The breakdown of glutamate clearance plays a major role in the pathogenesis of SIV encephalitis

Introduction: Clinical, neuroimaging and experimental data in SIV-infected macaques strongly suggest that basal ganglia dysfunction plays an important role in the pathogenesis of HIV encephalitis (HIVE). The regulation of glutamatergic neurotransmission in inflammation is a complex interaction between activation of immune mediators and adaptative changes of the functional elements of the glutamatergic synapse. Since glutamate is abundant in the brain and potentially toxic to neurons expressing NMDA receptors, protective mechanisms are required to prevent glutamate excitoxicity. 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.

Methods: Our immunohistochemical study included 25 uninfected controls and untreated animals in different stages of the disease and 25 animals treated by slegiline, L-dopa, apomorphine and memantine alone or combination with selegiline.

The differential expression of the glial excitatory amino acid transporter (EAAT)2 which is responsible for up to 95% of extracellular glutamate clearance was correlated with the occurence and degree of SIV-specific pathology, i.e. meningitis, perivascular cuffing, microglial nodules, multinucleated giant cells, astrocytosis 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 course immunoreactivity which was most obvious in the basal ganglia and already present in uninfected controls. The same EAAT expression pattern was observed in animals treated by apomorphine. Under treatment with memantine alone or in combination with selegiline, signs of SIV encephalitis (SIVE) were only discrete and number and size of vacuoles markedly reduced.

Conclusions: Our results show impairment of EAAT2 expression in SIV infection and suggest that breakdown of glutamate clearing contributes to the pathogenesis of HIVE and SIVE, probably due to activation of immune mediators. The synergistic interaction of dopamine or dopaminergic drugs and SIV infection may potentiate SIVE. In contrast, the NMDA antagonist memantine might be a suitable neuroprotective drug at least in the SIV model.

Supported by a grant of the BMBF o1 KI 0211