Stress-related over-enhancement of the hypothalamic-pituitary-adrenal axis causes experimental neurolathyrism in rats.

Neurolathyrism is a motor neuron disease that is caused by the overconsumption of grass peas (Lathyrus sativus L.) under stressful conditions. The neuro-excitatory ß-N-oxalyl-L-α,ß-diaminopropionic acid present in grass peas was proposed the causative agent of spastic paraparesis of the legs. Historical reports of neurolathyrism epidemics, studies of neurolathyrism animal models, and in vitro studies on the mechanism of ß-N-oxalyl-L-α,ß-diaminopropionic acid toxicity support the hypothesis that stress increases susceptibility to neurolathyrism. To elucidate the role of stress in neurolathyrism-induced motor dysfunction, we focused on the hypothalamic-pituitary-adrenal axis in a rodent model of neurolathyrism. Our results implicated increased glucocorticoid and neuroinflammation in the motor dysfunction (paraparesis) exhibited by the stress loaded rat models of neurolathyrism.

Expression of extracellular matrix genes: transforming growth factor (TGF)-beta1 and ras in tibial fracture healing of lathyritic rats.

Experimental osteolathyrism, induced by dietary aminoacetonitrile (AAN), was used to study the effect of altered extracellular matrix on the expression of connective tissue components in long bone healing. AAN inhibits lysyl oxidase, which is needed for the formation of collagen cross-link precursors, and is also shown to act as a regulator of Ras. Fractured tibias in lathyritic rats develop excessive amounts of mechanically weak callus tissue with irregular cartilage and reduced glycosaminoglycan accumulation. Cartilage-specific proteins (collagen types II, IX, and X and aggrecan) were expressed temporally much wider in lathyritic calluses than in the controls, and active transcription was observed even during the fibrous and ossifying stages. Soft connective tissue was still present in 2- and 3-week-old lathyritic calluses and could explain the elevated type III collagen, biglycan, and decorin mRNA levels. Both transforming growth factor (TGF)-beta1 and c-Ha-ras, which control cell growth and differentiation, were upregulated during the cartilaginous stage. The maximal expression of TGF-beta1 preceded that of ras in osteolathyrism.

In search of a new therapeutic target for the treatment of genetically triggered thoracic aortic aneurysms and cardiovascular conditions: insights from human and animal lathyrism.

Lathyrism, or the effect of certain plants on connective tissue disruption, particularly involving the vascular and skeletal systems, especially aortic dissection/rupture, has been well documented in animals. Its impact on the pathogenesis of connective tissue diseases in humans is still unclear. An extensive review of the scientific literature from the 1800s until the present time was performed to examine the common pathways between animal and human lathyrism and genetically triggered thoracic aortic aneurysms and cardiovascular conditions in humans, with special focus on the identification of potential therapeutic targets. Search areas covered the following subjects: lathyrism/spontaneous aortic dissection/rupture in animals; beta-aminopropionitrile, semicarbazide and their effects; collagen and elastin synthesis and cross-linking; genetic and molecular biology characteristics of the genetically triggered thoracic aortic conditions. Search results demonstrate Marfan syndrome as a model for the genetically triggered thoracic aortic aneurysms, has been linked to mutations of the fibrillin-1 gene, via transforming growth factor beta-1. Several other conditions do not share this mutation. Inhibition of semicarbazide-sensitive amine oxidase [vascular adhesion protein-1 (VAP-1)] in animals has been shown to result in aortic dilatation due to disruption of elastin cross-linking. Significantly low activity of this enzyme was identified in annulo-aortic ectasia; a condition similar to Marfan syndrome. In conclusion, the precise molecular and genetic pathways responsible for the clinical findings in Marfan syndrome and related conditions remain unclear. Observational and experimental findings relating to the vascular and systemic effects of molecular pathways implicated in the phenomenon of animal and human lathyrism suggest that VAP-1 seems to be involved in the molecular and developmental pathways of the genetically triggered thoracic aortic diseases and thus could be a potential therapeutic target for these conditions.