Neurochem. Res. [JOURNAL]
Sun
200 papers
Sex-Specific Differences in Amino Acids and Neurotransmitters in Multiple Sclerosis Patients Compared to Non-Neuroinflammatory Controls: A Retrospective Case-Control Study.
Meier P, Glasmacher S, Salmen A … +2 more , Chan A, Gertsch J
Neurochem Res · 2026 May · PMID 42082679 · Full text
Multiple sclerosis (MS) is an immune-mediated chronic neuroinflammatory and neurodegenerative disorder. Inflammation in MS disrupts the barriers between blood and central nervous system and affects transport and diffusio...
Multiple sclerosis (MS) is an immune-mediated chronic neuroinflammatory and neurodegenerative disorder. Inflammation in MS disrupts the barriers between blood and central nervous system and affects transport and diffusion of metabolites between blood and cerebrospinal fluid (CSF). In this exploratory retrospective case-control study, we used targeted metabolomics to evaluate differences in serum and CSF amino acid and neurotransmitter levels between patients with MS (n = 73) and non-neuroinflammatory controls (n = 78). The influence of patient characteristics, including sex, age, disease duration, severity and treatment status, was also analzyed. Although no significant differences in serum and CSF metabolite levels were found between MS and control patients, a stratification by sex uncovered significantly reduced metabolites in male MS patients compared to male controls in CSF but not in serum. While in male MS patients CSF histidine levels were decreased, female MS patients showed increased levels. Further, sex-specific associations of amino acids and neurotransmitters with disease duration and disability were observed. MS patients exhibited enhanced positive correlations between CSF and serum analyte levels. In serum, only a few amino acids, along with serotonin and glutathione, were associated with MS disease duration. Overall, this study suggests that targeted metabolomics of selected analytes in matched CSF and serum samples is a valuable approach for assessing alterations in CSF-serum metabolite associations in MS, as well as sex-specific imbalances between excitatory and inhibitory neurotransmitters across disease duration. Our findings further highlight the importance of considering sex as a key biological factor in MS.
Electroacupuncture Stimulation of the Head Motor Area Alleviates Brain Cell Pyroptosis and Neurobehaviors in Stroke Rats Through the NF-κB/NLRP3 Signaling Axis.
Hu Z, Yong Z
Neurochem Res · 2026 Apr · PMID 42043662 · Publisher ↗
Electroacupuncture (EA), a combination of acupuncture and electrical stimulation, is an efficient therapy for stroke. The paper intends to investigate the impact of EA stimulation of the head motor area on the neurologic...
Electroacupuncture (EA), a combination of acupuncture and electrical stimulation, is an efficient therapy for stroke. The paper intends to investigate the impact of EA stimulation of the head motor area on the neurological function of stroke rats and the underlying mechanism. An MCAO rat model was developed and intervened with EA, the NLRP3 activator Nigericin, and the NF-κB activator PMA. Motor function, coordination ability, neurological dysfunction, infarct volume, histopathological changes, and cortical nerve cell alterations were assessed using the Basso Beattie Bresnahan score, balance beam test, neurobehavioral score, and TTC, H&E, and Nissl stainings. Neuroinflammation degree, inflammatory cytokine levels, and cortical expression of NF-κB, NLRP3, Cleaved Caspase-1, and GSDMD-N were assessed using immunohistochemistry, immunofluorescence, ELISA, and western blot. MCAO rats treated with EA showed improved motor function and neurobehaviors. EA inhibited NF-κB/NLRP3-mediated brain cell pyroptosis and neuroinflammation, demonstrated by decreased cortical NF-κB expression and phosphorylation, NLRP3, Cleaved Caspase-1/Pro-Caspase-1 and GSDMD-N/GSDMD expression, and GSDMD-N-positive cell count, reduction of activated microglia (Iba-1+ and Iba-1+CD68+) and astrocytes (GFAP+), decreased IL-1β and IL-18, IL-6, and tumor necrosis factor-α levels, and increased IL-10 and transforming growth factor-β levels. These findings suggest that EA may improve motor function and neurobehaviors in MCAO rats by inhibiting the NF-κB/NLRP3 pathway. Conversely, activation of the NF-κB/NLRP3 pathway attenuated the ameliorative effects of EA. EA stimulation of the head motor area mitigated brain cortical pyroptosis and neuroinflammation via NF-κB/NLRP3 pathway suppression, thereby ameliorating motor function and neurobehaviors in MCAO rats.
FTDP-17T Mutations Promote Formation of Phosphorylated FTDP-17T TAU Oligomers That Cause Degeneration of Dopaminergic and Hippocampal Neurons via Activating ER Stress and Mitochondrial Pro-apoptotic Cascades.
Wang HL, Weng YH, Chiu CC … +3 more , Chen WS, Liu SY, Yeh TH
Neurochem Res · 2026 Apr · PMID 42043652 · Publisher ↗
Heterozygous missense mutations of TAU cause frontotemporal dementia with parkinsonism linked to chromosome 17 with tau pathology (FTDP-17T). FTDP-17T neurodegeneration of hippocampal and substantia nigra dopaminergic ce...
Heterozygous missense mutations of TAU cause frontotemporal dementia with parkinsonism linked to chromosome 17 with tau pathology (FTDP-17T). FTDP-17T neurodegeneration of hippocampal and substantia nigra dopaminergic cells causes dementia and parkinsonism motor deficits. FTDP-17T cellular model of mutant TAU-expressing differentiated dopaminergic or hippocampal neurons was utilized to test hypothesis that FTDP-17T (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs located in different domains of TAU cause neurodegeneration with the same pathomechanism. (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs caused degeneration of dopaminergic or hippocampal neurons via mutation-induced gain-of-neurotoxicity. (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) mutations promoted Ser/Ser/Ser phosphorylations of TAU and formation of phospho-FTDP-17T TAU oligomers in dopaminergic or hippocampal neurons. GSK-3β inhibitor AR-A014418 completely blocked (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs-induced neurotoxicity by preventing (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) mutations-augmented Ser/Ser/Ser phosphorylations and genesis of phospho-FTDP-17T TAU oligomers. Phospho-(R5H), phospho-(N279K), phospho-(K298E), phospho-(P301S), phospho-(K317M) or phospho-(G389R) TAU oligomers were found in ER of dopaminergic or hippocampal neurons and activated ER stress, UPR and ER stress apoptotic signaling. Overexpression of mitochondrial phospho-FTDP-17T TAU oligomers caused mitochondrial malfunction via depolarizing mitochondrial membrane potential and oxidative damage by increasing ROS. Phospho-FTDP-17T TAU oligomers-evoked upregulation of Noxa, Bim or Puma and mitochondrial defect and oxidative stress excited mitochondrial pro-apoptotic pathway. Our results suggest that shared pathomechanism underlying FTDP-17T (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs-induced neurotoxicity is mutation-augmented GSK-3β-mediated Ser/Ser/Ser phosphorylations and generation of phospho-FTDP-17T TAU oligomers, which cause neurodegeneration by stimulating ER stress and mitochondrial pro-apoptotic cascades.
Ca Signaling Enables Growth Hormone Secretion from Cultured Mice Pituitary Somatotrophs, Facilitating Outgrowth in Hypothalamic Neuron.
Shin S, Bikki S, Byrnes K … +1 more , Bandyopadhyay BC
Neurochem Res · 2026 Apr · PMID 42012561 · Publisher ↗
The hypothalamus regulates anterior pituitary (AP) hormone release via the hypophyseal portal system by secreting specific releasing and inhibiting peptide hormones. Growth hormone (GH) secretion from pituitary somatotro...
The hypothalamus regulates anterior pituitary (AP) hormone release via the hypophyseal portal system by secreting specific releasing and inhibiting peptide hormones. Growth hormone (GH) secretion from pituitary somatotrophs (PS) is regulated by a cholinergic mechanism that induces calcium (Ca2+) signaling, which in turn triggers vesicular exocytosis and GH release. Given that the transient receptor potential canonical channel 3 (TRPC3) regulates vesicle exocytosis in endocrine and neuroendocrine cells, we investigated its role in GH release from somatotrophs and whether GH release could support neuronal growth in the hypothalamus. Activation of TRPC3 by the diacylglycerol analog, 1-oleoyl-2-acetyl-sn-glycerol (OAG), resulted in a rapid increase in intracellular Ca2+ ([Ca2+]i) in wild type (WT) PS, attenuated by the TRPC3 inhibitor Pyr10, or by the knockout of TRPC3. ELISA assay confirmed that OAG exposure triggered GH release in WT PS. Conditioned media from OAG-stimulated PS promoted significant neurite outgrowth in hypothalamic neuronal cultures, suggesting a role for released GH in this process. Exposure of PS to H2O2-induced oxidative damage enhanced store-operated Ca2+ entry (SOCE) compared to control cells. Electrophysiological characterization revealed that somatotrophs under increased reactive oxygen species (ROS) conditions exhibited elevated SOCE, whereas cells under more native conditions exhibited receptor-operated Ca2+ entry. Furthermore, media from oxidative-stressed PS cultures, followed by the OAG exposure, induced neurite outgrowth, suggesting TRPC3 activation may provide an alternative pathway after ROS-induced damage in GH release. These findings indicate that Ca2+ signaling activation may promote GH secretion from control and ROS-induced AP cells, potentially leading to neurite outgrowth in hypothalamic cells. This study may provide insights into restoring neuronal connectivity following brain injury.
MicroRNA and Proteomic Landscape of Brain Development.
Jauhari A, Yadav SK, Singh T … +1 more , Yadav S
Neurochem Res · 2026 Apr · PMID 42010124 · Publisher ↗
Brain development is a complex and continuous process that begins during the gestation period and peeks in adolescence. This process unfolds in multiple phases and involves cellular events like cell proliferation, migrat...
Brain development is a complex and continuous process that begins during the gestation period and peeks in adolescence. This process unfolds in multiple phases and involves cellular events like cell proliferation, migration, axonal and dendritic outgrowth, apoptosis, synapse formation, myelination, and synaptic pruning. Each of these developmental processes is tightly regulated by intricate layers of gene expression. MicroRNAs (miRNAs) play a crucial role in regulating gene expression post-transcriptionally. Due to their ability to regulate multiple genes with a single miRNA and a single gene with multiple miRNAs, miRNAs are particularly well-suited to orchestrate gene expression during brain development. In this study, we utilized rat brain samples from various developmental stages: gestation day 15 (GD15), 0-days, 1-week, 3-weeks, 6-weeks, 12-weeks, and 1-year, to investigate the dynamic changes in brain development. We analyzed the global miRNA expression and proteomic profile at each time point using rat miRNA TaqMan Low Density Arrays and LC–MS/MS, respectively. Our analysis revealed that miRNA and protein expression are tightly regulated throughout brain development from GD15 to 1 year. Interestingly, the patterns of global expression of miRNAs and proteins are dramatically different in GD15 and 0-day. Some miRNAs exhibited stage-specific expression patterns, while others were consistently expressed at higher levels across the entire developmental period. Notably, the expression levels of certain miRNAs, including the miR-29 family, miR-34 family, miR-338, and miR-219, were found to increase as brain development progressed. These miRNAs had minimal expression at GD15 and reached their highest levels at 12-weeks or 1-year. Conversely, miR-296, miR-217, miR-20b-3p, and miR-214 exhibited peak expression at GD15, with levels decreasing by 12-weeks and 1-year. In addition, we examined phase-specific protein expression profiles using mass spectrometry to further complement our findings.
Antioxidant Activity of Flavonoid Glabranin by Upregulating Antioxidant Gene Expression via MEK/ERK and PI3K/Akt Pathways in Human Neuroblastoma SH-SY5Y Cells.
Nakatsuji M, Shibano M, Fujimori K
Neurochem Res · 2026 Apr · PMID 42010038 · Publisher ↗
Oxidative stress is associated with neuronal cell death in neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Glabranin, a flavonoid found in the stems and leaves of Glycyrrhiza glabra (li...
Oxidative stress is associated with neuronal cell death in neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Glabranin, a flavonoid found in the stems and leaves of Glycyrrhiza glabra (licorice), exhibits antioxidant and anti-inflammatory properties. However, the effect of glabranin on the antioxidant response and the underlying mechanism including the specific signaling pathways, remain unclear. In the current study, we investigated the protective effect of glabranin on hydrogen peroxide (H2O2)-induced neurotoxicity in human neuroblastoma SH-SY5Y cells and its underlying mechanisms. H2O2-induced death of SH-SY5Y cells was restored by glabranin in a concentration-dependent manner. The number of H2O2-increased apoptotic cells was reduced by co-treatment with glabranin. Moreover, glabranin attenuated H2O2-induced cleaved caspase-3/7 levels. In addition, glabranin decreased H2O2-induced intracellular ROS levels via promoting the nuclear translocation of nuclear factor erythroid 2-related factor 2 and upregulating the antioxidant gene expression. Furthermore, glabranin enhanced the phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) following H2O2 treatment. Inhibition of mitogen-activated protein kinase kinase (MEK)/ERK and phosphoinositide 3-kinase (PI3K)/Akt pathways abrogated glabranin-mediated elevation of antioxidant gene expression and neuroprotective effects. These findings suggest that glabranin mitigated H2O2-induced apoptosis by increasing the expression of antioxidant genes through activation of the MEK/ERK and PI3K/Akt pathways in SH-SY5Y cells. Therefore, glabranin has the potential to prevent and treat neurodegenerative diseases as an antioxidant agent.
Unpredictable Chronic Mild Stress Upregulates Dopamine Receptor Expression Independent of Fatty Acid-Binding Protein 7 Gene Deletion.
Lu H, Roeder N, Richardson B … +6 more , Hamilton J, Lagamjis G, Owada Y, Kagawa Y, Sharma A, Thanos PK
Neurochem Res · 2026 Apr · PMID 42009986 · Full text
Fatty acid-binding protein 7 (FABP7) assists in the intracellular trafficking of endogenous cannabinoids and polyunsaturated fatty acids (PUFAs) and has been implicated for various psychiatric diseases. Rising evidence d...
Fatty acid-binding protein 7 (FABP7) assists in the intracellular trafficking of endogenous cannabinoids and polyunsaturated fatty acids (PUFAs) and has been implicated for various psychiatric diseases. Rising evidence demonstrates the crosstalk between the endocannabinoid and dopaminergic systems, particularly in response to stress. The present study seeks to examine the role of FABP7 expression under chronic stress conditions and its impact on the dopaminergic system, specifically dopamine D1 receptor (D1R) and dopamine D2 receptor (D2R) levels. Adult male FABP7 and FABP7 mice underwent 28-day treatment of unpredictable chronic mild stress (UCMS) procedure. After the stress paradigm, D1R and D2R levels were measured with in vitro autoradiography using [H] SCH23390 and [H] Spiperone, respectively. Stressed mice, regardless of genotype, exhibited an increase in D1R binding across the entire striatum (dorsal caudate putamen (CPu), dorsolateral CPu, dorsomedial CPu, ventral CPu, ventrolateral CPu, ventromedial CPu, nucleus accumbens core and shell), substantia nigra and olfactory tract. Additionally, an increase in D2R binding induced by UCMS was observed in the olfactory tract and certain regions of the striatum (dorsal CPu and ventral CPu). The UCMS paradigm upregulates D1R and D2R binding independent of FABP7 gene deletion, suggesting a compensatory role of other FABPs in the brain in maintaining dopaminergic homeostasis. This stress-induced shift in D1R: D2R ratio may underlie the pathogenesis of major depressive disorder and substance use disorder, as well as the high comorbidity among these conditions.
Neto2 Phosphorylation Promotes Neuronal Loss in KA-Induced Epileptic Rat Hippocampus by Upregulating the Interaction with GluK2.
Fan J, Cao Y, Yin X … +3 more , Lu F, Li C, Yan J
Neurochem Res · 2026 Apr · PMID 41998398 · Publisher ↗
Kainate receptor, especially containing GluK2, hyperactivation plays an important role in epileptic excitotoxicity and neuronal damage, but the function of their key regulatory protein, neuropilin and tolloid-like protei...
Kainate receptor, especially containing GluK2, hyperactivation plays an important role in epileptic excitotoxicity and neuronal damage, but the function of their key regulatory protein, neuropilin and tolloid-like protein 2 (Neto2), in this process is unclear. This study aimed to elucidate the role and molecular mechanism of Neto2 in regulating GluK2-mediate hippocampal neuronal damage. Our findings indicated that in kainic acid-induced epileptic rats, the level of phosphorylation in Neto2 and GluK2 elevated, and their interaction enhanced, accompanying the loss of neurons in the hippocampal cornu ammonis 3 / dentate gyrus regions. Remarkably, the calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor effectively reduced this protein phosphorylation and the interaction of the GluK2-Neto2. In addition, in HEK293T cells, the interference peptide (Tat-GluK2) targeting to the M3-S2 domain of GluK2 specifically blocked GluK2-Neto2 binding, and significantly reduced calcium influx. Importantly, CaMKII inhibitor and Tat-GluK2 both significantly improved the pathological status related to epilepsy including the abatement of hippocampal long-term potentiation, the reduced loss in hippocampal neurons, and the recovery of learning and memory. Collectively, our findings suggest that CaMKII-mediated increase in GluK2-Neto2 interaction is a primary driver of hippocampal neuronal loss in kainic acid-induced epileptic rats, targeting the GluK2-Neto2 binding domain may be a potential therapy-target for epilepsy.
Expression and Localization of Branched-Chain Ketoacid Dehydrogenase E1 Subunits and LAT1 Transporter in Rat Retinal and Ocular Tissues.
Aldosari DI, Sarawi WS, Algarzae NK … +2 more , Alhomida AS, Ola MS
Neurochem Res · 2026 Apr · PMID 41998309 · Publisher ↗
Branched-chain amino acids (BCAAs) are essential for various metabolic and physiological functions. The enzymes responsible for breaking down and transporting them are organized in a tissue-specific manner, playing a cru...
Branched-chain amino acids (BCAAs) are essential for various metabolic and physiological functions. The enzymes responsible for breaking down and transporting them are organized in a tissue-specific manner, playing a crucial role in moving metabolites between cells but often being overlooked. This is particularly true for the rate-limiting enzyme, branched-chain keto-acid dehydrogenase (BCKD). To address this gap, our study investigated the expression and distribution of the BCKDE1 subunits and the BCAA transporter LAT1 in normal rat eye tissues, with a focus on the retina, by applying immunohistochemistry (IHC) and immunofluorescence (IF) with specific antibodies. Our findings show that BCKDE1 subunits are highly expressed in retinal neurons, specifically in the ganglion cell layer (GCL), inner and outer nuclear layers (INL/ONL), and the plexiform layers (IPL/OPL), although they are notably absent in Müller cells. Expression was also strong in the epithelial cells of the lens, iris, and ciliary body. Similarly, we observed LAT1 localized in the GCL and INL of the retina, as well as in the iris, ciliary body, and lens epithelium. These results complement our previous work, which indicated that branched-chain aminotransferase (BCAT) isozymes are widely expressed across most ocular tissues. Overall, this evidence strongly indicates that a complete BCAA metabolic pathway exists in the eye. This provides a comprehensive understanding of BCAA metabolism in eye tissues, highlighting its crucial role in maintaining amino acid balance, neurotransmitter production, and energy generation. Furthermore, this study lays a foundation for future studies on how disruptions in these enzymatic pathways might affect neurodegeneration in diabetic retinopathy and contribute to other eye conditions.
Resveratrol-Loaded Polymeric Nanoparticles Protect Against Rotenone-Induced Parkinsonian-Like Cellular Damage In Vitro: Association with NRF2/HMOX-1 Expression Changes.
Teixeira IMM, Duque BR, da Costa MDR … +11 more , da Silva ME, Fernandes MO, de Souza Freitas AG, Bezerra VM, Reis AVF, Pinheiro NML, de Freitas Clementino MA, Eloy JO, de Menenzes RRPPB, Martins AMC, Sampaio TL
Neurochem Res · 2026 Apr · PMID 41973181 · Full text
Parkinson’s disease (PD) is a progressive neurodegenerative disorder with limited treatment options. Several natural compounds have been investigated, particularly resveratrol (RSV), which exhibits antioxidant and anti-i...
Parkinson’s disease (PD) is a progressive neurodegenerative disorder with limited treatment options. Several natural compounds have been investigated, particularly resveratrol (RSV), which exhibits antioxidant and anti-inflammatory properties. However, its unfavorable pharmacokinetic profile limits its therapeutic application, making nanoencapsulation a promising strategy. This study evaluated the protective effects of resveratrol-loaded polymeric nanoparticles (NP RSV) and the involvement of the Keap1/NRF2/ARE pathway in a rotenone (ROT)-induced PD-like model in vitro. PC12 neuronal cells and astrocytes were pretreated with NP RSV, RSV, and dopamine for 1 h, followed by ROT exposure for 24 h. Cell viability was assessed by MTT, while cell death profile, reactive oxygen species production, and mitochondrial transmembrane potential (ΔΨm) were evaluated by flow cytometry. Morphological changes were evaluated by optical microscopy. Gene expression of NRF2 and heme oxygenase-1 (HMOX-1) was assessed by RT-qPCR. Pretreatment with NP RSV significantly protected cells by preserving viability, reducing reactive oxygen species, maintaining mitochondrial function, and decreasing apoptosis. Morphological analyses corroborated these results. Furthermore, NP RSV modulated ROT-induced NRF2 and HMOX-1 expression, suggesting involvement of the Keap1/NRF2/ARE pathway.
BDNF Protects Against Neuronal Damage Induced by TNF and β-Amyloid Peptides by Targeting JNK Activation.
Ramírez-Olvera A, Almazán JL, Pérez-Martínez L … +1 more , Pedraza-Alva G
Neurochem Res · 2026 Apr · PMID 41964857 · Full text
Neuroinflammation, driven by β-amyloid peptide accumulation, plays a critical role in the pathogenesis of Alzheimer’s disease, resulting in neurodegeneration and cognitive decline. Inflammatory cytokines, particularly tu...
Neuroinflammation, driven by β-amyloid peptide accumulation, plays a critical role in the pathogenesis of Alzheimer’s disease, resulting in neurodegeneration and cognitive decline. Inflammatory cytokines, particularly tumor necrosis factor (TNF), adversely affect neuronal function and survival by counteracting the neuroprotective effects of neurotrophins. Importantly, brain-derived neurotrophic factor (BDNF) has been shown to alleviate the neurotoxic effects of pro-inflammatory cytokines. While the mechanisms through which pro-inflammatory cytokines disrupt BDNF/TrkB signaling are well understood, the specific ways in which BDNF protects neurons from inflammatory damage remain unclear. We present evidence that BDNF reduces cytotoxicity and neuritic damage in cholinergic neurons (SN56) induced by TNF and β-amyloid peptide, through the downregulation of c-Jun N-terminal kinase (JNK) activation. BDNF inhibits TNF-induced JNK activation by stimulating p38 mitogen-activated protein kinase. These findings indicate that BDNF restores neuronal functionality by modulating the signaling pathways of inflammatory cytokines, such as TNF, and highlight potential therapeutic strategies to mitigate neuroinflammation-associated neurodegeneration in Alzheimer’s disease.
Mitochondrial Fission and Fusion Disorders and Autophagy Abnormalities in Parkinson's Disease.
Liu Y, Li H, Bai J
Neurochem Res · 2026 Apr · PMID 41964742 · Publisher ↗
Parkinson’s disease (PD) is a common neurodegenerative disease with multiple causes and complex mechanisms. Mitochondrial dysfunction is the main cause and central event of dopaminergic neuron degeneration in PD. Therefo...
Parkinson’s disease (PD) is a common neurodegenerative disease with multiple causes and complex mechanisms. Mitochondrial dysfunction is the main cause and central event of dopaminergic neuron degeneration in PD. Therefore, studying mitochondrial dysfunction plays an important role in understanding the pathogenesis of PD. In the future, mitochondrial dysfunction becomes an important therapeutic target for this disease. This article focuses on the mitochondrial molecular mechanism of neurodegeneration, including reactive oxygen species generation, mitochondrial autophagy, and mitochondrial dynamics, etc., and the potential targets for PD therapy. This article also discusses other potential treatment strategies, such as mitochondrial transplantation, targeted microRNA, use of stem cells and exercise, these may provide valuable insights for clinical practice. A better understanding of the role of mitochondria in the pathophysiology of PD may provide fundamental principles for designing new therapeutic interventions to combat PD.
Targeting Ferroptosis and Necroptosis to Treat Stroke.
Sandra Monserrat BP, Carlos Alfredo SI, Rosina ST … +3 more , Alejandra F, Diana BO, Perla D M
Neurochem Res · 2026 Apr · PMID 41964701 · Full text
Ischemic stroke is a leading cause of death and long-term disability worldwide. It results from cerebral blood flow obstruction (ischemia) and, in some cases, the restoration of cerebral blood flow (reperfusion), trigger...
Ischemic stroke is a leading cause of death and long-term disability worldwide. It results from cerebral blood flow obstruction (ischemia) and, in some cases, the restoration of cerebral blood flow (reperfusion), triggering a cascade of pathophysiological events collectively known as the ischemic cascade and reperfusion injury, which leads to the activation of different regulated cell death types, and this review focuses on necroptosis and ferroptosis. Both pathways are closely linked to oxidative stress and contribute significantly to neuronal death and inflammation following ischemic stroke. Dysregulation of redox homeostasis, iron dyshomeostasis, glutathione depletion, and mitochondrial dysfunction are key events in neuronal damage. Understanding the interplay between oxidative stress and these pathways is crucial for developing effective neuroprotective therapies. This review highlights recent advances in understanding necroptosis and ferroptosis in ischemic stroke, proposing redox-targeted interventions as promising strategies to mitigate brain injury and improve outcomes in patients affected by this condition.
Puerarin Alleviates Depression via Integrated Regulation of TLR4/MyD88/NF-κB Signaling and Gut Microbiota-Metabolic Axis.
Cao XY, Tian JJ, Zhang W … +2 more , Chen CL, Ma H
Neurochem Res · 2026 Apr · PMID 41961352 · Publisher ↗
Depression is a highly prevalent mental disorder in which dysfunction of the gut microbiota is implicated as a significant factor in its pathogenesis. Puerarin has been suggested to alleviate depression via the microbe-g...
Depression is a highly prevalent mental disorder in which dysfunction of the gut microbiota is implicated as a significant factor in its pathogenesis. Puerarin has been suggested to alleviate depression via the microbe-gut-brain axis (MGBA), although the precise mechanisms remain elusive. This study aimed to elucidate the association between the antidepressant effects of puerarin and its role in regulating intestinal flora imbalance and inhibiting subsequent activation of the LPS/TLR4 inflammatory pathway from metabolomics and metagenomics perspectives. A rat model of depression was established using a 6-week chronic unpredictable mild stress (CUMS) protocol. Depressive-like behaviors were assessed through the sucrose preference test (SPT), forced swim test (FST), and open field test (OFT). Inflammatory cytokines (TNF-α, IL-1β, IL-6), LPS, corticosterone, and 5-HT were measured via ELISA. Hippocampal and colonic protein expression of TLR4, MyD88, IκBα, and NF-κB was analyzed by western blot. Colon tissue integrity was evaluated using H&E staining, PAS staining, and transmission electron microscopy. Immunofluorescence was employed to detect Iba-1+ microglia, TLR4+ cells, and ZO-1 expression. Fecal metabolomics and metagenomics were conducted to identify differential metabolites and microbial composition, followed by KEGG and KO enrichment analyses to predict relevant pathways. Spearman correlation analysis was used to explore relationships among gut microbiota, metabolites, and behavioral indices. Puerarin markedly ameliorated depression-like behaviors in CUMS rats. Concurrently, puerarin inhibited the LPS/TLR4 signaling pathway and its downstream pro-inflammatory mediators in both the hippocampus and colon, resulting in a significant reduction in inflammatory responses across these regions, as well as in the serum. Metagenomic sequencing revealed that puerarin suppressed inflammation-associated bacteria, enhanced the abundance of Firmicutes, and induced alterations in the microbial community structure and composition. Metabolomic analysis demonstrated that puerarin could counteract dysregulated fecal metabolism, identifying 17 metabolites as potential key mediators in restoring metabolic homeostasis in CUMS rats. These biomarkers were implicated in several metabolic pathways, including Aminoacyl-tRNA biosynthesis, Pyrimidine metabolism, Alanine, Aspartate, and Glutamate metabolism. Puerarin may exert its antidepressant effects by modulating the gut microbial structure and metabolite profiles, thereby alleviating inflammatory stress in the colon, bloodstream, and hippocampus, potentially through inhibition of the LPS/TLR4 signaling pathway.
Correction: Protective Effects of TNF-α Neutralizing Antibody on the Neurovascular Unit Through Down-Regulating Calpain/NF-κB Inflammatory Pathway During Ischemic Stroke.
Jin C, Wang C, Zhao Y … +2 more , Wang B, Sun M
Neurochem Res · 2026 Apr · PMID 41944973 · Publisher ↗
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Mechanistic Insights into Bergapten by Modulation of Filamin A and GSK3β in STZ Induced Alzheimer's Disease: An Integrated In Silico, In Vitro and In Vivo Study.
Riaz M, Qadir H, Noman M … +6 more , Ahmed S, Shah FA, Malik MU, Bashir K, Farooq U, Irshad N
Neurochem Res · 2026 Apr · PMID 41944966 · Publisher ↗
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) aggregation, tau hyperphosphorylation, synaptic dysfunction and neuroinflammation. The study investigates bergapten (BG...
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) aggregation, tau hyperphosphorylation, synaptic dysfunction and neuroinflammation. The study investigates bergapten (BGN) as a potential AD treatment. Computational analysis revealed strong binding affinity of BGN with Filamin A (FLNA) and glycogen synthase kinase-3β (GSK3β). In vitro assays demonstrated acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition suggesting cholinergic modulation. In intracerebroventricular (i.c.v) streptozotocin (STZ) induced AD mice model, BGN (25 mg/kg, 50 mg/kg and 100 mg/kg i.p) was administered daily for 23 days. The blood and brain tissues samples were collected for biochemical and histopathological analysis. BGN showed dose-dependent cognitive improvements, with biochemical tests indicating renal and hepatic safety. Reduced C-reactive protein and lactate dehydrogenase levels suggested minimal systemic toxicity and neuroinflammation. Histology revealed preserved neurons, decreased amyloid deposits, and improved brain structure. Immunohistochemical analyses indicated BGN was associated with lower Tau, NF-κB, TLR4, and Caspase-3 expression and restored redox homeostasis. Critically, ELISA confirmed reduced FLNA along with Aβ and GSK-3β levels and thus highlights BGN novel modulation of this unexplored AD target. RT-PCR analysis showed downregulated expression of amyloid precursor protein, tau, discs large scaffold protein 4 and glial fibrillary acidic protein, while enhanced synaptic plasticity markers. Collectively, these findings suggest BGN as a promising multi-target neuroprotective and safer agent for AD.
Olfactory Dysfunction Exacerbates Hippocampal Aβ Accumulation, Tau Phosphorylation and Memory Deficits in Mice.
Du M, Ma S, Bai L … +4 more , Mou X, Gao Y, Zhang J, Chen Y
Neurochem Res · 2026 Apr · PMID 41931192 · Publisher ↗
Olfactory dysfunction is a frequent feature in patients with neurodegenerative disorders such as Alzheimer’s disease (AD). However, whether olfactory impairment is the cause or consequence of AD is unknown. We previously...
Olfactory dysfunction is a frequent feature in patients with neurodegenerative disorders such as Alzheimer’s disease (AD). However, whether olfactory impairment is the cause or consequence of AD is unknown. We previously found that olfactory dysfunction impairs learning and memory in mice in multiple experimental paradigms, but whether olfactory dysfunction increases AD-related neuropathological changes such as Aβ deposition and tau protein phosphorylation is not clear. In this study, mice were treated with bilateral intranasal zinc sulfate (ZnSO4) solution infusion, which resulted in olfactory dysfunction for about 1 month in mice. 1, 3, 6, and 9 months after that, the Y-maze learning and memory, as well as hippocampal Aβ deposition, tau and p-tau expression were tested. We found that olfactory dysfunction leads to a long period and irreversible learning and memory impairment in mice. Olfactory dysfunction also increased Aβ deposition, Aβ42 level, and increased p-tau expression in hippocampus (HPC), which were accompanied by increased beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and decreased presenilin-1 (PS1) expression. Compared with one time of ZnSO4 treatment, repetitive ZnSO4 treatment (three times, a month apart) resulted in more significant increases in tau phosphorylation in mice hippocampus. These results suggest that olfactory dysfunction lead to behavioral and pathological changes associated with AD in mice, which suggest that olfactory dysfunction can contribute to the development of AD.
Chronic Co-administration of Methylphenidate and Fluoxetine Reduces Striatal NMDA Receptor Binding in Adolescent Rats.
Lagamjis G, Slayton D, Lu H … +7 more , Hoerner C, Lantry AM, Marion M, Elman D, Hadjiargyrou M, Komatsu D, Thanos PK
Neurochem Res · 2026 Apr · PMID 41931177 · Full text
Methylphenidate (MP), a widely used medicine for attention deficit/hyperactivity disorder (ADHD), is commonly prescribed in combination with selective serotonin reuptake inhibitors (SSRI) e.g., fluoxetine (FLX). However,...
Methylphenidate (MP), a widely used medicine for attention deficit/hyperactivity disorder (ADHD), is commonly prescribed in combination with selective serotonin reuptake inhibitors (SSRI) e.g., fluoxetine (FLX). However, neurochemical effects of the MP + FLX combination have not been sufficiently elucidated. Given the pivotal role played by glutamatergic signaling in psychostimulant responses and corticostriatal plasticity, we employed a 2-level factorial design to assess how the individual treatments and their co-administration affect N-methyl-D-aspartate receptor (NMDAR) binding using [³H] MK-801 in vitro autoradiography. Three-week-old male rats were randomized into four groups: MP (30/60 mg/kg), FLX (20 mg/kg), MP + FLX (30/60 mg/kg and 20 mg/kg), and vehicle. Treatment was administered for four weeks using a dual bottle drinking paradigm that models human dosing and pharmacokinetics. Following the treatment, [³H] MK-801 in vitro autoradiography was performed on coronal brain sections. The MP + FLX group significantly decreased NMDA binding levels in the dorsal caudate-putamen (DCPU) (39%), ventral caudate-putamen (VCPU) (36%), and nucleus accumbens (Nac) (34%), compared to vehicle. Rats in the MP group demonstrated reduced NMDA binding in the DCPU only, and there were no significant differences in binding for the FLX group. These findings indicate that MP + FLX coadministration yields a reduction in NMDAR binding across the striatum, an effect not produced by either of the drugs. Thus, reduced NMDA binding following MP + FLX treatment may contribute to dysregulations in memory, motor, and reward systems. Further studies are warranted to evaluate the neurochemical, neurodevelopmental, and clinical correlates of MP + FLX glutamatergic effects in adolescent patients.
Curcumin and Glycyrrhiza glabra Synergistically Attenuate Alzheimer's Pathology via TLR4/NF-κB-Mediated Anti-inflammatory and Redox Modulation in a D-Gal/Sodium Nitrite-Induced Mouse Model.
Liu S, Yan J, Dong J
Neurochem Res · 2026 Apr · PMID 41920384 · Publisher ↗
This study investigates the early synergistic effects of curcumin and licorice through vertical cooperation, which can simultaneously target both the upstream and downstream components of neuroinflammation. It evaluates...
This study investigates the early synergistic effects of curcumin and licorice through vertical cooperation, which can simultaneously target both the upstream and downstream components of neuroinflammation. It evaluates their neuroprotective effects and potential mechanisms in a D-galactose/sodium nitrite-induced Alzheimer's disease mouse model.Eighty C57BL/6 mice were divided into eight groups (n = 10): wild-type (WT), AD model, curcumin monotherapy (AD + CL, 100 mg/kg), G. glabra monotherapy (AD + GG, 100 mg/kg), low-dose combination (AD + COM-L, 50 + 50 mg/kg), high-dose combination (AD + COM-H, 100 + 100 mg/kg), donepezil (3 mg/kg), and SN50 (NF-κB inhibitor, 400 µg/kg). Cognitive function was assessed via Morris Water Maze in WT, AD, AD + CL, AD + GG, and AD + COM-H groups, while all groups underwent molecular analyzes. The high-dose combination most effectively restored spatial memory, reducing escape latency by ~ 43% versus monotherapies. Molecularly, it synergistically reduced tau-related proteins (MAPT, GSK-3β) and suppressed the TLR4/MyD88/NF-κB axis, lowering inflammatory mediators (IL-6, TNF-α, CXCL1, PTGS2). IL-6 was further reduced by 28.6% and 40.0% compared to curcumin and G. glabra alone, respectively. The combination also enhanced antioxidant defense (increased SOD) and anti-apoptotic capacity (upregulated BCL-2) while reducing oxidative lipid damage (lower MDA). Network pharmacology identified 40 shared AD targets, with enrichment in NF-κB and IL-17 pathways, validated experimentally. In conclusion, curcumin and G. glabra exert synergistic neuroprotection by concurrently inhibiting the TLR4/NF-κB pathway and modulating IL-17 signaling, with G. glabra potentially targeting the TLR4/HMGB1 axis and curcumin directly inhibiting NF-κB activation, forming a complementary mechanistic interplay. This multi-target action disrupts the interplay between neuroinflammation and tau pathology, underscoring the combination's therapeutic potential for AD intervention.
MitoQ Triggers Mitochondrial Collapse and Apoptotic Death in Glioblastoma Associated with KATP Channel Expression Changes.
Karaaslan A, Hacioglu C
Neurochem Res · 2026 Mar · PMID 41910839 · Full text
Glioblastoma (GBM) is the most aggressive primary brain tumor and remains refractory to current therapies due to its pronounced metabolic heterogeneity and mitochondrial adaptability. Ion channels, particularly ATP-sensi...
Glioblastoma (GBM) is the most aggressive primary brain tumor and remains refractory to current therapies due to its pronounced metabolic heterogeneity and mitochondrial adaptability. Ion channels, particularly ATP-sensitive-potassium (KATP) channels, have emerged as critical regulators of cellular energy sensing in cancer. This study evaluated the mitochondrial-targeted agent MitoQ in GBM and explored its potential association with KATP channels. In this study, the cytotoxic potential of MitoQ was systematically evaluated in three genetically distinct GBM cell lines. Cell viability was assessed using concentration-response analyses to identify differential sensitivity. Baseline expression of KATP-channel components (KCNJ11/Kir6.2, ABCC8/SUR1, and CCDC51) was quantified by qRT-PCR and Western blotting. Mechanistic analyses were subsequently performed in the most sensitive cell line and included mitochondrial ROS measurement (MitoSOX), confocal assessment of mitochondrial morphology, Seahorse XF-based bioenergetic profiling, ATP/ADP ratio quantification, analysis of autophagic flux via LC3-II/p62 turnover with bafilomycin-A1, and caspase-3/7-based apoptosis detection. U87 cells exhibited the lowest IC₅₀ for MitoQ and showed significantly higher baseline expression of KATP channel subunits compared to U251 and T98G cells. Acute MitoQ exposure (10 µM, 6 h) in U87 cells induced marked mitochondrial superoxide accumulation, extensive mitochondrial fragmentation, severe suppression of oxidative phosphorylation, and ATP depletion. These effects were associated with selective downregulation of Kir6.2 and the mitochondrial KATP-associated component CCDC51, impaired autophagic flux with p62 accumulation, and robust activation of executioner caspases. In conclusion, MitoQ may induce mitochondrial dysfunction in metabolically primed GBM cells, and cellular sensitivity appears to correlate with a distinct KATP channel expression signature.
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