| Equine Nigropallidal Encephalomalacia (ENE) is an equine specific neurological disease resulting from chronic ingestion of yellow star thistle (Centaurea solstitialis). Clinical signs of ENE are similar and referable to the clinical signs of humans afflicted with Parkinson's disease. Horses eventually die due to starvation and dehydration, consequences of the impairment of motor centers necessary for prehension and mastication.;ENE is characterized by distinct and specific lesions in the substantia nigra and globus pallidus due to the selective death of dopaminergic neurons, pathology also characteristic of Parkinson's disease. While ENE is associated with the ingestion of C. solstitialis, the exact toxin has not been identified. Because of the selective death of dopaminergic neurons, we hypothesized that a putative neurotoxin(s) present within the weed would interact with the dopamine transporter.;To test this hypothesis, crude extracts of C. solstitialis were prepared and assayed for binding to the dopamine transporter site on equine striatal membrane homogenates by a competitive binding assay utilizing 3H mazindol. Extracts with binding activity were then further purified by repeated high performance liquid chromatography (HPLC) separation. The final preparation from HPLC purification consistently demonstrated a higher affinity for the dopamine transporter than cocaine, the non-specific binding control. Analysis of this preparation by gas chromatography/mass spectroscopy identified a compound; 2,3-dihydro-3,5-dihydroxy-6-methyl-4(H)-pyran-4-one (DDMP), similar in structure to 6-hydroxy-dopamine (6 - OH dopamine), a potent neurotoxin that experimentally produces lesions similar to those found in ENE. Further binding studies demonstrated that DDMP was selective and specific for the dopamine transporter. Additionally, this compound is structurally similar to known food flavoring additives and is found to occur naturally within biological systems. DDMP and its structurally related analogue, maltol, are both cytotoxic to cells grown in culture. The biological activity of this putative neurotoxin, isolated from C. solstitialis suggests that it is responsible for the destruction of dopammergic neurons in equine brain. The presence of this compound, as well as, its analogues within human biological systems and the human food chain, implicate it as a potential neurotoxin, which may be responsible for, or contribute to, the generation of Parkinson's disease in humans. |
