Neurolathyrism Research Articles

Vascular insult accompanied by overexpressed heme oxygenase-1 as a pathophysiological mechanism in experimental neurolathyrism with hind-leg paraparesis

Neurolathyrism (NL) is a motor neuron disease characterized by spastic paraparesis in the hind legs. β-N-oxalyl-l-α,β-diaminopropionic acid (l-β-ODAP), a component amino acid of the grass pea (Lathyrus sativus L.), has been proposed as the cause of this disease. In our NL rat model, we previously reported that transient intra-parenchymal hemorrhage occurred in the lower spinal cord during the early treatment period. We show here a possible pathological role of the hemorrhage in motor neuron damage and paraparesis pathology. In the lumbo-sacral spinal cord, blood vessel integrity was lost with numerous TdT-mediated dUTP nick end-labeling-positive blood vessel-like structures occurring simultaneously with the hemorrhage. We observed a coincident >10-fold increase in heme oxygenase-1 (HO-1) only in the lower spinal cord. The early period of paraparesis in the lower leg was greatly suppressed by pretreatment with zinc protoporphyrin IX, a HO-1 inhibitor. In vitro, l-β-ODAP was toxic to human umbilical vein endothelial cells compared to l-glutamate. The present data shed light on the role and the mechanism of vascular insult in causing dysfunction and moribund motor neurons in experimental NL.

Global gene expression analysis using microarray to study differential vulnerability to neurodegeneration

Neurodegenerative disorders such as Parkinson’s disease, motor neuron disease and Alzheimer’s disease is characterized by loss of specific cells within certain regions of the brain. One of the most compelling questions is to determine why specific cell populations are vulnerable to neurodegeneration. We addressed this question by studying global gene expression changes using an animal model of neurodegenerative disease. Human ingestion of “chickling peas” from the plant Lathyrus sativus containing an excitatory amino acid, L-?-N-oxalyl amino-L-alanine (L-BOAA) leads to a neurodegenerative disorder, neurolathyrism, a motor neuron disease characterized by spastic paraparesis that targets Betz cells in motor cortex (MC) and the anterior horn cells in the lumbosacral cord (LSC). Our laboratory has earlier shown that L-BOAA toxicity in mice is associated with mitochondrial dysfunction seen as loss of complex I activity in MC and LSC. While MC recovers after an initial insult, sustained injury is seen in LSC. We therefore, profiled global gene expression changes by microarray analyses in mice CNS regions during recovery from L-BOAA toxicity. Mouse cDNA arrays were hybridised with RNA from MC and LSC of control and L-BOAA treated mice. Data was analysed using Array vision and Spot-fire software. In concurrence with earlier results glutaredoxin, a thiol disulfide oxidoreductase was upregulated in both MC and LSC. Glutaredoxin is required for maintenance of complex I function. However, the up-regulation of NADH dehydrogenase (Complex I) was seen only in MC and not in LSC in agreement with the activity of complex I seen earlier. Upregulation of genes related to energy metabolism, antioxidant enzymes, MAP kinases and ubiquitin proteasomal pathways was seen in MC indicating their potential role in the recovery. In contrast in LSC, genes related to MAP kinases and anti-oxidant were not upregulated, instead programmed cell death gene was upregulated. These studies demonstrate the differential responses of CNS regions to a common excitotoxic insult and help identify factors responsible for differential vulnerability of CNS regions often seen in neurodegenerative diseases.

Cognitive evaluation of patients with chronic neurolathyrism

The object of the present study was to evaluate whether patients with neurolathyrism (NL) have cognitive abnormalities, and whether the cognitive decline, if found, correlates with the motor deficit. NL is a neurological syndrome that develops following ingestion of the grass pea (Lathyrus Sativus). These beans have excellent nutritional properties but contain the neurotoxin beta-N-oxalylamino-l-alanine (BOAA), suggested to be responsible for the development of CNL with the main symptom being spastic paraparesis. BOAA is closely related to beta-metyl-amino-alanine (BMA), the putatove phytotoxin involved in the pathogenesis of the ALS-PD complex of Guam. As the latter includes dementia, we investigated the cognitive functions of CNL patients. NL patients (n=30), all subjects over 65-years old, and 30 aged matched controls underwent a neurological examination including a structured cognitive evaluation diagnosed according to DSM-IV criteria. In addition, all the participants were tested with the Wechsler Memory Scale (WMS). Patients' motor function was divided into five stages according to disease severity. Statistical analysis was performed using Student's t-test. Only one patient was found to be demented. The 30 CNL patients had a mean total WMS score of 57.2+/-18.2 and a memory quotient (MQ) of 128.9+/-28.5. The corresponding values for controls were 57.1+/-13.2 and 124+/-15.2 and there were no significant statistical differences between the two groups. No correlation was found between the cognitive and motor state of the CNL patients. The cognitive state of CNL patients does not show a decline.

H reflex studies in neurolathyrism

H reflex studies in neurolathyrism