trisialoganglioside-gt1 and Parkinson-Disease

The symptoms of Parkinson's disease (PD) were first described nearly two centuries ago and its characteristic pathology identified nearly a century ago, yet its pathogenesis is still poorly understood. Parkinson's disease is the most prevalent neurodegenerative movement disorder and research into its pathogenesis recently accelerated following the identification of a number of causal genetic mutations. The mutant gene products all cause dysfunction of the ubiquitin-proteosome system, identifying protein modification and degradation as critical for pathogenesis. Modified non-degraded intracellular proteins accumulate in certain neuronal populations in all forms of the disease. However, neuronal degeneration is more highly selective and associates with substantial activation of microglia, the inflammatory cells of the brain. We review the current change in thinking regarding the role of microglia in the brain in the context of Parkinson's disease and animal models of the disease. Comparison of the cellular tissue changes across a number of animal models using diverse stimuli to mimic Parkinson's disease reveals a consistent pattern implicating microglia as the effector for the selective degeneration of dopaminergic neurons. While previous reviews have concentrated on the intracellular neuronal changes in Parkinson's disease, we highlight the cell to cell interactions and immune regulation critical for neuronal homeostasis and survival in Parkinson's disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Brain; Gangliosides; Humans; Immunologic Surveillance; Lipopolysaccharides; Microglia; Monitoring, Immunologic; Neurons; Oxidopamine; Parkinson Disease; Rotenone; Signal Transduction

We recently showed that trisialoganglioside (GT1b) induces cell death of dopaminergic neurons in rat mesencephalic cultures (Chung et al., Neuroreport 12:611-614, 2001). The present study examines the in vivo neurotoxic effects of GT1b on dopaminergic neurons in the substantia nigra (SN) of Sprague-Dawley rats. Seven days after GT1b injection into the SN, immunocytochemical staining of SN tissue revealed death of nigral neurons, including dopaminergic neurons. Additional immunostaining using OX-42 and OX-6 antibodies showed that GT1b-activated microglia were present in the SN where degeneration of nigral neurons was found. Western blot analysis and double-labeled immunohistochemistry showed that inducible nitric oxide synthase (iNOS) was expressed in the SN, where its levels were maximal at 8 h post-GT1b injection, and that iNOS was localized exclusively within microglia. GT1b-induced loss of dopaminergic neurons in the SN was partially inhibited by N(G)-nitro-L-arginine methyl ester hydrochloride, an NOS inhibitor. Our results indicate that in vivo neurotoxicity of GT1b against nigral dopaminergic neurons is at least in part mediated by nitric oxide released from activated microglia. Because GT1b exists abundantly in central nervous system neuronal membranes, our data support the hypothesis that immune-mediated events triggered by endogenous compounds such as GT1b could contribute to the initiation and/or the progression of dopaminergic neuronal cell death that occurs in Parkinson's disease.

Topics: Animals; Antigens, CD; Antigens, Neoplasm; Antigens, Surface; Avian Proteins; Basigin; Blood Proteins; Cell Death; Dopamine; Enzyme Inhibitors; Female; Gangliosides; Gliosis; Immunohistochemistry; Membrane Glycoproteins; Microglia; Neurons; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Parkinson Disease; Rats; Rats, Sprague-Dawley; Substantia Nigra