domoic-acid and Nervous-System-Diseases

California sea lions have been a repeated subject of investigation for early life toxicity, which has been documented to occur with increasing frequency from late February through mid-May in association with organochlorine (PCB and DDT) poisoning and infectious disease in the 1970's and domoic acid poisoning in the last decade. The mass early life mortality events result from the concentrated breeding grounds and synchronization of reproduction over a 28 day post partum estrus cycle and 11 month in utero phase. This physiological synchronization is triggered by a decreasing photoperiod of 11.48 h/day that occurs approximately 90 days after conception at the major California breeding grounds. The photoperiod trigger activates implantation of embryos to proceed with development for the next 242 days until birth. Embryonic diapause is a selectable trait thought to optimize timing for food utilization and male migratory patterns; yet from the toxicological perspective presented here also serves to synchronize developmental toxicity of pulsed environmental events such as domoic acid poisoning. Research studies in laboratory animals have defined age-dependent neurotoxic effects during development and windows of susceptibility to domoic acid exposure. This review will evaluate experimental domoic acid neurotoxicity in developing rodents and, aided by comparative allometric projections, will analyze potential prenatal toxicity and exposure susceptibility in the California sea lion. This analysis should provide a useful tool to forecast fetal toxicity and understand the impact of fetal toxicity on adult disease of the California sea lion.

Topics: Animals; Animals, Newborn; Diatoms; Eutrophication; Female; Fetal Development; Fetal Diseases; Food Chain; Kainic Acid; Marine Toxins; Maternal-Fetal Exchange; Mice; Nervous System Diseases; Pregnancy; Rats; Sea Lions

A novel type of intoxication in Canada in 1987 was traced to consumption of cultivated mussels contaminated with the excitotoxin domoic acid. Studies carried out in rats and monkeys revealed that parenterally administered domoic acid induces in rats neuroexcitatory phenomena culminating in seizures. Monkeys respond with gagging, emesis and less clearly evident seizure activity. CNS damage consisting of dendrotoxic and gliotoxic edema and nerve cell degeneration occurs in structures of the limbic system and the retina in both species. CNS lesion distribution similarities in animals treated with domoic acid or kainic acid suggest that these excitotoxins share a common pathogenesis mediated by glutamic acid, a putative endogenous excitatory neurotransmitter.

Topics: Animals; Central Nervous System; Disease Models, Animal; Kainic Acid; Nervous System Diseases; Nervous System Neoplasms; Neuromuscular Depolarizing Agents; Neurotoxins

Topics: Animals; Bird Diseases; Environmental Exposure; Eukaryota; Kainic Acid; Marine Toxins; Nervous System Diseases; Neurotoxins; Phytoplankton; Spheniscidae; United Kingdom; Water Pollutants

Domoic acid induces a time-dependent neuroexcitotoxic effect in neonatal rats characterized by hyperactivity, stereotypic scratching, convulsions, and death with observable behaviors occurring at exposures 40 times lower by body weight in neonates than reported in adults. Low doses of domoic acid (0.1 mg/kg) induced c-fos in the central nervous system which was inhibited in part by 2-amino-5-phosphonovaleric acid, an NMDA receptor antagonist. Domoic acid caused no evidence of structural alteration in the brain of neonates as assessed by Nissel staining and cupric silver histochemistry. Domoic acid induced reproducible behavioral effects at doses as low as 0.05 mg/kg and induced seizures doses as low as 0.2 mg/kg. Determination of serum domoic acid levels after 60 min exposure indicated that serum levels of domoic acid in the neonates corresponded closely to the serum levels that induce similar symptoms in adult rats and mice. We conclude that neonatal rats are highly sensitive to the neuroexcitatory and lethal effects of domoic acid and that the increased sensitivity results from higher than expected serum levels of domoic acid. These findings are consistent with other findings that reduced serum clearance of domoic acid is a predisposing factor to domoic acid toxicity.

Topics: Animals; Animals, Newborn; Behavior, Animal; Dose-Response Relationship, Drug; Kainic Acid; Lethal Dose 50; Nervous System Diseases; Neurotoxins; Rats; Rats, Inbred Strains

Domoic acid (DA) is an environmental neurotoxin to humans. This work examines whether repeated exposure to subsymptomatic or symptomatic nonlethal doses of domoic acid leads to enhanced symptomatic toxicity in ICR outbred and DBA inbred strains of laboratory mice. A multiple independent exposure paradigm was designed in which doses were administered intraperitoneally every other day for 7 days to achieve four separate exposures to domoic acid. We first examined the effect of repeated exposure on serum clearance of domoic acid. Serum domoic acid levels did not differ following a single or repeated exposure. We next examined the effect of repeated exposure on symptomatic toxicity. The mean toxicity scores did not show a significant difference between single and repeated exposures of either subsymptomatic (0.5 mg/kg) or symptomatic sublethal (2.0 mg/kg) doses of domoic acid. We then examined the effects of repeated domoic acid exposure on a second strain of mouse. DBA mice were chosen based upon their sensitivity to kainic acid-induced seizures; however, the ICR mice were more sensitive to low-dose domoic acid toxicity, particularly in terms of onset and duration of stereotypic scratching behavior. Our results indicate that both strains of mice have comparable concentration-dependent toxic responses to domoic acid; however, differences exist in the magnitude of the response and in specific symptoms. The mean toxicity scores did not show a significant difference when a single exposure (1.0 and 2.0 mg/kg domoic acid) and repeated exposure of the same dose were compared in the DBA mice. This study provides no evidence that short-term repeated exposure to domoic acid in laboratory mice alters domoic acid clearance from the serum, or leads to a more sensitive or a greater neurotoxic response.

Topics: Animals; Behavior, Animal; Excitatory Amino Acid Agonists; Female; Kainic Acid; Mice; Mice, Inbred DBA; Mice, Inbred ICR; Nervous System Diseases; Neurotoxins; Seizures; Species Specificity

The neuroexcitotoxin, domoic acid, was responsible for an episode of mussel poisoning in Eastern Canada in 1987. Severe neurologic impairment and some deaths occurred. We have characterized the nature of domoate-induced neuropathology in the mouse brain. Domoic acid was administered intraperitoneally at doses of 2, 3 or 7 mg/kg to Swiss-Webster mice. Brains were examined at 0.5, 1, 24, 48 or 72 h postinjection for evidence of damage. Significant pathologic changes occurred only after the largest dose of domoic acid. Damage was confined to circumventricular organs lacking a blood-brain barrier and their environs, including the organon vasculosum of the lamina terminalis, subfornical organ, mediobasal hypothalamus and area postrema. The neural damage induced by domoic acid was evident at as early as 30 min after injection and increased by 60 min postinjection. The loci of domoic acid-induced neuropathological changes accounts for several central and peripheral effects and toxicities observed following systemic domoate treatment, these included gastroduodenal lesions, hypodipsia, analgesia, and blood pressure fluctuations.

Topics: Animals; Brain; Injections, Intraperitoneal; Kainic Acid; Mice; Nervous System Diseases; Neuromuscular Depolarizing Agents

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.

Topics: Animals; Bivalvia; Brain; Disease Outbreaks; Electromyography; Food Contamination; Glucose; Humans; Kainic Acid; Marine Toxins; Memory Disorders; Motor Neurons; Myoclonus; Necrosis; Nervous System Diseases; Neuromuscular Diseases; Neurotransmitter Agents; Prince Edward Island; Seizures; Temporal Lobe; Tomography, Emission-Computed

Topics: Age Factors; Animals; Bivalvia; Food Contamination; Humans; Kainic Acid; Nervous System Diseases

Topics: Animals; Bivalvia; Canada; Eukaryota; Gastrointestinal Diseases; Humans; Kainic Acid; Marine Toxins; Nervous System Diseases; Neurotoxins; Shellfish Poisoning

Topics: Animals; Bivalvia; Brain; Humans; Kainic Acid; Marine Toxins; Nervous System Diseases; Neurotoxins; Shellfish Poisoning

The recent outbreak of "amnesic" mussel poisoning syndrome, attributed to domoic acid contamination of edible mussels claimed several lives and left many victims impaired with a peculiar loss of memory. We administered the whole mussel extract (WMX) and the mussel hepatopancreas extract (MHX, hepatopancreas being the major site for sequestration of domoic acid in mussels) in Swiss-Webster mice. A characteristic syndrome featuring sluggishness, scratching stereotypy, convulsions and death was noticed. Infant mice were some 3- to 4-fold more sensitive to the WMX toxicity. Kynurenic acid (KYN), an endogenous nonselective excitotoxin antagonist offered significant protection against the toxicosis after its onset had been provoked by the mussel extract. This observation emphasizes the feasibility of using KYN or related compounds in the therapy of poisoning from excitotoxins. As a logical extension of this possibility we examined the possibility that endogenous KYN could be exploited for similar protection against domoate toxicosis in our murine model. The time frame during which KYN was protective was increased by probenecid, a blocker of organic acid transport and by tryptophan, a precursor of endogenous KYN. We examined also the classical anticonvulsants phenytoin and ethosuximide, as well as dextromethorphan at its excitotoxin antagonistic dose. The infant mouse model of domoate-toxicity holds promise for being developed into a rapid, sensitive, reliable and inexpensive biological assay for screening commercial batches of mussel for excitotoxin contamination. Kynurenic acid and dextromethorphan should be further examined as antidotes for possible therapeutic use in existing victims and in the treatment of future domoate toxicosis occurring here or elsewhere.

Topics: Age Factors; Animals; Antidotes; Behavior, Animal; Bivalvia; Disease Models, Animal; Kainic Acid; Male; Marine Toxins; Mice; Nervous System Diseases; Neurotoxins

A rodent model of neurovisceral toxic syndrome induced by the neuroexcitant amino acid, domoic acid, is described, along with the activity of a putative antidote, the nonselective excitotoxin antagonist, kynurenic acid. Both an extract of contaminated mussels and pure domoic acid induced a characteristic syndrome including: sluggishness, scratching stereotypy, convulsions and death. Autopsy revealed gastric and duodenal lesions and peritoneal ascites. Kynurenic acid significantly obtunded these behavioral and physiological effects, particularly when given 60-75 min after the toxic insult. Probenecid, a blocker of organic acid transport, and tryptophan, a precursor of endogenous brain kynurenic acid, increased the time frame in which kynurenic acid exerted its protective effects. Kynurenic acid alone, in nontoxin-challenged animals significantly blocked cold-stress gastric lesions, significantly reduced basal gastric acid secretion and was protective to a lesser degree against ethanol-induced gastric mucosal injury. The murine model of domoate toxicity represents an inexpensive, reliable and sensitive biological assay for screening commercial shellfish for excitotoxin contamination. We are currently exploring kynurenic acid and other compounds for possible therapeutic use in both current and any future victims of neuroexcitant amino acid toxicosis.

Topics: Animals; Antidotes; Gastrointestinal Diseases; Kainic Acid; Kynurenic Acid; Male; Mice; Nervous System Diseases; Neurotoxins; Syndrome

Consumption of cultivated blue mussels from Prince Edward Island was recently associated with episodes of gastro-intestinal and neurological distress. Extracts of the toxic mussels, tested in the mouse bioassay for paralytic shellfish poison, caused an atypical response characterized by scratching, convulsions and death. The present investigation shows that the domoic acid present in toxic mussels can produce in mice and rats signs identical to those induced by mussel extracts. These studies, preliminary in nature by virtue of the scarcity of domoic acid, gave ip no-effect levels in mice of 0.59 mg/kg body weight based on the behavioural response (scratching) and 2.4 mg/kg for death. These levels correspond to levels of 24 and 94 ppm in mussels. When administered orally doses of between 35 and 70 mg domoic acid/kg body weight were required to produce toxicity in mice and rats. This reduced toxicity is consistent with a lack of absorption from the gastro-intestinal tract: faecal excretion accounted for 102 +/- 17% and 98 +/- 12% (mean +/- SE) of the domoic acid administered to mice and rats, respectively. Since human intoxication occurred at an estimated 1-5 mg domoic acid/kg body weight, susceptible individuals appear to be more sensitive than rodents to the oral toxicity of domoic acid.

Topics: Animals; Bivalvia; Dose-Response Relationship, Drug; Feces; Female; Hippocampus; Kainic Acid; Male; Mice; Nervous System Diseases; Rats; Retina; Seizures; Tissue Extracts