Page 1105 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Tremorgenic Mycotoxins Chapter | 74 1037

VetBooks.ir mycotoxins, with 5-month-old lambs being more suscepti- explained by a presynaptic inhibition of inhibitory
interneurons.
ble than 15-month-old sheep to verruculogen toxicity
(Patterson et al., 1981).
Similar mechanisms of action have been demonstrated
for other tremorgenic mycotoxins. Verruculogen-induced
tremors in rats have been associated with an increased
MECHANISM OF ACTION level of excitatory neurotransmitters (glutamate and aspar-
tate) in the lateral ventricle, suggesting subcortical,
It should be pointed out that, although related in structure, verruculogen-induced tremorgenic activity. Selala et al.
tremorgenic mycotoxins do not exert toxicity by a single (1989) demonstrated that tremorgenic mycotoxins can be
common mechanism, and the exact mechanisms involved partial agonists of GABA. Verruculogen increases sponta-
in neurotoxicity induced by these tremorgens are yet to be neous glutamate and aspartate release in vivo in guinea
fully elucidated. These mycotoxins work at a different pig ileum preparations and also causes an increase in con-
functional level of the nervous system than other myco- tractile responses to electrical field stimulation, which has
toxins having more widespread targets for toxicity associ- been attributed to the enhanced release of acetylcholine
ated with the inhibition of basic cellular functions, such as from presynaptic nerve terminals. Although paxilline
21
protein synthesis. Several pharmacological/toxicological blocks high-conductance Ca -activated K 1 channels,
mechanisms of tremorgenic action have been proposed, some related nontremorgenic fungal metabolites, such as
and, in general, tremorgenic mycotoxins interfere with paspaline, have also been shown to inhibit these particular
inhibitory neuroreceptors and enhance excitatory amino ion channels (Burrows and Tyrl, 2001). Paxilline also
acid neurotransmitter release mechanisms (Wilson, 1971; inhibits the cerebellar inositol 1,4,5-triphosphate receptor.
Norris et al., 1980; Selala et al., 1989). In experimental Paspalinine and the paspalitrems are thought to impair
studies, the inhibitory action of this type of mycotoxins at GABA- and glycine-mediated inhibitory pathways
gamma aminobutyric acid (GABA) receptors was demon- (Burrows and Tyrl, 2001).
strated (Stern, 1971; Hotujac and Stern, 1974; Hotujac
et al., 1976; Selala et al., 1989; Abramson, 1997). Gant
et al. (1987) studied the effects of four fungal tremorgens TOXICODYNAMICS
and one nontremorgenic mycotoxin on GABA A receptor-
Central Effects
binding in the rat’s brain, and, in high concentrations, the
tremorgenic action of these mycotoxins was, in part, most Tremorgenic mycotoxins are known to act on the CNS,
likely due to inhibition of GABA A receptor function. causing sustained tremors, convulsions, and, occasionally,
Conversely, other studies have shown how tremorgenic deaths in animals. In general, the clinical signs and symp-
mycotoxins increase the release of excitatory neurotrans- toms typically observed during tremorgenic mycotoxi-
mitters (Norris et al., 1980). coses include diminished activity and immobility,
Among the tremorgenic mycotoxins, penitrem A has followed by hyperexcitability, muscle tremor, ataxia,
been studied the most for the elucidation of its mechanism tetanic seizures, and convulsions (Cole and Cox, 1981;
of action and toxicity. There is convincing evidence sug- Valdes et al., 1985; Barker et al., 2013). These clinical
gesting that penitrem A acts on the CNS to induce sei- signs are reversible if the affected animal is removed
zures (Sobotka et al., 1978; Arp and Richard, 1981). from tremorgen-contaminated source. Death is limited by
Penitrem A was shown to increase the spontaneous the emetic effect of these tremorgens. In dogs, the clinical
release of aspartate and glutamate, as well as, interest- disease involves the development of muscle tremors and
ingly, GABA (Norris et al., 1980). Glutamate and aspar- seizures, vomiting, alterations in behavior, hyperthermia,
tate are the neurotransmitters of the parallel and climbing depression, coma, and pulmonary edema.
fibers, respectively, which are two major excitatory inputs Depending on the level of tremorgenic mycotoxin
to Purkinje cells. There is also evidence for a penitrem A- exposure, death can occur in some instances within 2 4h
induced partial decrease in glycine levels in the brain in and is usually secondary to respiratory compromise, meta-
association with pathology related to penitrem A exposure bolic acidosis, and/or hyperthermia. In severe cases, clini-
(Catovic et al., 1975). Cavanagh et al. (1998) demon- cal signs of toxicosis can persist for several days, and fine
strated that, in rats, penitrem A can cause widespread tremors can be seen for a week or more. The tremors pro-
degeneration of Purkinje cells and foci of necrosis in the duced by penitrem A are very similar in most species and
cerebellar granular cell layers. These striking lesions are begin within a few minutes of intraperitoneal (IP) injec-
confined to the cerebellum, with no lesions found else- tion and even sooner with IV injection. The tremors can
where in the brain. Cerebellar Purkinje cells are the pri- be sustained and lead to both ataxia and episodic spasms
mary targets cells for the adverse effects of penitrem (Cavanagh et al., 1998). Larger doses of penitrem A
A. Penitrem A-induced tremors might also be partly can cause seizures, massive liver necrosis, and death