摘要：The neurotoxicity of Parkinson's disease (PD)-related tetrahydroisoquinolines (TIQs) and organotins is reviewed. PD is one of the most common neurodegenerative diseases among aged people and characteristized by the selective death of nigrostriatal dopaminergic neurons, but its pathological mechanism remains unknown. 1-Benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), an endogenous brain amine, was proposed as a possible PD-inducing neurotoxin, and its characteristics relevant to PD were evaluated. 1BnTIQ was detected in the mouse brain and human cerebrospinal fluid (CSF), and 1BnTIQ content was found to increase in the patients with PD. Repeated administration of 1BnTIQ induced PD-like symptoms in monkey and mice. 1BnTIQ induced dopaminergic cell death and subsequent dopamine decreases in organotypic slice co-culture, an in vitro culture system similar to the in vivo physiological environment. 1BnTIQ treatment also inhibited NADH-ubiquinone oxidoreductase in the mitochondrial respiratory chain. Thus, 1BnTIQ might a causative factor for PD, although the concentration required for neurotoxicity is higher than that found in the parkinsonian cerebrospinal fluid. We propose that tributyltin is another neurotoxin that acts through the glutamatergic pathway. Glutamate is one of the most abundant neurotransmitters in the central nervous system (CNS), but excessive release of glutamate causes prolonged stimulation of NMDA receptors, inducing calcium overload and neuronal death that is collectively referred to as excitotoxicity. Glutamate-mediated toxicity is selective for the CNS because only the CNS possesses this system. We clarified that tributyltin induces extracellular glutamate release and that tributyltin-induced neuronal death is mediated by glutamate excitotoxicity in cultured rat cortical neurons.
Loading...
