Neurochem. Int. [JOURNAL]
Sun
200 papers
Allopregnanolone reduces the blocking properties of competitive antagonists of GABA(A) receptor.
Kondratenko RV, Bukanova JV, Solntseva EI
Neurochem Int · 2026 Jul · PMID 42398655 · Publisher ↗
The orthosteric site of the GABA receptor binds both the agonist (GABA) and the competitive antagonists bicuculline (Bic) and gabazine (GBZ). The endogenous neurosteroid allopregnanolone (Allo) is known to alter the conf...
The orthosteric site of the GABA receptor binds both the agonist (GABA) and the competitive antagonists bicuculline (Bic) and gabazine (GBZ). The endogenous neurosteroid allopregnanolone (Allo) is known to alter the conformation of the orthosteric site of the GABA receptor, increasing its affinity for GABA. The aim of this study was to investigate the effect of Allo on the blocking properties of Bic and GBZ. Experiments were conducted on isolated rat cerebellar Purkinje cells, in which the GABA-induced chloride current (I) was recorded using the patch-clamp method. The effect of Allo on the blocking properties of Bic and GBZ was studied using two approaches. First, we used functionally equivalent GABA concentrations to induce I in the absence or presence of 1 μM Allo and measured the magnitude of the I block induced by 0.5 μM GBZ or 5 μM Bic. It was shown that, in the presence of Allo, blocking effect was reduced for GBZ from 63 to 31 % (p < 0.05), and for Bic from 87 to 56 % (p < 0.001). The second approach was to study the behavior of dose-effect curve for antagonist (GBZ or Bic) in the presence of Allo. Allo caused the right shift of both dose-effect curves with the increase in the IC values from 0.22 to 0.60 μM for GBZ (p < 0.001), and from 1.1 to 2.4 μM for Bic (p < 0.05). Results suggest that Allo decreases the blocking properties of competitive antagonists Bic and GBZ of the GABA receptor.
Glial High-Mobility Group Box 1 Translocation Promotes Post-Stroke Epileptic Seizures.
Zhong C, Wang W, Li J … +10 more , Li Z, Fan X, Ying S, Yu Z, Cao J, Yang L, Wang Y, Chen Z, Wang Y, Fei F
Neurochem Int · 2026 Jul · PMID 42398654 · Publisher ↗
Post-stroke epilepsy (PSE) is a common type of epilepsy, often refractory to conventional pharmacological interventions. In the present study, we investigate the role of high mobility group box 1 (HMGB1) in PSE and evalu...
Post-stroke epilepsy (PSE) is a common type of epilepsy, often refractory to conventional pharmacological interventions. In the present study, we investigate the role of high mobility group box 1 (HMGB1) in PSE and evaluate therapeutic efficacy of the anti-HMGB1 monoclonal antibody therapy. We found that photothrombotic model of ischemic stroke enhanced seizure susceptibility, particularly in cases with extensive cortical lesions. Mechanistically, this vulnerability is driven by the nuclear-to-cytoplasmic translocation of HMGB1. Notably, the translocation rate in glial cells, rather than neurons, positively correlates with seizure severity. Treatment with an anti-HMGB1 monoclonal antibody not only markedly suppressed spontaneous seizures and pentylenetetrazol-induced susceptibility but also rescued cognitive deficits in PSE mice. These neuroprotective effects were mediated by the suppression of glial activation and the inhibition of HMGB1 translocation. Collectively, our findings identify glial HMGB1 translocation as a key driver of PSE and establish anti-HMGB1 therapy as a potent strategy for PSE intervention.
Mild Traumatic Brain Injury Produces Persistent Wake-State Instability and EEG Slowing Despite Carbon Monoxide Neuroprotection.
Broadhurst RY, Voltarelli VA, Weber J … +5 more , Gallo D, Meehan WP, Alves de Souza RW, Otterbein LE, Fuller PM
Neurochem Int · 2026 Jul · PMID 42386132 · Publisher ↗
Individuals who experience mild traumatic brain injury (mTBI) frequently report persistent sleep-wake disturbances that impair daytime function and recovery. However, the physiological nature of these disturbances remain...
Individuals who experience mild traumatic brain injury (mTBI) frequently report persistent sleep-wake disturbances that impair daytime function and recovery. However, the physiological nature of these disturbances remains incompletely understood. Using a closed-head lateral-impact model of single and repeated mTBI in mice, we examined the acute and chronic effects of injury on EEG activity and behavioral state organization. Although mTBI did not alter the total amount of time spent awake or asleep, both single and repeated injuries produced a marked and persistent fragmentation of wakefulness that remained evident for up to 12 weeks after injury. Spectral analysis further revealed increased low-theta (4-8 Hz) activity during wakefulness, consistent with reduced cortical activation and impaired arousal stability. Because low concentrations of carbon monoxide (CO) have been reported to exert neuroprotective effects in models of brain injury, we also examined whether inhaled CO could mitigate these abnormalities. While CO reduced acute injury-associated measures and glial stress marker expression, it did not rescue wake fragmentation or EEG spectral changes at the time points tested. Together, these findings identify persistent wake-state instability as a key consequence of mTBI and suggest that mechanisms governing the maintenance of consolidated wakefulness remain disrupted despite attenuation of acute injury-related pathology.
Tanshinone IIA alleviates cerebral ischemia-reperfusion injury by inhibiting pyroptosis: involvement of the KLF4/CHIP/NLRP3 pathway.
Zhong Z, Huang Z, Wu Z … +4 more , Nie X, Liang J, Wen J, Zhang X
Neurochem Int · 2026 Jul · PMID 42386131 · Publisher ↗
Cerebral ischemia/reperfusion injury (CI/RI) is a critical pathological process in ischemic stroke. Pyroptosis plays a central role in the development of CI/RI. NOD-like receptor protein 3 (NLRP3) inflammasome is a key i...
Cerebral ischemia/reperfusion injury (CI/RI) is a critical pathological process in ischemic stroke. Pyroptosis plays a central role in the development of CI/RI. NOD-like receptor protein 3 (NLRP3) inflammasome is a key initiator of pyroptosis and is associated with neuroinflammation. Although Tanshinone IIA (Tan-IIA) downregulates NLRP3 expression, its role in NLRP3-mediated neuronal pyroptosis during CI/RI remains unclear. In the current study, we aimed to evaluate the neuroprotective effects of Tan-IIA on CI/RI and elucidate the underlying molecular mechanisms. We used rat middle cerebral artery occlusion/reperfusion (MCAO/R) and PC12 cell oxygen-glucose deprivation/reoxygenation (OGD/R) models to investigate the underlying mechanisms. A range of methodologies were used, including neurological function scoring, western blotting, co-immunoprecipitation (Co-IP), dual-luciferase reporter assays, chromatin immunoprecipitation (ChIP), and cycloheximide (CHX) chase. Tan-IIA substantially improved neurological function, reduced cerebral infarction volume, and mitigated neuronal necrosis in MCAO/R rats. In PC12 cells, Tan-IIA showed a pronounced protective effect against OGD/R-induced damage in OGD/R. Mechanistically, in vitro evidence suggests that Tan-IIA upregulates Krüppel-like factor 4 (KLF4) expression. This, in turn, transcriptionally activates the Carboxy-terminus of Hsc70-interacting protein (CHIP). The increased CHIP expression appeared to promote ubiquitination and degradation of the NLRP3 protein, inhibiting the NLRP3 inflammasome activation, caspase-1 cleavage, and the maturation of Interleukin (IL)-1β and IL-18, suppressing neuronal pyroptosis. Our findings suggest that Tan-IIA alleviates CI/RI at least in part through a KLF4/CHIP/NLRP3-related mechanism, with strong in vitro support for this pathway. Direct causal validation in vivo remains to be established. This study provides evidence of the protective role of Tan-IIA in experimental models of CI/RI.
Attenuating effects of heat-processed Panax ginseng (Red and Black) on methamphetamine-induced behaviors via dopaminergic modulation.
Lee CK, Gu SM, Kim B … +4 more , Yoo T, Oh H, Kim J, Yun J
Neurochem Int · 2026 Jun · PMID 42361611 · Publisher ↗
Methamphetamine (METH) is one of the most widely used psychostimulants associated with substance use disorders. Korean red ginseng extract (RGE), produced by the single steaming process of Panax ginseng, has been reporte...
Methamphetamine (METH) is one of the most widely used psychostimulants associated with substance use disorders. Korean red ginseng extract (RGE), produced by the single steaming process of Panax ginseng, has been reported to inhibit drug-induced reward behavior in several animal models. However, research on the effects of Korean black ginseng extract (BGE), produced by repeated steaming cycles (typically at least three times) of Panax ginseng, on methamphetamine-induced conditioned place preference (CPP) in mice remains limited. In this study, male C57BL/6 N mice were treated according to the same schedule used for CPP, pretreated with RGE or BGE, followed by behavioral and biochemical analyses, including conditioned place preference (CPP), Western blotting (WB), immunohistochemistry (IHC), and high-performance liquid chromatography (HPLC) in the striatum and nucleus accumbens. Our results demonstrate that pretreatment with RGE and BGE inhibited METH-induced CPP. We also found that pretreatment with RGE and BGE reversed METH-induced changes in dopamine-related protein expression, neurotransmission, and dopamine levels, suggesting that ginseng extracts may modulate dopaminergic signaling associated with drug reward.
Mesenchymal stem cell secretome attenuates disease-associated microglial activation and cognitive decline in TBI-associated neuroinflammation.
Rasiah PK, Ismael S, Elshaer S … +10 more , Awad AM, Salman M, Wang Z, Cho H, Bajpai AK, Liao FF, Lu L, Pentecost M, Ishrat T, Gangaraju R
Neurochem Int · 2026 Jun · PMID 42342036 · Publisher ↗
Therapeutic options for traumatic brain injury (TBI) remain limited, in part due to injury-induced activation of microglia toward disease-associated microglia (DAM) phenotypes that contribute to persistent neuroinflammat...
Therapeutic options for traumatic brain injury (TBI) remain limited, in part due to injury-induced activation of microglia toward disease-associated microglia (DAM) phenotypes that contribute to persistent neuroinflammation and cognitive decline. We evaluated whether non-invasive intranasal delivery of mesenchymal stem cell secretome can enhance recovery after TBI by modulating microglial DAM signaling. Adult C57BL/6 mice underwent moderate controlled cortical impact (CCI) TBI. Adipose Stem Cell-derived Concentrated Conditioned Media (ASC-CCM) (∼20 ng protein/day, four doses) was administered intranasally, while sham and TBI controls received saline. Cognitive and memory functions assessed at 7 and 30 days post-injury showed TBI mice with impairments in learning, working, and long-term memory, while ASC-CCM-treated TBI mice performed similar to sham. These functional deficits correlated with increased astrogliosis (GFAP) and apoptosis (TUNEL), both of which were attenuated by ASC-CCM. TBI induced a time-dependent increase in astrocyte-associated APOE in the ipsilateral peri-lesion area and TYROBP in activated microglia near the impact site; ASC-CCM treatment significantly reduced both markers. Transcriptomic analysis of peri-lesion tissue at days 7 and 30 confirmed robust upregulation of DAM-associated genes (APOE, TYROBP, TREM2) after TBI, which was mitigated by intranasal ASC-CCM. Consistent with these findings, TREM2 expression in ipsilateral CD11b CD45 cells was markedly reduced following treatment. These data show that microglial DAM signaling is a modifiable neurochemical pathway after TBI, and that intranasal delivery of ASC-CCM reduces microglial activation and improves cognitive outcomes. This strategy potentially offers a translational path to a non-invasive therapeutic for acute and chronic TBI.
Cordycepin alleviates aluminium chloride-induced neurodevelopmental toxicity in zebrafish embryos by modulating inflammation and Wnt signaling.
Hu H, Xiong G, Liu F … +10 more , Peng J, Lin Y, Chen C, Zuo Y, Chen G, Liao X, Cao Z, Li W, Chen J, Lu H
Neurochem Int · 2026 Jun · PMID 42314834 · Publisher ↗
BACKGROUND: Cordycepin, a major bioactive constituent of Cordyceps militaris, exhibits diverse pharmacological properties including anti-inflammatory and antioxidant activities. However, its neuroprotective effects again...
BACKGROUND: Cordycepin, a major bioactive constituent of Cordyceps militaris, exhibits diverse pharmacological properties including anti-inflammatory and antioxidant activities. However, its neuroprotective effects against aluminum-induced neurotoxicity in aquatic organism models remain largely unexplored. METHODS: In this study, we investigated the neuroprotective effects and intrinsic regulatory pathways by which cordycepin alleviates aluminium chloride (AlCl)-induced neurotoxicity in zebrafish (Danio rerio) embryos using behavioral, molecular, and transcriptomic approaches. RESULTS: Exposure to low-dose AlCl significantly induced developmental neurotoxicity, as manifested by reduced body length and reduced heart rate. AlCl-treated larvae displayed locomotor deficits and cognitive dysfunction. Notably, cordycepin treatment markedly attenuated these AlCl-induced neurodevelopmental abnormalities and aluminum chloride (AlCl)-induced locomotor and anxiety-related behavioral impairments.RNA-Seq analysis revealed 605 upregulated and 241 downregulated genes following co-exposure to cordycepin and AlCl. Functional enrichment analyses based on Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) screened out defense reaction and inflammatory signaling cascades as the remarkably enriched functional pathways, which implied these biological processes exert key functions in the nerve protection produced by cordycepin. Furthermore, pharmacological inhibition targeting the Wnt cascade via IWR-1-endo (IWR-1) markedly counteracted cordycepin's protective capacity to reverse AlCl-triggered behavioral impairments, indicating that Wnt signaling is essential for its neuroprotective action. CONCLUSION: Collectively, these findings demonstrate that cordycepin effectively mitigates AlCl-induced neurotoxicity and AlCl-induced locomotor and anxiety-related behavioral impairments in zebrafish by regulating inflammatory reactions and the Wnt signal cascade, highlighting its promising value for the clinical intervention of AD.
PPARα activation with fenofibrate confers hippocampal neuroprotection but lacks disease-modifying efficacy in chronic temporal lobe epilepsy.
Zubareva OE, Melik-Kasumov TB, Sinyak DS … +7 more , Velikoborets GS, Kovalenko AA, Zhabinskaya AA, Kolyhan SA, Korneeva MA, Zakharova MV, Zaitsev AV
Neurochem Int · 2026 Jun · PMID 42309244 · Publisher ↗
Activation of peroxisome proliferator-activated receptor alpha (PPARα) suppresses neuroinflammation and may interrupt epileptogenesis. We tested whether early intervention with the PPARα agonist fenofibrate exerts diseas...
Activation of peroxisome proliferator-activated receptor alpha (PPARα) suppresses neuroinflammation and may interrupt epileptogenesis. We tested whether early intervention with the PPARα agonist fenofibrate exerts disease-modifying effects in the chronic phase of the lithium-pilocarpine model of temporal lobe epilepsy. Male Wistar rats received fenofibrate (100 mg/kg, i.p., daily for 15 days) initiated 1 h after status epilepticus. Outcomes were assessed 1-3 months later. Fenofibrate significantly attenuated neuronal loss in the dorsal CA1 subfield and ventral hilus of the hippocampus, partially reduced astrogliosis in the hilus, and decreased the proportion of amoeboid microglia in CA1. Behaviorally, fenofibrate prevented the TLE-induced reduction in risk-assessment exploration in the elevated plus maze, without affecting general locomotion or anxiety. Critically, fenofibrate did not alter the incidence of spontaneous recurrent seizures, interictal spike frequency, or the pathological reduction in delta and theta EEG power. It also failed to normalize the aberrant cortical response to pentylenetetrazol or reduce seizure severity. These findings demonstrate that early PPARα activation confers region-restricted neuroprotection and modest behavioral benefit, but does not suppress the core pathophysiological features of chronic epilepsy. The results dissociate neuroprotection from antiepileptogenesis and caution against assuming that anti-inflammatory interventions alone are sufficient for disease modification in temporal lobe epilepsy.
Ayurvedic Herbs as neurogenesis modulators: Current understanding on their potential therapeutic relevance in enhancing neuroplasticity and cognition in aging and neurodegeneration.
Muralidhara M, Vismaya, Lalith Kumar V
Neurochem Int · 2026 Jun · PMID 42309243 · Publisher ↗
Ayurvedic medicine, an ancient Indian health system, promotes a category of Ayurvedic herbs (AH) known as Medhya Rasayanas (nootropic rejuvenators) for cognitive enhancement and neuroprotection. Currently, AH are increas...
Ayurvedic medicine, an ancient Indian health system, promotes a category of Ayurvedic herbs (AH) known as Medhya Rasayanas (nootropic rejuvenators) for cognitive enhancement and neuroprotection. Currently, AH are increasingly being studied for their potential to boost neuroplasticity and neurogenesis, as they can stimulate the growth of new neurons, improve the complexity of existing ones, and support cognitive resilience. Recent evidence-based research suggests the potential to use these AH and their formulations to develop new therapies for addressing cognitive decline during aging and neurodegenerative disorders (NDD). Neurogenesis is known to be compromised in mild cognitive impairment (MCI) and is impaired early in animal models of Alzheimer's disease (AD), suggesting that rescuing neurogenesis may restore hippocampal plasticity and attenuate neuronal vulnerability and memory loss. Several AH, including Brahmi (Bacopa monnieri), Gotu Kola (Centella asiatica), Ashwagandha (Withania somnifera), Shankhapushpi (Convolvulus pluricaulis), Guduchi (Tinospora cordifolia), and Yashtimadhu (Glycyrrhiza glabra), are well recognized for their cognitive-enhancing and neuroprotective properties. Further, in chronic stress models, the neurogenic effects of AH are proposed to be mediated by mechanisms including antioxidant and anti-inflammatory effects, modulation of neurotransmitters, and effects on the gut microbiota. Neurotrophins (particularly brain-derived neurotrophic factor -BDNF) are important mediators of neuroplasticity as they modulate multiple processes, including synaptic plasticity, axonal and dendritic growth, spine morphogenesis, and neurogenesis. BDNF is compromised in depression and recovered by conventional antidepressants. The antidepressant-like effects of AH are associated with the reversal of chronic stress-induced impairment in neuroplasticity, most notably through up-regulation of BDNF, activation of downstream signaling pathways, and increased neurogenesis in the hippocampus and/or prefrontal cortex. This review summarizes current developments regarding AH's propensity to enhance neuronal plasticity and its therapeutic role as a modulator of neurogenesis. It also emphasizes the importance of using them as adjuvant therapy to attenuate cognitive deficits associated with aging and neurodegeneration.
Heme oxygenase/carbon monoxide in thermoregulation and neuroenergetics.
Carnio EC, Branco LGS
Neurochem Int · 2026 Jun · PMID 42309242 · Publisher ↗
This review explores the heme oxygenase/carbon monoxide (HO/CO) pathway as a central integrator of thermoregulation and neuroenergetics during inflammatory and oxidative stress. Thermoregulation is framed not merely as a...
This review explores the heme oxygenase/carbon monoxide (HO/CO) pathway as a central integrator of thermoregulation and neuroenergetics during inflammatory and oxidative stress. Thermoregulation is framed not merely as a homeostatic process, but as a continuous problem of energy allocation where body temperature (Tb) serves as an indicator of an organism's bioenergetic capacity. The core mechanistic thesis identifies the HO/CO system as a state-dependent "coupling pathway" that links inflammatory and redox tone to mitochondrial performance and, through central autonomic hierarchies, to the selection of thermal phenotypes, such as fever, regulated hypothermia, or torpor-like states. While fever supports "resistance" at a high metabolic cost, regulated hypothermia aligns with "tolerance" by conserving energy when resources or oxygen delivery are constrained. Key knowledge gaps remain regarding the precise cell-type-specific roles of HO-1 in the central nervous system (CNS) and the context-dependent nature of CO signaling via soluble guanylyl cyclase (sGC) in vivo. Therapeutically, targeting the HO/CO pathway via inhaled CO, CO-releasing molecules (CORMs), or HO-1 induction offers prospects for modulating neuroinflammation and metabolic resilience. However, translational constraints include timing-dependent effects and the need for precision phenotyping to identify which patients might benefit from interventions. In conclusion, the HO/CO system is discussed as a sophisticated modulator that biases thermoregulatory strategy based on the immediate physiological constraints of oxygen delivery and energetic reserve.
Naringenin as a multi-target neuroprotective agent in neurodegenerative diseases.
Gurung N, Choi DY, Park PH
Neurochem Int · 2026 Jun · PMID 42276279 · Publisher ↗
Neurodegenerative diseases (ND) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), and Multiple sclerosis (MS) are characterized by progressive neu...
Neurodegenerative diseases (ND) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), and Multiple sclerosis (MS) are characterized by progressive neuronal loss driven by complex and multifactorial pathogenic mechanisms. Naringenin (NAR), a citrus-derived flavanone, has attracted considerable interest as a neuroprotective molecule due to its pleiotropic pharmacological activities such as antioxidant, anti-inflammatory and ability to modulate multiple cellular targets. This review provides a comprehensive overview of NAR pharmacokinetic profile, mechanistic actions, and therapeutic potential across major ND. We highlight how NAR's multi-target effects-including redox homeostasis maintenance, suppression of neuroinflammation, protein aggregation inhibition, and modulation of signaling pathways-contribute to neuroprotection in various experimental models of AD, PD, HD, ALS, and MS. Preclinical studies demonstrate that NAR can ameliorate cognitive and motor deficits in toxin and transgenic models of neurodegeneration, attenuate pathological hallmarks such as amyloid-beta toxicity, dopaminergic neuronal loss, and neuroinflammation, and induce cytoprotective pathways including Nrf2-mediated antioxidant response and autophagy. However, NAR's clinical translation is challenged by poor bioavailability; thus, novel delivery systems are being explored to enhance brain uptake. NAR emerges as a promising multi-functional neuroprotective agent that can simultaneously target diverse pathogenic processes in ND. Further research including advanced formulation development and well-designed clinical trials is warranted to fully establish NAR's therapeutic efficacy and safety in humans.
Adaptive immune signals shape neural circuit development through CNS Border-Glia pathways.
Wei X, Liu F, Shi Z
Neurochem Int · 2026 Jun · PMID 42269876 · Publisher ↗
The central nervous system (CNS) has long been considered a relatively immune-privileged site. However, accumulating evidence indicates that CNS border structures, including the meninges, choroid plexus, blood-brain barr...
The central nervous system (CNS) has long been considered a relatively immune-privileged site. However, accumulating evidence indicates that CNS border structures, including the meninges, choroid plexus, blood-brain barrier (BBB), and perivascular spaces, are not merely passive barriers but dynamic immune interfaces that enable regulated communication between the peripheral immune system and the brain microenvironment. This review discusses how adaptive immune signals are filtered, integrated, and translated at CNS borders during critical developmental windows, and how these signals subsequently influence neural circuit development through microglia and astrocytes. Meningeal-resident T cells, B cells, plasma cells, and related innate-like lymphocytes can establish cytokine milieus characterized by IL-4, IL-17 A, IFN-γ, and other immune mediators within border niches. Once sensed by glial cells, these signals can regulate complement-dependent synaptic pruning, receptor-mediated phagocytosis, astrocyte-derived synaptic homeostatic factors, and excitatory/inhibitory (E/I) balance. Because glial cells exhibit marked heterogeneity across brain regions and developmental stages, the same immune bias may produce time-window-dependent and region-specific neurodevelopmental consequences. These processes do not usually determine the onset of a specific disease directly; rather, they reshape developmental trajectories of neural circuits and thereby alter susceptibility to neurodevelopmental and neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia (SCZ). Overall, this review highlights glial cells as pivotal cellular hubs linking adaptive immunity, CNS border microenvironments, and neural circuit development, and provides a mechanistic framework for understanding neuroimmune interactions and their translational relevance.
Complement system-mediated immunomodulation in epilepsy: From pathogenesis to therapeutic opportunities.
Peng L, Lu M, Chen M … +3 more , Liu R, Xia S, Tan G
Neurochem Int · 2026 Jun · PMID 42269875 · Publisher ↗
Epilepsy is a prevalent neurological disorder characterized by recurrent seizures and aberrant neuronal hyperexcitability. Although several antiseizure medications are clinically available, current treatments are primari...
Epilepsy is a prevalent neurological disorder characterized by recurrent seizures and aberrant neuronal hyperexcitability. Although several antiseizure medications are clinically available, current treatments are primarily symptomatic and fail to prevent epileptogenesis or disease progression. Moreover, nearly one-third of patients develop resistance to these drugs. The absence of effective disease-modifying therapies underscores the urgent need to identify novel pathogenic mechanisms and therapeutic targets. As a core component of innate immunity, the complement system has recently emerged as a key regulator of injury and repair processes in the central nervous system. Accumulating preclinical evidence indicates that abnormal complement activation contributes to epileptogenesis. This suggests that complement dysregulation is not merely an epiphenomenon of neuroinflammation but rather a potential driver of seizure development and progression. However, clinical evidence remains limited and heterogeneous, and has not yet been systematically integrated. This review summarizes current preclinical and clinical evidence on complement-mediated mechanisms in epilepsy, with a focus on neuroinflammation, synaptic remodeling, glial proliferation, biomarkers, and therapeutic targets. It also discusses the challenges and opportunities associated with developing complement-based disease-modifying strategies for epilepsy.
An emerging therapeutic strategy for major depressive disorder: targeting the protein-protein interactions.
Huang X, Lin J, Zhang YW
Neurochem Int · 2026 Jun · PMID 42264040 · Publisher ↗
Major depressive disorder (MDD) is a highly heterogeneous psychiatric condition. For decades, drugs targeting serotonin transporter (SERT), such as selective serotonin reuptake inhibitors (SSRIs), have been the mainstay...
Major depressive disorder (MDD) is a highly heterogeneous psychiatric condition. For decades, drugs targeting serotonin transporter (SERT), such as selective serotonin reuptake inhibitors (SSRIs), have been the mainstay of treatment. However, SSRI antidepressants face significant limitations. This paper discusses the mechanistic defects of conventional antidepressants that directly target serotonin (5-HT) synthesis, degradation, and reuptake and the dual-role dilemma of the 5-HT receptors in the neuropsychopharmacology. In addition, recent findings of regional regulation of SERT by protein-protein interactions (PPIs) open up a promising strategy for future antidepressant development. These PPIs specifically and rapidly regulate SERT capability for 5-HT uptake by modulating its membrane trafficking under physiological conditions. Agents disrupting the SERT-neuronal nitric oxide synthase (nNOS) or soluble guanylate cyclase (sGC) interaction are highlighted as examples to illustrate their mechanism of action by which they selectively deactivate the 5-HT autoreceptors in the dorsal raphe nucleus (DRN) without directly affecting the postsynaptic 5-HT heteroreceptors in 5-HT projection areas. Consequently, these agents enhance 5-HT release in the hippocampus and cortex and produce a fast-onset antidepressant-like activity in depressive animal models. Thus, this emerging strategy can achieve a regional, precise, rapid, and fine-tuning regulation of 5-HT uptake activity by modulating the interactions between SERT and its regulatory proteins in the DRN, while avoiding dysregulation of the essential neurological functions in other brain regions. Targeting the PPI interfaces rather than the transporter itself represents a paradigm shift from the conventional pharmacological approaches to a novel strategy for the precise control of the serotonergic system.
Disturbed lipid metabolism in microglia after cerebral ischemia-reperfusion.
Li X, Chu S, Zhang Z … +1 more , Chen N
Neurochem Int · 2026 Jun · PMID 42248465 · Publisher ↗
Cerebral ischemia-reperfusion injury (CIRI) frequently compromises neurological outcomes in stroke patients despite successful recanalization therapy. While the brain's dense lipid network is integral to immune regulatio...
Cerebral ischemia-reperfusion injury (CIRI) frequently compromises neurological outcomes in stroke patients despite successful recanalization therapy. While the brain's dense lipid network is integral to immune regulation and tissue repair, the spatiotemporal disruption of lipid metabolism during CIRI remains incompletely synthesized. This review critically evaluates the dynamic alterations in brain lipid profiles following ischemic injury, with a specific focus on the microglial niche. We detail how the excessive influx of extracellular lipid debris forces microglia into maladaptive, lipid-droplet-accumulating states, thereby amplifying lipotoxicity, the neuroinflammatory storm, and microglial vulnerability to ferroptosis. By integrating current evidence on lipid-driven microglial dysfunction, this review highlights the "lipid-inflammation-ferroptosis" axis as a contributing pathogenic mechanism in CIRI. Finally, we discuss the translational potential and current limitations of targeting microglial lipid metabolism, offering a balanced perspective on developing targeted metabolic interventions to enhance stroke recovery.
Phytochemical engineered quantum dots as potential therapy to counter alpha synuclein aggregation in Parkinson's disease.
Shashwat P, Kirthi AV, Selvaraj M … +2 more , Karnwal A, Dutta J
Neurochem Int · 2026 Jun · PMID 42235756 · Publisher ↗
Parkinson's disease (PD) is a prevalent neurodegenerative disorder that critically impairs human health and presently lacks effective cellular-level therapeutic interventions. The disease is primarily characterized by pa...
Parkinson's disease (PD) is a prevalent neurodegenerative disorder that critically impairs human health and presently lacks effective cellular-level therapeutic interventions. The disease is primarily characterized by pathological aggregation of misfolded α-synuclein in presynaptic neurons, leading to dopaminergic neuronal loss. The limited efficacy of current pharmacological treatments stems largely from challenges in crossing the blood-brain barrier. Recent studies suggest that nano-phytomedicine approaches offer promising alternatives for PD management. Specifically, phytochemical-engineered carbon quantum dots (CQDs) show potential to modulate key pathological processes, including α-synuclein aggregation, mitochondrial dysfunction, oxidative stress, and neuronal degeneration. Evidence from related neurodegenerative models, such as Alzheimer's disease, reveals that multifunctional CQDs can scavenge reactive oxygen species, influence protein aggregation, and mitigate neurotoxicity. The synergistic integration of bioactive phytochemicals into CQDs could enhance drug bioavailability, pharmacokinetic properties, and cellular repair mechanisms while reducing toxicity. This review discusses the design strategies, therapeutic mechanisms, and biological interactions of phytochemical-engineered CQDs, emphasizing their potential as next-generation nanocarriers and intrinsic neurotherapeutic agents for PD treatment.
Iron overload inhibits neuronal extracellular vesicles secretion via SNARE dysfunction.
Wang X, Li Y, Mi X … +6 more , Yang T, Li Y, Zhang J, Jia F, Xie J, Song N
Neurochem Int · 2026 May · PMID 42203129 · Publisher ↗
Iron deposition in the brain is observed in several neurodegenerative diseases and aging. Extracellular vesicles (EVs), including exosomes, are critical mediators of intercellular communication. Neuron-derived EVs are re...
Iron deposition in the brain is observed in several neurodegenerative diseases and aging. Extracellular vesicles (EVs), including exosomes, are critical mediators of intercellular communication. Neuron-derived EVs are recently recognized as promising biomarkers in the plasma for neurological disorders. However, it remains unclear whether and how neuronal iron overload affects EVs (exosomes) secretion. In this study, we used L1 cell adhesion molecule (L1CAM) to label neuron-derived EVs and observed a significant reduction in L1CAM-positive vesicle concentration in the plasma of mice with brain iron deposition. Iron-reduced EVs secretion was also observed in PC12 cells with ferric ammonium citrate treatment. We then reported the inhibition of iron overload on exosomes secretion was independent of cell proliferation, exosomal trafficking pathway and lysosomal degradation pathway, however, probably via disrupting SNARE complex function. Finally, we observed that neuron-derived EVs are more abundant in the plasma of mice during ageing. Our results indicate that iron overload inhibits neuronal EVs secretion both in vivo and in vitro, potentially through dysfunction of the SNARE complex.
Regular light-intensity exercise accelerates contextual fear extinction with reduced dorsal CA3 activation in male rats.
Hiraga T, Shimoda R, Hata T … +3 more , Torma F, Okamoto M, Soya H
Neurochem Int · 2026 May · PMID 42203128 · Publisher ↗
Exercise has gained attention as a low-cost, non-pharmacological approach for stress-related disorders such as post-traumatic stress disorder (PTSD). Regular light-intensity exercise (LIE), which is feasible even for vul...
Exercise has gained attention as a low-cost, non-pharmacological approach for stress-related disorders such as post-traumatic stress disorder (PTSD). Regular light-intensity exercise (LIE), which is feasible even for vulnerable populations, has been reported to promote contextual fear memory (CFM) extinction learning, a critical process for alleviating PTSD. However, its underlying neural signatures remain unclear. Given that LIE effectively promotes hippocampal brain-derived neurotrophic factor and adult hippocampal neurogenesis (AHN), both key modulators that facilitate CFM extinction, a hippocampus-dependent mechanism of fear suppression is likely to underlie this effect. Specifically, CFM recall depends on the reactivation of dorsal hippocampal neurons that were recruited during acquisition, particularly in the CA3, and AHN suppresses this reactivation. Therefore, we hypothesized that LIE reduces dorsal CA3 (dCA3) recruitment during CFM extinction learning. To test this, male rats underwent LIE using a treadmill exercise model with intensity defined relative to the lactate threshold, and hippocampal neuronal activity during CFM extinction learning was evaluated using a contextual fear conditioning and c-Fos immunohistochemistry. Our results showed that regular LIE reduced neuronal activity in the dCA3 during CFM extinction learning, and this reduction was positively correlated with decreased freezing behavior. Additionally, neuronal activity in the ventral dentate gyrus, implicated in anxiety regulation, was attenuated by regular LIE. These findings reveal a selective hippocampal neural signature of the LIE-facilitated CFM extinction learning, suggesting that reduced fear recall-as well as anxiety-related hippocampal recruitment underlies its behavioral efficacy. Collectively, our study provides neurobiological support for LIE as a clinically feasible strategy for PTSD.
Effects of chemogenetic regulation of CaMKⅡα positive neurons in the ventral hippocampus on working memory impairment in the hemiparkinsonian rat.
Zhang L, Du C, Shi M … +4 more , Hu H, Li F, Guo Y, Liu J
Neurochem Int · 2026 May · PMID 42203127 · Publisher ↗
Neurons expressing Ca/calmodulin-dependent protein kinase Ⅱα (CaMKⅡα) in the ventral hippocampus (vHIP) play a crucial role in working memory. However, its role in Parkinson's disease (PD)-related working memory impairme...
Neurons expressing Ca/calmodulin-dependent protein kinase Ⅱα (CaMKⅡα) in the ventral hippocampus (vHIP) play a crucial role in working memory. However, its role in Parkinson's disease (PD)-related working memory impairment remains unclear. In the present study, PD model was established by unilateral lesions of the medial forebrain bundle (MFB) by 6-hydroxydopamine in rats. The effects of chemogenetic activation or inhibition of CaMKⅡα positive neurons in the vHIP on working memory, theta (θ) rhythm of the medial prefrontal cortex (mPFC) and levels of dopamine (DA) and 5-hydroxytryptamine (5-HT) in the dorsal hippocampus (dHIP), vHIP and mPFC were observed in sham and the lesioned rats. The results indicated that neither chemogenetic activation nor inhibition of CaMKⅡα positive neurons in the vHIP influenced the working memory, the peak θ rhythm of the mPFC or the levels of DA and 5-HT in the dHIP, vHIP and mPFC in sham rats. In the MFB lesioned rats, activation of CaMKⅡα positive neurons in the vHIP ameliorated the working memory impairment, increased peak of θ rhythm of the mPFC and increased the levels of DA in the dHIP, vHIP and mPFC. While, inhibition of CaMKⅡα positive neurons exacerbated working memory impairment, reduced the peak of θ rhythm of the mPFC and decreased the levels of 5-HT in the mPFC. These results suggest vHIP CaMKⅡα neurons regulate PD-related working memory impairment in rats, possibly via altered peak of θ rhythm of the mPFC and monoamine levels in related brain regions.
Neuro-nutraceutical role of Indian spices, spice mixes and their bio-actives: An update.
Vismaya, Rajini PS
Neurochem Int · 2026 May · PMID 42176806 · Publisher ↗
Neurodegenerative disorders (NDD), one of the major health care challenges, are exponentially increasing as the elderly segment of the population continues growing in size worldwide. Currently, the role of nutraceuticals...
Neurodegenerative disorders (NDD), one of the major health care challenges, are exponentially increasing as the elderly segment of the population continues growing in size worldwide. Currently, the role of nutraceuticals, in general and particularly for brain health, has generated immense research interest. Ancient, traditionally used culinary spices have been recognized for their potential health benefits. Abundant evidence clearly suggests that spices do impart considerable biological activity in the central nervous system (CNS). Owing to the multi-mechanistic actions of spices/bioactives, scientific interest is resurgent in characterizing, understanding, and exploring their neuro-nutraceutical role. The current review summarizes experimental evidence on the nutraceutical attributes of a subset of Indian spices. Major molecular mechanisms by which these compounds counteract neuropathology-such as antioxidant activity, anti-inflammatory effects, modulation of signaling pathways (e.g., Nrf2, NF-κB, MAPK), enhancement of synaptic plasticity, and stimulation of neurogenesis are discussed. The neuroprotective efficacy of Spice extract/bioactives as therapeutics is dependent on bioavailability, pharmacokinetics, and delivery challenges that prevent adequate concentrations from reaching the brain. However, the development of several nano-formulations for various spice bioactives has significantly addressed these issues. Further, the data limitations, potential obstacles to be overcome, and current research on metabolic engineering and the nanotechnology of spice bioactives are also presented. Although the randomized controlled trials (RCTs) in humans are limited, and restricted to a few spice bio-actives, abundant evidence in various preclinical models prompts one to hypothesize that Indian spices/bio-actives are quite promising as neuro-nutraceuticals in the management of NDD.
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