Pharmacological Study Of The New Compound FLZ-52A On Experimental Parkinson's Models

Parkinson's disease (PD), also called parkinsonism, is a chronic neuro-degenerative disease caused by disturbance of extrapyramid system's function. The characteristic pathogenesis of PD is degeneration of dopaminergic neurons in nigra zona compacta and decrease of the neuron-transmitter dopamine content in striatum, which lead to dysfunction of the dopaminergic neurons and relative domination of cholinergic function. All the above alterations will result in development of dyskinesia. The incidence of PD is about 10% in aged people over 65. The causes of PD are still unknown. Genetic factors, infections, immunological abnormalities, aging, toxins (endogenous and exogenous) may all involve in the development of PD. In addition, oxygen free radical toxicity and impaired mitochondrial function may also play important roles in PD.Drugs currently used for PD therapy can only improve clinical symptoms but can not retard the course of the disease. Moreover, severe side effects will appear in the long-term treatment. New drugs with good curative effect and fewer side effects are eagerly needed. Very recently, a new concept for pharmacotherapy of PD called neuroprotective strategy has been proposed. Several kind of such drugs are under investigation in foreign countries.FLZ-52A (FLZ) is a synthetic new compound that can be patenble. Our previous study demonstrated that FLZ has strong antioxidant property and can protect against damage of primary cultured rat brain neurons exposed to hydrogen peroxide, glutamate, N-methyl-D-asparatate ( NMDA ) , hemoglobin and ischemia/reoxygenation. All these results indicate that FLZ may possess neuroprotective property. It is very interest to further study whether FLZ has the potential as an anti-PD drug. Therefore, the effect of FLZ on Parkinson's models and its active mechanism were studied from several levels including animal behavior, dopamine and its metabolites, damage of neuron cell line and brain mitochondrial function, protein polymers formation and dopamine auto-oxidation as well as D₂ receptor binding activity. The results are described as follows:1. Effect of FLZ on abnormal behavior in trembling model miceIn order to evaluate the efficacy of FLZ in improving the abnormal behavior in PD model mice, MPTP was used to induced abnormal behavior, and arecolinum and oxytremorine were injected (i.v.) to induce trembling in mice. Male adult C₅₇/BL mice were injected interperitoneally with 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) ( 150mg/kg × 2, 16hr interval ). As a result, mice developed abnormal pole climbing behavior that lasted for 4 days. FLZ...