title: Clavulanic acid inhibits MPP⁺-induced ROS generation and subsequent loss of dopaminergic cells.
abstract: Clavulanic acid is a psychoactive compound that has been shown to modulate central nervous system activity. Importantly, in neurotoxin-induced animal models, clavulanic acid has been shown to improve motor function (Huh et al., 2010) suggesting that it can be neuroprotective; however, the mechanism as how clavulanic acid can induce neuroprotection is not known. We demonstrate here that clavulanic acid abrogates the effects of the neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)) which mimics Parkinson's disease (PD) by inducing neurodegeneration. To further establish the mechanism we identified that clavulanic acid inhibits neurotoxin-induced loss of mitochondrial membrane potential and ROS production. Consistent with these results, neurotoxin-induced increase in Bax levels was also decreased in clavulanic acid treated cells. Importantly, neurotoxin-induced release of cytochrome c levels as well as caspase activation was also inhibited in clavulanic acid treated cells. In addition, Bcl-xl levels were also restored and the Bcl-xl/Bax ratio that is critical for inducing apoptosis was increased in clavulanic acid treated cells. Overall, these results suggest that clavulanic acid is intimately involved in inhibiting neurotoxin-induced loss of mitochondrial function and induction of apoptosis that contributes towards neuronal survival.
authors: Rexahn Pharmaceuticals, Inc., Rockville, MD 20850, United States. chung@rexahn.com
authors: Gina Chun
authors: GC
authors: Kost
authors: Senthil
authors: S
authors: Selvaraj
authors: Young Bok
authors: YB
authors: Lee
authors: Deog Joong
authors: DJ
authors: Kim
authors: Chang-Ho
authors: CH
authors: Ahn
authors: Brij B
authors: BB
authors: Singh
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D019818:Clavulanic Acid / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D019818:Clavulanic Acid; D045304:Cytochromes c; D053148:Caspase 3; D053453:Caspase 9; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine