FGA139, a novel cysteine protease inhibitor, exhibits anti-inflammatory and neuroprotective activity and reveals
Ania Canseco-Rodríguez1, Florenci V González2, Ana María Sánchez-Pérez1
1Department of Medicine, Universitat Jaume I, 12071 Castellón de la Plana, Spain.
Abstract:
Neuroinflammation is a key driver in the progression of numerous brain disorders, with cysteine proteases such as calpains, caspases, and cathepsins playing central roles in inflammatory signaling. This study investigates FGA139, a novel irreversible inhibitor targeting cysteine proteases. We evaluated the anti-inflammatory properties of FGA139 in lipopolysaccharide (LPS)-activated macrophages (RAW264.7) and microglia (HMC3). In addition, its neuroprotective effects were assessed in differentiated SH-SY5Y neuron-like cells exposed to conditioned media (CM+) derived from the activated immune cells. FGA139 exhibited a favorable safety profile and robust anti-inflammatory activity, significantly reducing nitric oxide (NO) production in macrophages and TNFα levels in microglia. Conditioned media from both LPS-stimulated immune cells lines (CM+) reduced neurite length in neuronal cells. However, CM+ from HMC3 cells impaired neuronal viability, whereas CM+ from RAW264.7 cells elevated reactive oxygen species (ROS) and NO levels-indicating distinct neurotoxic signatures. Preincubation of neuron-like cells with FGA139 effectively mitigated most of these adverse effects. Metabolomic analysis of the activated microglia supernatant revealed that FGA139 increased extracellular levels of neuroprotective metabolites, including purines, linoleic acid, and phenyllactic acid. Proteomic data confirmed that FGA139 attenuated M1-like microglial polarization, likely through modulation of pathways associated with zinc transport and vesicle trafficking. In conclusion, FGA139 demonstrates potent neuroprotective effects and modulates microglial activation. These findings uncover novel mechanisms underlying the beneficial effects of cysteine protease inhibition and support the therapeutic potential of FGA139 in treating neuroinflammatory conditions, positioning it as a promising modulator of microglial function.
Insights
FGA139, a novel cysteine protease inhibitor, reduces neuroinflammation and protects neurons from immune cell-derived toxins. It modulates microglial activation and increases neuroprotective metabolites, showing therapeutic potential for brain disorders.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Neuroinflammation is a critical factor in brain disorder progression.
- Cysteine proteases (calpains, caspases, cathepsins) are key mediators of neuroinflammatory signaling.
Purpose of the Study:
- To investigate the anti-inflammatory and neuroprotective effects of FGA139, a novel irreversible cysteine protease inhibitor.
- To elucidate the mechanisms by which FGA139 modulates immune cell activation and protects neurons.
Main Methods:
- Evaluated FGA139 in lipopolysaccharide (LPS)-activated macrophages (RAW264.7) and microglia (HMC3).
- Assessed neuroprotective effects in SH-SY5Y neuron-like cells exposed to activated immune cell conditioned media (CM+).
- Utilized metabolomic and proteomic analyses to identify molecular mechanisms.
Main Results:
- FGA139 demonstrated anti-inflammatory activity, reducing nitric oxide (NO) and TNFα levels.
- FGA139 protected neurons from CM+-induced damage, including reduced viability and increased reactive oxygen species (ROS).
- Metabolomic analysis showed FGA139 increased neuroprotective metabolites; proteomic data indicated attenuated M1-like microglial polarization.
Conclusions:
- FGA139 exhibits potent anti-inflammatory and neuroprotective properties.
- FGA139 modulates microglial activation and increases neuroprotective metabolites, offering a novel therapeutic strategy.
- These findings support the potential of FGA139 for treating neuroinflammatory conditions.
