Marine biotoxins in shellfish - Domoic acid : Marine biotoxins in shellfish - Domoic acid

In Canada in late 1987 there was an outbreak of an acute illness characterized by gastrointestinal symptoms and unusual neurologic abnormalities among persons who had eaten cultivated mussels. Health departments in Canada solicited reports of this newly recognized illness. A case was defined as the occurrence of gastrointestinal symptoms within 24 hours or of neurologic symptoms within 48 hours of the ingestion of mussels. From the more than 250 reports received, 107 patients met the case definition. The most common symptoms were vomiting (in 76 percent of the patients), abdominal cramps (50 percent), diarrhea (42 percent), headache, often described as incapacitating (43 percent), and loss of short-term memory (25 percent). Nineteen patients were hospitalized, of whom 12 required intensive care because of seizures, coma, profuse respiratory secretions, or unstable blood pressure. Male sex and increasing age were associated independently with the risks of hospitalization and memory loss. Three patients died. Mussels associated with this illness were traced to cultivation beds in three river estuaries on the eastern coast of Prince Edward Island. Domoic acid, which can act as an excitatory neurotransmitter, was identified in mussels left uneaten by the patients and in mussels sampled from these estuaries. The source of the domoic acid appears to have been a form of marine vegetation, Nitzschia pungens, also identified in these waters in late 1987. The contaminated mussels from Prince Edward Island were removed from the market, and no new cases have occurred since December 1987. We conclude that the cause of this outbreak of a novel and severe intoxication was the ingestion of mussels contaminated by domoic acid, a potent excitatory neurotransmitter.

Glutamate receptors (GluRs) mediate most of the excitatory neurotransmission in the mammalian central nervous system (CNS). In addition, they are involved in plastic changes in synaptic transmission as well as excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders. The GluRs are divided into two distinct groups, ionotropic and metabotropic receptors. The ionotropic receptors (iGluRs) are further subdivided into three groups: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), kainate and N-methyl-D-aspartate (NMDA) receptor channels. The metabotropic receptors (mGluRs) are coupled to GTP-binding proteins (G-proteins), and regulate the production of intracellular messengers. The application of molecular cloning technology has greatly advanced our understanding of the GluR system. To date, at least 14 cDNAs of subunit proteins constituting iGluRs and 8 cDNAs of proteins constituting mGluRs have been cloned in the mammalian CNS, and the molecular structure, distribution and developmental change in the CNS, functional and pharmacological properties of each receptor subunit have been elucidated. Furthermore, the obtained clones have provided valuable tools for conducting studies to clarify the physiological and pathophysiological significances of each subunit. For example, the generation of gene knockout mice has disclosed critical roles of some GluR subunits in brain functions. In this article, we review recent progress in the research for GluRs with special emphasis on the molecular diversity of the GluR system and its implications for physiology and pathology of the CNS.

In late 1987 there was an outbreak in Canada of gastrointestinal and neurologic symptoms after the consumption of mussels found to be contaminated with domoic acid, which is structurally related to the excitatory neurotransmitter glutamate. We studied the neurologic manifestations in 14 of the more severely affected patients and assessed the neuropathological findings in 4 others who died within four months of ingesting the mussels. In the acute phase of mussel-induced intoxication, the patients had headache, seizures, hemiparesis, ophthalmoplegia, and abnormalities of arousal ranging from agitation to coma. On neuropsychological testing several months later, 12 of the patients had severe anterograde-memory deficits, with relative preservation of other cognitive functions. Eleven patients had clinical and electromyographic evidence of pure motor or sensorimotor neuronopathy or axonopathy. Positron-emission tomography of four patients showed decreased glucose metabolism in the medial temporal lobes. Neuropathological studies in the four patients who died after mussel-induced intoxication demonstrated neuronal necrosis and loss, predominantly in the hippocampus and amygdala, in a pattern similar to that observed experimentally in animals after the administration of kainic acid, which is also structurally similar to glutamate and domoic acid. We conclude that intoxication with domoic acid causes a novel and distinct clinicopathologic syndrome characterized initially by widespread neurologic dysfunction and then by chronic residual memory deficits and motor neuronopathy or axonopathy.