RESUMEN
Mitochondria are essential for various physiological functions in astrocytes in the brain, such as maintaining ion and pH homeostasis, regulating neurotransmission, and modulating neuroinflammation. Mitophagy, a form of autophagy specific to mitochondria, is essential for ensuring mitochondrial quality and function. Benzo[a]pyrene (BaP) accumulates in the brain, and exposure to it is recognized as an environmental risk factor for neurodegenerative diseases. However, while the toxic mechanisms of BaP have been investigated in neurons, their effects on astrocytes-the most prevalent glial cells in the brain-are not clearly understood. Therefore, this study aims to investigate the toxic effects of exposure to BaP on mitochondria in primary astrocytes. Fluorescent probes and genetically encoded indicators were utilized to visualize mitochondrial morphology and physiology, and regulatory factors involved in mitochondrial morphology and mitophagy were assessed. Additionally, the mitochondrial respiration rate was measured in BaP-exposed astrocytes. BaP exposure resulted in mitochondrial enlargement owing to the suppression of mitochondrial fission factors. Furthermore, BaP-exposed astrocytes demonstrated reduced mitophagy and exhibited aberrant mitochondrial function and physiology, such as altered mitochondrial respiration rates, increased mitochondrial superoxide, disrupted mitochondrial membrane potential, and dysregulated mitochondrial Ca2+. These findings offer insights into the underlying toxic mechanisms of BaP exposure in neurodegenerative diseases by inducing aberrant mitophagy and mitochondrial dysfunction in astrocytes.
RESUMEN
Compared to other organs, the brain has limited antioxidant defenses. In particular, the hippocampus is the central region for learning and memory and is highly susceptible to oxidative stress. Glial cells are the most abundant cells in the brain, and sustained glial cell activation is critical to the neuroinflammation that aggravates neuropathology and neurotoxicity. Therefore, regulating glial cell activation is a promising neurotherapeutic treatment. Quinic acid and its derivatives possess anti-oxidant and anti-inflammatory properties. Although previous studies have evidenced quinic acid's benefit on the brain, in vivo and in vitro analyses of its anti-oxidant and anti-inflammatory properties in glial cells have yet to be established. This study investigated quinic acid's rescue effect in lipopolysaccharide (LPS)-induced behavior impairment. Orally administering quinic acid restored social impairment and LPS-induced spatial and fear memory. In addition, quinic acid inhibited proinflammatory mediator, oxidative stress marker, and mitogen-activated protein kinase (MAPK) activation in the LPS-injected hippocampus. Quinic acid inhibited nitrite release and extracellular signal-regulated kinase (ERK) phosphorylation in LPS-stimulated astrocytes. Collectively, quinic acid restored impaired neuroinflammation-induced behavior by regulating proinflammatory mediator and ERK activation in astrocytes, demonstrating its potential as a therapeutic agent for neuroinflammation-induced brain disease treatments.
RESUMEN
Nanoplastics, arising from the fragmentation of plastics into environmental pollutants and specialized commercial applications, such as cosmetics, have elicited concerns due to their potential toxicity. Evidence suggests that the oral ingestion of nanoplastics smaller than 100 nm may penetrate the brain and induce neurotoxicity. However, comprehensive research in this area has been hampered by technical challenges associated with the detection and synthesis of nanoplastics. This study aimed to bridge this research gap by successfully synthesizing fluorescent polystyrene nanoplastics (PSNPs, 30-50 nm) through the incorporation of IR-813 and validating them using various analytical techniques. We administered PSNPs orally (10 and 20 mg/kg/day) to mice and observed that they reached brain tissues and induced cognitive dysfunction, as measured by spatial and fear memory tests, while locomotor and social behaviors remained unaffected. In vitro studies (200 µg/mL) demonstrated a predominant uptake of PSNPs by microglia over astrocytes or neurons, leading to microglial activation, as evidenced by immunostaining of cellular markers and morphological analysis. Transcriptomic analysis indicated that PSNPs altered gene expression in microglia, highlighting neuroinflammatory responses that may contribute to cognitive deficits. To further explore the neurotoxic effects of PSNPs mediated by microglial activation, we measured endogenous neuronal activity using a multi-electrode array in cultured hippocampal neurons. The application of conditioned media from microglia exposed to PSNPs suppressed neuronal activity, which was reversed by inhibitors of microglial activation. Our findings offer detailed insights into the mechanisms by which nanoplastics damage the brain, particularly emphasizing the potential environmental risk factors that contribute to cognitive impairment in neurodegenerative diseases.
