Neurochem. Res. [JOURNAL]
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200 papers
Vitamin D Attenuates Alzheimer's Disease-Like Pathology via Remodeling Amyloid Protein Production and Clearance Pathway in Wistar Rats.
Tripathi P, Shah J
Neurochem Res · 2026 Mar · PMID 41910814 · Publisher ↗
Alzheimer's disease widely affects millions of people worldwide, accounting for 60% of dementia cases. Clinically classified by the presence of cognition impairment, pathophysiological representation includes deposited s...
Alzheimer's disease widely affects millions of people worldwide, accounting for 60% of dementia cases. Clinically classified by the presence of cognition impairment, pathophysiological representation includes deposited senile plaques, neurofibrillary tangles, and neuroinflammation. The pathogenesis of Alzheimer's disease (AD) remains multifaceted and is governed by multiple hypotheses. However, it undeniably involves amyloid-β (Aβ) accumulation and hyperphosphorylated tau (p-tau) pathology as the crucial events in disease initiation. Substantial evidence has correlated Vitamin D as a vital supplementation for the prevention of dementia and delays the progression of AD. The presence of localized Vitamin D receptors (VDR) in the brain and their capacity to convert absorbed Vitamin D to its active form have established a robust link between Vitamin D and Alzheimer's disease. The current study aims to explore the role of Vitamin D on specific parameters related to Alzheimer's disease in the Streptozotocin ICV-induced sporadic AD rat model. The study protocol included a single bilateral ICV STZ intrahippocampal injection to induce AD, followed by 21 days of treatment with two different doses of Vitamin D or Calcitriol (1alpha,25-dihydroxyvitamin D)i.e., 2.5 μg/kg and 5.0 μg/kg. Results demonstrated that Vitamin D attenuates AD-specific parameters of amyloid plaque (Aβ and Aβ), p-tau, and BACE-1. Moreover, a significant increase in the levels of both neprilysin (NEP) and insulin-degrading enzyme (IDE) was observed, both of which play a crucial role in the clearance of senile plaques. Vitamin D treatment also demonstrated a significant improvement in cognitive performance, along with attenuation of neuroinflammatory and oxidative stress parameters. Conclusively, optimal levels of Vitamin D impart neuroprotection in AD by attenuating production and increasing clearance of amyloid proteins.
Considerations for Carnosine Actions in Biology.
Parmeggiani B, Ferreira BK, Schuck PF … +1 more , Ferreira GC
Neurochem Res · 2026 Mar · PMID 41894036 · Full text
Carnosine is a histidinic dipeptide mainly identified for its pH buffering, antioxidant and metal chelating capacities. Several studies have explored the potential benefits of carnosine as a supplement for exercise, as w...
Carnosine is a histidinic dipeptide mainly identified for its pH buffering, antioxidant and metal chelating capacities. Several studies have explored the potential benefits of carnosine as a supplement for exercise, as well as an adjuvant treatment in several pathologies; however, roles and impacts of carnosine on most tissues, including the brain, are still under debate, especially in earlier stages of development. There is evidence that carnosine may impact a myriad of physiological parameters. It includes potential roles of carnosine as a modulator of cell survival, redox homeostasis, signaling and metabolism, among other functions. Many variables seem to impact the outcomes of carnosine actions (e.g., carnosine concentrations, length of exposure, target cell/tissue, biological sex, metabolic state, and developmental stage). Considering that the physiology and metabolism of histidine dipeptides change throughout life, impacts of carnosine during development should be carefully considered. This is particularly relevant in light of carnosinemia, an inherited disorder of carnosine catabolism characterized by the accumulation of carnosine and presenting neuropsychomotor dysfunction. Thus, rethinking the applications of carnosine is crucial for realization of the full potential of this promising molecule.
Urocanic Acid Alleviates Cognitive Impairment by Targeting ZCCHC3 and Suppressing the cGAS-STING-Mediated Senescence.
Hu S, Kou Z, Chen B … +2 more , Yang Y, You Y
Neurochem Res · 2026 Mar · PMID 41885959 · Publisher ↗
This study aimed to investigate the role of urocanic acid (UCA) modulates cognitive impairment in a D-galactose (DG)-induced aging model, providing new insights and a theoretical foundation for the treatment of related d...
This study aimed to investigate the role of urocanic acid (UCA) modulates cognitive impairment in a D-galactose (DG)-induced aging model, providing new insights and a theoretical foundation for the treatment of related diseases. Mouse senescence and astrocyte model was created by DG-induced stimuli to assess the effects of UCA. Molecular docking was utilized to confirm potential targets of UCA, and the interaction was validated using the Drug Affinity Responsive Target Stability assay combined with Western blot analysis. The molecular mechanism of UCA was elucidated through in vivo and in vitro experiments. The result showed that UCA treatment ameliorated learning and memory capabilities in DG-induced mice, maintains astrocyte morphology while reducing apoptosis and senescent cells, and inflammatory factors. Additionally, UCA treatment alleviated cell cycle arrest. Molecular docking revealed direct binding between UCA and the ZCCHC3 protein. ZCCHC3 overexpression exacerbated cellular senescence, increased apoptosis and senescent cells, and inflammatory factor levels, while simultaneously activating the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway. UCA treatment reversed the effects of ZCCHC3 overexpression. Mechanistically, UCA inhibited the cGAS/STING pathway by binding to ZCCHC3, thereby alleviating cellular senescence. In vivo experiments further confirmed that ZCCHC3 overexpression or exogenous cGAS activation negated the cognitive protective effects of UCA. The study demonstrates that UCA alleviates cognitive impairment and astrocyte senescence by directly binding to ZCCHC3 to suppress the cGAS‑STING pathway. These results identify ZCCHC3 as a novel therapeutic target and clarify the molecular basis of related disorders.raci.
YY1 Transcriptionally Activates USP19 to Mediate TRAF6 Deubiquitination to Promote Microglial Inflammation and M1 Polarization in Depression Development.
Zhang Z, Cao L, Wang Y … +2 more , Yao P, Zhou L
Neurochem Res · 2026 Mar · PMID 41882442 · Publisher ↗
The pathophysiology of depression is associated with inflammation. This study aims to investigate the mechanism by which Yin Yang 1 (YY1) participates in microglial inflammatory activation and M1 polarization in depressi...
The pathophysiology of depression is associated with inflammation. This study aims to investigate the mechanism by which Yin Yang 1 (YY1) participates in microglial inflammatory activation and M1 polarization in depression. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to quantify Tumor Necrosis Factor Receptor-Associated Factor 6 (TRAF6) mRNA in serum from depressed patients and healthy controls. A chronic unpredictable mild stress (CUMS) depression mouse model was established, and proteins were detected by Western blot (WB). Receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic value of TRAF6 for depression. Depressive-like behaviors were assessed by behavioral tests. Inflammatory factors were detected via Enzyme-linked immunosorbent assay (ELISA), M1 polarization markers were analyzed via flow cytometry, and WB, respectively. CHX stability and WB-based ubiquitination assays were used to examine the regulatory effect of Ubiquitin-Specific Protease 19 (USP19) on TRAF6 ubiquitination. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were conducted to verify the transcriptional activation effect of YY1 on USP19. TRAF6 was highly expressed in patient serum and mouse hippocampi, with potential diagnostic value for depression. Silencing TRAF6 improved depressive-like behaviors and reduced inflammation. USP19 was highly expressed in mouse hippocampi, and stabilized TRAF6 via deubiquitination. TRAF6 overexpression reversed inflammation and M1 polarization inhibition from USP19 silencing. YY1 was also highly expressed in mouse hippocampi and activated USP19 transcription. USP19 overexpression reversed the inhibition from YY1 silencing. YY1 activates USP19 to promote TRAF6 deubiquitination and its stabilization, thereby enhancing microglial inflammation and M1 polarization that exacerbates depression progression. This axis may provide a novel direction for depression diagnosis and treatment.
The Diminished Availability of 2-AG in Aged Synaptic Terminals is Ameliorated by a Full-Spectrum Cannabis Extract with a High THC Content.
Salas SR, Pascual AC, Musso FA … +3 more , Milano PG, Murray AP, Pasquaré SJ
Neurochem Res · 2026 Mar · PMID 41880097 · Publisher ↗
We have previously demonstrated that the endocannabinoid system is dysregulated in the synaptic terminals of the cerebral cortex in aged rats. Specifically, the availability of the neuroprotective endocannabinoid 2-arach...
We have previously demonstrated that the endocannabinoid system is dysregulated in the synaptic terminals of the cerebral cortex in aged rats. Specifically, the availability of the neuroprotective endocannabinoid 2-arachidonoylglycerol (2-AG) is reduced due to impairments in the enzymes involved in its metabolism, a deficit only partially compensated by the binding of cannabinoid receptor ligands. Given that ∆9-tetrahydrocannabinol (THC) acts as a ligand for cannabinoid receptors (CBR), we designed the present study to investigate the effects of a full-spectrum cannabis extract with a high THC content, the THC-free fraction of this cannabis extract, and pure THC on the previously mentioned aging model. Thus, 2-AG metabolic enzymes were assayed incubating synaptosomes from aged and adult rat cerebral cortex, with ethanolic cannabis extract, the THC-free fraction of this cannabis extract or pure THC, and the corresponding radiolabeled substrates. Our key findings indicate that the age-related decline in 2-AG bioavailability: (a) is exacerbated in the presence of either the THC-free fraction from the cannabis extract or pure THC, primarily due to a significant decrease in 2-AG synthesis; and (b) is partially mitigated by the inhibition of 2-AG hydrolysis when the extract contains THC. These results provide compelling evidence for the regulation of 2-AG metabolism by a full-spectrum cannabis extract with high THC content, supporting the theory of the entourage effect among cannabis phytochemicals. This highlights the potential of high THC content extracts as therapeutic agents for restoring the decreased 2-AG levels observed in the aging brain.
STING Mediates Microglial Polarization to Promote Neuroinflammation in Epilepsy-Related Cognitive Dysfunction.
Yang H, Wang W, Liu X … +5 more , Shi M, Wang H, Wu X, Liu Y, Yu Y
Neurochem Res · 2026 Mar · PMID 41880095 · Publisher ↗
Epilepsy is a chronic neurological disorder characterized by recurrent seizures and frequently accompanied by cognitive deficits for which effective treatments are lacking. Neuroinflammation, particularly microglia-media...
Epilepsy is a chronic neurological disorder characterized by recurrent seizures and frequently accompanied by cognitive deficits for which effective treatments are lacking. Neuroinflammation, particularly microglia-mediated immune responses, is pivotal in epileptogenesis. Although the stimulator of interferon genes (STING) pathway is a key cytosolic DNA-sensing mechanism driving innate immunity, its specific role in epilepsy-related cognitive dysfunction remains unclear. This study investigated the function of the STING pathway in epilepsy pathology and its therapeutic potential. Adult male Sprague-Dawley rats (250-300 g) were subjected to lithium chloride-pilocarpine-induced status epilepticus (SE). The study consisted of two parts. In the first part, the temporal expression of hippocampal STING was examined at 1, 3, 7, 14, and 30 days after SE. In the second part, rats were randomly divided into control (Con+Vehicle), epilepsy (EP+Vehicle), and C-176-treated (EP + C-176) groups. Vehicle (1000 µL) or C-176 (2 mg/rat in 1000 µL) was administered intraperitoneally once daily from 1 day before SE to 6 days after SE. Seizure severity was assessed using the Racine scale. Hippocampal tissues were collected on day 7 after SE for analysis, and cognitive function was evaluated by the Morris water maze test on days 30-35 after SE. The results showed that hippocampal STING expression peaked on day 7 after SE compared with the control group, accompanied by cytosolic double-stranded DNA (dsDNA) accumulation and a shift of microglia toward a pro-inflammatory M1 phenotype. C-176 treatment significantly inhibited STING expression, reduced p-TBK1 and p-NF-κB p65 levels, reversed M1 microglial polarization with decreased iNOS and increased Arg-1 expression, decreased levels of pro-inflammatory cytokines (including IL-6, cleaved IL-1β, and TNF-α), attenuated neuronal damage, and improved learning and memory in SE rats. Our findings suggest that status epilepticus induces neuronal injury and dsDNA release, activating the STING pathway in microglia and driving neuroinflammation via the TBK1/NF-κB axis, leading to cognitive dysfunction. Inhibiting STING alleviates these effects by promoting microglial phenotypic switching from M1 to M2 via regulation of the TBK1/NF-κB pathway. This study identifies STING as a critical regulator of neuroinflammation and a novel therapeutic target for epilepsy-related cognitive dysfunction.
The Neuroameliorative Effects of Enzymatically Modified Isoquercitrin and Sodium R-lipoate on the Rotenone rat Model of Parkinson's Disease.
Hassouna I, Hassanein OH, El-Elaimy IA … +1 more , Ibrahim HM
Neurochem Res · 2026 Mar · PMID 41880086 · Full text
Parkinson's disease (PD) is a neurodegenerative condition distinguished by both motor and non-motor signs. Currently, therapeutic interventions effectively mitigate motor symptoms; however, they fail to impede the progre...
Parkinson's disease (PD) is a neurodegenerative condition distinguished by both motor and non-motor signs. Currently, therapeutic interventions effectively mitigate motor symptoms; however, they fail to impede the progression of neurodegeneration. Enzymatically modified isoquercitrin (EMIQ) is a variant of isoquercitrin with enhanced bioavailability and potentially greater health benefits. Sodium R-Lipoate (NaRLA) is a modified form of lipoic acid with improved stability and efficacy. The current work assessed EMIQ and NaRLA neuroameliorative properties in a rotenone (ROT) model of PD in rats. The study employed open field and hanging tests to evaluate motor effects, and used dopamine (DA) estimation and tyrosine hydroxylase (TH) immunoreactivity to confirm motor abnormalities and neurodegeneration. Furthermore, neuroinflammation was evaluated through ELISA of proinflammatory cytokines (IL-1β, IL-6), expression of Toll-like receptor 4 (TLR4) via qRT-PCR, and immunoreactivity of ionized calcium-binding adaptor molecule 1 (IBA1). The findings indicated that the use of EMIQ and NaRLA with ROT reduced the neuroinflammation via decreasing: the expression level of TLR4, IL-1β and IL-6 levels, and the number of IBA1 microglial cells. Moreover, EMIQ and NaRLA ameliorated motor impairments induced with ROT through the enhancement of rats' behavior, increasing DA concentration and TH immunoreactivity in the striatum. In the light of the findings of the current investigation, EMIQ and NaRLA exerted neuroameliorative effects against the ROT-induced PD model. These results provide support for the potential impact of EMIQ and NaRLA in the treatment of PD and other diseases related to mitochondrial dysfunction and neuroinflammation.
Astrocytic Neurovascular Signalling Dysfunction in Glaucoma: Neurochemical Mechanisms and Translational Implications.
Prabhu AV, Pradeep R, Bhandary A
Neurochem Res · 2026 Mar · PMID 41880038 · Publisher ↗
Glaucoma is increasingly conceptualized as a chronic neurodegenerative disorder in which retinal ganglion cell loss cannot be fully attributed to intraocular pressure dependent mechanisms alone. Mounting evidence implica...
Glaucoma is increasingly conceptualized as a chronic neurodegenerative disorder in which retinal ganglion cell loss cannot be fully attributed to intraocular pressure dependent mechanisms alone. Mounting evidence implicates dysfunction of the neurovascular unit, with astrocytes playing a central role through their neurochemical regulation of vascular tone, metabolic coupling, and redox homeostasis. Under physiological conditions, astrocytes mediate neurovascular coupling via calcium dependent signalling and controlled release of vasoactive and metabolic mediators, ensuring alignment between neuronal energy demand and local perfusion. In glaucoma, mechanical strain, ischemia, and oxidative stress induce reactive astrogliosis, leading to altered calcium dynamics, impaired nitric oxide signalling, and enhanced endothelin-driven vasoconstriction. These changes promote neurovascular uncoupling, chronic hypo perfusion, and sustained metabolic stress within the optic nerve head, even in the presence of controlled intraocular pressure. In parallel, inflammation-associated downregulation of connexin-43 disrupts astrocytic syncytial networks, impairing glutamate clearance, potassium buffering, and metabolic substrate redistribution, thereby amplifying excitotoxic and oxidative injury. Emerging transcriptomic data further demonstrate astrocyte heterogeneity, with distinct neurochemical phenotypes exerting either protective or neurotoxic effects. Collectively, these findings position astrocytic neurochemical dysfunction as a key driver of glaucomatous neurodegeneration and identify glial signalling pathways as rational targets for disease-modifying intervention.
Blockade of Presynaptic αδ Subunits of Voltage-Gated Ca²⁺ Channels Attenuates Neurobiochemical and Sensorimotor Deficits After Traumatic Brain Injury in Mice.
Justus JS, Rodolphi MS, Kopczynski A … +12 more , Strogulski NR, Herasinczuk GCS, Valdameri B, Limberger C, Geller CA, Vinadé LH, Dal-Belo C, Nedel WL, Portela LOC, de Oliveira VG, Smith DH, Portela LV
Neurochem Res · 2026 Mar · PMID 41880029 · Full text
Traumatic brain injury (TBI) to the motor cortex disrupts corticospinal tracts and induces persistent sensorimotor impairments, largely driven by secondary neurobiochemical cascades. Excessive synaptic glutamate release,...
Traumatic brain injury (TBI) to the motor cortex disrupts corticospinal tracts and induces persistent sensorimotor impairments, largely driven by secondary neurobiochemical cascades. Excessive synaptic glutamate release, mitochondrial Ca²⁺ overload, and progressive neurodegeneration critically shape these outcomes, with preclinical and clinical data revealing neuronal loss and proteinopathy resembling motor neuron disorders. Here, we investigated whether pregabalin blockade of the presynaptic α2δ1-2 subunit of voltage-gated Ca²⁺ channels could mitigate excitotoxicity and promote sensorimotor recovery after TBI. Mice subjected to controlled cortical impact (CCI) received daily pregabalin (i.p., 60 mg.kg-1) or saline for 10 days, and neurobehavioral performance was assessed at 24 h, 11-, and 12-days post-injury. In addition to robust and persistent deficits detected by the modified neurological severity score (mNSS), complementary tests including open field, grip strength, cylinder, wire-hanging, and inverted screen, captured sensitive impairments in corticospinal integrity and global motor function. Pregabalin treatment downregulated α2δ2 subunit expression, reduced cerebrospinal fluid glutamate levels, and restored mitochondrial Ca²⁺ handling by improving influx–efflux dynamics through Na⁺/Ca²⁺ exchange. At the molecular level, pregabalin decreased hallmarks of neurodegeneration, including Cyclin dependent kinase 5, TauSer396 hyperphosphorylation, caspase-12, and caspase-3 within synaptic terminals. These neuroprotective effects translated into significant improvements in both mNSS and multidimensional sensorimotor outcomes following TBI. Together, our findings confirm the neurodegenerative trajectory underlying TBI-induced neuromotor deficits and highlight the presynaptic α2δ1–2 subunit antagonism as a promising therapeutic target to mitigate long-term neurological sequelae.
Cofilin-1 Exacerbates Tau-Induced Mitochondrial Damage, Oxidative Stress, and Apoptosis in Alzheimer's Disease.
Chen Y, Zhang D, Zhang Q … +7 more , Li Q, Yan D, Qin H, Xiong Y, Zhang C, Wan Y, Yan M
Neurochem Res · 2026 Mar · PMID 41879865 · Publisher ↗
Alzheimer’s disease (AD) is characterized by the accumulation of neurofibrillary tangles (NFTs) composed of misfolded tau and by early mitochondrial dysfunction. Although tau aggregation has been closely linked to mitoch...
Alzheimer’s disease (AD) is characterized by the accumulation of neurofibrillary tangles (NFTs) composed of misfolded tau and by early mitochondrial dysfunction. Although tau aggregation has been closely linked to mitochondrial impairment and neuronal toxicity, the molecular factors that amplify tau-induced mitochondrial damage remain incompletely understood. Previous studies have shown that cofilin-1, an actin-binding protein, facilitates tau aggregation and propagation under pathological conditions. In the present study, using tauopathy-based cellular models, we investigated whether cofilin-1 modulates tau-induced mitochondrial dysfunction. We found that tau aggregates and cofilin-1 exhibit spatial proximity to mitochondria as assessed by fluorescence microscopy, and that the presence of cofilin-1 markedly exacerbates tau-induced mitochondrial structural abnormalities, impaired fusion dynamics, oxidative stress, and activation of intrinsic apoptotic signaling. Importantly, these effects were consistently more pronounced in cells treated with tau/cofilin-1 composite fibrils compared with tau fibrils alone. Together, our findings indicate that cofilin-1 functions as a critical amplifier of tau-mediated mitochondrial toxicity under pathological conditions. Rather than demonstrating a direct physical interaction, this study supports a model in which cofilin-1 synergistically enhances tau-induced mitochondrial dysfunction, oxidative stress, and cell death, thereby contributing to tau-driven neurodegenerative processes relevant to AD.
Tamoxifen as a Therapeutic Intervention for Neurobehavioral Deficits in a Propionic Acid-Induced Autism Model via Anti-inflammatory Mechanisms.
Erdoğan MA, Koyu A, Oyar EÖ … +4 more , Güneş B, Şirin C, Uyanıkgil Y, Erbaş O
Neurochem Res · 2026 Mar · PMID 41872571 · Publisher ↗
This study aims to evaluate the neuroprotective and anti-inflammatory effects of tamoxifen in mitigating neurobehavioral deficits induced by propionic acid (PPA), an autism model in rats. Specifically, the study examines...
This study aims to evaluate the neuroprotective and anti-inflammatory effects of tamoxifen in mitigating neurobehavioral deficits induced by propionic acid (PPA), an autism model in rats. Specifically, the study examines tamoxifen’s impact on sociability, locomotion, neuron integrity, and inflammation within the hippocampus and cerebellum. Thirty male Wistar rats were assigned to three groups: control, PPA+saline, and PPA+tamoxifen. PPA was administered intraperitoneally to induce autism-like symptoms, followed by tamoxifen treatment in the designated group. Sociability was assessed using the three-chamber sociability test, and locomotion was measured with the open-field test. Histopathological assessments, including GFAP immunostaining and cresyl violet staining, were conducted to examine astrocyte activity and neuronal integrity in brain sections. Additionally, biochemical analyses were performed to measure oxidative stress markers and inflammatory cytokines. Tamoxifen significantly improved sociability and locomotor function compared to the PPA+saline group. Histopathological evaluation revealed tamoxifen’s potential in preserving neuronal structure, indicated by increased Purkinje cell counts and reduced glial activation. Biochemical analyses demonstrated that tamoxifen reduced oxidative stress markers such as malondialdehyde (MDA) and inflammatory cytokines, including TNF-α and iNOS, while increasing levels of brain-derived neurotrophic factor (BDNF). These findings suggest that tamoxifen may offer neuroprotective and anti-inflammatory benefits in addressing neurobehavioral and neuroinflammatory deficits associated with autism models induced by PPA. However, further studies are necessary to investigate potential gender-specific effects and optimize dosing strategies for broader therapeutic applications.
Ibogalogs Activate the 5-HT Receptor through a Mechanism Involving Outward and Inward Movements of the Respective Transmembrane Segment TM6 and TM7.
Rudin D, Ren X, Liechti ME … +2 more , Huang N, Arias HR
Neurochem Res · 2026 Mar · PMID 41870698 · Publisher ↗
The objective of this study is to determine the binding and functional activity of a variety of ibogalogs and their pyridoindole homologs at the serotonin subtype 2 A receptor (5-HTR) and compare the molecular mechanisms...
The objective of this study is to determine the binding and functional activity of a variety of ibogalogs and their pyridoindole homologs at the serotonin subtype 2 A receptor (5-HTR) and compare the molecular mechanisms with that at the 5-HTR. The binding results showed that ibogalos and their pyridoindole homologs (2MePI, 8MeO-2MePI) have affinities in the nM concentration range. In contrast, ibogalogs and PNU-22,394, but not catharanthalog (CAG) or pyridoindole homologs, activated the 5-HTR with relatively high potency and high efficacy. Subsequently, we determined the inhibitory activity of the least potent partial agonists, CAG and pyridoindole homologs, via functional competition experiments. Functionally, 2MePI and 8MeO-2MePI, but not CAG, behaved as relatively more potent competitive antagonists than agonists. To assess the mechanistic differences between agonists (ibogalogs) and antagonits (pyridoindole homologs) at the 5-HTR as well as the differences with the 5-HTR, molecular docking and molecular dynamics simulations were performed. The results showed that ibogalogs induce coordinated conformational changes across multiple microswitch networks in the 5-HTR, stabilizing the active state characterized by an outward movement of TM6 and inward movement of TM7. In the 5-HTR, most ibogalogs (except DM506 and PNU-22394) behave as competitive antagonists by promoting the ionic lock, characterized by a reduced distance between TM3 and TM6.
Senescence as a Central Node in Alzheimer's Disease: Molecular Triggers, Cellular Effectors, and RNA-Based Interventions.
Some A, Naskar N, Thomas DM … +2 more , Jeengar MK, Nassar A
Neurochem Res · 2026 Mar · PMID 41870677 · Publisher ↗
Alzheimer's disease (AD) is the most frequent neurodegenerative disorder. It is characterized by the buildup of amyloid-β (Aβ) plaques, as well as of tangles made out of tau that increasingly damage and kill neurons whil...
Alzheimer's disease (AD) is the most frequent neurodegenerative disorder. It is characterized by the buildup of amyloid-β (Aβ) plaques, as well as of tangles made out of tau that increasingly damage and kill neurons while also impairing memory and thinking. Recent findings indicate that cellular senescence is implicated in the pathogenesis of AD. Senescence occurs when cells irreversibly stop dividing under stress. In the brain, it can be induced by chronic activation of astrocytes and microglia, Aβ toxicity, tau hyperphosphorylation and oxidative stress. Senescent cells secrete proinflammatory factors, i.e., the senescence-associated secretory phenotype (SASP). These molecules promote inflammation, destroy mitochondria and interfere with synapses in ways that speed up the progress of the disease. Blocking those senescent cells may offer a new approach to treatment. Approaches including VEGFR-1 and SIRT5 interference, senolytics or senomorphs drugs, NLRP3 antagonist, PAI-1 inhibitors and small vessels inhibitors (including aspirin, curcumin derivatives and sildenafil) have been suggested to promisingly mitigate brain injury. RNA based therapy (miRNAs- and lncRNAs-targeted) and exosomal derived biomarkers are also an optimistic approach. A clearer understanding of how senescence is implicated in AD would have implications regarding the design and application of novel treatments aimed at delaying disease onset, slowing down progression or preserving brain function.
3-Methylcrotonyl-CoA Carboxylase Expression Among Astrocytes and Neurons in the Human Brain and the Effect of Hyperglycemia on the Catabolic Flux of C, N-Leucine in Cultured Astrocytes.
Murín R, Šofranko J, Kováč A … +2 more , Murínová M, Gondáš E
Neurochem Res · 2026 Mar · PMID 41854924 · Full text
Leucine is an essential amino acid which is imported into the brain parenchyma with high capacity. Animal studies have demonstrated that leucine plays a significant role in several cellular and physiological processes in...
Leucine is an essential amino acid which is imported into the brain parenchyma with high capacity. Animal studies have demonstrated that leucine plays a significant role in several cellular and physiological processes in brain parenchyma. In addition to its role in protein synthesis, leucine possesses signaling and regulatory functions. Furthermore, leucine catabolism may provide brain cells with amino nitrogen for the synthesis of glutamate and glutamine with an impact on sustaining glutamatergic and GABA-ergic neurotransmission. The entry of leucine's carbon skeleton into the intermediary metabolism of astrocytes yields the production of ketone bodies and acetyl-CoA. In order to investigate the metabolic capabilities of human astrocytes regarding leucine, we enriched their culture media with C₆,N-leucine and conducted a metabolomic study using liquid chromatography-mass spectrometry (LC-MS) to identify and quantify isotopically labelled metabolites. Furthermore, we employed an antiserum against 3-methylcrotonyl-CoA carboxylase (MCC), the unique enzyme in the irreversible phase of leucine catabolism, to identify MCC-expressing cells both in culture and in situ. Our results indicate that cultured human astrocytes efficiently removed leucine from the medium, which was then enriched with several compounds containing nitrogen and/or carbon atoms derived from leucine. Among the released metabolites, glutamine and citrate were the most abundant. Leucine uptake was independent of glucose concentration; however, hyperglycemic conditions stimulated the capacity for the irreversible catabolism of the leucine-derived carbon skeleton. Immunoprobing with the MCC antiserum confirmed the mitochondrial expression of MCC in astrocytes in culture as well as in situ. In addition to astrocytes, immunofluorescent double-labelling revealed the colocalization of MCC with a neuronal marker in human brain sections. This study confirms that human astrocytes are capable of catabolizing leucine and incorporating leucine-derived atoms into the intermediary metabolism. The presence of MCC in cultured astrocytes underscores their ability to convert leucine into acetyl-CoA and ketone bodies. Additionally, MCC expression in astrocytes and neurons present in brain parenchyma suggests that these cells are enzymatically equipped to catabolize leucine into compounds entering their cellular metabolism.
Nanomolar Cadmium Disrupts Neurotransmitter Release Timing via a ROS-dependent Mechanism at the Mouse Neuromuscular Junction: Modulation by Nanomolar Zn.
Khaziev AN, Tsentsevitsky AN, Kapliukhina EA … +1 more , Petrov AM
Neurochem Res · 2026 Mar · PMID 41854772 · Publisher ↗
Among heavy metals, cadmium (Cd) is the most widespread pollutant, exhibiting pronounced neurotoxicity and exacerbating neurodegenerative diseases. Even at nanomolar concentrations in plasma, Cd increases the risk of mul...
Among heavy metals, cadmium (Cd) is the most widespread pollutant, exhibiting pronounced neurotoxicity and exacerbating neurodegenerative diseases. Even at nanomolar concentrations in plasma, Cd increases the risk of multiple disorders. The mechanisms underlying the detrimental effects of nanomolar Cd on the nervous system are far from fully understood. Using microelectrode recordings and fluorescence approaches, we investigated the effects of low Cd concentrations on acetylcholine release and redox balance at the mouse neuromuscular junction. Similar to voltage-gated Ca channel blockers, Cd (≥ 100 nM) suppressed evoked neurotransmitter release, but at a concentration of 20 nM Cd selectively desynchronized exocytotic events. The latter effect was completely prevented by general (N-acetyl-L-cysteine) and mitochondrial (mitoTEMPO) antioxidants, but not by a TRPV1 antagonist. Cd (20 nM) markedly increased reactive oxygen species (ROS) production, which was accompanied by lipid peroxidation and was blocked by mitoTEMPO. An NADPH oxidase inhibitor, VAS 2870 had no effect on Cd-dependent elevation of ROS levels. Zn at nanomolar concentration completely prevented both the Cd-induced desynchronization of neurotransmitter release and the associated increase in ROS production. At the same time, nanomolar Zn itself did not affect either the timing of acetylcholine release or redox status. Thus, Cd at a nanomolar concentration disturbs the synchrony of evoked exocytotic events at the mouse neuromuscular synapse by enhancing mitochondrial ROS production. Zn might be considered as an effective modulator of the synaptotoxicity of low-level Cd exposure.
Sphingosine-1-Phosphate Receptor 3 Mediated Neuroinflammation is Critically Involved in the Development of Brain Injury Following Cardiac Arrest in Mice.
Wang X, Cai SQ, Gao Y … +5 more , Fan JJ, Ren LW, Gao HC, Chen XD, Duan ML
Neurochem Res · 2026 Mar · PMID 41851363 · Publisher ↗
Brain injury after cardiac arrest (CA) is a major cause of death and disability, with neuroinflammation increasingly recognized as a key driver. Although the sphingosine-1-phosphate receptor 3 (S1PR3)-a G protein-coupled...
Brain injury after cardiac arrest (CA) is a major cause of death and disability, with neuroinflammation increasingly recognized as a key driver. Although the sphingosine-1-phosphate receptor 3 (S1PR3)-a G protein-coupled receptor-has been linked to neurological disorders, its role in CA-induced brain injury remains unclear. We induced CA in mice via intravenous potassium chloride injection. S1PR3 expression and subcellular localization were assessed in cortex and hippocampus. Mice received intraperitoneal CAY10444 (a selective S1PR3 antagonist) alone or with Colivelin TFA (a Janus Kinase 2 (JAK2)/Signal Transducer and Activator of Transcription 3 (STAT3) agonist). Survival after return of spontaneous circulation (ROSC) was recorded. Neurological function was evaluated using neurological deficit score, rotarod, adhesive removal, and novel object recognition tests. Brain pathology was examined by H&E, Nissl, immunohistochemistry, and Golgi staining. Microglial and astrocyte activation were quantified by immunohistochemistry; IL-1β, TNF-α, and IL-6 mRNA levels were measured; and JAK2/STAT3 pathway activity was assessed by Western blot for p-JAK2 and p-STAT3. CA/CPR upregulated S1PR3 in the brain and increased its co-localization with neurons and glia. CAY10444 improved survival and all behavioral outcomes. It reduced neuronal loss, axonal damage, dendritic spine loss, and suppressed microglial and astrocytic activation in the hippocampus. CAY10444 also lowered IL-1β, TNF-α, and IL-6 expression and decreased CA-induced JAK2/STAT3 phosphorylation. Colivelin TFA partially reversed these benefits. CAY10444 confers neuroprotection after CA/CPR by inhibiting S1PR3 and downstream JAK2/STAT3 signaling, thereby dampening neuroinflammation and neuronal death. S1PR3 is therefore a promising therapeutic target for CA-induced brain injury.
GPR40 Attenuates Glioma TMZ-Resistance Through Ferroptosis Inhibition.
Yang J, Zou Y, Xu S … +6 more , Mu Z, Wu S, Xu X, Miao Z, Zhao X, Zhou Y
Neurochem Res · 2026 Mar · PMID 41838210 · Publisher ↗
Glioblastoma (GBM), a highly aggressive primary brain tumor, presents substantial treatment challenges due to its resistance to genotoxic therapies and frequent recurrence. Oncogenic alterations significantly impact lipi...
Glioblastoma (GBM), a highly aggressive primary brain tumor, presents substantial treatment challenges due to its resistance to genotoxic therapies and frequent recurrence. Oncogenic alterations significantly impact lipid metabolism in GBM cells. G Protein-Coupled Receptor 40 (GPR40), a receptor for polyunsaturated fatty acids (PUFAs), plays a key role in neural development and neurogenesis. Additionally, ferroptosis induction in GBM relies on PUFA peroxidation within cell membranes. Considering the persistent oxidative stress in the central nervous system, aberrant GPR40 activation in glioma lipid metabolism might suppress ferroptosis, thus contributing to chemotherapy resistance. Transcriptomic analysis of TCGA data revealed upregulated GPR40 expression in malignant gliomas, alongside alterations in ferroptosis-related and drug resistance pathways. To model GBM temozolomide (TMZ) resistance, a TMZ-resistant GL261 cell line was established. Additionally, key ferroptosis markers, including iron metabolism, lipid peroxidation, and glutathione levels, as well as TMZ treatment sensitivity, were assessed. Our findings confirm that GPR40 reduces glioma sensitivity to TMZ chemotherapy by inhibiting ferroptosis. These results highlight the GPR40-ferroptosis regulatory axis as a potential therapeutic target to enhance ferroptosis-induced treatment and overcome TMZ chemotherapy resistance in GBM.
Morin Improves Cognitive Deficits in an in Vivo Model of Vascular Dementia by Modulating the N-methyl-D-aspartate Receptor Signaling Pathways.
Gu C, Bostani A, Wang H
Neurochem Res · 2026 Mar · PMID 41838188 · Full text
The research on the pathoetiology of vascular dementia (VaD) highlights a notable deficiency in effective therapies within present medical practices. Morin exhibits promising therapeutic benefits due to its strong antiox...
The research on the pathoetiology of vascular dementia (VaD) highlights a notable deficiency in effective therapies within present medical practices. Morin exhibits promising therapeutic benefits due to its strong antioxidant and anti-inflammatory properties. However, its specific functions and mechanisms in VaD require further elucidation. In this study, VaD animals were established by permanent bilateral common carotid artery occlusion (2VO). Cognitive functions and behavioral analysis were performed in rats. Moreover, the state of oxidative stress, inflammation, and apoptosis was evaluated. Western blotting and ELISA were performed to investigate synaptic plasticity-related proteins, such as SYP, PSD-95, and NMDA receptor proteins (NR1, NR2A, NR2B). The results revealed that morin reduced oxidative stress in the hippocampus by lowering MDA and recombinant reactive oxygen species modulator 1 (Romo-1) levels, while simultaneously enhancing the activities of SOD and GPx. In addition, morin increased the levels of anti-inflammatory cytokines (IL-10 and IL-4), while reducing the levels of pro-inflammatory cytokines (IL-1β and IL-6), and suppressed apoptosis through downregulation of caspase 3 and upregulation of BCL-2. Additionally, morin promoted the expression of PSD95, SYP, and NMDAR proteins in animals with VaD. The obtained data suggest that morin is associated with improved cognitive impairments in VaD rats, which may be mediated by the reduction of apoptosis, oxidative stress, and inflammation in the hippocampus, as well as by restoring the signaling of NMDARs.
Glutamatergic Neurotransmission Disruption as a Pathomechanism of Brain Damage in Disorders of Amino Acid and Organic Acid Metabolism: Insights from Animal and Cellular Studies.
Marcuzzo MB, Benati MPDV, Souza DO … +2 more , Wajner M, Leipnitz G
Neurochem Res · 2026 Mar · PMID 41831085 · Full text
Inborn errors of metabolism (IEMs) are inherited disorders biochemically characterized by the accumulation of potentially toxic metabolites in tissues and body fluids of the affected patients. Although clinical findings...
Inborn errors of metabolism (IEMs) are inherited disorders biochemically characterized by the accumulation of potentially toxic metabolites in tissues and body fluids of the affected patients. Although clinical findings are heterogeneous, neurological symptoms, including coma and seizures associated with brain abnormalities, are very frequent. The mechanisms of neurotoxicity of the accumulated metabolites and their effects on cellular functions are still poorly established in many of these disorders. However, animal and cellular studies have shown that disturbances in glutamatergic neurotransmission, potentially leading to excitotoxicity, may represent a relevant mechanism of brain damage in some of these disorders. In agreement with this, treatments for some IEMs aim to mitigate overstimulation of N-methyl-D-aspartate (NMDA) receptors by NMDA receptor antagonists and to reduce the levels of the accumulated metabolites that activate these receptors. This review will focus on pre-clinical data showing disturbed glutamatergic neurotransmission in cells and animal models of IEMs that may offer perspectives for the development of novel adjuvant treatments for these diseases.
Effects of tDCS on Cognitive Function in MCAO/R Rats by Regulating Mitochondrial Autophagy Mediated by the PINK1/Parkin Signaling Pathway.
Shang M, Yu Y, Wen T … +6 more , Xu B, Rao G, Xie C, Wei X, Tang L, Wen Y
Neurochem Res · 2026 Mar · PMID 41824147 · Publisher ↗
Cognitive dysfunction is a common and disabling consequence of stroke. Transcranial direct current stimulation (tDCS), a non-invasive neuromodulation technique, has shown promise in rehabilitation; however, its molecular...
Cognitive dysfunction is a common and disabling consequence of stroke. Transcranial direct current stimulation (tDCS), a non-invasive neuromodulation technique, has shown promise in rehabilitation; however, its molecular mechanisms remain unclear, and the lack of standardized stimulation parameters limits its clinical application. This study aimed to investigate the effects of tDCS with different intensities on cognitive function in rats subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) and to elucidate the underlying mechanisms. A male Sprague-Dawley rat MCAO/R model was established, and animals were treated with varying intensities of anodal tDCS (a-tDCS). Cognitive function was assessed using the Morris water maze and a novel object recognition test, while neurological deficits were evaluated through neurological scoring and 2,3,5-triphenyltetrazolium chloride staining. Mitochondrial autophagy was examined by transmission electron microscopy, and the expression of PINK1/Parkin-mediated autophagy pathway proteins was analyzed by Western blot and immunohistochemistry. The results showed that 0.2 mA medium-intensity a-tDCS produced the most significant therapeutic effect, alleviating mitochondrial damage, reducing excessive mitochondrial accumulation, and attenuating neuronal apoptosis. Mechanistically, these effects were associated with activation of the PINK1/Parkin pathway, ultimately leading to improved learning and memory function. Mechanistically, these effects were associated with PINK1/Parkin pathway activation, and were attenuated when PINK1 was knocked down. Medium-intensity a-tDCS exerts neuroprotective effects in MCAO/R rats by enhancing mitophagy through the PINK1/Parkin signaling pathway, which providing a potential experimental basis for optimizing clinical rehabilitation strategies.
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