lolitrem-b and Tremor

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

The neuroactive mycotoxin lolitrem B causes a neurological syndrome in grazing livestock resulting in hyperexcitability, muscle tremors, ataxia and, in severe cases, clonic seizures and death. To define the effects of the major toxin lolitrem B in the brain, a functional metabolomic study was undertaken in which motor coordination and tremor were quantified and metabolomic profiling undertaken to determine relative abundance of both toxin and key neurotransmitters in various brain regions in male mice. Marked differences were observed in the duration of tremor and coordination between lolitrem B pathway members, with some showing protracted effects and others none at all. Lolitrem B was identified in liver, kidney, cerebral cortex and thalamus but not in brainstem or cerebellum which were hypothesised previously to be the primary site of action. Metabolomic profiling showed significant variation in specific neurotransmitter and amino acid profiles over time. This study demonstrates accumulation of lolitrem B in the brain, with non-detectable levels of toxin in the brainstem and cerebellum, inducing alterations in metabolites such as tyrosine, suggesting a dynamic catecholaminergic response over time. Temporal characterisation of key pathways in the pathophysiological response of lolitrem B in the brain were also identified.

Topics: Animals; Biosynthetic Pathways; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Indole Alkaloids; Metabolomics; Mice; Mycotoxins; Organ Specificity; ROC Curve; Tremor

The indole diterpenoid toxin lolitrem B is a tremorgenic agent found in the common grass species, perennial ryegrass (Lolium perenne). The toxin is produced by a symbiotic fungus Epichloë festucae (var. lolii) and ingestion of infested grass with sufficient toxin levels causes a movement disorder in grazing herbivores known as 'ryegrass staggers'. Beside ataxia, lolitrem B intoxicated animals frequently show indicators of cognitive dysfunction or exhibition of erratic and unpredictable behaviours during handling. Evidence from field cases in livestock and controlled feeding studies in horses have indicated that intoxication with lolitrem B may affect higher cortical or subcortical functioning. In order to define the role of lolitrem B in voluntary motor control, spatial learning and memory under controlled conditions, mice were exposed to a known dose of purified lolitrem B toxin and tremor, coordination, voluntary motor activity and spatial learning and memory assessed. Motor activity, coordination and spatial memory were compared to tremor intensity using a novel quantitative piezo-electronic tremor analysis. Peak tremor was observed as frequencies between 15 and 25Hz compared to normal movement at approximately 1.4-10Hz. A single exposure to a known tremorgenic dose of lolitrem B (2 mg/kg IP) induced measureable tremor for up to 72 h in some animals. Initially, intoxication with lolitrem B significantly decreased voluntary movement. By 25 h post exposure a return to normal voluntary movement was observed in this group, despite continuing evidence of tremor. This effect was not observed in animals exposed to the short-acting tremorgenic toxin paxilline. Lolitrem B intoxicated mice demonstrated a random search pattern and delayed latency to escape a 3 h post intoxication, however by 27 h post exposure latency to escape matched controls and mice had returned to normal searching behavior indicating normal spatial learning and memory. Together these data indicate that the tremor exhibited by lolitrem B intoxicated mice does not directly impair spatial learning and memory but that exposure does reduce voluntary motor activity in intoxicated animals. Management of acutely affected livestock suffering toxicosis should be considered in the context of their ability to spatially orientate with severe toxicity.

Topics: Animals; Escape Reaction; Indole Alkaloids; Indoles; Memory; Mice, Inbred C57BL; Motor Activity; Mycotoxins; Orientation, Spatial; Spatial Learning; Tremor

To investigate a possible interaction between lolitrem B and ergovaline by comparing the incidence and severity of ryegrass staggers in sheep grazing ryegrass (Lolium perenne) containing lolitrem B or ryegrass containing both lolitrem B and ergovaline.. Ninety lambs, aged approximately 6 months, were grazed on plots of perennial ryegrass infected with either AR98 endophyte (containing lolitrem B), standard endophyte (containing lolitrem B and ergovaline) or no endophyte, for up to 42 days from 2 February 2010. Ten lambs were grazed on three replicate plots per cultivar. Herbage samples were collected for alkaloid analysis and lambs were scored for ryegrass staggers (scores from 0-5) weekly during the study. Any animal which was scored ≥4 was removed from the study.. Concentrations of lolitrem B did not differ between AR98 and standard endophyte-infected pastures during the study period (p=0.26), and ergovaline was present only in standard endophyte pastures. Ryegrass staggers was observed in sheep grazing both the AR98 and standard endophyte plots, with median scores increasing in the third week of the study. Prior to the end of the 42-day grazing period, 22 and 17 animals were removed from the standard endophyte and AR98 plots, respectively, because their staggers scores were ≥4. The cumulative probability of lambs having scores ≥4 did not differ between animals grazing the two pasture types (p=0.41).. There was no evidence for ergovaline increasing the severity of ryegrass staggers induced by lolitrem B. In situations where the severity of ryegrass staggers appears to be greater than that predicted on the basis of concentrations of lolitrem B, the presence of other tremorgenic alkaloids should be investigated.

Topics: Animal Feed; Animals; Endophytes; Ergotamines; Incidence; Indole Alkaloids; Lolium; Mycotoxins; New Zealand; Proportional Hazards Models; Severity of Illness Index; Sheep; Sheep Diseases; Tremor

Perennial ryegrass staggers is purported to be a common neurological mycotoxicosis of horses but the case description lacks detail and evidence.. To describe the clinical syndrome of lolitrem B intoxication in horses, limiting tests to those that are applicable to clinical practice, and to assess the potential value of enzyme-linked immunosorbent assay (ELISA) tests for lolitrem B in horse body fluids.. Seven horses in 2 separate groups were fed perennial ryegrass seed and hay containing 2 ppm lolitrem B. Paired data were collected prior to and after 2 weeks exposure to lolitrem B, including video-documented neurological examination and clinical examination.. All horses developed a variable degree of tremor and ataxia when exposed to lolitrem B. Tremor depended on the level of activity and included a subtle, rapid tremor of the eyeball. Ataxia was exaggerated by blindfolding and primarily involved a truncal sway and irregular, but predictable, limb placements. No change was detected in urine lolitrem B levels and, although plasma lolitrem B increased during the treatment period, levels did not correlate with the severity of clinical signs displayed. Limb swelling, heel lesions and serous nasal discharge were also observed in horses most severely intoxicated.. The clinical effects of lolitrem B intoxication in horses primarily involve action-related tremors and symmetrical vestibular ataxia. Ergovaline may have caused the limb swelling, heel lesions and serous nasal discharge. Plasma ELISA for lolitrem B may be of diagnostic use in the future.. This study provides a clearer appreciation of the clinical signs and variability of perennial ryegrass intoxication in horses.

Topics: Animal Feed; Animals; Ataxia; Ergotamines; Female; Horse Diseases; Horses; Indole Alkaloids; Lolium; Male; Mycotoxins; Plant Poisoning; Plants, Toxic; Seeds; Tremor

Fescue foot, summer syndrome, reproductive problems, and ryegrass staggers are all diseases of livestock related to endophyte toxins in pasture grasses. Range finding experiments and case studies of fescue foot relative to ergovaline toxin found in endophyte infected tall fescue and lolitrem B present in endophyte infected perennial ryegrass were conducted. Within 42 d of initiating a feeding trial with chopped tall fescue straw containing 825 ppb ergovaline and at environmental temperatures of 15.9 C clinical signs of fescue foot were seen in cattle. Sheep on tall fescue pastures in November consuming feed with 540 ppb ergovaline and at environmental temperatures of 7.8 C developed fescue foot in 21 d while sheep on the adjacent field in the previous 2 mo with environmental temperatures of 16.6 C and 12.8 C and 458 ppb ergovaline in the pasture grasses did not. In a field outbreak of fescue foot affecting 42/425 feeder lambs in November, the ergovaline of sample pasture grasses had a mean concentration of 813 ppb. Perennial ryegrass staggers was seen in 42/237 feeder lambs when mean lolitrem B in the sampled grass was 2,135 ppb. Overgrazing both tall fescue and ryegrass fields increased probability of clinical disease since the highest levels of toxin were found in the crowns and basal leaf sheaths of tall fescue and perennial ryegrass respectively. Based on these findings, ergovaline dietary levels of 400 to 750 ppb to cattle and 500 to 800 ppb to sheep and lolitrem B levels of 1,800 to 2,000 ppb in feed for both species are approximated threshold values for disease. Cold environmental temperatures are equally important to toxin concentrations in precipitating fescue foot disease.

Topics: Acremonium; Animal Feed; Animals; Cattle; Chromatography, High Pressure Liquid; Cold Temperature; Ergotamines; Female; Foot Diseases; Indole Alkaloids; Male; Mycotoxicosis; Mycotoxins; Plant Poisoning; Plants, Toxic; Poaceae; Retrospective Studies; Sheep; Sheep Diseases; Tremor

In the course of several days most of the 40 riding-school horses turned out in paddocks developed ataxia of variable severity. Five of these horses showed severe ataxia and tremors, became paralyzed and were euthanized. Eleven privately-owned horses which were stabled on the same premises showed no clinical signs. The most likely diagnosis seemed to be the 'neurological form of EHV1', although the signs were not entirely typical. A few weeks later a second outbreak occurred among the riding-school horses and one of the privately-owned horses also showed signs of ataxia. In the meantime it had been shown that EHV1 titers in paired serum samples had not increased and that the cerebrospinal fluid of one of the severely affected horses was normal. Toxicological examination of hay, delivered just before the first outbreak and stored for the winter, showed a significantly increased concentration of lolitrem B mycotoxin (5-6 mg/kg). The hay appeared to have been made of ryegrass used for lawns and playing fields. Retrospectively it became probable that this hay occasionally been fed to the horses just before the onset of clinical problems. It is concluded that the horses showed the 'ryegrass-stagger syndrome'.

Topics: Animal Feed; Animals; Ataxia; Diagnosis, Differential; Disease Outbreaks; Herpesviridae Infections; Herpesvirus 1, Equid; Horse Diseases; Horses; Indole Alkaloids; Mycotoxicosis; Mycotoxins; Neurotoxins; Paralysis; Poaceae; Tremor

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

Topics: Animals; Animals, Domestic; Chromatography, Thin Layer; Indole Alkaloids; Mycotoxins; Neurotoxins; New Zealand; Poaceae; Tremor