Neurochemical Research最新文献

Neuronal cell damage resulting from ischemic and hypoxic injury is a major pathological event in stroke, with ferroptosis increasingly recognized as a contributing mechanism. In this study, we observed that oxygen-glucose deprivation (OGD) triggered ferroptosis in neuronal cells. By screening of naphthoquinone compounds intervening oxidative stress, we have identified phylloquinone (VK1, also known as vitamin K1) as a potent inhibitor of ferroptosis with significant neuroprotective effects. Phylloquinone also alleviated OGD-induced cellular senescence. Mechanistic investigation revealed that Kruppel-like factor 2 (Klf2) is a potential target of phylloquinone and participates in its neuroprotective effects. These findings indicate that phylloquinone protects neurons from OGD-induced injury by inhibiting ferroptosis through the xCT/GPX4 pathway, highlighting its potential as a therapeutic candidate for ischemic neuronal damage.

Graphical Abstract

The catabolism of the proteinogenic amino acid L-proline in mammalian cells is mediated by mitochondrial enzymes that can oxidize proline to provide energy for mitochondrial ATP regeneration. To investigate the potential of astrocytes to consume and metabolize L-proline, we incubated cultured primary rat astrocytes with L-proline in the absence or the presence of other energy substrates and investigated L-proline consumption, cellular ATP content and cell viability. In the absence of glucose, the cells consumed L-proline which allowed the cells to maintain a high cellular ATP level as long as extracellular L-proline was detectable. This L-proline consumption was saturable and followed apparent Michaelis-Menten kinetics with a calculated K_M value of around 320 µM and a V_max value of around 100 nmol/(h x mg). In contrast to L-proline, D-proline was not consumed by the cells and was unable to prevent a cellular ATP loss in starved astrocytes. L-Proline consumption was lowered in a concentration-dependent manner by known inhibitors of proline dehydrogenase. The potential of 1 mM L-proline to maintain a high cellular ATP content in starved astrocytes and to prevent cell death was almost identical to that found for 1 mM glucose and a co-application of both substrates had additive ATP-maintaining effects. The presence of L-proline hardly affected the consumption of glucose, while glucose, glucose-derived lactate as well as other energy substrates severely slowed down the astrocytic L-proline consumption. In addition, application of L-proline prevented the rapid loss in cellular ATP level and the subsequent toxicity induced in glucose-deprived astrocytes in the presence of inhibitors of the mitochondrial uptake of pyruvate and fatty acids. These protective effects of proline were abolished by an inhibitor of proline dehydrogenase. The data presented demonstrate that L-proline is an excellent energy substrate for cultured astrocytes especially for conditions of limited availability of other energy substrates.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder shaped by genetic, metabolic, environmental, and sex-specific factors. Emerging evidence highlights the estrogen–gut microbiota–brain (EGMB) axis as a critical framework linking endocrine regulation, microbial activity, and cognitive outcomes. Estrogen exerts neuroprotective effects by modulating synaptic plasticity, oxidative stress, amyloid and tau pathology, and neuroinflammation, while its decline during menopause increases AD vulnerability. Parallel to this, gut dysbiosis and altered microbial metabolites, particularly short-chain fatty acids (SCFAs) and secondary bile acids (sBAs), contribute to barrier dysfunction, chronic inflammation, and synaptic impairment. Importantly, estrogen remodels microbial composition and metabolite profiles, whereas microbial β-glucuronidase (β-GUS) activity sustains estrogen bioavailability, establishing a reciprocal regulatory loop. Preclinical studies demonstrate that depletion of gut microbiota diminishes estrogen’s protective effects, underscoring the central role of microbial metabolites as signaling bridges.

Therapeutically, these insights support the integration of hormone replacement therapy with microbiota-targeted interventions such as probiotics, prebiotics, and fecal microbiota transplantation. Such combined strategies may synergistically enhance neuroprotection, though their efficacy depends on timing, dosage, and individual variability. Future precision approaches integrating multi-omics profiling and sex-specific stratification hold promise for identifying predictive biomarkers and optimizing treatment windows. In summary, the EGMB axis offers a mechanistic foundation for understanding sex differences in AD and a translational framework for developing individualized, multidimensional strategies for early diagnosis, prevention, and therapy.

An analeptic camfetamine (CFA) is a psychostimulant with complex effects, however, its psychobehavioral characteristics are unclear. As escalating evidence suggests that psychostimulant-induced behaviors are associated with oxidative stress and dopaminergic alterations, we examined whether CFA-mediated psychobehavioral mechanism requires these alterations. Conditioned place preference (CPP) and behavioral sensitization (BS) induced by CFA (7.5 mg/kg, i.p.) were evaluated in male wild-type (WT) and glutathione peroxidase (GPx)-1 knockout (KO) mice. Redox parameters, dopamine D1/D2 receptor expression, and nuclear factor kappa B (NFκB) DNA binding activity were examined in the striatum. The D1 receptor antagonist SCH 23,390 and NFκB inhibitor pyrrolidine dithiocarbamate (PDTC) were applied to investigate the psychotoxic mechanism of CFA. CFA significantly enhanced superoxide dismutase (SOD)-1 and SOD-2 levels without compensative inductions of GPx/GPx-1 level, leading to increases in oxidative markers. CFA did not significantly affect D2 receptor expression, but significantly increased D1 receptor expression and NFκB activity. D1 receptor immunoreactivity and phospho-NFκB-immunoreactivity induced by CFA were co-localized in the same cells. These changes, along with CFA-induced CPP and BS, were more prominent in GPx-1 KO mice than those in WT mice, suggesting a protective role of GPx-1. SCH 23,390 and PDTC mitigated CPP and BS; PDTC attenuated CFA-induced D1 receptor upregulation, whereas SCH 23,390 did not affect NFκB activity, suggesting NFκB is an upstream molecule for CFA-induced D1 receptor activation. Combined results suggest that CFA-induced abnormal behaviors require oxidative stress, NFκB and D1 receptor activations. GPx/GPx-1 serves as a protective modulator against CFA-induced neuropsychotoxicity.

Parkinson’s disease (PD), the second most common neurodegenerative disorder worldwide, currently lacks effective treatment options due to its complex pathogenesis. Growing evidence in recent years demonstrates that intracellular Calcium (Ca²⁺) homeostasis disruption plays a critical role in PD development and progression. Ca²⁺ imbalance not only causes Ca²⁺-dependent synaptic dysfunction and impaired neuronal plasticity but also leads to progressive neuronal loss, collectively forming the core pathological characteristics of PD neurodegeneration. Notably, mitochondrial Ca²⁺ imbalance has been identified as a key pathogenic factor in PD. As vital intracellular Ca²⁺ regulators, dysfunctional mitochondria can induce abnormal opening of the mitochondrial permeability transition pore (mPTP), triggering apoptotic cascades. Furthermore, mitochondrial Ca²⁺ overload disrupts oxidative phosphorylation, resulting in excessive reactive oxygen species production that exacerbates neuronal damage. Recent studies reveal the essential role of mitochondria-endoplasmic reticulum interactions in maintaining Ca²⁺ homeostasis, with these organelles forming structurally and functionally integrated connections through mitochondrial ER-associated membrane (MAM) to cooperatively regulate Ca²⁺ ion dynamics. This review describes the molecular mechanisms of mitochondrial Ca²⁺ imbalance in PD pathogenesis and summarizes the potential of mitochondrial channels and MAM-associated proteins as PD therapeutic targets. By thoroughly analyzing these targets mechanisms, we aim to provide a theoretical foundation for developing novel PD treatment strategies based on Ca²⁺ homeostasis regulation. These findings not only expand our understanding of PD pathogenesis but also point toward developing targeted neuroprotective therapies.

This study investigated the effects of osteopontin (OPN) combined with milk fat globule membrane (MFGM) proteins on scopolamine-induced learning and memory impairment in mice. A dementia model was established through intraperitoneal injection of scopolamine, followed by random allocation into seven experimental groups: blank control, model control, OPN alone, MFGM alone, and three combination groups (low-, intermediate-, and high-dosage OPN + MFGM). Cognitive performance was evaluated using the Morris water maze test, accompanied by quantification of hippocampal acetylcholinesterase (AChE) activity, antioxidant enzyme activities (superoxide dismutase [SOD], glutathione peroxidase [GSH-Px]), malondialdehyde (MDA)) from both hippocampal tissue and serum. We found significant cognitive improvements in the intermediate- and high-dosage combination group to the model group, which had reduced escape latency, increased platform crossings, and prolonged target quadrant duration in the water maze test. Biochemical results suggest that these combination treatments significantly suppressed AChE activity in hippocampal tissue while they enhanced antioxidant capacity through elevated SOD and GSH-Px activities, accompanied by reduced MDA levels in both brain and serum. Our study demonstrates that the combination of OPN and MFGM administration improved learning and memory in mice with scopolamine-induced dementia through dose-dependent effects on the central cholinergic nervous and antioxidant system.

Excitatory/inhibitory balance, oxidative and antioxidative regulatory systems play a role in the pathophysiology of epilepsy. In addition, intestinal dysbiosis is also involved in the pathophysiology of epilepsy. The aim of this study was to investigate the effects of Lacticaseibacillus rhamnosus GG (L. rhamnosus or LBR) on epileptic seizures and gamma aminobutyric acid (GABA), malondealdehyde (MDA), superoxide dismutase (SOD, glutathione peroxidase (GPx) and catalase (CAT) levels in serum and brain tissue in a penicillin-induced acute seizure model in rats. The study included 70 adult Wistar albino rats, which were divided into 10 groups: Control(CONT), Penicillin (PEN), only LBR-4 (OLBR-4), Diazepam-4 + Penicillin (DZM-4 + PEN), LBR-4 + Penicillin (LBR-4 + PEN), LBR + Diazepam-4 + Penicillin (LBR-DZM-4 + PEN), only LBR-10 (OLBR-10), Diazepam-10 + Penicillin (DZM-10 + PEN), LBR-10 + Penicillin (LBR-10 + PEN), and LBR + Diazepam-10 + Penicillin (LBR-DZM-10 + PEN). 1 × 10¹⁰ cfu/mL of L. rhamnosus was given to the L. rhamnosus groups via gavage for 4 or 10 weeks depending on the duration of administration. The DZM groups received 2 mg/kg DZM intramuscularly. The rats were anesthetized and electrodes were placed in the somatomotor area after the left side of the skull was opened. Penicillin was administered intracortically and ECoG was recorded for 120 min. Levels of GABA, MDA, SOD, CAT, and GPx were determined using the ELISA method. L. rhamnosus administration reduced spike-wave frequency (SWF), total spike-wave frequency (TSWF), spike-wave amplitude (SWA), and MDA levels (p < 0.05). In contrast, it increased levels of GABA, SOD, CAT, and GPx (p < 0.05). L. rhamnosus may exert a preclinical antiepileptiform effect in an acute seizure model of epilepsy.

Astrocytes are essential partners of neurons and have many important functions in the brain. Almost all of these astrocytic functions require energy that is provided by cellular adenosine triphosphate (ATP). Accordingly, astrocytes contain a millimolar concentration of cellular ATP that is maintained by continuous and rapid regeneration from adenosine diphosphate (ADP) and adenosine monophosphate (AMP), the main products of cellular energy-consuming reactions. In this article we describe the current knowledge on the cellular content, the consumption and the metabolic regeneration of ATP in astrocytes, explore the consequences of an application of metabolic inhibitors on astrocytic ATP metabolism and summarize the importance of endogenous energy stores and exogenous energy substrates for the maintenance of a high cellular ATP content. In addition, we give insight in recent studies on the visualization of ATP in astrocytes by genetically encoded ATP sensors, summarize the importance of astrocytic ATP release and extracellular ATP processing and discuss recent data on the restoration of ATP in ATP-deprived astrocytes. The current knowledge on the ATP metabolism of astrocytes clearly demonstrates the high potential of this important brain cell type to flexibly use different metabolic pathways and a broad range of endogenous and exogenous sources to maintain, regenerate and restore cellular ATP levels. These processes secure that ATP is continuously available for the many ATP consuming processes that enable astrocytes to perform their functions in the healthy brain.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the NOTCH3 gene. We reported a novel mutation in the exon 10 of the NOTCH3 gene (NOTCH3 p.C533S) in a Chinese family with CADASIL. This study aimed to identify NOTCH3 p.C533S-induced CADASIL-like pathogenic mechanisms and to observe the therapeutic effects of edaravone dexborneol (EDB) on CADASIL, which is clinically used for acute ischemic stroke in China. We generated human cerebral microvascular endothelial cells (hCMEC) carrying NOTCH3 p.C533S mutation (NOTCH3 p.C533S hCMECs) using CRISPR/Cas9-mediated NOTCH3 knock-in with a donor plasmid. The NOTCH3 p.C533S hCMECs exhibited CADASIL-like pathology, characterized by a loss of tight junctions, diminished proliferative and migratory capacities, and an upregulation in pro-inflammatory cytokines. The NOTCH3 p.C533S hCMECs induced neuronal ferroptosis, pro-inflammatory activation of astrocytes and microglia with accumulated lipid droplets and oligodendrocytes damage. Mechanistically, utilizing metabolomics and multiple biochemical approaches, we identified that downregulated vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway contribute to the reduced activities of glutathione reductase (GR) and argininosuccinate synthase 1 (ASS1), resulting in reduced glutathione and arginine levels, as well as NOTCH3 p.C533S hCMECs degeneration. EDB treatment could partially reverse CADASIL- and non-hereditary cerebral small vessel disease-like pathology by restoring the VEGF/VEGFR-regulated ASS1 and GR. The NOTCH3 p.C533S mutation causes hCMEC degeneration associated with VEGF/VEGFR pathway impairment-mediated cellular metabolic reprogramming and inflammation. The progression of CADASIL is intensified by a cascade of interactions between compromised hCMEC and surrounding neurons and glial cells. EDB may offer a promising therapeutic approach for cerebral small vessel disease including CADASIL and non-hereditary one.