Brain Res. [JOURNAL]
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200 papers
Cutamesine attenuates hippocampal damage via sigma-1 receptor activation following oxygen-glucose deprivation in vitro.
Puente-Sanz A, Mazzantini C, Venturini M … +6 more , Mainolfi F, Herrero-González A, Pugliese AM, Fernández-López A, Pellegrini-Giampietro DE, Landucci E
Brain Res · 2026 May · PMID 41724420 · Publisher ↗
Cerebral ischemia is a leading cause of death and disability worldwide, due to neuronal energy failure, calcium overload, ER stress and inflammation. Sigma-1 receptor activation regulates calcium signaling between ER and...
Cerebral ischemia is a leading cause of death and disability worldwide, due to neuronal energy failure, calcium overload, ER stress and inflammation. Sigma-1 receptor activation regulates calcium signaling between ER and mitochondria and reduces the activation of ER stress and inflammation pathways. In the present study, we investigated the neuroprotective effects of the sigma-1 receptor agonist cutamesine in rat organotypic, and acute hippocampal slices exposed to oxygen-glucose deprivation (OGD), two in vitro models of global ischemia. In organotypic hippocampal slices obtained from both sexes exposed to 30 min of OGD, we evaluated the neuroprotective effects of cutamesine by quantifying CA1 cell death via propidium iodide fluorescence. We also assessed mRNA and protein levels of key ER stress and inflammation markers via RT-qPCR and Western blot. In acute hippocampal slices, we evaluated the effects of cutamesine on recorded extracellular field excitatory postsynaptic potentials following OGD. Cutamesine exhibited neuroprotective effects at 10 µg/mL in organotypic hippocampal slices exposed to 30 min of OGD, and this effect was reduced by the sigma-1 receptor antagonist BD1047. Cutamesine reduced ER stress and inflammation pathways by decreasing GRP78, GRP94, p-p65, and MMP-9 protein levels and these effects were partially decreased by BD1047. Cutamesine also delayed the onset of anoxic depolarization latency on acute hippocampal slices obtained from male rats. These findings evidence the notion that the sigma-1 receptor may be a promising therapeutic target for ischemic injury. Abbreviations: aCSF, artificial cerebrospinal fluid; AD, anoxic depolarization; Cornu Ammonis 1, CA1; ER, endoplasmic reticulum; fEPSP, field excitatory postsynaptic potentials; GRP78, 78-kDa glucose-regulated protein; GRP94, glucose-regulated protein 94; IL-1β, interleukin-1 beta; MAMs, mitochondria-associated membranes; MMP-9, matrix metalloproteinase-9; OGD, oxygen and glucose deprivation; PI, propidium iodide; p-NF-κB, phosphorilated nuclear factor -kappa-B p65 subunit (p-p65); ROS, reactive oxygen species; Sig-1 receptor, sigma-1 receptor; TNF-α, tumor necrosis factor-alpha; UPR, unfolded protein response.
Patterns of subthalamic synchronized oscillatory neurons are characteristics of motor subtypes of Parkinson's disease.
Feng H, Zhuang P, Zhang Y … +6 more , Li J, Guo S, Li J, Hu Y, Hallett M, Li Y
Brain Res · 2026 Jun · PMID 41724419 · Publisher ↗
OBJECTIVE: The pathological mechanisms underlying the subtypes of Parkinson's disease (PD) remain unclear. The aim of the study was to explore whether synchronized subthalamic oscillatory neurons are associated with the...
OBJECTIVE: The pathological mechanisms underlying the subtypes of Parkinson's disease (PD) remain unclear. The aim of the study was to explore whether synchronized subthalamic oscillatory neurons are associated with the motor symptoms of PD. METHOD: Thirty patients undergoing subthalamic nucleus (STN) deep brain stimulation were included. They were classified tremor dominant (TD, n = 8), indeterminate type (IT, n = 9), and postural instability and gait disorder (PIGD, n = 13) groups. Microelectrode recordings in the STN and the electromyogram (EMG) were recorded. Neuronal background activity was extracted. Spectral and coherence analysis and correlation analysis was used. The locations of the oscillatory neurons were noted. RESULTS: Of total oscillatory neurons, 95.0% β frequency and 83.3% tremor frequency oscillatory neurons were coherent with their background. Of 76 synchronized β frequency oscillatory neurons, 13.2% were coherent with limb rigidity in PIGD group whereas of 30 synchronized tremor frequency oscillatory neurons, 20% were coherent with tremor in TD group. Tremor frequency and β frequency oscillatory neurons correlated with tremor (r = 0.80 [95% CI 0.23,0.98], P < 0.02) and rigidity/bradykinesia (r = 0.81[95% CI 0.47,0.94], P < 0.0008) sub-scores, respectively. All three subbands of β frequency oscillatory neurons correlated with rigidity/bradykinesia subscores; however, the subband of 13-20 Hz had the strongest correlation (r = 0.64 [95% CI 0.38,0.81], P < 0.0002). The majority of synchronized oscillatory neurons were located in the dorsal STN. CONCLUSION: Synchronized tremor frequency and β frequency oscillatory neurons seem to associate with the TD and PIGD subtypes of PD respectively. The low β frequency of 13-20 Hz oscillatory neurons is more implicated for rigidity/bradykinesia. Synchronized oscillatory neurons in the dorsal STN support the idea that the neurons can be used to guide optimal electrode placement.
Effects of tea polyphenols on brain structure and function of hippocampus in aged type 2 diabetes mellitus rats with anxiety and depression-like behavior.
Song X, Lv C, Feng W … +6 more , Cheng L, Xue L, Zhang C, Zhang K, Zhao H, Zhang J
Brain Res · 2026 May · PMID 41724418 · Publisher ↗
OBJECTIVES: This study aimed to investigate changes in brain structure and function of hippocampus in aged type 2 diabetes mellitus (T2DM) rats and the effects of tea polyphenol (TP) intervention using magnetic resonance...
OBJECTIVES: This study aimed to investigate changes in brain structure and function of hippocampus in aged type 2 diabetes mellitus (T2DM) rats and the effects of tea polyphenol (TP) intervention using magnetic resonance imaging (MRI) and tissue-level molecular analyses. METHODS: Rats were randomly assigned to six groups: Control, Aged, Aged T2DM, Aged T2DM + TP, Aged T2DM + rosiglitazone, and Aged T2DM + piracetam intervention groups. Anxiety- and depression-like behaviors were assessed using the open field test, the forced swimming test and elevated plus maze. Brain structure, blood flow and neuro-associated metabolites were evaluated via MRI. The number of nerve cells, neurons, microglia and astrocytes, the expression of BDNF/CREB/p-CREB protein, the levels of inflammatory factors, and the integrity of the myelin sheath in the hippocampus were evaluated. Relationships between behavioral, cellular and molecular changes and MRI-derived indicators were evaluated by Pearson correlation analysis. RESULTS: Aged T2DM rats exhibited severe anxiety- and depression-like behaviors accompanied by brain atrophy, reduced blood flow and decreased brain metabolites. At the microstructural level, the number of hippocampal neurons in the Aged T2DM group was significantly reduced, accompanied by increased counts of microglia and astrocytes. Meanwhile, the expression levels of hippocampal p-CREB and BDNF were decreased, the concentration of the inflammatory factor IL-1β, IL-6, TNF-α was elevated, and myelin integrity was impaired. Intervention with TP alleviated anxiety- and depression-like behavior, with MRI-detected abnormalities and in vitro histopathological molecular changes improved (except for myelin integrity). CONCLUSION: TP intervention mitigated alterations in brain structure and function as well as anxiety and depression-like behaviors in aged T2DM rats.
People who play games regularly are no more robust to unpleasant images compared to those who do not in preparation for brain research.
O'Hare L, Kalaj J, Föcker J
Brain Res · 2026 Jun · PMID 41722755 · Publisher ↗
It has been suggested that flickering, striped patterns may be unpleasant to look at as they are difficult stimuli for the visual system to process, and so result in an inefficient, excessive neural response. Some people...
It has been suggested that flickering, striped patterns may be unpleasant to look at as they are difficult stimuli for the visual system to process, and so result in an inefficient, excessive neural response. Some people such as people who experience migraine, may be more susceptible to unpleasant stimuli, and have greater neural responses. Others, such as people who spend a lot of time playing computer games, may have more efficient visual processing and so be more resilient to these unpleasant images. We measured neural responses using steady-state visual evoked potentials (SSVEP, an EEG technique) in both these groups to test this theory. We found that the spatial and temporal frequency content of flickering striped images affects both unpleasantness judgments and SSVEP responses. In line with the ideas of inefficient coding, stimuli eliciting greater SSVEP responses tend to be rated as less pleasant. There was a non-significant trend for greater SSVEP responses in people with migraine compared to controls. Number of hours spent gaming does not relate to unpleasantness ratings in the current study, indicating these individuals are no more robust than others. Future studies might consider a broader range of environmental and individual factors such as sensory sensitivity in terms of understanding neural correlates of visual discomfort.
Electrophysiological markers of altered affective information processing in post-traumatic stress disorder.
Popescu M, Popescu EA, DeGraba TJ … +1 more , Hughes JD
Brain Res · 2026 May · PMID 41713637 · Publisher ↗
We used magnetoencephalography (MEG) to characterize the cortical and autonomic nervous system activity associated with affective information processing in PTSD. Participants were service members assigned to one of two g...
We used magnetoencephalography (MEG) to characterize the cortical and autonomic nervous system activity associated with affective information processing in PTSD. Participants were service members assigned to one of two groups based on whether they met (n = 36) or did not meet (n = 48) the DSM-V criteria for PTSD. MEG recordings were performed while participants viewed and rated for pleasantness images with positive affective valence (set 1) and neutral images (set 2). Higher amplitudes of the early (75 ms-150 ms) neuromagnetic evoked responses to positive vs. neutral images indicated that the pleasantness evoked by visual stimuli may be associated with increased early activation within a distributed cortical network. PTSD was associated with attenuated amplitude of the early evoked responses to all stimuli predominantly in right ventral and medial temporal regions. PTSD was also associated with less suppression of alpha and beta band power during the image presentation interval, as well as with delayed heart rhythm deceleration for all stimuli. Our findings are consistent with (1) an impairment in early automatic sensory processing reflecting potential difficulties with the fast engagement of a neuronal network of the appetitive motivational system in PTSD, (2) an impairment in sustained attentional control and suppression of competing neuronal activity in PTSD reflected in alterations of oscillatory brain activity, and (3) a slower engagement of the parasympathetic system in PTSD. These alterations in cortical and autonomic nervous system activity may contribute to symptoms of anhedonia/emotional numbing and can provide targets for treatments in PTSD.
Differential effects of the microbial metabolite acetate on murine microglia in in vitro sepsis and trauma models.
Yang Q, Dave A, Clark RSB … +2 more , Bayır H, Simon D
Brain Res · 2026 May · PMID 41702482 · Publisher ↗
BACKGROUND: Short chain fatty acids (SCFAs) including acetate, produced by gut microbiota, are key signaling molecules and impact microglial maturation and metabolism. Microglia play a dual role in maintaining homeostasi...
BACKGROUND: Short chain fatty acids (SCFAs) including acetate, produced by gut microbiota, are key signaling molecules and impact microglial maturation and metabolism. Microglia play a dual role in maintaining homeostasis and neuroinflammation when activated. Despite evidence suggesting acetate's anti-inflammatory effects on lipopolysaccharide (LPS)-stimulated microglia, no studies have examined its impact on mechanically stretched microglia, a model for traumatic brain injury (TBI). METHODS: We investigated the effects of acetate at physiological doses and a frequently used higher experimental concentration in in vitro sepsis and TBI models in EOC20 mouse microglial cells. The impact of acetate was assessed using assays of cell death, cytokine production and inducible nitric oxide synthase (iNOS) expression. RESULTS: In LPS-stimulated microglia, acetate did not reduce pro-inflammatory cytokine secretion or intracellular iNOS expression. Surprisingly, in moderate mechanically stretched microglia, physiological doses of acetate (100 µM and 300 µM) significantly reduced tumor necrosis factor-alpha (TNFα) production without affecting cell viability. Additionally, stretch injury increased nuclear localization of NF-κB that was attenuated with physiological doses of sodium acetate. CONCLUSION: Acetate exerted anti-inflammatory effects in microglial stretch but not LPS stimulation. Further studies are warranted to elucidate acetate's regulatory role in sterile etiologies of neuroinflammation and its therapeutic potential for TBI.
Mesenchymal stem cell-derived exosomes rescue stress-dependent morphological deficits in primary hippocampal neurons via Wnt5a/β-catenin/WAVE2 pathway.
Liu C, Liu Y, Zhu J … +4 more , Xiao T, Xu M, Duan J, Chen J
Brain Res · 2026 May · PMID 41698632 · Publisher ↗
OBJECTIVES: Increasing evidence indicates that chronic stress impairs dendritic branching and synaptic plasticity in hippocampal neurons. Mesenchymal stem cell-derived exosomes (MSC-Exos) are crucial for tissue injury re...
OBJECTIVES: Increasing evidence indicates that chronic stress impairs dendritic branching and synaptic plasticity in hippocampal neurons. Mesenchymal stem cell-derived exosomes (MSC-Exos) are crucial for tissue injury repair, facilitating cell communication and transporting bioactive cargo like lipids, proteins, and nucleic acids. Herein, we investigate the therapeutic effects and molecular mechanism of MSC-Exos against stress-dependent morphological deficits in primary hippocampal neurons. METHODS: MSC-Exos were obtained and identified. Primary hippocampal neurons were exposed to corticosterone (CORT) to simulate stress in vitro. Adeno-associated virus (AAV) that targets MSC was used to knock down Wnt5a in MSC-Exos. MSC-Exos, Wnt5a-sh RNA MSC-Exos and small molecule compound inhibitor interventions were conducted respectively to study the therapeutic impact and molecular mechanisms in primary hippocampal neurons under CORT stimulation. Western blotting and immunofluorescence labeling were applied for evaluating protein levels. GEO database analysis was used to screen potential targeting gene of MSC-Exos in neurons. Sholl analysis was employed to evaluate morphology of primary hippocampal neurons. RESULTS: This study found that MSC-Exos improved the morphological deficits of primary hippocampal neurons under CORT stimulation. This improvement was associated with enhanced nuclear translocation of β-catenin and increased expression of downstream genes N-cadherin and Cyclin D3. These effects were reversible with the β-catenin inhibitor ICG-001.We also discovered that Wnt5a was contained in MSC-Exos, knockdown of Wnt5a in MSC-Exos significantly abrogated activation of β-catenin signaling and promotion of dendrite morphogenesis. Gene expression array data from the GEO database linked to a chronic stress animal model indicated a significant down-regulation of WAVE2 in the hippocampus. In addition, MSC-Exos induced Wnt5a/β-catenin signaling exhibited the capacity to increase the expression of WAVE2, thereby rescued the morphological deficit in primary hippocampal neurons. CONCLUSIONS: Our study indicates that MSC-Exos ameliorate stress-dependent morphological deficits in primary hippocampal neurons via the exosomal Wnt5a/β-catenin/WAVE2 pathway.
Ido1 and Ido2 deficiencies attenuate kainic acid-induced ictogenesis.
MacDowell Kaswan ZA, Hurtado M, Chen EY … +1 more , McCusker RH
Brain Res · 2026 Apr · PMID 41698631 · Publisher ↗
Insults to the brain in the form of injury, infection and exposure to seizurogenic chemicals can induce seizures (ictogenesis). Seizure episodes during any of these events is one of the biggest risk factors for the devel...
Insults to the brain in the form of injury, infection and exposure to seizurogenic chemicals can induce seizures (ictogenesis). Seizure episodes during any of these events is one of the biggest risk factors for the development of treatment-resistant epilepsy, making the acute ictogenic period a critical time for intervention. Indoleamine-2,3-dioxygenases (Ido1 & Ido2) modulate systemic and central neuroprotective and inflammatory responses through both enzymatic and non-enzymatic mechanisms. We have previously found that Ido1 (knockout) mice have increased seizure incidence following viral encephalitis suggesting a protective role of Ido1 during this inflammatory model of ictogenesis. Here, we assessed ictogenesis with Ido1 and Ido2 mice using intraperitoneal injections of the chemoconvulsant kainic acid (KA). We found that Ido1 and Ido2 mice have reduced seizure incidence after systemic KA treatment compared to WT controls. However, neither Ido1 nor Ido2 expression was induced by KA and indices of inflammation (hippocampal cytokine expression) did not vary across genotypes. Nevertheless, Ido2 mice were also protected from the KA-induced hyperlocomotion observed with WT mice. Because Ido1 and Ido2 are expressed by multiple cell types within the brain,we evaluated KA-induced ictogenesis using mice with cell-type-specific Ido1 and Ido2 deficiencies. Ido1 or Ido2 deficiency in neurons, astrocytes and myeloid-derived cells all increase ictogenesis, whileonly a deficiency of microglial Ido2 (not Ido1) had this enhancing effect. Thus, the results of cell-type-specific Ido1 and Ido2 deficiencies differed from that of the global knockout, suggesting that neurons, astrocytes, microglia and macrophages utilize Ido1 and Ido2 to protect against ictogenesis, whereas Ido1 or Ido2 within other cells of the brain or the periphery drive ictogenesis. Thus, peripheral Ido1 and Ido2 may provide a novel target for anti-seizure drug discovery, but input from individual cell types should be carefully considered.
S-nitrosylation of Dexras1 attenuates fear memory generalization in the infralimbic cortex.
Qin C, Chen K, Chen YY … +3 more , Li JR, Tao Y, Bian XL
Brain Res · 2026 Apr · PMID 41698630 · Publisher ↗
Fear memory generalization is a fundamental hallmark of post-traumatic stress disorder (PTSD) that enables animals to use past experience to adapt to changing conditions. The infralimbic cortex (IL) is implicated in supp...
Fear memory generalization is a fundamental hallmark of post-traumatic stress disorder (PTSD) that enables animals to use past experience to adapt to changing conditions. The infralimbic cortex (IL) is implicated in suppressing generalized fear, but the underlying molecular mechanisms remain unknown. Here, we demonstrate that S-nitrosylation of Dexras1 (SNO-Dexras1) in the IL drives fear generalization. Dexras1 is activated by nitric oxide (NO) donors as well as by N-methyl-D-aspartic acid (NMDA) receptor-stimulated NO synthesis in cortical neurons. It is found that the level of SNO-Dexras1 is significantly increased in the IL of generalized mice and downregulation of SNO-Dexras1 attenuates fear generalization. Mechanistically, inhibition of SNO-Dexras1 increases the expression of phosphorylated extracellular regulated protein kinases (pERK) and brain derived neurotrophic factor (BDNF), implicating synaptic remodeling in the IL. Our study reveals a key role of SNO-Dexras1 in the fear generalization, which may provide a potential therapeutic strategy for PTSD.
Marine-Derived bioactive compounds from Aquaculture: Receptor-Mediated neuroprotection in neurodegenerative disorders.
Patwekar F, Patwekar M, Wei LS … +6 more , Rather GA, Mohammed A, Hussain MS, Gupta G, Fuloria S, Fuloria NK
Brain Res · 2026 May · PMID 41698629 · Publisher ↗
Neurodegenerative diseases, like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and ischemic stroke (IS), are a major global health challenge because o...
Neurodegenerative diseases, like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and ischemic stroke (IS), are a major global health challenge because of their complex, multifactorial pathology, and the lack of effective disease-modifying therapies. In recent years, aquaculture-derived marine bioactive molecules like fucoidan, phlorotannins, fucoxanthin, laminarin, alginate oligosaccharides, and C-phycocyanin have developed as promising agents for neuroprotection with their structural diversity and multi-target biological activity. This review showcase predominantly preclinical evidence, including in silico molecular docking analyses, in vitro functional assays, and in vivo animal models, to critically understand the receptor-mediated mechanisms with the neuroprotective actions of marine bioactives originated from aquaculture systems. Available studies shows these compounds can modulate large neuro-receptor systems, like cholinergic, dopaminergic, GABAergic, glutamatergic, toll-like, and nuclear receptors, leading in attenuation of oxidative stress, lowering of neuro-inflammation, regulation of neurotransmission, and conservation of mitochondrial and synaptic function. However, the positive approach of mechanistic evidence varies across compounds and receptor classes, with large interactions assisted by functional outcomes instead of direct receptor-binding validation. The review even discusses emerging and enabling technologies like brain organoids, multi-electrode array platforms, omics-based profiling, and artificial intelligence assisted drug discovery, which are increasingly utilized to refine mechanistic understanding and optimize marine-derived products. Importantly, current evidence stay largely preclinical, with little human studies and a lack of validated receptor-specific biomarkers. Overall, this review provides a well-balanced, evidence-based assessment of aquaculture-derived marine bioactive as potential neurotherapeutic agents.
Impact of IDH mutation and MGMT methylation as Independent prognostic markers in uniformly treated high grade glioma Patients: A Real-World evidence in the Indian Population.
Kumar A, Gurav M, Sarkar J … +11 more , Bapat P, Madhu K, Shetty O, Chatterjee A, Sahay A, Dasgupta A, Moiyadi A, Shetty P, Gupta T, Goda JS, Epari S
Brain Res · 2026 Apr · PMID 41692256 · Publisher ↗
IDH-mutant (IDHmt) high-grade gliomas (HGG) differ significantly from IDH-wildtype (IDHwt) HGG, or glioblastoma (GBM). MGMT promoter methylation (MGMTp) is an established prognostic marker in GBM, but its role in IDHmt H...
IDH-mutant (IDHmt) high-grade gliomas (HGG) differ significantly from IDH-wildtype (IDHwt) HGG, or glioblastoma (GBM). MGMT promoter methylation (MGMTp) is an established prognostic marker in GBM, but its role in IDHmt HGG remains unclear. We evaluated the prognostic impact of IDH mutation and MGMTp in 395 uniformly treated HGG patients in India. All patients underwent maximal safe resection followed by adjuvant radiotherapy and concurrent plus maintenance temozolomide (TMZ). MGMTp was assessed by methylation-specific PCR, and IDH1/2 mutations by immunohistochemistry and targeted sequencing. Median age was 50 years; median follow-up was 63 months. IDH mutations were present in 15.4 % of patients, and MGMTp in 36.7 %. Median overall survival (OS) was 19 months; 2-year OS was 41.5 %. Age > 50 years (HR 1.77, p < 0.001), <6 cycles of TMZ (HR 2.3, p < 0.001), and IDHwt status (HR 3.02, p < 0.001) predicted poorer outcomes. MGMTp status did not impact OS in IDHmt patients (p = 0.97). However, in IDHwt patients, unmethylated status was associated with worse OS (HR 3.66, p < 0.001) compared to methylated (HR 2.16, p = 0.009). These findings reaffirm the prognostic significance of IDH mutations and MGMTp methylation in GBM, underscoring their relevance in clinical stratification and treatment planning.
A peptide drug targeting SASH1-PKM2 interaction promotes recovery of traumatic brain injury in mice.
Huang X, Kong R, Huang Y … +6 more , Hu X, Wang P, Wu R, Liu Y, Liu M, Yang L
Brain Res · 2026 Apr · PMID 41690666 · Publisher ↗
Traumatic brain injury (TBI) has the highest incidence rate and remains a major therapeutic challenge. After TBI, astrocytes are rapidly activated, with these reactive astrocytes contributing to glial scar formation, whi...
Traumatic brain injury (TBI) has the highest incidence rate and remains a major therapeutic challenge. After TBI, astrocytes are rapidly activated, with these reactive astrocytes contributing to glial scar formation, which hinders neural regeneration. Thus, strategies that limit astrocyte activation can promote functional recovery post-TBI. SASH1, a multifunctional scaffold protein, is primarily expressed in astrocytes and regulates their maturation and activation, as demonstrated in our previous study. This study aims to determine whether inhibiting SASH1 function aids in TBI repair and to explore the underlying molecular mechanisms. Our data demonstrate that SASH1 interacts with PKM2, and silencing SASH1 in astrocytes leads to increased nuclear accumulation of PKM2. Additionally, in SASH1-deficient astrocytes, glucose uptake and lactate release were significantly elevated, suggesting a shift toward aerobic glycolysis. Furthermore, mRNA expression of the glucose transporter Glut1 and lactate dehydrogenase A was markedly increased following SASH1 depletion, implying that PKM2's nuclear translocation facilitates its role in transcriptional regulation. To further investigate this interaction, this study designed a peptide to block the SASH1-PKM2 interaction and applied it in a mouse TBI model. Disrupting the SASH1-PKM2 interaction significantly reduced astrocytic activation and enhanced wound healing. In conclusion, our findings suggest that SASH1 sequesters PKM2 in astrocytes, and the blocking peptide releases PKM2, thereby promoting aerobic glycolysis and facilitating tissue repair after TBI. This study offers novel insights into the role of SASH1 in TBI.
Neuroprotective and memory-enhancing effects of Aloysia gratissima extract and rutin in an MPTP-induced model of Parkinson's disease.
Erminda Schreiner G, Smolski Dos Santos L, Berny Pereira C … +8 more , Pereira de Oliveira C, Vieira Jacques G, Muller de Moura Sarmento S, Escalante Brittes G, Monteiro Fidelis E, Gonçalves IL, Pinton S, Manfredini V
Brain Res · 2026 Apr · PMID 41679683 · Publisher ↗
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide and currently has no cure. Available treatments mainly alleviate symptoms but show limited long-term efficacy, underscoring the n...
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide and currently has no cure. Available treatments mainly alleviate symptoms but show limited long-term efficacy, underscoring the need for new therapeutic strategies. This work aimed to investigate the neuroprotective potential of Aloysia gratissima leaf extract and the flavonoid rutin on memory deficits, inflammatory markers, and neurotransmitter bioavailability in an MPTP-induced model of PD in rats. At 12-13 weeks of age Wistar rats were intranasally administered 1 mg of MPTP to induce PD-like symptoms. Animals were treated by oral gavage for 14 days with A. gratissima extract (100 or 200 mg/kg) or rutin (50 or 100 mg/kg). Behavioral evaluations included the social recognition and Y-maze tests on treatment days 7 and 14. After treatment, hippocampal and cortical levels of dopamine, serotonin, and inflammatory markers were quantified. MPTP exposure caused significant memory deficits, neurotransmitter depletion, and increased neuroinflammatory markers. Treatment with A. gratissima (200 mg/kg) or rutin (100 mg/kg) significantly reversed these effects, improving memory performance, restoring dopamine and serotonin levels, and reducing neuroinflammation. A. gratissima extract and rutin demonstrated potential neuroprotective activity in the MPTP model of PD, likely through anti-inflammatory and neurotransmitter-regulating mechanisms. These findings support their potential as alternative therapeutic strategies for PD management.
Xuming tongmai decoction modulates astrocyte polarization and mitophagy via the PINK1/Parkin pathway in a rat model of acute ischemic stroke.
Ran L, Lan X, Zeng Z … +3 more , Yu X, Yang R, Tang J
Brain Res · 2026 Apr · PMID 41679682 · Publisher ↗
BACKGROUND: Acute ischemic stroke (AIS) is a leading global cause of disability and mortality, with limited therapeutic options beyond reperfusion strategies. Evidence suggests that mitophagy and astrocyte polarization p...
BACKGROUND: Acute ischemic stroke (AIS) is a leading global cause of disability and mortality, with limited therapeutic options beyond reperfusion strategies. Evidence suggests that mitophagy and astrocyte polarization play critical roles in neuronal survival and inflammatory regulation after stroke. Xuming tongmai (XMTM) decoction has shown clinical potential in improving AIS outcomes, but the underlying mechanisms remain unclear. This study aimed to investigate the molecular mechanisms of XMTM in the middle cerebral artery occlusion (MCAO) model rats, with a specific focus on its role in regulating astrocyte polarization and mitophagy. METHODS: In vivo, the MCAO model rats were established and administered 12.90 g/kg and 25.80 g/kg XMTM decoction, with 20 mg/kg aspirin serving as the positive control. In vitro, an oxygen-glucose deprivation/reperfusion (OGD/R) model was induced in astrocytes. Serum containing XMTM (XMTM serum) was prepared from rats administered XMTM decoction. The optimal working concentration of XMTM serum was determined using the CCK-8 assay before cell treatment. OGD/R-induced astrocytes were treated with negative serum, XMTM serum, Mdivi-1 (a mitophagy inhibitor), si-NC, si-PINK1, or their combination. The therapeutic effects of XMTM on MCAO rats were evaluated through pathological analysis, cerebral infarct volume measurement, and neurological deficit scoring. Astrocyte polarization was assessed using A1-type markers (C3, iNOS) and A2-type markers (Arg1, S100A10), while XMTM serum components were characterized by LC-MS/MS. Mitophagy activity was determined by measuring the mitochondrial membrane potential (MMP) and quantifying the expression levels of PINK1, Parkin, LC3II/I, p62, and reactive oxygen species (ROS). RESULTS: 25.80 g/kg XMTM decoction significantly reduced cerebral infarct volume, ameliorated neurological deficits, and improved pathological outcomes in AIS rats. LC-MS/MS results revealed that the main components of XMTM in the blood were alkaloids, anthraquinones, flavonoids, and phenolic acids. Both in vivo and vitro experiments demonstrated that XMTM upregulated Arg1 and S100A10 expression but downregulated C3 and iNOS, activated the PINK1/Parkin signaling pathway, and induced mitophagy in astrocytes. However, these beneficial effects of XMTM serum were abolished by si-PINK1 and mdivi-1. CONCLUSION: XMTM decoction exerts its neuroprotective effects in AIS rats by targeting the PINK1/Parkin-mediated mitophagy pathway, which subsequently promotes the polarization of astrocytes toward the neuroprotective A2 phenotype.
Increased hemispheric functional connectivity compensates speech perception in older adults with hearing loss.
Liu Y, Ding J, Wang S … +2 more , Kou N, Wang S
Brain Res · 2026 Apr · PMID 41662986 · Publisher ↗
Age-related hearing loss (ARHL) is associated with widespread cortical reorganization, yet the adaptive mechanisms of functional connectivity across disease stages and brain states remain unclear. Using functional near-i...
Age-related hearing loss (ARHL) is associated with widespread cortical reorganization, yet the adaptive mechanisms of functional connectivity across disease stages and brain states remain unclear. Using functional near-infrared spectroscopy (fNIRS), we examined both resting-state and speech perception-evoked functional connectivity (FC) in older adults with normal hearing, mild hearing loss, or moderate-to-severe hearing loss. FC alterations were found to be both state-dependent (i.e., varying with the cognitive state) and stage-dependent (i.e., depending on the severity of hearing loss). At rest, only the most impaired group showed localized increases in right-hemispheric FC. During speech perception, the mildly impaired group exhibited widespread FC enhancements across cross-hemispheric networks. These task-evoked enhancements were absent in the severely impaired group, suggesting a breakdown in adaptive recruitment. Subnetwork-level analyses further revealed spatially specific alterations in right-lateralized frontoparietal and frontotemporal circuits, as well as interhemispheric pathways linking left-hemisphere language hubs with right-hemisphere regions supporting attention, executive function, and top-down linguistic prediction. Collectively, our findings delineate a nonlinear trajectory of neural adaptation in ARHL, highlight a temporally bounded window of plasticity in early stages, and underscore the essential role of cross-hemispheric reorganization in sustaining speech processing under cognitive load.
Cerebellar iTBS ameliorates post-stroke cognitive impairment via the dentate nucleus-ventromedial thalamus pathway.
Pan Y, Huai Y, Lv Y … +6 more , Liang Y, Li Q, Zou Y, Zhong Z, Gong J, Wang X
Brain Res · 2026 May · PMID 41655937 · Publisher ↗
This study investigated whether the cognitive benefits of intermittent theta-burst stimulation (iTBS) in post-stroke cognitive impairment (PSCI) are mediated through modulation of the cerebellar dentate nucleus-contralat...
This study investigated whether the cognitive benefits of intermittent theta-burst stimulation (iTBS) in post-stroke cognitive impairment (PSCI) are mediated through modulation of the cerebellar dentate nucleus-contralateral ventromedial thalamus (DN-VM) circuit. The PSCI mice model were created using photothrombotic stroke, and the animals were assigned to five groups: Sham, PSCI, PSCI + iTBS, PSCI + iTBS + chemogenetic inhibition, and PSCI + chemogenetic excitation. Each group received its corresponding intervention. Behavioral changes were assessed before and after the intervention, and local field potentials (LFPs) were recorded from the medial prefrontal cortex (mPFC) and ventral hippocampus (vHPC) using in vivo electrophysiology. We analyzed oscillatory power within each region, as well as interregional coherence and theta-gamma coupling between the mPFC and vHPC. After 21 days of cerebellar iTBS, PSCI mice showed significant improvements in Y-maze performance, accompanied by increased theta band power in both the mPFC and vHPC, as well as enhanced interregional coherence and theta-gamma coupling. When chemogenetic inhibition of DN-VM excitability was applied with iTBS, these improvements were markedly reduced. Conversely, 21 days of chemogenetic excitation of the DN-VM circuit produced behavioral and electrophysiological effects comparable to those observed in the iTBS group. These findings suggest that cerebellar iTBS improves post-stroke cognition in mice by modulating the DN-VM circuit. Furthermore, the DN-VM pathway appears closely associated with cognitive function and may serve as a novel neuromodulatory target for PSCI.
Alpha suppression during non-painful tactile stimulation.
Güdücü Ç, Akın Öztürk G, Ülgen Z
Brain Res · 2026 Apr · PMID 41654100 · Publisher ↗
Alpha-band power is considered as a marker of sensory processing-related cortical states, including sensory suppression and the temporal organization of sensory input. This study aimed to investigate whether alpha-band p...
Alpha-band power is considered as a marker of sensory processing-related cortical states, including sensory suppression and the temporal organization of sensory input. This study aimed to investigate whether alpha-band power of electrophysiological brain responses is modulated by different interstimulus intervals during repetitive, non-painful tactile stimulation. Non-painful tactile stimuli were delivered to the index finger of the right hand with different interstimulus intervals (ISI) of 2 s (s), 4 s, and 8 s via a pneumatic stimulator. A separate session was conducted for each ISI in a pseudorandomized order. The electroencephalogram was recorded in all sessions with 24 volunteers. The results of the analysis showed that the alpha activity was lowest at ISI and highest at ISI. This pattern was consistently observed in both the central and parietal regions. In the ISI session, although no notable variation among the frontal, central, and parietal areas was observed, the most pronounced activity was observed in the frontal region in the ISI session. The highest level of alpha activity was observed in the central area during the ISI session. Variations in interstimulus intervals affect inhibitory control and sensory processing in the brain. The frontal cortex appears to manage attention and cognitive control more efficiently at intermediate intervals (ISI), whereas the central region shows greater involvement in processing tactile inputs at longer intervals (ISI).
Hydrogen sulfide in the paraventricular nucleus attenuates endoplasmic reticulum stress in Spontaneous hypertension.
Zhang D, Ren Y, Zhang S … +12 more , Yin X, Song H, Xing H, Wang H, Li Y, Yu M, Gao Y, Hu Y, Li B, Liu Q, Bi X, Liang Y
Brain Res · 2026 Apr · PMID 41651393 · Publisher ↗
Hydrogen sulfide (HS), known as a metabolic modulator, is a gaseous signaling molecule with functions similar to those of nitric oxide and carbon monoxide, all of which possess vasodilatory, antioxidant, and other proper...
Hydrogen sulfide (HS), known as a metabolic modulator, is a gaseous signaling molecule with functions similar to those of nitric oxide and carbon monoxide, all of which possess vasodilatory, antioxidant, and other properties. In the central nervous system, HS is a signaling molecule that is crucial for neuroprotection and the control of neurological processes. The paraventricular nucleus (PVN) of the hypothalamus is an important central nucleus that regulates and integrates cardiovascular and peripheral sympathetic activity. This study aimed to investigate whether intra-PVN injection of the endogenous HS synthase CBS activator S-adenosylmethionine (SAMe) or the endogenous HS synthase CBS inhibitor hydroxylamine (HA) modulates HS expression in the PVN, whether microglia in the PVN are targeted by HS, and whether PVN HS further induces alterations in blood pressure(BP) by affecting endoplasmic reticulum(ER) stress in the PVN of spontaneously hypertensive rats (SHR). Healthy male Wistar-Kyoto (WKY) rats and SHR were fed a normal diet for 8 weeks, followed by intra-PVN injections of SAMe, HA, or vehicle for 4 weeks. Plasma norepinephrine levels and mean arterial pressure were elevated in the SHR group. The expression of factors related to ER stress, such as p-PERK, GRP78, and p-IRE1α, was also elevated. Levels of these parameters were lower in the SHR + SAMe group, whereas the SHR + HA group presented with higher levels of these indicators. These findings suggest that endogenous HS attenuates sympathetic activity and hypertensive responses in the PVN, in part by modulating ER stress.
Ghrelin-based interventions in preclinical models of Parkinson's disease: a systematic review.
Cavalcanti Bezerra Gouveia HJ, Dos Santos-Júnior OH, Frasnelli J … +6 more , Fisette A, Dos Santos Júnior JP, da Silva Araújo MA, da Silva-Araújo ER, Toscano AE, Manhães de Castro R
Brain Res · 2026 Apr · PMID 41643910 · Publisher ↗
Ghrelin plays a crucial role in metabolism and gastrointestinal function. In the central nervous system, ghrelin modulates both hedonic and homeostatic control of eating behavior. Ghrelin promotes neuron survival by redu...
Ghrelin plays a crucial role in metabolism and gastrointestinal function. In the central nervous system, ghrelin modulates both hedonic and homeostatic control of eating behavior. Ghrelin promotes neuron survival by reducing apoptosis, inflammation, and oxidative stress, making it a potential therapeutic agent for neurodegenerative diseases. Parkinson's Disease (PD) is a neurodegenerative disease characterized by motor and non-motor symptoms. The motor impairments result primarily from the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta. Individuals with PD exhibit reduced levels of fasting and postprandial plasma ghrelin, and its receptors (GHSR) are expressed in the substantia nigra. Thus, this review aimed to evaluate the effects of ghrelin or GHSR agonists administration in experimental models of PD. A systematic search was conducted across PubMed, Scopus, Web of Science, and Embase. The 12 included studies involved PD models induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), as well as A53T transgenic mice. Interventions were performed with acylated and/or des-acylated ghrelin, in addition to the GHSR agonist HM01. Intervention with ghrelin was able to reduce dopaminergic neurodegeneration and improve motor function, while also positively impacting metabolic and gastrointestinal functions, expanding its relevance to non-motor consequences of PD. Considering that most results were obtained using acute toxin-induced models and only male animals, further studies using progressive PD models and evaluating sex differences are needed. Thus, although preclinical evidence supports ghrelin or GHSR agonists as promising agents for treatment, future studies will be essential to inform clinical translation and optimize therapeutic strategies for individuals with PD.
Identification of repopulated microglia-associated genes in microglia depleted/repopulated mice after spinal cord injury.
Xue S, Hu D, Li L … +6 more , Sun Y, Wei X, Xiao Y, Jiang Q, Qi C, Fu H
Brain Res · 2026 Apr · PMID 41633463 · Publisher ↗
This study aimed to investigate the effects of repopulated microglia on neural repair and functional recovery and identify repopulated microglia-associated repair-promoting genes after spinal cord injury (SCI) in mice fo...
This study aimed to investigate the effects of repopulated microglia on neural repair and functional recovery and identify repopulated microglia-associated repair-promoting genes after spinal cord injury (SCI) in mice following depletion of microglia via the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX3397. Mice were divided into control, sustained microglial depletion, and microglial depletion/repopulation groups according to being treated standard or PLX3397 diet. Mice in all groups were subjected to a complete spinal cord crush injury. Comprehensive assessments were performed using behavioral scoring, immunofluorescence staining 21 days post-injury, and RNA sequencing 21 days post-injury. Results demonstrated that PLX3397 effectively eliminated approximately 95 % of microglia in the mouse spinal cord. Upon drug withdrawal, microglia rapidly repopulated and exhibited a pro-regenerative phenotype. Repopulated microglia significantly promoted post-injury motor functional recovery, increased neuronal survival, and reduced glial scar formation. Transcriptomic analysis identified genes associated with repopulated microglia, which were enriched in immune response, complement activation, phagocytosis, and cytokine signaling pathways. Protein-protein interaction (PPI) network analysis of these associated genes further pinpointed key genes, includingIl1b,Ccr2, and Il15. This study reveals that repopulated microglia may exert neuroprotective effects by modulating the immune microenvironment. The 336 repopulated microglia-associated genes identified in this study, and the identified key genes that are preferentially upregulated in repopulated microglia may represent novel therapeutic targets for SCI.
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