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Actions of tremorgenic fungal toxins on neurotransmitter release
Abstract:
The neurochemical effects of the tremorgenic mycotoxins Verruculogen and Penitrem A, which produce a neurotoxic syndrome characterised by sustained tremors, were studied using sheep and rat synaptosomes. The toxins were administered in vivo, either by chronic feeding (sheep) or intraperitoneal injection 45 min prior to killing (rat), and synaptosomes were subsequently prepared from cerebrocortical and spinal cord/medullary regions of rat, and corpus striatum of sheep. Penitrem A (400 mg mycelium/kg) increased the spontaneous release of endogenous glutamate, GABA (gamma-aminobutyric acid), and aspartate by 213%, 455%, and 277%, respectively, from cerebrocortical synaptosomes. Verruculogen (400 mg mycelium/kg) increased the spontaneous release of glutamate and aspartate by 1300% and 1200%, respectively, but not that of GABA from cerebrocortical synaptosomes. The spontaneous release of the transmitter amino acids or other amino acids was not increased by the tremorgens in spinal cord/medullary synaptosomes. Penitrem A pretreatment reduced the veratrine (75 microM) stimulated release of glutamate, aspartate, and GABA from cerebrocortical synaptosomes by 33%, 46%, and 11%, respectively, and the stimulated release of glycine and GABA from spinal cord/medulla synaptosomes by 67% and 32% respectively. Verruculogen pretreatment did not alter the veratrine-induced release of transmitter amino acids from cerebrocortex and spinal cord/medulla synaptosomes. Penitrem A pretreatment increased the spontaneous release of aspartate, glutamate, and GABA by 68%, 62%, and 100%, respectively, from sheep corpus striatum synaptosomes but did not alter the synthesis and release of dopamine in this tissue. Verruculogen was shown to cause a substantial increase (300-400%) in the miniature-end-plate potential (m.e.p.p.) frequency at the locust neuromuscular junction. The response was detectable within 1 min, rose to a maximum within 5-7 min, and declined to the control rate over a similar period. No change in the amplitude of the m.e.p.p.'s was observed. These effects of the tremorgens on transmitter release are interpreted in terms of their mode of action.
Insights
Tremorgenic mycotoxins, Verruculogen and Penitrem A, disrupt neurotransmitter release in the brain. These toxins, particularly Penitrem A, significantly increase spontaneous release of glutamate and GABA, affecting central nervous system function.
Area of Science:
- Neuroscience
- Toxicology
- Biochemistry
Context:
- Tremorgenic mycotoxins, Verruculogen and Penitrem A, are known to induce neurotoxic syndromes characterized by tremors.
- Understanding their neurochemical effects is crucial for assessing their toxicological impact and potential mechanisms of action.
Purpose:
- To investigate the neurochemical effects of Verruculogen and Penitrem A on neurotransmitter release in mammalian and invertebrate models.
- To elucidate the specific mechanisms by which these mycotoxins affect synaptic transmission.
Summary:
- Penitrem A and Verruculogen were administered to rats and sheep, and their effects on synaptosomes from different brain regions were analyzed.
- Penitrem A significantly increased spontaneous release of glutamate, GABA, and aspartate in rat cerebrocortical synaptosomes and sheep corpus striatum.
- Verruculogen markedly elevated glutamate and aspartate release in rat cerebrocortical synaptosomes and increased miniature-end-plate potential frequency in locust neuromuscular junctions.
Impact:
- This study reveals distinct neurochemical actions of Verruculogen and Penitrem A, highlighting their differential effects on excitatory and inhibitory neurotransmitter systems.
- The findings provide insights into the molecular targets and mechanisms underlying tremorgen-induced neurotoxicity.
- Understanding these effects is vital for diagnosing and managing mycotoxin poisoning and for developing potential countermeasures.