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Toxicol In Vitro. 2018 Oct;52:279-285. doi: 10.1016/j.tiv.2018.07.004. Epub 2018 Jul 11.

Long-term neurotoxic effects of domoic acid on primary dopaminergic neurons.

Author information

1
Department of Pathology, College of Medicine, King Khalid University, Abha, Saudi Arabia; Department of Pathology, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt. Electronic address: khaledradad@hotmail.com.
2
Department for Biomedical Sciences, Institute of Medical Biochemistry, University of Veterinary Medicine, Vienna, Austria.
3
Department of Pathology, College of Medicine, King Khalid University, Abha, Saudi Arabia.
4
Department of Pathology, College of Medicine, King Khalid University, Abha, Saudi Arabia; Forensic and Toxicology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.

Abstract

Domoic acid, an excitatory neurotoxin produced by certain algae, reaches the food chain through accumulation in some sea organisms. To investigate its long-term neurotoxicity on dopaminergic neurons, prepared primary mesencephalic cell cultures were exposed to different concentrations of domoic acid (0.1, 1, 10, 100 μM) on the 8th day in vitro (DIV) for 4 days. On the 12th DIV, culture media were collected for measurement of lactate dehydrogenase and cultured cells were subjected to immunohistochemistry against tyrosine hydroxylase, neuronal nuclear antigen and glial fibrillary acidic protein, and fluorescence staining using H2DCFDA, JC-1 and Hoechst 33342 dyes. Moreover, roles of AMPA/KA and NMDA receptors in domoic acid neurotoxicity were also investigated. Domoic acid significantly decreased the number of dopaminergic neurons and adversely affected their morphology, and slightly reduced the expression of neuronal nuclear antigen and glial fibrillary acidic protein. Co-treatment of cultures with domoic acid and the AMPA/KA or NMDA receptor antagonists NBQX and MK-801 rescued significant number of dopaminergic neurons. Domoic acid significantly decreased red:green fluorescence ratio of JC-1 and did not affect production of reactive oxygen species and apoptotic cell death. In conclusions, the present study reveals that long-term treatment of primary mesencephalic cell culture with domoic acid significantly destroyed dopaminergic neurons. This effect appears to be attributed to activation of AMPA/KA and NMDA receptors and mitochondrial damage.

KEYWORDS:

AMPA; Domoic acid; Dopaminergic neurons; In vitro; KA; Marine; Neurotoxicity; Parkinson's disease

PMID:
30017864
DOI:
10.1016/j.tiv.2018.07.004
[Indexed for MEDLINE]

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