Astrocyte Metallothioneins (MTs) and Their Neuroprotective Role^a

Abstract

I have briefly detailed in this review the role of astrocytes in MeHg neurotoxicity, emphasizing the mechanisms and significance of astrocytic swelling in neuropathological conditions. I have also described the functions of brain MTs and have reported recent observations on their propensity to attenuate cytotoxicity. While it is unclear why three different MT genes are expressed in the brain, this redundancy should allow for greater accumulation of MTs under stressful conditions compared to its accumulation if only a single gene was present. Another explanation may be that genes encoding functionally identical MTs might be regulated independently, thus permitting cell-specific MT expression. Finally, each of the three MT isoforms may have distinct functions. As discussed herein, astrocytic MTs afford protection from the acute cytotoxic effects of MeHg, reversing the effect of this organometal on RVD and inhibition of taurine release. Whether other vital cellular functions are protected by MTs will have to await future studies, as will the mechanisms associated with MT-induced cellular protection. That the resistance to heavy metal toxicity is closely related to the cellular ability to synthesize MTs, raises interesting questions regarding the potential involvement of heavy metals in neurodegenerating (amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease) under conditions of compromised MT synthesis. Future studies on the expression and regulation of MT genes are likely to culminate in novel strategies for manipulating intracellular MT levels, providing insight to their role in both health and disease.

Primary Cultures of Astrocytes: Their Value in Understanding Astrocytes in Health and Disease

“…We here provide citations of articles that the interested reader may find helpful. These include articles on AIDS (astrocytes are believed to represent the major neuroepithelial “reservoir” for HIV-1 in the CNS) (236-240); metal toxicity (241, 242); Wernicke's encephalopathy (vitamin B1 deficiency) (243); experimental autoimmune encephalomyelitis (EAE, a model of multiple sclerosis) (244); neuromyelitis optica (245), and Alexander's disease (246, 247). …”

Channa punctata brain metallothionein is a potent scavenger of superoxide radicals and prevents hydroxyl radical‐induced in vitro DNA damage

“…In fish, cadmium exposure is reported to upregulate MT-I and MT-II gene expression in the brain of zebrafish (Danio rerio) [9]. It has been suggested that MT-III might play a role in protecting the cells from zinc toxicity by facilitating transport of zinc from plasma membrane to synaptic vesicles, or protecting the cells against oxidative damage in mammals [7]. MT-I expression by transient transfection in MT-I and MT-II null astrocytes has been reported to confer increased protection against acute methylmercury cytotoxicity [10].…”

“…Three isoforms of MT (I, II, and III) have been identified in mammalian brain [7]. MT-III is strictly a brainspecific isoform predominantly expressed in neuron and choroid plexus [8].…”

Altered Central Nervous System Cytokine-Growth Factor Expression Profiles and Angiogenesis in Metallothionein-I+II Deficient Mice

“…The physiologic roles of MT-I+II are not fully elucidated however, data describing MT-I+II as tissue protective factors are accumulating (Aschner, 1996(Aschner, ,1997Aschner et al, 1997;Kondo et al, 1997;Lazo et al ,1998Liu et al, 1999;Penkowa et al, 1999a,b;Rossman et al, 1997;Schwarz et al, 1995;Van Lookeren Campagne et al, 1999). MT-I+II can protect against reactive oxygen species causing oxidative damage and stress, ionizing radiation, anti-cancer drugs, and interestingly, MT-I+II may prevent neuronal apoptosis (Aschner, 1998;Lazo et al, ,1998Penkowa et al, 1999aPitt et al, 1997;Schwarz et al, 1995;Tamai et al, 1993;Thornalley and Vasak, 1985).…”