Neurochemical Research最新文献

Toll-like receptors (TLRs) in the brain significantly contribute to various central nervous system (CNS) disorders, including addiction. Morphine’s interaction with TLR4 contributes to dependence and withdrawal. Alpha-pinene, a monoterpene with anti-inflammatory properties, has not been studied for its effects on TLR signaling in morphine dependence and withdrawal. This study investigated alpha-pinene’s impact on hippocampal TLR pathways in morphine-dependent and withdrawing rats. Male Wistar rats were divided into two categories: dependence and withdrawal. The three dependence groups received saline + dimethyl sulfoxide 5% (DMSO), morphine (10 mg/kg) + DMSO, or morphine + alpha-pinene (20 mg/kg) for 10 days. The three withdrawal groups received the same saline or morphine treatments as the dependent groups for ten days. Following this, they went through a 30-day morphine washout phase with daily DMSO (the first and second groups) or alpha-pinene (the third group) administration. Rats in all groups were sacrificed either on day 10 (after repeated injections) or 30 days post-withdrawal. Hippocampal tissues were then dissected and analyzed via Western blot and ELISA to assess protein level changes. Results showed increased hippocampal expression of TLR2, TLR4, TLR10, and MyD88 following morphine dependence and withdrawal, while levels of PI3K, p-AKT1B, and IL-1Ra decreased. Alpha-pinene treatment, whether administered during the 10-days dependence induction period or the 30-days withdrawal period, partially restored these alterations in the TLR pathway. These findings suggest alpha-pinene modulates central immune responses by regulating TLR signaling. This highlights therapeutic potential of alpha-pinene for controlling neuroinflammation and subsequent morphine-related complications like tolerance, addiction, and withdrawal.

Chronic stress disrupts immune-endocrine balance and contributes to major depressive disorder (MDD) through dysregulated autophagy and neuroinflammation pathways, yet their interactions and persistence remain unclear. This study investigated these mechanisms using chronic restraint stress (CRS) in male Wistar rats and in silico MDD gene analysis. Rats were exposed to CRS for 15 days (Res15) or 30 days (Res30), followed by a 30-day stress-free recovery period without intervention (Res30/Rec30). Behavioral assessments (anxiety, depression-like behaviors, and cognition) were conducted via standard tests. Blood samples were analyzed for neutrophil-to-lymphocyte ratio (NLR) and corticosterone levels. Hippocampal cytokine expression (TNF-α, IL-1β, IL-16), Beclin1 levels, and neuronal damage were evaluated via molecular and histopathological methods. In silico analysis linked these pathways to human MDD by identifying upregulated autophagy- and inflammation-related genes (including IL1B, PTGS2, GNAI3, RAB1A, MAP1LC3B, SQSTM1, and KIF5B), bridging rodent stress models to clinical depression. CRS induced anxiety- and depression-like behaviors, cognitive impairment, hippocampal neurodegeneration, elevated corticosterone and NLR, and upregulation of pro-inflammatory and autophagy markers. Although partial recovery in depression-like behaviors and cytokine levels was observed after 30 days, anxiety-like behaviors, cognitive impairment, elevated NLR, and hippocampal neurodegeneration persisted. These findings reveal persistent neurobiological consequences of chronic stress, advancing understanding of MDD pathophysiology and suggesting that targeting autophagy and neuroinflammation could offer novel treatments for depression, particularly for symptoms that endure post-stress.

Ilex paraguariensis (IP) is a plant native to South America, traditionally consumed as a beverage and holding significant economic and social value. This plant has been associated with a range of pharmacological activities, including anti-inflammatory and antioxidant effects. Although some studies have suggested its neuroprotective properties, the effects of IP on glial cells, particularly astrocytes, remain poorly understood. Astrocytes play a crucial role in the neuroinflammatory response, and dysfunction in these cells can contribute to the development of neurodegenerative diseases. This study aimed to investigate the glioprotective mechanisms of a standardized IP extract against inflammatory and oxidative damage induced by lipopolysaccharide (LPS) in primary astrocyte cultures. Astrocytes were treated with IP extract (10, 30, 100, and 300 µg/mL) for 24 h, followed by a 3-hour exposure to LPS (1 µg/mL). LPS exposure resulted in the up-regulation of mRNA expression of interleukin-1β and nuclear factor-kappa B genes, increased cell proliferation, and acetylcholinesterase activity, elevated levels of reactive oxygen and nitrogen species, and reduced astrocytic viability, Na⁺, K⁺-ATPase activity, and antioxidant defenses. Treatment with IP extract was able to prevent these effects by reducing pro-inflammatory and oxidative mediators, modulating acetylcholinesterase and Na⁺, K⁺-ATPase activity, enhancing antioxidant defenses, and up-regulating mRNA expression of superoxide dismutase 2, glutathione peroxidase, and nuclear factor erythroid-derived 2-like 2 genes. To the best of our knowledge, this is the first study to demonstrate the glioprotective effects of IP extract on astroglial cells, laying the groundwork for future research into the neuroprotective mechanisms of IP related to neuroinflammation.

AD, a progressive neurodegenerative disorder, imposes an increasingly heavy burden on global public health, with its pathogenesis remaining incompletely understood. Meanwhile, EDCs—widely present in the environment, food, and consumer products—have emerged as a significant public health concern due to their diverse health risks, including potential contributions to neurodegenerative processes such as AD by disrupting neurohomeostasis. Furthermore, as natural compounds, ginsenosides and other AS have been the focus of numerous studies exploring their role in treating AD, thanks to their advantages of multi-target properties and low side effects. However, the specific molecular pathways through which EDCs induce AD, as well as the mechanisms by which AS may counteract EDC-induced toxicity and intervene in AD, remain unclear. Against this background, this study sought to: (1) explore the molecular pathways through which EDCs may induce AD by disrupting neurohomeostasis; (2) preliminarily investigate the potential of AS in treating AD and antagonizing EDC-induced AD at the molecular level. To achieve these goals, we integrated network toxicology, network pharmacology, and molecular docking to construct a multi-dimensional interaction network among EDCs, AD, and AS. By establishing intersecting target sets for EDCs-AD and AS-AD, core targets were identified via topology analysis of protein-protein interaction (PPI) networks. GO and KEGG enrichment analyses highlighted key pathways, including serotonergic synapse and neuroactive ligand-receptor interaction. Molecular docking further explored interactions between EDCs/AS and core target proteins. The results suggest that EDCs may drive neurodegeneration in AD by impairing synaptic function, while AS may counteract these effects by enhancing synaptic activity, stabilizing membrane microenvironments, inhibiting Aβ aggregation, alleviating neuroinflammation, and restoring metabolic homeostasis. Further analysis indicated that AS exhibit stronger binding ability to core targets compared to EDCs, implying a potential antagonistic effect of AS against EDCs. This study provides insights into the molecular mechanisms underlying EDC-induced AD and establishes a multi-target theoretical framework for AS-mediated antagonism of EDC toxicity, offering a reference for the prevention and treatment of neurodegenerative diseases.

Rational polytherapy is increasingly gaining attention when monotherapy fails to control seizures. Accordingly, the current study investigated the effects of topiramate and brivaracetam, administered individually (10 mg/kg each) or combined, on seizure progression alongside electroencephalographic (EEG) changes and neuroinflammatory responses in Pentylenetetrazole (PTZ)-induced kindled mice. Eleven doses of PTZ (40 mg/kg) were administered on alternate days over three weeks. Monotherapy with topiramate and brivaracetam delayed the development of generalized tonic-clonic seizures during the first week. However, it did not prevent seizures later, resulting in 80% and 60% kindled mice with 25% and 16.16% mortality, respectively. Combination therapy demonstrated 100% protection against kindling progression, with no mortality. EEG recordings revealed progressively increasing epileptiform spikes in PTZ and monotherapy-treated groups throughout the kindling period. Conversely, the combination-treated group exhibited significantly consistent reduction in epileptiform spike activity across all EEG sessions, indicating a better anticonvulsant effect. Post-kindling brain analysis revealed elevated levels of neuroinflammatory markers in the monotherapy-treated groups, while these markers were absent in the combination-treated group. RT-PCR confirmed substantial downregulation of proinflammatory and excitatory markers, including BDNF, TrkB, and TNF-α, indicating suppression of neuroinflammation and excitotoxicity in combination-treated group. Histopathological examination showed neuronal damage in the hippocampal tissues of monotherapy-treated mice, whereas no neuronal degenerations were seen in the brains of combination-treated mice. The results indicate that dual therapy with topiramate and brivaracetam provides superior neuroprotection by modulating neuroinflammatory pathways, thereby preventing seizure development and ictogenesis. These findings support the potential clinical utility of rational polytherapy in drug-resistant epilepsy.

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The figure was generated with https://www.biorender.com (LA28FJGRRL; Dated June 25, 2025).

The medical field has spent many years investigating Parkinson's disease (PD), primarily focusing on its main pathogenic feature, dopaminergic neuronal degeneration. Recent studies indicate that PD develops through a complex pathogenic model that links mitochondria to astrocytes and neurons, creating a destructive metabolic loop, a protein aggregation cycle, and oxidative stress. This review examines how mitochondria integrate with astrocytes and neurons in the “triad hypothesis,” offering a multifaceted perspective on PD progression. Despite being previously overlooked, we have observed that astrocytic mitochondria play a central role in maintaining neuroprotection and homeostasis. Given that, dysfunctional mitochondria in astrocytes and neurons lead to metabolic failure, compromised glutamate regulation, while also enhancing α-synuclein aggregation, amplifying neuroinflammation, ferroptotic vulnerability and oxidative stress. Henceforth, this report discusses current insights into astrocyte–neuron metabolic coupling, mitochondrial quality control, and lipid redox imbalance, highlighting the role of astrocytic mitochondria as a strong therapeutic strategy. We discuss experimental and translational approaches that aim to restore triad integrity, including mitophagy enhancement, metabolic reprogramming, mitochondrial transfer, and astrocyte-to-neuron reprogramming. By positioning astrocytic mitochondria at the core of PD pathogenesis, this review advocates novel interventions focused on glial metabolic resilience. This integrated approach addresses three major pathogenic axes. It offers promising potential for disease modification and developing effective therapeutics beyond symptomatic dopamine replacement to correct neurodegenerative conditions.

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The p75 neurotrophin receptor (p75NTR) plays a dual role in regulating both pro-survival and pro-apoptotic cascades in various physiological and pathological conditions, including within dopaminergic neuronal population. Notably, its overexpression has been documented in post-mortem Parkinson’s disease (PD) brains, where it correlates with a significant downregulation in neuroprotective intracellular mediators. In this study, we aimed at investigating the neuroprotective effects of p75NTR modulation by the small molecule LM11A-31 in a rotenone-induced neuronal model of PD. Differentiated SH-SY5Y cells were treated with 100 nM rotenone, with or without 500 nM LM11A-31. Our results show that LM11A-31 effectively mitigates PD phenotype by enhancing cell viability, reducing apoptosis, mitigating α-synuclein aggregation, and partially restoring neuromorphological features. Mitochondrial integrity was preserved, likely through the upregulation of transcription factors involved in mitochondrial biogenesis, namely PGC-1α and PPARs. LM11A-31 treatment also reduced oxidative damage to macromolecules, normalizing Nrf2 expression and enhancing protein S-glutathionylation. The antioxidant effect of p75NTR modulation may be partially attributed to the suppression of the NADPH oxidase regulatory subunits p22PHOX and p47PHOX. Additionally, LM11A-31 restored cholesterol homeostasis disrupted by rotenone, as evidenced by the increased NPC1 expression and lysosomal localization, normalized HMGCR levels, and reduced intracellular cholesterol accumulation. Collectively, these findings demonstrate that p75NTR modulation via LM11A-31 exerts neuroprotective effects by targeting key pathological features of PD, including oxidative damage, mitochondrial derangements, and cholesterol dysmetabolism, supporting its potential as a promising therapeutic tool in PD treatment.

Traumatic brain injury (TBI) can lead to secondary brain damage, with post-traumatic neuroinflammation being a crucial indicator of the condition’s progression and a predictor of patient prognosis. However, effective, evidence-based pharmacotherapy targeting post-TBI neuroinflammation remains lacking. In our study, we show that the use of the mechanosensitive ion channel inhibitor GsMTx4 effectively alleviated neuronal apoptosis and neuroinflammation, thereby ameliorating abnormal neurological behaviors in mice following TBI. Transcriptomic analysis of the tissue surrounding the injury site indicated downregulation of the extracellular matrix(ECM) degradation and inflammation-related signaling pathways. Complementary metabolomic profiling revealed the metabolic signature and a reduced abundance of metabolites associated with inflammatory responses and ECM degradation after treatment. We speculate that GsMTx4 may modulate various proteases, thereby disrupting the ECM degradation–neuroinflammation feedback loop and ultimately attenuating the progression of neuroinflammation-driven secondary brain damage. Immunostaining and functional assays further confirmed that GsMTx4 treatment preserved ECM-related proteins. These findings suggest that GsMTx4 may offer a promising therapeutic approach for the management of secondary damage following TBI.

Neuron-specific enzyme CYP46A1 converts cholesterol to 24-hydroxycholesterol (24-HC), which crosses the brain blood barrier, entering the systemic circulation. Production of 24-HC depends on synaptic and metabolic activity and changes significantly during aging and neurodegenerative diseases. Previously, it was shown that prolonged application of 24-HC (0.4 µM) suppressed recruitment of synaptic vesicles to exocytosis during 20 Hz nerve stimulation acting via elevation of NO synthesis at the mouse neuromuscular junctions (NMJs). Here, using microelectrode recording of postsynaptic responses and fluorescent trackers for endo-exocytosis, NO and reactive oxygen species (ROS) production, the effect of 24-HC on neuromuscular transmission at 10 Hz and 70 Hz nerve firing was studied. At 10 Hz stimulation, 24-HC decreased neurotransmitter release and synaptic vesicle involvement in exocytosis. This was associated with elevation of NO synthesis without marked changes in ROS generation. However, at 70 Hz activity, 24-HC increased the recruitment of synaptic vesicles in exocytosis in combination with attenuation of NO synthesis and enhancement of ROS production. 24-HC-mediated increase in ROS production was suppressed by NADPH-oxidase inhibitor VAS2870, and antioxidant N-acetylcysteine completely prevented 24-HC-dependent potentiation of neurotransmission and suppression of NO synthesis during 70 Hz activity. Similarly, protein kinase C inhibitor chelerythrine blocked 24-HC-mediated enhancement of exocytosis and attenuation of NO generation at 70 Hz stimulation. Thus, 24-HC suppresses neurotransmission at moderate-frequency activity, probably via elevation of NO synthesis, but it potentiates neurotransmitter release and synaptic vesicle recruitment into exocytosis during high-frequency nerve firing via an NADPH oxidase/ROS/protein kinase C pathway.

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