Regional Susceptibility to Domoic Acid in Primary Astrocyte Cells Cultured from the Brain Stem and Hippocampus

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, NM-DAR 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-α, IL-1B, IL-6, the small inducible cytokine, interferon protein IP-10, CXC chemokine LIX, and IGF binding proteins. The Bax, Bcl-2, Trk A and Trk B were all downregulated. Interestingly, only the hippocampal astrocytes were affected. Our findings suggest Mar. Drugs 2008, 6(1) 26 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.

Kainic Acid-Induced Neurodegenerative Model: Potentials and Limitations

“…However, a new concept of neuron-glial intercommunication that astrocytes play a dynamic role by integrating neuronal inputs and modulating synaptic activity, whereby contributing to neurodegenerative development, has been recently acknowledged [35, 36]. Astrocytes can prevent neurons from death and promote proliferation and differentiation of precursor cells by producing growth factors [37–39].…”

Toxicity of a seafood toxin, domoic acid, in the retina via modulation of the NRF2 and NF-κB pathways

“…Mayer et al (2001) reported increased expression of TNFα and MMP9 in cultured DA-treated rat neonatal microglia. DA treatment has been reported to upregulate expression of IL-1β, IL-6 and TNFα in cultured rat primary astrocytes (Gill et al, 2008); similarly, DA-treated mice had higher levels of proinflammatory mediators, including IL-1β, TNFα, GFAP and COX2, in the hippocampus (Lu et al, 2013). In the current study, our data also showed markedly increased expression of IL-1, IL-6, IL-8, and TNF- in human RPE cells and in zebrafish embryos.…”

Inflammatory Factor IL1α Induces Aberrant Astrocyte Proliferation in Spinal Cord Injury Through the Grin2c/Ca2+/CaMK2b Pathway

“…Thus, IL1α appears to be involved in neurotrauma-related astrocyte activity. In other models of neurotoxicity, IL1α expression levels increase and NMDAR expression levels decrease [ 42 ]. In our study, an intraperitoneal injection [ 43 ] of neutralizing antibodies for 7 days reduced the level of IL1α and decreased the proliferation of astrocytes and lesion scar/volume in SCI model mice.…”