metallothionein and Cerebral-Hemorrhage

Metallothioneins (MTs) are metal-binding proteins that can be upregulated in the brain after injury and are associated with neuroprotection. A recent genomics study has shown that brain MT-1 and MT-2 mRNA levels are upregulated following intracerebral hemorrhage (ICH) in rats. Our study examines whether brain MT-1 and MT-2 protein levels are increased after ICH. We also investigated the effect of exogenous MT-1 in perihematomal edema formation in vivo and iron-induced cell death in vitro. We found that MT-1/-2 immunoreactivity in ipsilateral basal ganglia was significantly increased after ICH and exogenous MT-1 attenuated perihematomal edema formation. In addition, MT-1 also reduced cell death induced by iron in cultured astrocytes. These results suggest a role for MT in ICH-induced brain injury, and MT could be a therapeutic target for ICH.

Topics: Analysis of Variance; Animals; Animals, Newborn; Astrocytes; Basal Ganglia; Brain Injuries; Cells, Cultured; Cerebral Cortex; Cerebral Hemorrhage; Disease Models, Animal; Dose-Response Relationship, Drug; L-Lactate Dehydrogenase; Male; Metallothionein; Rats; Rats, Sprague-Dawley; Up-Regulation

After intracerebral hemorrhage (ICH), many changes of gene transcription occur that may be important because they will contribute to understanding mechanisms of injury and recovery. Therefore, gene expression was assessed using Affymetrix microarrays in the striatum and the overlying cortex at 24 h after intracranial infusions of blood into the striatum of adult rats. Intracerebral hemorrhage regulated 369 of 8,740 transcripts as compared with saline-injected controls, with 104 regulated genes shared by the striatum and cortex. There were 108 upregulated and 126 downregulated genes in striatum, and 170 upregulated and 69 downregulated genes in the cortex. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) confirmed upregulation of IL-1-beta, Lipcortin 1 (annexin) and metallothionein 1,2, and downregulation of potassium voltage-gated channel, shaker-related subfamily, beta member 2 (Kcnab2). Of the functional groups of genes modulated by ICH, many metabolism and signal-transduction-related genes decreased in striatum but increased in adjacent cortex. In contrast, most enzyme, cytokine, chemokine, and immune response genes were upregulated in both striatum and in the cortex after ICH, likely in response to foreign proteins from the blood. A number of these genes may contribute to brain edema and cellular apoptosis caused by ICH. In addition, downregulation of growth factor pathways and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway could also contribute to perihematoma cell death/apoptosis. Intracerebral hemorrhage-related downregulation of GABA-related genes and potassium channels might contribute to perihematoma cellular excitability and increased risk of post-ICH seizures. These genomic responses to ICH potentially provide new therapeutic targets for treatment.

Topics: Animals; Annexin A1; Brain; Cerebral Hemorrhage; Cluster Analysis; Disease Models, Animal; Down-Regulation; gamma-Aminobutyric Acid; Gene Expression Profiling; Genomics; Growth Substances; Interleukin-1; Male; Metallothionein; Oligonucleotide Array Sequence Analysis; Phosphatidylinositol 3-Kinases; Potassium Channels, Voltage-Gated; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Transcription, Genetic; Up-Regulation

To study the neurophysiological functions of metallothioneins (MTs), localization of MT-I and -II was examined immunohistochemically in a variety of brain lesions in dogs, including infarct, laminar cortical necrosis, hemorrhage, invasive growth of tumour, inflammatory lesions in granulomatous meningoencephalitis and distemper encephalitis. MT-I and -II were demonstrated in both nucleus and cytoplasm of hypertrophic astrocytes in most brain lesions examined regardless of the type, size, localization and duration of the lesions. In addition, MT expression was stronger in a population of hypertrophic astrocytes localizing inside of the surviving brain tissue rather than those localizing at the boundary between the surviving brain tissue and necrotic area, where severe inflammatory changes were developing. These results suggest that MT-I and -II may play roles not only in protection of neurons from metals and free radicals ubiquitous in the inflammatory lesions but also in repair of injured neural tissues.

Topics: Adenocarcinoma; Animals; Astrocytes; Brain Diseases; Brain Neoplasms; Cerebral Hemorrhage; Cerebral Infarction; Distemper; Dog Diseases; Dogs; Encephalitis, Viral; Female; Glial Fibrillary Acidic Protein; Hypertrophy; Inflammation; Male; Meningoencephalitis; Metallothionein; Necrosis; Neoplasm Invasiveness; Pituitary Neoplasms