{"doi":"10.17615/tsgq-qa39","title":"Novel Neuroprotective Mechanisms of Memantine: Increase in Neurotrophic Factor Release from Astroglia and Anti-Inflammation by Preventing Microglial Activation","abstract":"Memantine provides clinically relevant efficacy in patients with Alzheimer's disease and Parkinson’s diseases. In addition to blockade of N-methyl-D-aspartate receptor on neurons, memantine has neurotrophic and neuroprotective effects in in vivo and in vitro studies, however, the mechanism underlying these effects remains unclear. To address this question, primary midbrain neuron-glia cultures and reconstituted cultures were used, and lipopolysaccharide (LPS), an endotoxin from bacteria, was used to produce inflammation-mediated dopaminegic neuronal death. Here, we show that memantine exerted both potent neurotrophic and neuroprotective effects on dopaminergic neurons in rat neuron-glia cultures. The neurotrophic effect of memantine was glia-dependent, since memantine failed to show any positive effect on dopaminergic neurons in neuron-enriched cultures. More specifically, it appears that astroglia, not microglia, are the source of the memantine-elicited neurotrophic effects through the increased production of GDNF. Mechanistic studies revealed that GDNF upregulaton was associated with histone hyperacetylation by inhibiting the cellular histone deacetylase activity. In addition, memantine also displays neuroprotective effects against LPS-induced dopaminergic neuronal damage through its inhibition of microglia over-activation revealed by both OX-42 immunostaining and by the reduction of pro-inflammatory factors production such as extracelluar superoxide anion, intracellular reactive oxygen species, nitric oxide, prostaglandin E2, and tumor necrosis factor-α. These results suggest that memantine therapy for neurodegenerative diseases acts in part through alternative novel mechanisms by reducing microglia-associated inflammation and stimulating the release of neurotrophic factors from astroglia.","journal":"UNC Libraries","year":2020,"id":144224,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9531,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":595577,"name":"Patrick M. Flood","orcid":null,"position":1,"is_corresponding":false},{"id":613177,"name":"Nian Sheng Tzeng","orcid":null,"position":2,"is_corresponding":false},{"id":330097,"name":"Scott M. Rawls","orcid":null,"position":3,"is_corresponding":false},{"id":307177,"name":"Qian Li","orcid":"0000-0001-7614-5618","position":4,"is_corresponding":false},{"id":592457,"name":"Shih Heng Chen","orcid":null,"position":5,"is_corresponding":false},{"id":276867,"name":"Jau‐Shyong Hong","orcid":"0000-0002-3056-8401","position":6,"is_corresponding":false},{"id":592455,"name":"Hung Ming Wu","orcid":null,"position":7,"is_corresponding":false},{"id":592456,"name":"Ru Band Lu","orcid":null,"position":8,"is_corresponding":false},{"id":597441,"name":"Xiaoming Hu","orcid":"0000-0003-0177-1993","position":9,"is_corresponding":false},{"id":483191,"name":"Sung‐Jen Wei","orcid":"0000-0002-9810-9041","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:17:45.339291Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}