Hind-Limb Paraparesis in a Rat Model for Neurolathyrism Associated With Apoptosis and an Impaired Vascular Endothelial Growth Factor System in the Spinal Cord

Neurolathyrism is a motor neuron disease characterized by lower limb paraparesis. It is associated with ingestion of a plant excitotoxin, beta-N-oxalyl-L-alpha beta-diaminopropionic acid (L-beta-ODAP), an agonist of alpha-amino-3-hydroxy-5-methyl-4-i soxazolepropionic acid (AMPA)/kainate-type glutamatergic receptors. Previously, a limited model of neurolathyrism was reported for the rat. To improve upon the model, we stressed rat pups by separation from their mothers, followed by the subcutaneous L-beta-ODAP treatment, resulting in a 4.6-fold higher incidence (14.0 -15.6%) of the paraparesis compared with the prior study. The number and size of motor neurons in these rats were decreased only in the lumbar and sacral cord segments, at approximately 13-36 weeks after treatment. Only lumbar and sacral spinal cord tissue revealed pathological insults typical of physical and ischemic spinal cord injury in the surviving motor neurons. In addition, extensive but transient hemorrhage occurred in the ventral spinal cord parenchyma of the rat, and numerous TdT-mediated dUTP-biotin nick end-labeling (TUNEL)-positive cells were also observed. In parallel, vascular endothelial growth factor receptor (VEGFR)-2 (Flk-1) levels were significantly lowered in the lumbosacral spinal cord of the paraparetic rats compared with their controls, suggesting a failure of the VEGF system to protect neurons against L-beta-ODAP toxicity. We propose, based on these data, a novel pathological process of motor neuron death induced by peripheral L-beta-ODAP. For the first time, we present a model of the early molecular events that occur during chemically induced spinal cord injury, which can potentially be applied to other neurodegenerative disorders. J. Comp. Neurol. 518:928-942, 2010. (C) 2009 Wiley-Liss, Inc.