Amantadine protects dopamine neurons by a dual action: Reducing activation of microglia and inducing expression of GNDF in astroglia

Abstract

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 neuroprotection 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 different 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 PD models. Second, our studies revealed that amantadine reduced both LPS- and MPP+ -induced toxicity of dopamine neuron through 1) the inhibition of the release of microglial pro-inflammatory factors, 2) an increase in expression of neurotrophic factor 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.

Amantadine Alleviates Postoperative Cognitive Dysfunction Possibly by Increasing Glial Cell Line-derived Neurotrophic Factor in Rats

“…27,28 Recent studies suggest that amantadine can reduce neuroinflammation induced by lipopolysaccharide in cell cultures or in mice. 8,13 We and others have shown that neuroinflammation may be the underlying pathology for the cognitive impairment after anesthesia and surgery. 11,12 Thus, we proposed that amantadine could reduce cognitive impairments after surgery and designed this study to test this possibility.…”

“…6,7 Amantadine has been found to have significant neuroprotective effects. 7,8 One of the mechanisms for these effects as shown in cell culture studies is to enhance the production of glial cell line-derived neurotrophic factor (GDNF). 9 GDNF can inhibit microglial activation and neuroinflammation.…”

“…9 GDNF can inhibit microglial activation and neuroinflammation. 8,9 Neuroinflammation is a basic neuropathological process for many neurodegenerative diseases. 10 Neuroinflammation may also be the underlying pathology for POCD.…”

Amantadine preserves dopamine level and attenuates depression-like behavior induced by traumatic brain injury in rats

“…The amantadine's pleiotropic mechanism makes it a promising anti-depression drug for TBI patients, including: (1) facilitating dopamine release, delaying reabsorption in the presynapse and increasing the number of DA receptors in the post-synapse [58]; (2) uncompetitive NMDA receptor inhibition to regulate the glutamate-induced excitotoxicity [59]; and (3) restraint of the release of proinflammatory factors and stimulation of the production of glial cell-line-derived neurotropic (GDNF) [60]. Amantadine may directly stimulate dopamine release and act as an exogenous dopaminergic supplement to preserve the dopaminergics' concentration in the striatum.…”

Comparison of the Analgesic Activity of Antiparkinsonian Aminoadamantane Derivatives Amantadine and Hemantane

“…Specifically, amantadine 20 mg/kg exhibited antiradical activity by reducing the intensity of lipid peroxidation and increasing glutathione content in the substantia nigra of rats with 6-hydroxydopamine-induced Parkinson's disease [49]. This drug reduced lipopolysaccharide-and 1-methyl-4-phenylpyridinium ion (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 [50]. Consequently, the anti-inflammatory properties of amantadine and hemantane contribute to their neuroprotective activity.…”