verruculogen and Tremor

Topics: Fungi; Indole Alkaloids; Indoles; Magnetic Resonance Spectroscopy; Mass Spectrometry; Molecular Conformation; Mycotoxins; Pyrans; Pyrazines; Pyrones; Tremor

Topics: Animals; Aspergillus; Cattle; Cattle Diseases; England; Indoles; Mycotoxins; Penicillium; Poaceae; Sheep; Sheep Diseases; Soil Microbiology; Tremor; Wales

The tremorgenic mycotoxin verruculogen was administered directly into the brain of freely moving rats by the use of cannula systems that superfused either the cortical surface or the lateral ventricular space. The tremor produced by these CNS routes was compared with that produced by i.p. administration of the toxin or the dried mycelium of the fungus that synthesizes the verruculogen. The nature and degree of tremor produced by the central vs peripheral routes suggest that the site of action of verruculogen is not immediately adjacent to the cannula sites in the brain. Measures of the amino acids in the superfusates collected during the verruculogen-induced tremor showed an increase in the excitatory neurotransmitters, glutamate and aspartate in superfusates from the lateral ventricle but not in superfusates from the cortical surface. The differential effect on transmitter release suggests that a subcortical action of verruculogen is responsible for its tremorgenic activity.

Topics: Amino Acids; Animals; Brain; Indoles; Male; Mycotoxins; Neurotransmitter Agents; Rats; Rats, Inbred Strains; Tremor

The moulds Penicillium simplicissimum and P crustosum and the tremorgenic mycotoxins, verruculogen and penitrem A, isolated from them, were given to sheep and pigs to compare their potencies. Pigs were generally less susceptible and in both species penitrem A was less potent than verruculogen. Five-month-old lambs seemed more susceptible to mycelium containing verruculogen than were 15-month-old sheep given a similar oral dose relative to bodyweight. Repeated daily dosing of lambs and sheep for five days with P simplicissimum failed to enhance the effect, indicating that verruculogen toxicity was not cumulative. Long and short acting barbiturate anaesthesia blocked the effects of lethal doses of tremorgens. Sedation with diazepam diminished, but did not block, mycotoxin-induced tremors suggesting that there was no specific action of this anticonvulsant sedative on tremorgens.

Topics: Animals; Barbiturates; Diazepam; Dose-Response Relationship, Drug; Drug Antagonism; Indoles; Mycotoxins; Penicillium; Sheep; Sheep Diseases; Swine; Swine Diseases; Tremor

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.

Topics: Amino Acids; Animals; Aspartic Acid; Cerebral Cortex; Corpus Striatum; gamma-Aminobutyric Acid; Glutamates; Indoles; Medulla Oblongata; Mycotoxins; Neurotransmitter Agents; Potassium; Rats; Sheep; Spinal Cord; Synaptosomes; Tremor

In our previous work we examined the mechanism of action of the new tremorogenic substance verruculogen isolated by Cole and coworkers. Examining the effect of various substances with known mechanisms of action on verruculogen-induced tremor, we concluded that this tremor was probably related to decrease of GABA levels in CNS. In order to further define the mechanisms of action of verruculogen, we determined brain GABA levels in animals in which tremor was produced by verruculogen administration. Verruculogen administration produced a decrease in GABA levels in mouse CNS. This finding substantiates our earlier suggestion that verruculogen-induced tremor is mediated by a loss of inhibitory GABA function.

Topics: Aminobutyrates; Animals; Brain; Depression, Chemical; gamma-Aminobutyric Acid; Indoles; Male; Mice; Mycotoxins; Tremor

Topics: Aminobutyrates; Animals; Brain; Indoles; Injections, Intraperitoneal; Mice; Mycotoxins; Penicillium; Tremor