SIV-associated vacuolar leukoencephalopathy: role of the dopaminergic system in the development of neurodegeneration
Project management at the University of Würzburg:
HIV infects the central nervous system and induces neurological deficiencies in a great proportion of HIV-patients. There is ample evidence that the dopaminergic system plays a major role in the pathogenesis of this disease. Using the infection of rhesus monkeys with simian immunodeficiency viruses (SIV) as animal model, we could demonstrate early abnormalities in neurotransmitter systems. Already few weeks after infection, we found decreased levels of dopamine, alterations in amino acid neurotransmitters and reduced activity of the enzyme choline-azetyl tranferase (ChAT). Treatment of the infected animals with dopaminergic drugs like selegiline or L-Dopa normalized dopamine levels and restored ChAT activity. However, close neuropathological investigation revealed that these dopaminergic therapies increased brain viral load and induced vacuolization of the gray matter in SIV-infected monkeys. In additional experiments, animals were treated with dopamine agonists and antagonists. We could demonstrate that the observed negative effects of the increased dopamine availability in SIV-infected animals is not caused by receptor-mediated mechanisms. Rather, oxidative stress induced by dopamine or its metabolites might be responsible. This is emphasized by our findings that dopamine activates HIV in vitro by oxidative mechanisms. Our results bear important consequences for targeted neuropharmacological treatment strategies of HIV-induced neurological disease.
Projekt period: from 01.1999 to 12.2001