Differential expression of excitatory amino acid transporters in relation to dopaminergic treatment and SIV specific pathology

Introduction: HIV-associated encephalopathy (HIVE) still remains a frequent complication in HIV-infection despite antiretroviral therapy and shares many clinical symptoms with Parkinson's disease. However, previous studies in the Simian immundeficiency virus (SIV) macaque model have shown that increased dopamine availibility does not result in symptomatic benefit like in Parkinson's disease but leads to acceleration of SIV encephalitis (SIVE) rather than neuroprotection. The aim of our study in the SIV model was to analyse the effect of various dopaminergic drugs and the NMDA antagonist memantine on the glutamatergic system in order to develop possible therapeutic strategies.

Methods: Our immunohistochemical study included 15 uninfected controls and untreated animals in different stages of the disease and 25 animals treated by selegiline, L-dopa, apomorphine and memantine alone or in combination with selegiline. The differential expression of the glial excitatory amino acid transporters (EAAT) 1 and 2 that regulate the re-uptake of glutamate in order to prevent glutamate excitotoxicity was correlated with the occurence and degree of SIV specific pathology, i.e. meningitis, perivascular cuffing, microglial nodules, multinucleated giant cells, astrocytic gliosis and spongiform poliodystrophy.

Results: Treatment with selegiline alone or in combination with L-dopa lead to an increase in SIV specific features including marked vacuolar gray matter changes. The latter were even more pronounced than in untreated animals with rapid Neuro-AIDS. The expression of EAAT 2 showed a shift towards a more spot-like and coarse immunoreactivity which was most obvious in the basal ganglia. The same EAAT expression pattern was observed in animals treated by apomorphine, however with lack of vacuolisation. Under treatment with memantine alone or in combination with selegiline, signs of SIVE were only discrete and number and size of vacuoles markedly reduced. EAAT expression was normal or only slightly increased.

Conclusions: Our data show that neurotransmitter dysregulation as well as imbalance of astroglial transport contribute to the pathogenesis of HIVE and SIVE. The synergistic interaction of dopamine or dopaminergic drugs and SIV infection may potentiate SIVE. In contrast, our results strongly suggest that the NMDA antagonist memantine might be a suitable therapeutic neuroprotective drug at least in the SIV animal model.

Supported by a grant of the BMBF 01 KI 0211