A growing body of evidence suggests a potential link between neuroinflammation, directly or indirectly triggered by viral infections, and the initiation or progression of neurodegenerative diseases such as Parkinson's disease (PD). Viral infections can potentially induce pathological alterations in amyloidogenic proteins such as a-synuclein (αSyn) implicated in pathogenesis of this disease. However, the exact molecular mechanisms of virus-induced neuroinflammation remain unclear.To get insights into mechanisms of viral RNA-induced neurotoxicity, we treated rat neuronal-glial co-cultures (CGC) with RNA-virus mimetic Loxoribin (Lox, 1-100 µg/ml) and pre-aggregated 1 µM αSyn for 72 h.We found that 100 µg/ml Lox caused loss of viable neurons without increasing neuronal apoptosis or necrosis and stimulated microglial proliferation. Lower concentrations of Lox (1-10 µg/ml) have no effect on CGC after 72h. Treatment of CGC cultures with 1µM αSyn did not affect neuronal viability or densities in cultures. However in cultures primed with 1 µg/ml Lox, αSyn induced loss of viable neurons without increasing neuronal death. Such treatment also stimulated microglial proliferation and caused changes in microglial morphology suggesting microglial activation.In conclusion, our data suggest that high concentrations of Lox cause microglial activation, leading to neuronal loss in mixed neuronal-glial cell cultures. At lower concentrations Lox may act synergistically with pre-aggregated αSyn inducing the loss of viable neurons in neuronal-glial co-cultures.This work was supported by the Research Council of Lithuania, Researcher Groups project No S-MIP-23-98 (APNEVIR).