lolitrem-b and Nervous-System-Diseases

"Ryegrass staggers" is a neurological condition of unknown mechanism that impairs motor function in livestock. It is caused by infection of perennial ryegrass pastures by an endophytic fungus that produces neurotoxins, predominantly the indole-diterpenoid compound lolitrem B. Animals grazing on such pastures develop uncontrollable tremors and become uncoordinated in their movement. Lolitrem B and the structurally related tremor inducer paxilline both act as potent large conductance calcium-activated potassium (BK) channel inhibitors. Using patch clamping, we show that their different apparent affinities correlate with their toxicity in vivo. To investigate whether the motor function deficits produced by lolitrem B and paxilline are due to inhibition of BK ion channels, their ability to induce tremor and ataxia in mice deficient in this ion channel (Kcnma1(-/-)) was examined. Our results show that mice lacking Kcnma1 are unaffected by these neurotoxins. Furthermore, doses of these substances known to be lethal to wild-type mice had no effect on Kcnma1(-/-) mice. These studies reveal the BK channel as the molecular target for the major components of the motor impairments induced by ryegrass neurotoxins. Unexpectedly, when the response to lolitrem B was examined in mice lacking the beta4 BK channel accessory subunit (Kcnmb4(-/-)), only low-level ataxia was observed. Our study therefore reveals a new role for the accessory BK beta4 subunit in motor control. The beta4 subunit could be considered as a potential target for treatment of ataxic conditions in animals and in humans.

Topics: Animals; Cattle; Cattle Diseases; Indole Alkaloids; Indoles; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Large-Conductance Calcium-Activated Potassium Channel beta Subunits; Lolium; Mice; Mice, Knockout; Mycotoxins; Nervous System Diseases; Patch-Clamp Techniques

Tremor dose-response curves were determined for mice dosed with the ryegrass neurotoxin lolitrem B, and the tremor-genic mycotoxin aflatrem. A family of characteristic curves was revealed for each tremorgenic, with lolitrem B eliciting a sustained tremor response persisting for over 24 h.

Topics: Animals; Dimethyl Sulfoxide; Dose-Response Relationship, Drug; Female; Indole Alkaloids; Indoles; Kinetics; Mice; Mycotoxins; Nervous System Diseases; Tremor

Enhanced unstimulated release of the excitatory amino acid neurotransmitters aspartic acid and glutamic acid was measured in cerebrocortical synaptosomes prepared from sheep showing severe symptoms of ryegrass staggers. A similar pattern of deviation from neurologically normal animals was seen whether the sheep had contracted the disorder naturally or whether they had been deliberately caused to develop the disorder by grazing specific pastures rich in endophyte infected ryegrass. Deranged neurotransmitter release may reasonably be involved in the chemical pathology of ryegrass staggers and the findings are in accord with the putative synonymy of lolitrem toxicosis and ryegrass staggers.

Topics: Animals; Aspartic Acid; Cerebral Cortex; Glutamates; Glutamic Acid; Indole Alkaloids; Mycotoxins; Nervous System Diseases; Neurotransmitter Agents; Sheep; Sheep Diseases; Synaptosomes