tetrodotoxin and Brain-Diseases

Toxins formed by organic micro-organisms may accumulate within certain tissues of predacious sea animals, which may serve as a source of seafood poisoning for the higher food chain. Such toxins are distinct from inorganic chemicals or infectious agents which may have contaminated the seafoods. Distinct clinical syndromes have emerged, and the individual toxins have been identified. Clinical manifestations of each begin with a gastrointestinal prodrome and headache, followed by sensorimotor deficits. Bulbar and cognitive changes are associated with the more lethal tetrodotoxin, saxitoxin, and domoic acid toxin. Tetrodotoxin and saxitoxin block sodium channels, while ciguatoxin opens them. Domoic acid stimulates excitatory amino acids at the NMDA receptors.

Topics: Brain Diseases; Bulbar Palsy, Progressive; Ciguatoxins; Cognition Disorders; Foodborne Diseases; Gastrointestinal Diseases; Headache; Humans; Mannitol; Psychomotor Disorders; Receptors, N-Methyl-D-Aspartate; Saxitoxin; Seafood; Sodium Channels; Tetrodotoxin

Topics: Aged; Alzheimer Disease; Amino Acids; Animals; Brain; Brain Diseases; Calcium; Cations; gamma-Aminobutyric Acid; Humans; Huntington Disease; Kainic Acid; Middle Aged; Neurotoxins; Tetrodotoxin

Studying epileptogenesis in a genetic model can facilitate the identification of factors that promote the conversion of a normal brain into one chronically prone to seizures. Synapsin triple-knockout (TKO) mice exhibit adult-onset epilepsy, thus allowing the characterization of events as preceding or following seizure onset. Although it has been proposed that a congenital reduction in inhibitory transmission is the underlying cause for epilepsy in these mice, young TKO mice are asymptomatic. We report that the genetic lesion exerts long-term progressive effects that extend well into adulthood. Although inhibitory transmission is initially reduced, it is subsequently strengthened relative to its magnitude in control mice, so that the excitation to inhibition balance in adult TKOs is inverted in favor of inhibition. In parallel, we observed long-term alterations in synaptic depression kinetics of excitatory transmission and in the extent of tonic inhibition, illustrating adaptations in synaptic properties. Moreover, age-dependent acceleration of the action potential did not occur in TKO cortical pyramidal neurons, suggesting wide-ranging secondary changes in brain excitability. In conclusion, although congenital impairments in inhibitory transmission may initiate epileptogenesis in the synapsin TKO mice, we suggest that secondary adaptations are crucial for the establishment of this epileptic network.

Topics: Age Factors; Analysis of Variance; Animals; Brain Diseases; Electric Stimulation; Entorhinal Cortex; Excitatory Amino Acid Agents; GABA Agents; In Vitro Techniques; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuronal Plasticity; Patch-Clamp Techniques; Receptors, Nicotinic; RNA, Messenger; Sodium Channel Blockers; Synapsins; Tetrodotoxin

The production of the broad spectrum excitatory amino acid receptor antagonist kynurenic acid was assessed by hippocampal microdialysis in freely moving rats. Extracellular kynurenic acid, determined spectrophotometrically, was measured following the perfusion of its bioprecursor L-kynurenine (500 microM) through the dialysis probe. In this paradigm, the concentration of kynurenic acid reached plateau levels within 2 h. These steady state levels were more than doubled in gliotic quinolinate-lesioned tissue. The non-specific inhibitor of kynurenine aminotransferase, aminooxyacetic acid (300 microM), and the depolarizing agent veratridine (50 microM), introduced through the dialysis membrane, caused a 69 and 57% decrease, respectively, in extracellular kynurenic acid. The effect of veratridine was rapidly reversible and was blocked by 5 microM tetrodotoxin or in the quinolinate-lesioned hippocampus. In contrast, the effect of aminooxyacetic acid was longer lasting upon drug discontinuation, and was not reversed by tetrodotoxin or in lesioned tissue. These data demonstrate that hippocampal kynurenic acid can be regulated by direct interference with its biosynthetic enzyme and by a distinct process involving neuron-glia interactions.

Topics: Aminooxyacetic Acid; Animals; Brain Diseases; Dialysis; Drug Interactions; Hippocampus; Kynurenic Acid; Kynurenine; Male; Quinolinic Acid; Quinolinic Acids; Rats; Rats, Inbred Strains; Tetrodotoxin; Veratridine