bims-medebr 2026-01-18 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–01–18
thirteen papers selected by
Regina F. Fernández, Johns Hopkins University

The metabolic reprogramming of lactate in the nervous system.
Refining human brain metabolism trajectories: Convergence, uncertainties, and the value of arteriovenous data.
Lipid-laden endothelial cells exhibit a transcriptomic signature linked to blood-brain barrier dysfunction, metabolic reprogramming, and increased inflammation in the aging brain.
Characterization of the Lipidome of Neurons in Mouse Brain Nuclei Using Imaging Mass Spectrometry.
β-Hydroxybutyrate improves glymphatic system function and alleviates cerebral edema in mice after ischemic stroke.
Dynamic Spatial Metabolomics Reveals Region-Specific Metabolic Reprogramming and Markers during Vascular Cognitive Impairment Progression.
Electrocorticographic, Astrocytic and Transcriptomic Signatures in the Triple Transgenic Mouse Model of Alzheimer's Disease submitted to Stearoyl-CoA Desaturase Inhibition.
Association of choroid plexus volume with brain atrophy and glucose metabolism in multiple system atrophy.
Sex-Dependent Differences in Bioenergetics of Young Mouse Brain Microvasculature: Implications for Oxygen-Glucose Deprivation and Reoxygenation Injury.
Mapping brain growth and sex differences across prenatal to postnatal development.
Hepatic HMGCS2-derived β-hydroxybutyrate attenuates hippocampal insulin resistance and neuroinflammation to promote MASLD-induced cognitive function.
Molecular carriers enable precision delivery and region-specific neuroprotection by dietary DHA in the mouse brain.
The Anti-proliferative Effects of Anandamide and Oleamide in Glioblastoma Cell Lines Recruit Mitochondrial and PPAR-γ Receptor Modulation.

Exp Neurol. 2026 Jan 14. pii: S0014-4886(26)00006-3. [Epub ahead of print] 115643

The metabolic reprogramming of lactate in the nervous system.

Yu Gu, Botao Zhang, Chunyan Lei, Yanjiao Guan, Binger Fan, Wenyan Xu, Ansong Jin, Qionghua Deng, Ruolong Xue, Xinglong Yang, Xiaoyan Zhu.

  Lactate, a critical energetic substrate and signaling molecule in the central nervous system (CNS), plays a pivotal role in maintaining neurophysiological homeostasis and driving the pathogenesis of neurodegenerative disorders through metabolic reprogramming. Herein, this review systematically summarizes recent progress in molecular mechanisms governing lactate metabolic reprogramming as well as its multiple biological functions in the central nervous system. Under physiological conditions, lactate regulates energy distribution via the astrocyte-neuron lactate shuttle, while mediates neural communication through receptors including G Protein-Coupled Receptor 81 and N-Methyl-d-Aspartate Receptor, thereby modulating synaptic plasticity and memory consolidation. In neurodegenerative pathologies (such as Alzheimer's and Parkinson's diseases), dysregulated lactate reprogramming is observed in the form of dynamic lactate imbalance, altered expression of monocarboxylate transporters and lactate dehydrogenase, and defective mitochondrial energy coupling. These perturbations further enhance neuronal damage by triggering neuroinflammation and perturbing epigenomic homeostasis (e.g., histone lactylation). Critical knowledge gaps remain unresolved: (1) The temporal dynamics of lactate flux during disease progression remain uncharacterized; (2) The spatial heterogeneity of lactate distribution across brain nuclei and its regulatory mechanisms are debated; (3) Consensus is lacking regarding functional alterations of core lactate metabolic components; and (4) The precise signaling cascades through which lactate modulates neurodegeneration require elucidation. By integrating contemporary research on central nervous system lactate reprogramming, this work provides novel perspectives on neurodegenerative disease mechanisms and establishes a theoretical framework for developing targeted therapeutic strategies that modulate lactate metabolism.

Keywords:  Lactate; Lactate metabolism; Metabolic reprogramming; Mitochondrial energy metabolism; Neurodegenerative diseases; Neuroinflammation

DOI:  https://doi.org/10.1016/j.expneurol.2026.115643
J Cereb Blood Flow Metab. 2026 Jan 16. 271678X251409609

Refining human brain metabolism trajectories: Convergence, uncertainties, and the value of arteriovenous data.

Manu S Goyal, Tyler M Blazey, Marcus E Raichle, Andrei G Vlassenko.

  Structural brain aging trajectories are increasingly well characterized in very large datasets, but metabolic trajectories remain less clear. It has been proposed that CMRglc may fall faster than CMRO2 with age, though this view has been questioned. In this context, Duffy et al. now provide a rare contribution by assembling brain arteriovenous data from >200 adults aged 19-45 years. Their results offer an opportunity to refine our understanding of brain metabolism trajectories and highlight the challenges in studying this question.

Keywords:  Aerobic glycolysis; PET; aging; arteriovenous sampling; brain

DOI:  https://doi.org/10.1177/0271678X251409609
Geroscience. 2026 Jan 16.

Lipid-laden endothelial cells exhibit a transcriptomic signature linked to blood-brain barrier dysfunction, metabolic reprogramming, and increased inflammation in the aging brain.

Sarah Otu-Boakye, Duraipandy Natarajan, Bhuvana Plakkot, Ilakiya Raghavendiran, Paulina Hoppa, Tamas Kiss, Madhan Subramanian, Priya Balasubramanian.

  Dysregulation in lipid metabolism is increasingly recognized as a key contributor to age-related diseases, including neurodegeneration and cerebrovascular dysfunction. While prior studies have largely focused on glial cells, the impact of lipid dysregulation on brain endothelial aging remains poorly understood. In this study, we conducted a secondary analysis of single-cell transcriptomic data from young and aged mouse brains, with a specific focus on endothelial cells (ECs). Our analyses revealed that aging promotes lipid droplet accumulation in brain ECs. These lipid-laden brain ECs exhibit a transcriptomic signature indicative of impaired blood-brain barrier function, increased cellular senescence, and inflammation in aging. Furthermore, lipid accumulation is associated with an altered metabolic phenotype characterized by increased fatty acid oxidation and decreased glycolysis and impaired mitochondrial electron transport chain activity in the ECs of the aging brain. We have also validated lipid accumulation in aged ECs in vivo. Collectively, our findings indicate that lipid accumulation may drive structural, functional, and metabolic impairments in the brain ECs, likely contributing to cerebrovascular aging. Understanding the mechanisms underlying lipid accumulation-induced endothelial dysfunction may offer novel therapeutic strategies for mitigating microvascular dysfunction and cognitive decline in aging.

Keywords:  Aging brain; Blood–brain barrier dysfunction; Fatty acid oxidation; Lipid-laden endothelial cells; Neuroinflammation; Senescence

DOI:  https://doi.org/10.1007/s11357-025-01986-y
Anal Chem. 2026 Jan 12.

Characterization of the Lipidome of Neurons in Mouse Brain Nuclei Using Imaging Mass Spectrometry.

Cristina Huergo, Laura de Las Heras-García, Jone Razquin, Yuri Rueda, Cristina Miguélez, José A Fernández.

Understanding the molecular composition of the brain at cellular level is essential for deciphering the metabolic alterations associated with brain diseases. Furthermore, the different prevalence of some neurological diseases between males and females highlight the importance of incorporating gender factor in such studies. Here, we demonstrate that using imaging mass spectrometry in negative polarity it is possible to isolate and characterize the lipidome of specific neuronal populations in the mouse brain, including the locus coeruleus (LC), mesencephalic neurons and the substantia nigra pars compacta (SNc). Neuronal identity was validated through immunofluorescence on adjacent serial sections. Comparative analysis revealed that each neuronal population presents a distinct and well-defined lipidic profile, with differences extending across all lipid classes analyzed. Regarding sex-based differences, we found discrete differences in phosphatidylcholine/phosphatidylethanolamine-ether, phosphatidylinositol and sphingomyelin LC neurons. Lipidomic differences were more pronounced in mesencephalic neurons, whereas no significant sex-dependant differences were observed in SNc lipid composition. These findings lay the groundwork for future studies aimed at identifying lipid metabolic dysregulations in the context of neurodegenerative diseases.

DOI: https://doi.org/10.1021/acs.analchem.5c08016
Acta Pharmacol Sin. 2026 Jan 14.

β-Hydroxybutyrate improves glymphatic system function and alleviates cerebral edema in mice after ischemic stroke.

Ming-Jia Yu, Rui-Qi Xiong, Jing-Wen Wu, Yong-Chuan Li, Jia-Xin Xie, Hai-Ping Zhou, Guan-Yu Ye, Yuan Chang, Kai-Bin Huang, Su-Yue Pan.

  Cerebral edema is a severe complication following ischemic stroke. Recent studies have highlighted the crucial role of the glymphatic system (GS) in the clearance of water and macromolecules. GS dysfunction involving the disorders of AQP4 polarization may be crucial in the pathophysiology of cerebral edema. β-Hydroxybutyrate (BHB), the main component of the ketone body, has been shown to alleviate neurological deficits by restoring GS function in subarachnoid hemorrhage models and to reduce Aβ deposition in Alzheimer's disease models. In this study we investigated the effects of BHB on cerebral edema following ischemic stroke and its mechanisms. The mice were fed a ketogenic diet (KD) or a normal diet for 4 weeks before transient middle cerebral artery occlusion (MCAO). Alternatively, the mice received BHB (5 g·kg-1·d-1) or vehicle post-MCAO. By using brain section analysis, transcranial macroimaging, two-photon in vivo imaging and MRI, we demonstrated that both KD and BHB treatment significantly enhanced GS function under normal and MCAO conditions. BHB reduced cerebral edema and infarct volume post-MCAO. Notably, delayed BHB treatment initiated 10 h post-MCAO still improved GS function, but did not influence infarct volume. Furthermore, we revealed that BHB increased α1-syntrophin expression and H3K27ac levels in α1-syntrophin (Snta1) enhancer, restoring AQP4 polarization. In addition, BHB also reduced HDAC3 expression and elevated p300 expression. These results suggest that a KD and BHB treatment enhance GS function in mice and that BHB also mitigates brain edema after MCAO. The potentiation of GS function by BHB is likely mediated by the inhibition of HDAC3 activity and the increase in p300 activity, which upregulate α1-syntrophin expression and restore AQP4 polarization.

Keywords:  beta-hydroxybutyrate; brain edema; epigenetic modulation; glymphatic system; ischemic stroke; ketogenic diet

DOI:  https://doi.org/10.1038/s41401-025-01706-4
ACS Chem Neurosci. 2026 Jan 15.

Dynamic Spatial Metabolomics Reveals Region-Specific Metabolic Reprogramming and Markers during Vascular Cognitive Impairment Progression.

Lin Liu, Yang Yang, Zhongyuan Qu, Shuang Wu, Xiang Zou, Dongxue Wang.

  Vascular cognitive impairment (VCI) significantly contributes to dementia; however, the precise metabolic mechanisms underlying its region-specific pathological progression remain poorly understood. We hypothesized that spatially resolved metabolomics could uncover detailed spatiotemporal metabolic disruptions and key therapeutic windows. Using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), we systematically mapped metabolite alterations in hippocampal subregions (CA1, CA3, dentate gyrus) and cortical areas of a rat model of chronic cerebral hypoperfusion (2-VO) at early (7 days), intermediate (28 days), and late (56 days) stages. MALDI-MSI enabled region-resolved visualization of lipid, energy, and inflammatory metabolic signatures at a spatial resolution of 20 μm, allowing comparative analysis of spatiotemporal metabolic trajectories across disease progression. Our analysis revealed distinct temporal patterns: early depletion of membrane lipids and cholinergic precursors primarily in CA1 and DG, midphase ceramide accumulation and glycolytic shift notably in CA3 at day 28, and widespread mitochondrial dysfunction with necroptotic signaling by day 56. Critical metabolic putative markers─including PC(15:0/16:0), CerP(d18:1/18:0), and LysoPA(0:0/18:1)─delineated disease stages, establishing day 28 as a pivotal therapeutic intervention window. These findings provide novel mechanistic insights and metabolic targets for therapeutic strategies in VCI.

Keywords:  MALDI-MSI; metabolic markers; region-specific metabolic reprogramming; spatial metabolomics; temporal metabolic profiling; vascular cognitive impairment

DOI:  https://doi.org/10.1021/acschemneuro.5c00528
Neuropharmacology. 2026 Jan 13. pii: S0028-3908(26)00008-0. [Epub ahead of print] 110835

Electrocorticographic, Astrocytic and Transcriptomic Signatures in the Triple Transgenic Mouse Model of Alzheimer's Disease submitted to Stearoyl-CoA Desaturase Inhibition.

Audrey Hector, Tanya Leduc, Maria João da Costa Caiado, Benoît Delignat-Lavaud, Julien Dufort-Gervais, Caroline Daneault, Christine Des Rosiers, Clément Bourguignon, Jean-Marc Lina, Karl Fernandes, Jonathan Brouillette, Valérie Mongrain.

  Alzheimer's disease (AD) is associated with cognitive deficits and sleep disturbances. Research suggests the involvement of dysfunctions in lipid metabolism in the brain of AD patients and animal models. The inhibition of stearoyl-CoA desaturase (SCD), a lipid-converting enzyme, was shown to restore memory in triple transgenic (3xTg)-AD mice. In the brain, astrocytes regulate the synthesis of specific lipids. This project tested whether the inhibition of SCD restores sleep in 3xTg-AD mice, and whether this associates with modifications in lipids, astrocytic function and the transcriptome. Wild-type (WT) and 3xTg-AD female mice received a SCD inhibitor (SCDi) or vehicle, which was followed by an electrocorticographic (ECoG) recording. Brain slices were stained for lipid droplets, astrocytic markers or processed for spatial transcriptomics. The reduced time spent awake (increased time spent in slow wave sleep) in 3xTg-AD mice was not restored by SCDi treatment. Rhythmic and scale-free ECoG activities were markedly altered in 3xTg-AD mice for all wake/sleep states, and SCDi changed these ECoG signatures differently in mutant in comparison to WT mice. GFAP-positive cell density and lipid droplet count were elevated in hippocampal CA1, and rescued by SCDi. The treatment also rescued the expression of several genes in a manner mainly overlapping between brain regions. The findings suggest that the multiple wake/sleep alterations in 3xTg-AD mice are not mitigated by SCD inhibition, but that this treatment can revert changes in hippocampal astrocytes, lipids and in the brain transcriptome. This work will benefit the understanding of the AD pathophysiology and associated sleep disturbances.

Keywords:  3xTg-AD mice; ALDH1L1; GFAP; astrocytes; lipid-related treatment; scale-free activity; slow wave sleep; spatial transcriptomics; spectral analysis of the electrocorticogram

DOI:  https://doi.org/10.1016/j.neuropharm.2026.110835
Sci Rep. 2026 Jan 16.

Association of choroid plexus volume with brain atrophy and glucose metabolism in multiple system atrophy.

Chae Jung Park, Yeeun Sun, Hyun-Jae Jeong, Han Kyu Na, So Hoon Yoon, Seung-Koo Lee, Chul Hyoung Lyoo, Young H Sohn, Seong Ho Jeong, Phil Hyu Lee.

  The choroid plexus (CP), a component of the glymphatic system, is essential in homeostasis and producing cerebrospinal fluid. Role of CP in multiple system atrophy (MSA) remains unclear. This study aimed to investigate the implication of the CP in MSA. This retrospective cross-sectional study included 87 MSA patients who underwent the Unified MSA Rating Scale (UMSARS), brain MRI, and18F-fluorodeoxyglucose PET scan, along with 84 healthy controls (HCs). Multivariate linear regression analyses were performed to examine the associations between CP volume (CPV) and UMSARS scores, as well as the volumes and cerebral metabolism. Compared with HCs, MSA had significantly reduced CPV (1.00 ± 0.27 vs. 1.30 ± 0.26, P < 0.001). CPV showed no association with UMSARS, however, it was positively correlated with regional cerebellar volumes. Reduced CPV was associated with lower cerebral glucose metabolism in MSA-susceptible regions, consistent with the positive association between CPV and regional cerebral glucose metabolism observed in multivariate analyses. Notably, CPV positively correlated with glucose metabolism in the brainstem (β = 0.110, P = 0.003) and cerebellar white matter (β = 0.080, P = 0.004). This study suggests that CPV is positively associated with disease burden in MSA, with CPV decreasing as disease severity increases. Further research is warranted to determine whether CPV could serve as a potential biomarker for MSA.

Keywords:  Brain atrophy; Brain glucose metabolism; Choroid plexus; Multiple system atrophy

DOI:  https://doi.org/10.1038/s41598-026-35850-6
Am J Physiol Heart Circ Physiol. 2026 Jan 12.

Sex-Dependent Differences in Bioenergetics of Young Mouse Brain Microvasculature: Implications for Oxygen-Glucose Deprivation and Reoxygenation Injury.

Venkata N Sure, Lokanatha Oruganti, Siva S V P Sakamuri, Swathi Chitra Pasupulati, Raed Y Ageeli, Partha Chandra, Ibolya Rutkai, Xiaoying Wang, Sarah H Lindsey, Ricardo Mostany, David W Busija, Prasad V G Katakam.

  Sex differences are evident in vascular mitochondrial function, however, the impact of sex on microvascular bioenergetics has never been studied. We investigated the bioenergetics of freshly isolated mouse brain microvessels (BMVs) from young mice (6-8 weeks). Oxygen consumption rate and extracellular acidification rates of BMVs were measured utilizing Agilent Seahorse XFe24 analyzer. The Real-Time ATP Rate assay showed reduced total ATP production with contributions from both glycolysis and oxidative phosphorylation (OxPhos) in BMVs from females compared with males. The Mitochondrial Stress test revealed lower basal respiration and ATP production in BMVs of females versus males. The Glycolytic Rate assay indicated reduced basal glycolysis and proton efflux rate (PER) in females, with no sex differences in basal PER and post-2-DG acidification. Mito Fuel Flex Test found no differences in fuel substrate utilization. Measurements utilizing homogenates of BMVs confirmed lower ATP levels in females, with no sex differences in citrate synthase activity or key mitochondrial protein/mRNA levels. Ex vivo oxygen-glucose deprivation followed by reoxygenation (OGD/R) of mouse BMVs displayed significantly reduced mitochondrial respiratory function as well as glycolytic activity in females versus males. However, OGD/R paradoxically increased lactate dehydrogenase release, a marker of cellular injury, from male BMVs but has no effect on female BMVs. Thus, female BMVs exhibited decreased mitochondrial respiratory and glycolytic function compared with males, despite similar substrate utilization for energy production. In young mice, the sex-dependent differences in OxPhos and glycolysis may increase the vulnerability of the microvasculature to OGD/R injury in males and vasoprotection in females.

Keywords:  Bioenergetics; Brain Microvessels; Glycolysis; Mitochondrial respiration; Sex differences

DOI:  https://doi.org/10.1152/ajpheart.00195.2025
Sci Rep. 2026 Jan 15.

Mapping brain growth and sex differences across prenatal to postnatal development.

Yumnah T Khan, Alex Tsompanidis, Marcin A Radecki, Carrie Allison, Meng-Chuan Lai, Richard A I Bethlehem, Simon Baron-Cohen.



Keywords:  Brain development; Brain growth; MRI; Neonatal; Prenatal; Sex differences

DOI:  https://doi.org/10.1038/s41598-025-33981-w
Commun Biol. 2026 Jan 10.

Hepatic HMGCS2-derived β-hydroxybutyrate attenuates hippocampal insulin resistance and neuroinflammation to promote MASLD-induced cognitive function.

Lijuan Nie, Jing Sun, Weilong Xu, Xinyi Yang, Gaoxiang Wang, Ying Wang, Tao Jiang, Yutian Cao, Hao Chen, Qingrong Xia, Xiqiao Zhou.

Cognitive impairment is a known complication of metabolic dysfunction-associated steatotic liver disease (MASLD), and β-hydroxybutyrate (BHB), a ketone body providing alternative brain energy under metabolic stress, may exert neuroprotective effects. This study explored BHB's role in MASLD-related cognitive impairment and its underlying mechanisms using a 20-week high-fat diet (HFD)-induced MASLD mouse model with cognitive dysfunction, comparing 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) knockout (KO), wild-type (WT), and exogenous BHB-supplemented mice. Key outcomes included hippocampal pathology, neuroinflammation, insulin resistance, amyloid-β (Aβ) deposition, tau phosphorylation, glucose/lipid homeostasis, and cognitive function. Results showed Hmgcs2 KO mice exhibited worse metabolic dysregulation (elevated triglycerides, cholesterol, hepatic lipid accumulation, impaired glucose tolerance, increased insulin, reduced BHB), cognitive decline (confirmed by Y-maze and novel object recognition tests), hippocampal p-Tau/Aβ aggregation, neuroinflammation (elevated iNOS, COX-2, IL-1β), and impaired IRS/PI3K/AKT/GSK3β signaling, whereas exogenous BHB supplementation alleviated these phenotypes. Collectively, reduced Hmgcs2 expression and BHB levels critically contribute to MASLD-induced cognitive impairment via cerebral insulin signaling disruption and neuroinflammation, highlighting BHB's therapeutic potential.

DOI: https://doi.org/10.1038/s42003-026-09513-1
Nutr Neurosci. 2026 Jan 11. 1-19

Molecular carriers enable precision delivery and region-specific neuroprotection by dietary DHA in the mouse brain.

Xiaochun Chen, Wei Sun, Hongliang Zhang, Yanjiao Li, Ruikun He, Zhengjiang Qian.

   OBJECTIVE: Docosahexaenoic acid (DHA) is indispensable for neurological health, yet its therapeutic potential is hampered by poor bioavailability and non-specific brain distribution. We hypothesized that co-administering DHA with specific molecular carriers - eicosapentaenoic acid (EPA) or phosphatidylserine (PS) - would exploit distinct cellular transport pathways to achieve region-specific brain enrichment and associated neuroprotection.
METHODS: By dietary intervention using C57BL/6J mice, we employed regional lipidomics, ELISA, and western blotting to assess brain fatty acid incorporation, neurotrophic factor levels, inflammatory signaling, and transporter expression following supplementation with DHA alone or in combination with EPA or PS.
RESULTS: Lipidomic analyses revealed striking, carrier-dependent spatial modulation of DHA. Co-administration with EPA enriched the cortex and striatum, while PS co-administration preferentially targeted the hippocampus and cortex. Mechanistically, both carrier-DHA complexes enhanced the expression of the key blood-brain barrier (BBB) transporter MFSD2A. Functionally, this precision delivery activated distinct neuroprotective programs. PS + DHA robustly upregulated the CREB-BDNF neurotrophic pathway, while EPA + DHA uniquely suppressed the NF-κB pathway, demonstrating potent anti-inflammatory effects. These results demonstrate that the choice of molecular carrier dictates both the spatial distribution of DHA and the nature of the ensuing neuroprotective response.
DISCUSSION: Our findings establish that dietary co-supplementation with specific lipid carriers enables precise spatial delivery of DHA by engaging specific transporters, thereby activating distinct neuroprotective programs in a region-specific manner. This work provides a mechanistic framework for a precision nutrition strategy, tailoring DHA formulations to target specific neuroanatomical and cellular vulnerabilities in neurological disorders.

Keywords:  BDNF; Docosahexaenoic acid (DHA); MFSD2A; blood brain barrier; molecular carriers; neuroinflammation; precision nutrition; spatial targeting

DOI:  https://doi.org/10.1080/1028415X.2025.2608369
Neurochem Res. 2026 Jan 14. 51(1): 43

The Anti-proliferative Effects of Anandamide and Oleamide in Glioblastoma Cell Lines Recruit Mitochondrial and PPAR-γ Receptor Modulation.

Ana Laura Torres-Román, Alette Ortega-Gómez, Carolina Y Reyes-Soto, Omar Emiliano Aparicio-Trejo, Belén Cuevas-López, Fernando E García-Arroyo, Erika Ruíz-García, Juan A Matus-Santos, Beatriz Ferrer, Michael Aschner, Gustavo Jardón, Tessy López-Goerne, Anayansi Molina-Hernández, Juan Carlos Tenorio-Monterrubio, Abel Santamaría.

  The endocannabinoid anandamide (AEA) and the related metabolite oleamide (ODA) have been demonstrated to possess anti-proliferative properties by recruiting apoptotic mechanisms in glioblastoma cells; however, the role of receptors other than the canonical cannabinoid receptors in their pattern of anti-proliferative mechanisms has been poorly investigated. Here, we evaluated the role of mitochondrial function and PPAR-γ membrane receptors in the anti-proliferative mechanisms induced by AEA and ODA in the glioblastoma cell lines C6 and RG2. Cell viability and lipid peroxidation assessments in both cell lines showed antiproliferative and pro-oxidant effects of the tested cannabinoids, respectively, compared to primary astrocyte cultures used as a non-tumor negative control. AEA and ODA also reduced mitochondrial membrane potential in C6, but not in RG2 cells, while impairing mitochondrial Complex I activity in C6. The PPAR-γ receptor antagonist GW9662 showed differential effects on the AEA- and ODA-induced loss of cell viability in both cell lines, as well as in mitochondrial membrane potential. The ontogenetic origin and metabolic differences between RG2 and C6 cell lines may establish differential responses evoked by endogenous cannabinoids and PPAR-γ receptor modulation. Combined, our results demonstrate that AEA and ODA modulate mitochondrial function in glioblastoma cells by inhibiting the activity of mitochondrial Complex 1, which in turn increases markers of oxidative damage and interferes with glioblastoma proliferation.

Keywords:  Antitumor activity; Brain cancer; Endocannabinoid system; Mitochondrial metabolism; Oxidative stress; PPAR-γ

DOI:  https://doi.org/10.1007/s11064-025-04654-x