even though TgMT mice were more susceptible to KA, the cerebral MT-I overexpression decreases the hippocampal inflammation and delayed neuronal degeneration and cell death as measured 3 days after KA administration. Hence, the proinflammatory responses of microglia/macrophages and lymphocytes and their expression of interleukin (IL)-1, IL-6, IL-12, tumor necrosis factor-alpha and matrix metalloproteinases (MMP-3, MMP-9) were significantly reduced in hippocampi of TgMT mice relative to wild-type mice. Also by 3 days after KA, the TgMT mice showed significantly less delayed damage, such as oxidative stress (formation of nitrotyrosine, malondialdehyde, and 8-oxoguanine), neurodegeneration (neuronal accumulation of abnormal proteins), and apoptotic cell death (judged by TUNEL and activated caspase-3). This reduced bystander damage in TgMT mice could be due to antiinflammatory and antioxidant actions of MT-I but also to direct MT-I effects on the neurons, in that significant extracellular MT presence was detected. Furthermore, MT-I overexpression stimulated astroglia and increased immunostaining of antiinflammatory IL-10, growth factors, and neurotrophins (basic fibroblastic growth factor, transforming growth factor-beta, nerve growth factor, brain-derived neurotrophic factor, glial-derived neurotrophic factor) in hippocampus. Accordingly, MT-I has different functions that likely contribute to the increased neuron survival and improved CNS condition of TgMT mice. The data presented here add new insight into MT-induced neuroprotection and indicate that MT-I therapy could be used against neurological disorders.

Ghrelin attenuates kainic acid-induced neuronal cell death in the mouse hippocampus

“…The underlying mechanisms of this inhibitory effect of ghrelin on glial activation in the hippocampus may involve the suppression of certain proinflammatory mediators, such as TNF-a, IL-1b, and COX-2. Moreover, in the present study, we found that Mmp3 expression was significantly increased in KA-injected mice as previously reported (Penkowa et al 2005), while ghrelin treatment suppressed Mmp3 levels through the activation of GHSR1a. Considering that MMP-3 plays a pivotal role in dopaminergic neurodegeneration in PD (Kim et al 2005 and ghrelin suppresses MPTP-induced Mmp3 expression ), ghrelin-mediated inhibition of Mmp3 expression in KA-induced neurotoxicity may provide another plausible therapeutic target to prevent progressive neurodegeneration.…”

“…It has been previously reported that Mmp3 is up-regulated in the hippocampus of KA-treated mice (Penkowa et al 2005), and Mmp3 is known to play an important role in dopaminergic neuronal cell death and neuroinflammation (Kim et al 2005. Therefore, we performed immunohistochemistry and RT-PCR to investigate the effect of ghrelin on KA-induced Mmp3 expression in the hippocampus.…”

Neuroprotective Effect of Visnagin on Kainic Acid-induced Neuronal Cell Death in the Mice Hippocampus

“…Previous studies suggest that inflammatory and apoptotic processes contribute to the later stages of the damage induced by brain injuries, and that these detrimentally affect neurologic outcome [5,21,22]. Therefore, we investigate the course alteration of proinflammatory cytokines mRNA on KA injection in the hippocampus.…”

“…glutamate), which are massively released as a consequence of energy depletion and which result in excitotoxic neuron death [2,3]. Recent studies have demonstrated that the KA-induced neuronal death is associated with the activation of microglia and astrocytes in the hippocampus, and that these processes are induced by enhanced reactive oxygen species (ROS) production and cytokine expressions [4,5]. The microglia also can be detected using the complement receptor type 3 (OX-42) IR.…”

“…After brain injury, astrocytes undergo a number of cellular syntheses and release of a variety of growth factors and immunomodulatory cytokines [7]. In addition, recent studies have demonstrated that inflammatory and apoptotic processes contribute to the later stages of the damage induced by various brain injuries, and that these detrimentally affect neurologic outcome [5,8]. Among them, it has been reported well that pro-inflammatory mediators such as IL-1β, TNF-α, IL-6, and COX-2 can lead to deteriorative effect in the brain, and KA can trigger an aberrant inflammatory cytokine response by microglial cells and accelerated disease progression [4].…”