domoic-acid and Necrosis

Neuronal excitotoxicity causes energetic impairment and the ensuing cell death has historically been regarded as necrotic. Recent findings, however, indicate that apoptosis may participate in excitotoxicity. Here we examined the neuroprotective mechanisms of the well-characterized viral caspase inhibitors, p35 and crmA, following domoic acid-induced excitotoxicity in hippocampal neurons. We show that though p35 and crmA rescued neurons from toxicity, they did so under conditions of negligible caspase activation and morphological apoptosis. Thus, we characterized the novel neuroprotective effects of p35 and crmA and found that they attenuated the drop in the mitochondrial potential and blunted the decline in ATP levels. These data, to our knowledge, are the first detailed descriptions of the cell death mechanisms following domoic acid treatment of neurons. Moreover, in demonstrating the previously unexplored modulation of these processes, these data underline the capacity for classically "anti-apoptotic" proteins to alter other branches of cell death processes.

Topics: Animals; Caspase 1; Caspase 3; Caspase Inhibitors; Caspases; Cells, Cultured; Chlorocebus aethiops; Cysteine Proteinase Inhibitors; Enzyme Activation; Genetic Vectors; Kainic Acid; Membrane Potentials; Necrosis; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Serpins; Simplexvirus; Vero Cells; Viral Proteins

To determine the regional distribution of neuronal damage caused strictly by status epilepticus (SE) without systemic complications, underlying brain pathology, or a history of preexisting epilepsy.. The medical records and electroencephalograms (EEGs) of three deceased patients who developed SE in the hospital were reviewed. Their brains were formalin-fixed, and 17 brain regions were selected, embedded in paraffin, and sectioned. Alternate sections were stained with either hematoxylin and eosin and cresyl violet to determine the extent of neuronal loss and gliosis or glial fibrillary astrocytic protein to confirm the extent of astrocytic proliferation.. The three patients died 11 to 27 days after the onset of focal motor SE; none had hypotension, hypoxemia, hypoglycemia, or significant hyperthermia. Two patients had no prior seizures and no underlying brain pathology. The third patient, who had leptomeningeal carcinomatosis, had one seizure 2 months before the onset of SE. The duration of SE was 8.8 hours to 3 days. EEGs showed unilateral temporal lobe sharp-wave discharges in one patient and independent temporal lobe sharp-wave discharges bilaterally in the other two patients. In addition to widespread neuronal loss and reactive gliosis in the hippocampus, amygdala, dorsomedial thalamic nucleus, and Purkinje cell layer of the cerebellum, we report for the first time periamygdaloid (piriform) and entorhinal cortical damage occurring acutely after SE in humans.. In the absence of systemic complications or preexisting epilepsy, SE produces neuronal loss in a distribution similar to that from domoic acid-induced SE in humans and from kainic acid- and pilocarpine-induced SE in rats.

Topics: Animals; Astrocytes; Brain; Cell Death; Electroencephalography; Entorhinal Cortex; Gliosis; Hippocampus; Humans; Kainic Acid; Medical Records; Necrosis; Neocortex; Neuroglia; Neurons; Pilocarpine; Rats; Status Epilepticus

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