Amantadine Protects Dopamine Neurons by a Dual Action: Reducing Activation of Microglia and Inducing Expression of GDNF in Astroglia [corrected]

Amantadine is commonly given to alleviate L-DOPA-induced dyskinesia of Parkinson's disease (PD) patients. Animal and human evidence showed that amantadine may also exert neuroprotection in several neurological disorders. Additionally, it is generally believed that this neuroprotection results from the ability of amantadine to inhibit glutamatergic NMDA receptor. However, several lines of evidence questioned the neuroprotective capacity of NMDA receptor antagonists in animal models of PD. Thus the cellular and molecular mechanism of neuroprotection of amantadine remains unclear. Using primary cultures with different composition of neurons, microglia, and astroglia we investigated the direct role of these glial cell types in the neuroprotective effect of amantadine. First, amantadine protected rat midbrain cultures from either MPP(+) or lipopolysaccharide (LPS), two toxins commonly used as PD models. Second, our studies revealed that amantadine reduced both LPS- and MPP(+)-induced toxicity of dopamine neurons through 1) the inhibition of the release of microglial pro-inflammatory factors, 2) an increase in expression of neurotrophic factors such as GDNF from astroglia. Lastly, differently from the general view on amantadine's action, we provided evidence suggesting that NMDA receptor inhibition was not crucial for the neuroprotective effect of amantadine. In conclusion, we report that amantadine protected dopamine neurons in two PD models through a novel dual mechanism, namely reducing the release of pro-inflammatory factors from activated microglia and increasing the expression of GNDF in astroglia.