Abstract
Metallothioneins I and II (MTI/II) are metal-binding proteins overexpressed in response to brain injury. Recently, we have designed a peptide, termed EmtinB, which is modeled after the beta-domain of MT-II and mimics the biological effects of MTI/II in vitro. Here, we demonstrate the neuroprotective effect of EmtinB in the in vitro and in vivo models of kainic acid (KA)-induced neurotoxicity. We show that EmtinB passes the blood-brain barrier and is detectable in plasma for up to 24 hr. Treatment with EmtinB significantly attenuates seizures in C57BL/6J mice exposed to moderate (20 mg/kg) and high (30 mg/kg) KA doses and tends to decrease mortality induced by the high KA dose. Histopathological evaluation of hippocampal (CA3 and CA1) and cortical areas of mice treated with 20 mg/kg KA shows that EmtinB treatment reduces KA-induced neurodegeneration in the CA1 region. These findings establish EmtinB as a promising target for therapeutic development.
(c) 2009 Wiley-Liss, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blood-Brain Barrier / drug effects
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Blood-Brain Barrier / metabolism
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Cells, Cultured
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Cerebral Cortex / drug effects
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Cerebral Cortex / pathology
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Cerebral Cortex / physiopathology
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Epilepsy, Temporal Lobe / drug therapy
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Epilepsy, Temporal Lobe / metabolism
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Epilepsy, Temporal Lobe / physiopathology
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Hippocampus / drug effects
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Hippocampus / pathology
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Hippocampus / physiopathology
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Intercellular Signaling Peptides and Proteins
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Kainic Acid / antagonists & inhibitors*
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Kainic Acid / toxicity
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Male
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Metallothionein / agonists*
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Metallothionein / metabolism
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Mice
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Mice, Inbred C57BL
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Nerve Degeneration / chemically induced
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Nerve Degeneration / drug therapy
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Nerve Degeneration / physiopathology
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Neuroprotective Agents / blood
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Neuroprotective Agents / pharmacokinetics*
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Neuroprotective Agents / therapeutic use
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Neurotoxins / antagonists & inhibitors*
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Neurotoxins / toxicity
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Peptides / blood
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Peptides / pharmacokinetics*
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Peptides / therapeutic use
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Rats
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Rats, Wistar
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Seizures / chemically induced
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Seizures / drug therapy
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Seizures / physiopathology
Substances
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EmtinB peptide
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Intercellular Signaling Peptides and Proteins
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Neuroprotective Agents
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Neurotoxins
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Peptides
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Metallothionein
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Kainic Acid