Biology subjects

Sanchez-Perez, A. M.

Publications and source records attributed to Sanchez-Perez, A. M..

3 recordsLinked to original sources

bioRxiv2025

FGA139, a Novel Cysteine Protease Inhibitor, Exhibits Anti-Inflammatory and Neuroprotective Activity and Reveals Microglial Modulation via Multi-Omics Profiling

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 TNF 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. HighlightsO_LIFGA139, an irreversible cysteine protease inhibitor, exhibits anti-inflammatory effects, significantly reducing LPS-induced pro-inflammatory markers (NO in macrophages, TNF in microglia). C_LIO_LIFGA139 prevented the damaged neurons exposed to conditioned media (CM) from LPS-stimulated immune cells (reduced viability, reduced neurite length and increased ROS/NO). C_LIO_LIFGA139 boosted secretion of neuroprotective metabolites (e.g., purines, linoleic acid) in LPS-stimulated microglia C_LIO_LIProteome analysis in FGA139 pretreated microglia showed a prevention of LPS-induced M1-like polarization, revealing novel mechanistic pathways. C_LIO_LIFGA139s ability to modulate microglial activation and protect neurons positions it as a promising candidate for neuroinflammatory diseases. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/652036v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1968c35org.highwire.dtl.DTLVardef@ceef77org.highwire.dtl.DTLVardef@1cb849corg.highwire.dtl.DTLVardef@6f4190_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Abscisic Acid rescues behavior in adult female mice in Attention Deficit Disorder with Hyperactivity model of dopamine depletion by regulating microglia and vesicular GABA transporter

BackgroundAttention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental syndrome influenced by both genetic and environmental factors. While genetic studies have highlighted catecholamine dysfunction, emerging epidemiological evidence suggest neuroinflammation as a significant trigger. However, understanding the relative contributions of these alterations to ADHD symptomatology remains elusive. MethodThis study employed 93 female Swiss mice of the ADHD dopamine deficit model. Dopaminergic lesions were induced via 6-hydroxidopamine (6-OHDA) injection on postnatal day 5. The impact of these lesions during development was examined by comparing young and adult mice (at postnatal day 21 and 90, respectively). We sought to mitigate adult symptoms through abscisic acid (ABA) administration during two-months. Postmortem analyses encompassed the evaluation of neuroinflammation (microglia morphology, NLRP3 inflammasome activation, cytokine expression) and excitatory/inhibitory (E/I) ratio in specific brain regions. ResultsNeonatal dopaminergic lesions elicited hyperactivity, impulsivity, hypersensitivity increased social interaction in both one-month and three-month females and induced impaired memory in three-month mice. ABA exposure significantly ameliorated hyperactivity, impulsivity, anxiety, hypersensitivity, and social interaction alterations, but not cognitive impairment. In the anterior cingulate cortex (ACC) of one-month mice dopamine-deficit elevated IL-1{beta} and TNF expression and reduced Arg1 mRNA levels, along with E/I imbalance. ABA intervention restored microglia morphology, IL-1{beta}, Arg1 expression and enhanced vGAT levels. ConclusionsThis study strongly suggest that dopamine deficit induced alteration of microglia and E/I ratio underling distinct ADHD symptoms. Reinstating healthy microglia by anti-inflammatory agents in specific areas emerges as a promising strategy for managing ADHD.

neuroscience↗

bioRxiv2022

Targeting neuroinflammation with Abscisic Acid reducespain sensitivity in females and hyperactivity in males of an ADHD mice model

AimsAttention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental syndrome characterized by dopaminergic dysfunction. In this study, we aimed to demonstrate the link between dopaminergic deficit and neuroinflammation underlying ADHD symptoms. Subjects and TreatmentWe used a validated ADHD mice model, that involves perinatal 6-OHDA lesion. Animals were treated with 20mg/L (drinking water) of Abscisic acid (ABA) for one month. We tested behaviour (learning and memory, anxiety, social interactions, and pain) in both females and male mice, in all eight groups (control and lesioned, with/without ABA). Postmortem, we analyzed microglia morphology and Ape1 expression in specific brain areas related to the descending pain inhibitory pathway. ResultsIn females, dopaminergic deficit increased pain sensitivity, but not hyperactivity, in contrast to males. This behaviour was associated with inflammatory microglia and lower Ape1 levels in the anterior cingulate cortex (ACC) and posterior insula cortex (IC). ABA treatment reduced inflammation and alleviated pain. In males, ABA reduced hyperactivity, but had no significant effect on inflammation. ConclusionsThis is the first study proving a sex-dependent association between dopamine dysfunction and inflammation in specific brain areas, leading to different behavior outcomes in a mouse model of ADHD. These findings provide new clues for potential treatments.

neuroscience↗