Abstract
Domoic acid is a marine biotoxin associated with harmful algal blooms and is the causative agent of amnesic shellfish poisoning in marine animals and humans. It is also an excitatory amino acid analog to glutamate and kainic acid which acts through glutamate receptors eliciting a very rapid and potent neurotoxic response. The hippocampus, among other brain regions, has been identified as a specific target site having high sensitivity to DOM toxicity. Histopathology evidence indicates that in addition to neurons, the astrocytes were also injured. Electron microscopy data reported in this study further supports the light microscopy findings. Furthermore, the effect of DOM was confirmed by culturing primary astrocytes from the hippocampus and the brain stem and subsequently exposing them to domoic acid. The RNA was extracted and used for biomarker analysis. The biomarker analysis was done for the early response genes including c-fos, c-jun, c-myc, Hsp-72; specific marker for the astrocytes- GFAP and the glutamate receptors including GluR 2, NMDAR 1, NMDAR 2A and B. Although, the astrocyte-GFAP and c-fos were not affected, c-jun and GluR 2 were down-regulated. The microarray analysis revealed that the chemokines / cytokines, tyrosine kinases (Trk), and apoptotic genes were altered. The chemokines that were up-regulated included - IL1-alpha, IL-Beta, IL-6, the small inducible cytokine, interferon protein 10P-10, CXC chemokine LIX, and IGF binding proteins. The Bax, Bcl-2, Trk A and Trk B were all down-regulated. Interestingly, only the hippocampal astrocytes were affected. Our findings suggest that astrocytes may present a possible target for pharmacological interventions for the prevention and treatment of amnesic shellfish poisoning and for other brain pathologies involving excitotoxicity.
Highlights
Astrocytes account for 50% of the total cellular volume [1,2] and 90% of the number of brain cells
Electron microscopy revealed morphological changes in the CA 3 region of the hippocampus of animals treated for 64 days with 5.0 mg/kg/day of DOM as compared to the control and to animals receiving 0.1 mg/kg/bw
To further evaluate the effects of DOM on astrocytes, primary astrocytes were cultured from two different regions of the brain focusing on the brain stem and the hippocampus
Summary
Astrocytes account for 50% of the total cellular volume [1,2] and 90% of the number of brain cells These cells were traditionally thought to provide structural support for neuronal growth and differentiation and to remove toxic metabolites from the extracellular environment [1,2,3]. It is known that astrocytes and microglia are involved in the initiation, maintenance, and suppression of immune responses, they have been shown to propagate CNS damage [10,11,12,13]. These cells may be involved in neurodegenerative disorders. The signal transduction pathways and gene-activation events that link these chemical messengers to glial activation are not yet fully characterized
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