Neuropharmacology[JOURNAL]
Sun
200 papers
Deferoxamine attenuates bone cancer pain via modulation of the RIG-I/CCL5 signaling pathway in rats.
Hang LH, Ju JJ, He M … +1 more , Zhou J
Neuropharmacology · 2026 Aug · PMID 41999973 · Publisher ↗
Bone cancer pain (BCP) severely compromises the quality of life, and its molecular mechanisms are not fully understood. Increasing evidence implicates spinal iron overload in pain-related neuroinflammation, with the chem...
Bone cancer pain (BCP) severely compromises the quality of life, and its molecular mechanisms are not fully understood. Increasing evidence implicates spinal iron overload in pain-related neuroinflammation, with the chemokine CCL5 acting as a critical mediator. Given that retinoic acid-inducible gene I (RIG-I) regulates CCL5 expression in pathological conditions, we hypothesized that a spinal Fe/RIG-I/CCL5 signaling axis contributes to BCP. Using rat spinal cord neurons in vitro, we found that erastin increased levels of Fe, RIG-I, and CCL5, effects that were reversed by the iron chelator deferoxamine. RIG-I knockdown reduced CCL5 expression but did not affect Fe accumulation. In a rat model of BCP, spinal iron accumulation was associated with the development of mechanical allodynia and the upregulation of RIG-I and CCL5; immunofluorescence further revealed that RIG-I was predominantly expressed in spinal neurons. Intrathecal administration of deferoxamine or RIG-I siRNA attenuated pain behaviors and downregulated the expression of both RIG-I and CCL5. These findings demonstrate the spinal Fe/RIG-I/CCL5 pathway as a critical promoter of BCP and highlight the potential therapeutic strategies targeting iron chelation or RIG-I signaling.
P2X receptors in immune cells: key regulators of inflammation and immune function.
Adinolfi E, Falzoni S, Fortuna F … +5 more , Ricci L, Ruo L, Grignolo M, Giuliani AL, Pegoraro A
Neuropharmacology · 2026 Aug · PMID 41997249 · Publisher ↗
P2X receptors are a family of ATP-gated ion channels comprising seven subtypes (P2X1-P2X7). These receptors mediate rapid cation fluxes and downstream signaling events that regulate inflammation, synaptic transmission, a...
P2X receptors are a family of ATP-gated ion channels comprising seven subtypes (P2X1-P2X7). These receptors mediate rapid cation fluxes and downstream signaling events that regulate inflammation, synaptic transmission, and cell death. P2X receptors are widely expressed in immune cells of both myeloid and lymphoid lineages, including macrophages, microglia, dendritic cells, neutrophils, eosinophils, natural killer cells, myeloid-derived suppressor cells, T, B, and innate lymphocytes. Through these diverse populations, P2X receptors influence cytokine secretion, chemotaxis, phagocytosis, antigen presentation, and the balance between immune activation and suppression. Beyond initiating inflammatory responses to infectious or sterile insults, P2X signaling contributes to immune tolerance and homeostasis. This review summarizes current and emerging insights into the immunomodulatory roles of P2X receptors across innate and adaptive compartments, highlighting mechanistic pathways and translational relevance. Collectively, P2X receptors act as central integrators of metabolic and inflammatory cues, representing promising therapeutic targets for inflammatory, autoimmune, and neuroimmune diseases, as well as cancer.
Targeting the purinergic P2X7 receptor in epilepsy: Cell types matter.
Engel T, Salari V, Sun MJ … +1 more , Mitra M
Neuropharmacology · 2026 Aug · PMID 41990969 · Publisher ↗
Epilepsy affects up to 70 million people worldwide, making it one of the most prevalent chronic neurological disorders and a major burden on healthcare systems. Although more than 30 anti-seizure medications (ASMs) are c...
Epilepsy affects up to 70 million people worldwide, making it one of the most prevalent chronic neurological disorders and a major burden on healthcare systems. Although more than 30 anti-seizure medications (ASMs) are currently in clinical use, drug refractoriness remains a major clinical challenge. In addition, ASMs often cause life quality-reducing side effects and do not significantly modify the underlying course of the disease. Purinergic signalling mediated by extracellular ATP has gained increasing attention as a contributor to seizures and epilepsy, particularly through activation of the ionotropic P2X7 receptor (P2X7R). Accumulating evidence demonstrates that P2X7R antagonism can modulate acute seizures and reduce the seizure burden in epilepsy. Given the prominent expression of P2X7Rs on immune cells such as microglia, P2X7R-dependent effects on seizures have mainly been attributed to the initiation of proinflammatory signalling cascades. Consistent with this, studies have reported reduced seizure severity in mice lacking microglial P2X7Rs, and P2X7R-induced inflammatory responses have been implicated in resistance to pharmacotherapy. However, P2X7Rs participate in a wide range of pathological cellular processes, therefore, restricting their contribution to hyperexcitability and epilepsy solely to inflammation likely represents an oversimplification. In this line, emerging research indicates that P2X7R signalling exerts cell type-specific effects, with both pro- and anticonvulsive functions depending on the cellular context. The main aim of this review is to provide a critical discussion of the role of P2X7Rs in epilepsy, with a particular focus on their potential cell type-specific contributions.
Endogenous TRPV1 agonist OLDA prevents mu-opioid receptor desensitization and preserves analgesia in sensitized nociceptive circuits.
Heles M, Vasconcelos D, Palecek J
Neuropharmacology · 2026 Aug · PMID 41990968 · Publisher ↗
Opioid analgesics acting primarily through the μ-opioid receptor (MOR) are profoundly limited by receptor desensitization, tolerance and opioid-induced hyperalgesia. Recent work has identified functional crosstalk betwee...
Opioid analgesics acting primarily through the μ-opioid receptor (MOR) are profoundly limited by receptor desensitization, tolerance and opioid-induced hyperalgesia. Recent work has identified functional crosstalk between MOR and the transient receptor potential vanilloid 1 (TRPV1) channel, whereby TRPV1 activation can suppress β-arrestin-dependent MOR desensitization. Whether endogenous TRPV1 ligands contribute to this regulation in intact nociceptive circuits has remained unknown. Here we show that N-oleoyldopamine (OLDA), an endogenous vanilloid, preserves MOR signaling and opioid analgesia by preventing MOR desensitization in the spinal cord. Using electrophysiological recordings from rat spinal cord dorsal horn neurons, we demonstrate that prolonged exposure to the MOR agonist DAMGO induces robust functional desensitization, abolishing opioid-mediated inhibition of synaptic transmission. Co-incubation with OLDA prevents this desensitization in a concentration-dependent manner, maintaining DAMGO efficacy without altering basal synaptic activity. Under neuropathic conditions induced by chronic constriction injury, low concentrations of OLDA that are ineffective in naïve tissue become sufficient to preserve MOR responsiveness, consistent with enhanced TRPV1 sensitization after nerve injury. In vivo, intrathecal OLDA restores opioid-evoked thermal and mechanical hypoalgesia in a chemokine-induced MOR desensitization model. Together, these findings identify OLDA as an endogenous regulator of TRPV1-MOR crosstalk that selectively preserves opioid signaling in sensitized nociceptive circuits. Our results extend recent mechanistic insights into TRPV1-dependent control of β-arrestin pathways and reveal an intrinsic modulatory system that may be harnessed to improve the durability and safety of opioid analgesia in chronic pain.
Microdosing: Fact or fiction?
Halberstadt AL, Young JW
Neuropharmacology · 2026 Aug · PMID 41990967 · Publisher ↗
Abstract loading — click title to view on PubMed.
Corrigendum to "Chronic morphine differentially impacts glutamatergic synaptic plasticity in the ventral tegmental area of adult versus adolescent mice" [Neuropharmacology (2026) DOI: 10.1016/j.neuropharm.2026.110925].
Edwards JG, Ostlund I, Von Gunten M
Neuropharmacology · 2026 Aug · PMID 41982039 · Publisher ↗
Abstract loading — click title to view on PubMed.
Optimizing cognitive enhancement through dopamine transporter modulation.
Niello M, Kalaba P, Cybulska-Klosowicz A … +15 more , Kirchhofer M, Spreitzer I, Spreitzer M, Wackerlig-Damle J, Santoni M, Sagheddu C, Sartori SB, Ebner K, Lubec J, Hussein AM, Stojanovic T, Singewald N, Pistis M, Lubec G, Sitte HH
Neuropharmacology · 2026 Aug · PMID 41980668 · Publisher ↗
Psychostimulants act on monoamine systems including the dopamine transporter (DAT), a key regulator of dopamine reuptake following synaptic release. While these compounds can enhance energy, cognition, and sociability, t...
Psychostimulants act on monoamine systems including the dopamine transporter (DAT), a key regulator of dopamine reuptake following synaptic release. While these compounds can enhance energy, cognition, and sociability, their clinical utility is often limited by their abuse potential and peripheral side effects. Research has traditionally focused more on their addictive properties rather than their therapeutic potential. However, certain psychostimulants, such as R-modafinil, enhance cognitive performance without inducing significant euphoria or addiction, making them promising lead candidates for clinical application. In this study, we hypothesized that R-modafinil analogs with extended residence time at DAT (i.e., slow k) would enhance cognitive function more effectively. To test this, we evaluated a series of R-modafinil analogs using in vitro equilibrium and non-equilibrium measurements, in vivo fast-scan cyclic voltammetry, and highly translational cognitive assays in both healthy and scopolamine-treated rats modelling cognitive impairment. Our findings show that prolonging DAT occupancy improves dopamine signalling and leads to more robust enhancements in cognitive flexibility. Compounds with longer DAT resident time-such as S-MK-26 and (S,S)-CE-158-produced the strongest cognitive effects. These results highlight the importance of DAT binding kinetics in shaping the behavioural actions of psychostimulants and support the development of safer and more effective dopamine-based cognitive enhancers.
KBN2201 attenuates Aβ pathology and neuroinflammation while promoting neuroprotective and neurogenesis-related changes in a late-stage 5xFAD mouse model of Alzheimer's disease.
Lee SY, Kim JC, Song J … +7 more , Lee Y, Kim M, Chang SH, Kim JS, Park JS, Choi MR, Lee SR
Neuropharmacology · 2026 Aug · PMID 41974315 · Publisher ↗
Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, neuroinflammation, neuronal loss, and cognitive decline. Here, we report that KBN2201, a derivative of 2-hydroxy-4-(trifluoromethyl)benzoic acid,...
Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, neuroinflammation, neuronal loss, and cognitive decline. Here, we report that KBN2201, a derivative of 2-hydroxy-4-(trifluoromethyl)benzoic acid, exerts multi-target effects in 5xFAD mice. To evaluate its efficacy at a late disease stage, daily oral administration of KBN2201 (5 or 20 mg/kg) was initiated in 9-month-old 5xFAD mice and continued for three months. KBN2201 significantly reduced hippocampal amyloid precursor protein C-terminal fragments (APP-CTFs), indicating decreased accumulation of APP-derived fragments. In addition, KBN2201 lowered insoluble Aβ42 levels, supporting on overall reduction in amyloid burden. The compound also reduced both fibrillar and total Aβ plaque burden in the cortex and hippocampus, as demonstrated by thioflavin S and 4G8 staining. Astrocytic and microglial activation was significantly suppressed. Preservation of the hippocampal CA1 region and cortical dendritic structure was observed. In addition, markers associated with neurogenesis were increased in the subventricular zone (SVZ) and hippocampus, as indicated by elevated Ki67 and doublecortin (DCX) levels. These effects were accompanied by improved spatial working memory in the Y-maze test and enhanced recognition memory in the novel object recognition (NOR) test, with greater effects observed at the 5 mg/kg dose. Together, these findings suggest that KBN2201 mitigates AD-related pathology and improves cognitive function, supporting its potential as a multi-target therapeutic candidate for AD.
The role of TIPE2 in alleviating alcohol-related cognitive impairment via suppression of neuroinflammation.
Ruan M, Ma S, Wang X … +2 more , Zhang F, Zhang H
Neuropharmacology · 2026 Aug · PMID 41967700 · Publisher ↗
BACKGROUND: Alcohol use disorder (AUD) induces neuroinflammation and cognitive impairment. Although TIPE2 (tumor necrosis factor-α-induced protein 8-like protein 2) shows neuroprotective effects by regulating neuroinflam...
BACKGROUND: Alcohol use disorder (AUD) induces neuroinflammation and cognitive impairment. Although TIPE2 (tumor necrosis factor-α-induced protein 8-like protein 2) shows neuroprotective effects by regulating neuroinflammation, its specific role and mechanisms in AUD remains unclear. This study aimed to elucidate the potential therapeutic mechanisms of TIPE2 in the context of AUD. METHODS: We employed a chronic ethanol exposure (CEE) model in seven-week-old C57 male mice by providing ad libitum 20% ethanol for 90 days. Robust TIPE2-overexpression (OE) was achieved via stereotaxic AAV delivery into the hippocampus, as confirmed by Western blotting. The behavioral consequences of TIPE2 upregulation were then evaluated. Subsequent analyses combined biochemical and morphological techniques to investigate the role of TIPE2 in mitigating neuroinflammation and synaptic impairments. RESULTS: Compared to the control group, CEE mice showed impairments in learning ability and memory in the behavioral tests; this was attenuated by TIPE2-OE. In addition, TIPE2-OE in CEE mice reduced neuroinflammation in the hippocampus, including decreased levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), nuclear factor kappa-B (NF-κB), and diminished microglial activation. Further, TIPE2-OE also improved synaptic function, as evidenced by increased total dendritic length and enhanced dendritic spine density. CONCLUSION: In summary, our findings identify TIPE2 as a key regulator that counteracts CEE-induced cognitive deficits, neuroinflammation, and synaptic damage through suppression of the TLR4/NF-κB pathway. These results suggest that TIPE2 serves as a potential therapeutic target for AUD.
Ozanimod and other sphingosine-1-phosphate receptor 1 modulators normalize neuropathic injury-enhanced inhibition of central lateral amygdala neurons expressing corticotropin-releasing hormone.
Hines RC, O'Sullivan-Duffy AE, Sheets PL
Neuropharmacology · 2026 Aug · PMID 41966521 · Publisher ↗
A key brain structure in the processing of chronic pain is the central nucleus of the amygdala (CeA), which has justifiably been termed the "nociceptive amygdala." Prior work shows that a major subclass of neurons in the...
A key brain structure in the processing of chronic pain is the central nucleus of the amygdala (CeA), which has justifiably been termed the "nociceptive amygdala." Prior work shows that a major subclass of neurons in the lateral region of the CeA (CeL) expressing corticotropin-releasing hormone (CRH; CeL neurons) is sensitized in the acute, but not chronic, stage of neuropathic pain. However, the signal transduction regulation of synaptic activity in CeL neurons remains poorly understood. The goal of this work was to elucidate the modulation of CeL neuron synaptic activity by sphingosine-1-phosphate receptor 1 (S1PR) signaling in neuropathic pain. Here we performed whole-cell patch-clamp electrophysiological recordings in acute brain slices from male mice subjected to the spared nerve injury (SNI) model of neuropathic pain to measure how pharmacological modulation of S1PR alters synaptic properties of CeL neurons. In sham, but not SNI mouse, we found S1PR agonism reduced the frequency of excitatory input onto CeL neurons, while S1PR antagonism had no effect on either surgical group. We also show SNI increased the frequency of inhibitory input onto CeL neurons which was normalized by both an S1PR agonist and antagonist, as well as the clinically relevant S1PR agonist, Ozanimod. Together, our data suggest SNI alters excitatory and inhibitory inputs onto CeL neurons, and each type of input is differentially modulated by S1PR signaling, highlighting CeL neurons as key nodes in neuropathic pain circuitry and identifying S1PRs as a potential target for the development of new analgesic pharmacotherapies.
Differential effects of wheel running and treadmill exercise on spatial memory, adult hippocampal neurogenesis and the cerebrospinal fluid proteome in rats.
Caruso MG, Dohm-Hansen S, Donoso F … +6 more , Rynikova M, Lavelle A, English JA, Nicolas S, O'Leary OF, Nolan YM
Neuropharmacology · 2026 Aug · PMID 41966520 · Publisher ↗
High levels of physical activity have been shown to induce changes in anxiety and cognitive function and to stimulate adult hippocampal neurogenesis (AHN). In rodents, wheel running and treadmill exercise paradigms are t...
High levels of physical activity have been shown to induce changes in anxiety and cognitive function and to stimulate adult hippocampal neurogenesis (AHN). In rodents, wheel running and treadmill exercise paradigms are typically employed to increase physical activity to model human exercise training, but have yielded inconsistent effects on AHN and related behaviours. Thus, investigation into shared and differential molecular responses to exercise modalities is warranted. The cerebrospinal fluid (CSF) is a proposed mediator of peripheral factors on brain plasticity and behaviours but exercise-induced changes in the CSF proteome have not yet been determined. Moreover, there is a paucity of studies directly comparing different exercise paradigms using the same durations of exercise and the same behavioural tests, on AHN and CSF proteome. This study compared the effects of eight weeks of voluntary wheel running and treadmill exercise on hippocampal-dependent behaviours, AHN and the CSF proteome in adult male Sprague-Dawley rats. While both exercise paradigms induced modest anxiolytic effects, only treadmill exercise enhanced spatial memory, a cognitive function linked to AHN. Conversely, increased AHN was observed in response to wheel running exercise only. Myelin oligodendrocyte glycoprotein and calcitonin-related polypeptide-beta were elevated in CSF by both paradigms. However, the eight-week duration of exercise may have limited the detection of molecular changes that peaked at earlier timepoints during behavioural testing. Overall, these findings demonstrate that exercise paradigms in rodents induce shared protein mediators in CSF but differentially affect hippocampal neurogenesis and suggest that exercise-induced behavioural outcomes may rely on mechanisms beyond hippocampal neurogenesis.
The atypical antidepressant tianeptine causes opioid-receptor-dependent beta oscillations in the rat hippocampus.
Burt SG, Phillips GD, Lambert JJ … +1 more , Martin SJ
Neuropharmacology · 2026 Aug · PMID 41956239 · Publisher ↗
Tianeptine is an atypical antidepressant and cognitive enhancer. Previous research indicates that its antidepressant-like efficacy in animals depends on the phosphorylation of GluA1-subunit-containing AMPA receptors (AMP...
Tianeptine is an atypical antidepressant and cognitive enhancer. Previous research indicates that its antidepressant-like efficacy in animals depends on the phosphorylation of GluA1-subunit-containing AMPA receptors (AMPARs), and the activation of μ-opioid receptors on hippocampal interneurons. Both actions might alter synaptic strength and network activity; we therefore studied the effects of tianeptine on evoked synaptic responses and local-field-potential (LFP) oscillations in area CA1 of male urethane-anaesthetised rats. Electrodes were implanted to record CA1 LFP and field excitatory postsynaptic potentials (fEPSPs) elicited by stimulation of CA3. A temperature probe was implanted in the contralateral hippocampus. Subcutaneous injection of tianeptine (10 & 30 mg/kg) caused a dose-dependent increase in hippocampal beta-frequency activity and a modest increase in fEPSP slope that were blocked by the opioid-receptor antagonist naloxone. Injection of the opioid buprenorphine (0.03 mg/kg) had similar effects, but ketamine (10 mg/kg), another atypical antidepressant, caused a distinct pattern of LFP changes characterised by a naloxone-insensitive increase in slow-gamma activity. Injection of 30 mg/kg tianeptine and 0.03 mg/kg buprenorphine was associated with an increase in brain temperature of ∼0.6 °C, sufficient to fully explain the increase in fEPSP slope, but not the increase in LFP activity. Injection of tianeptine also caused a reduction in the amplitude of the inhibitory 'tail' of the fEPSP, consistent with a blockade of feedforward inhibition. These results indicate that tianeptine, like several other atypical antidepressant drugs, enhances hippocampal beta/gamma-frequency LFP activity. This action is dependent on opioid-receptor activation and may depend on the disinhibition of principal neurons, a possibility that we are exploring.
CXCL10 activates STAT3 signaling to promote ferroptosis in the spinal dorsal horn during neuropathic pain.
Ni R, Bi S, Cheng Z … +4 more , Ni S, Guo Y, Xiang Y, Peng B
Neuropharmacology · 2026 Aug · PMID 41951153 · Publisher ↗
Neuropathic pain (NP) remains a clinical challenge due to the limited efficacy and significant side effects of current treatments, highlighting the need for a deeper understanding of its pathogenesis. While dysfunction o...
Neuropathic pain (NP) remains a clinical challenge due to the limited efficacy and significant side effects of current treatments, highlighting the need for a deeper understanding of its pathogenesis. While dysfunction of GABAergic inhibitory neurons in the spinal dorsal horn is a known key driver of central sensitization, the mechanisms precipitating this neuronal injury remain obscure. In this study, using a spinal nerve ligation (SNL) model, we aimed to investigate whether the chemokine CXCL10 drives NP progression by promoting ferroptosis, a process that is associated with and ultimately leads to the loss of GABAergic neurons. We observed that mechanical hypersensitivity in post-SNL rats coincided with progressive spinal ferroptosis, characterized by iron accumulation, lipid peroxidation, and suppression of the GPX4/xCT system. Notably, CXCL10 expression mirrored the trajectory of ferroptosis. Interventional studies established CXCL10 as an upstream initiator, rather than a consequence, of the ferroptotic process. Mechanistically, we demonstrated that CXCL10 activates STAT3 through the CXCR3 receptor; activated STAT3 then acts as a transcriptional repressor to downregulate the cystine transporter xCT, thereby triggering ferroptosis. This molecular cascade resulted in a significant loss of spinal GABAergic neurons, which could be partially reversed by CXCL10 inhibition. Collectively, our findings uncover a novel mechanism of NP maintenance, wherein the CXCL10/CXCR3/STAT3 axis disrupts the spinal excitation-inhibition balance by promoting ferroptosis-mediated loss of inhibitory neurons. These results offer a fresh perspective on NP pathology and identify this signaling axis as a promising therapeutic target.
Single transient exposure to low-frequency low-intensity electrical stimulation produces ketamine-like effects in human iPSC-derived dopaminergic neurons via Ca2-dependent BDNF and mTOR signaling.
Marcotto GS, Borghetti M, Bitraj J … +6 more , Cavalleri L, Serpelloni M, Zoli M, Memo M, Sardini E, Collo G
Neuropharmacology · 2026 Aug · PMID 41942002 · Publisher ↗
Electrical stimulation (ES) is emerging as a non-pharmacological neuromodulation strategy, but its direct impact on human dopaminergic neurons and its relationship to rapid-acting antidepressant mechanisms remain unclear...
Electrical stimulation (ES) is emerging as a non-pharmacological neuromodulation strategy, but its direct impact on human dopaminergic neurons and its relationship to rapid-acting antidepressant mechanisms remain unclear. This study aimed to investigate whether brief biphasic low-frequency low-intensity (LF-LI) ES can induce structural and molecular plasticity in human induced pluripotent stem cell (iPSC)-derived mesencephalic dopaminergic neurons, identify the underlying signaling mechanisms, and evaluate its potential to rescue cortisol-induced impairments as in-vitro endocrine model of depression. iPSC-derived dopaminergic neurons were exposed to LF-LI ES using a custom culture-compatible stimulator, and structural plasticity was quantified three days later by computer-assisted morphometry. Pharmacological blockers, quantitative PCR and Western blot analyses were employed to assess calcium influx, brain-derived neurotrophic factor (BDNF)-TrkB-extracellular signal-regulated kinase (ERK)-mTOR signaling, and dopamine D3 auto-receptor roles in mediating LF-LI ES effects. A single 1h LF-LI ES session at 4 mA induced robust increases in maximal dendrite length, primary dendrite number, and soma area, comparable to 1 μM ketamine. LF-LI ES rapidly enhanced ERK and p70-S6K phosphorylation and required L-type voltage-gated calcium channels, TrkB and mTOR, as their inhibition prevented structural remodeling. LF-LI ES increased dopamine D3 auto-receptors mRNA, and its antagonism attenuated LF-LI ES-induced plasticity. In cortisol-treated neurons, LF-LI ES fully reversed dendritic hypotrophy and soma shrinkage. In conclusion, brief LF-LI ES elicits long-lasting, ketamine-like structural and molecular plasticity in human dopaminergic neurons and rescues stress hormone-induced impairments, supporting LF-LI ES-based neuromodulation approaches targeting dopaminergic circuits in major depressive disorder and treatment-resistant depression.
Targeting purinergic receptors in glioblastoma with nanobody-displaying AAV vectors.
Jargalsaikhan S, Schäfer W, Zapf N … +10 more , Reetz M, Rodríguez DG, Malatesta P, Bannas P, Dührsen L, Mohme M, Lamszus K, Koch-Nolte F, Maire CL, Mann AM
Neuropharmacology · 2026 Aug · PMID 41933830 · Publisher ↗
The standard therapy for glioblastoma, surgery followed by radio- and chemotherapy, results in ATP release from damaged and stressed cells. The GPI-anchored ecto-enzyme CD73 and the ATP-gated P2X7 ion channel are often e...
The standard therapy for glioblastoma, surgery followed by radio- and chemotherapy, results in ATP release from damaged and stressed cells. The GPI-anchored ecto-enzyme CD73 and the ATP-gated P2X7 ion channel are often expressed on glioblastoma cells. CD73 contributes to the cold tumor microenvironment by generating immunosuppressive adenosine. P2X7 promotes tumor growth by enhancing cell proliferation and survival. Here we show that these membrane proteins can serve as entry receptors for recombinant Adeno-associated viruses (AAV). To this end, we genetically inserted CD73-specific or P2X7-specific nanobodies into a surface loop of the AAV9 capsid. These nanobody-displaying AAV greatly enhanced the transduction of CD73- or P2X7-expressing HEK cells in vitro and patient-derived glioblastoma cells ex vivo. Our results pave the way for the therapeutic application of these nanobody-displaying AAV, for example, to express immune-activating cytokines or checkpoint inhibitors in the tumor cells to turn a cold tumor microenvironment hot.
Anterior cingulate cortex activation of claustrum projection neuron subtypes is enhanced by alcohol.
Wulff AB, Sheats SH, Douglass EA … +1 more , Mathur BN
Neuropharmacology · 2026 Aug · PMID 41921604 · Publisher ↗
Cognitive impairment is a major component of Alcohol Use Disorder. Optimal cognitive performance requires anterior cingulate input activation of the claustrum, a subcortical nucleus that orchestrates cortical activity. Y...
Cognitive impairment is a major component of Alcohol Use Disorder. Optimal cognitive performance requires anterior cingulate input activation of the claustrum, a subcortical nucleus that orchestrates cortical activity. Yet the impact of chronic alcohol exposure on the ability for the anterior cingulate cortex to drive activity of claustrum projection neuron subtypes is unknown. In adult male and female mice, we found that the majority of non-burst firing Type 1 claustrum projection neurons did not express the vesicular glutamate transporter 2 (VGLUT2), while the majority of burst firing Type 2 projection neurons were VGLUT2-expressing. Following chronic intermittent vaporized ethanol exposure (CIE), we found that all claustrum neuron types exhibited increased responsivity to anterior cingulate cortex input activation. In Type 1 and VGLUT2-non-expressing neurons this was associated with increased postsynaptic membrane excitability. In contrast, Type 2 and VGLUT2-expressing projection neurons exhibited increased responsivity to anterior cingulate cortex input due to strengthened pre- and post-synaptic transmission mechanisms. Altogether, we uncovered a hyper-excitatory drive of the claustrum by the anterior cingulate cortex following chronic alcohol exposure. The data provide a foundational resource for the complex effects of chronic alcohol exposure on the claustrum, a critical cognitive control nucleus.
Effects of acute fluctuations of extracellular Zinc on network activity of human iPSC-derived neurons; impact of NMDA Receptor and L-Type Calcium Channel Activation.
Alsaqati M, Haddon JE, Hall J … +2 more , Harwood AJ, Wilkinson LS
Neuropharmacology · 2026 Jul · PMID 41905643 · Publisher ↗
BACKGROUND AND PURPOSE: Zinc is an essential trace element involved in numerous biological processes including in the central nervous system. Strong genetic evidence has implicated dysregulation of free Zn levels in the...
BACKGROUND AND PURPOSE: Zinc is an essential trace element involved in numerous biological processes including in the central nervous system. Strong genetic evidence has implicated dysregulation of free Zn levels in the pathophysiology of schizophrenia and there is evidence for its involvement in other psychiatric and neurological disorders. This study aimed to investigate the effects of fluctuations in extracellular Zn levels on human neuronal function to better understand possible pathophysiological mechanisms. EXPERIMENTAL APPROACH: Using multi-electrode array (MEA) methods, we examined the effects of manipulating extracellular Zn on intrinsic neuronal function and coordinated neuronal network activity in human induced pluripotent stem cell-derived neurons. We confirmed effects were related to extracellular free Zn ions using the specific membrane-impermeable chelator ZX1. We then manipulated NMDA receptors (NMDARs) and L-type calcium channels (LTCCs) with drug compounds and assessed gene expression with qPCR to probe molecular mechanisms of Zn effects. KEY RESULTS: Extracellular Znaffected network activity in a dose-dependent manner. Addition of nMolar concentrations of ZnCl within the physiological range had specific effects on neuronal synchrony that were reversible by chelation of free Zn and by NMDAR or LTCC activation. Following addition of higher, μMolar, concentrations of ZnCl the effects of Zn were associated with impaired intrinsic neuronal excitability, irreversible network dysfunction that was resistant to NMDAR or LTCC activation and upregulation of the apoptosis cell death marker cleaved caspase-3. CONCLUSIONS AND IMPLICATIONS: Acute fluctuations in extracellular Zncan impact both phasic neuronal connectivity and at higher levels can lead to neuronal toxicity in human neurons. The data may have relevance for, and explain in part, the known links between Zn and conditions such as schizophrenia, where the malfunctioning synapse is increasingly the focus of pathology, and neurological conditions associated with neurotoxicity.
Targeting ME1 rescues redox-metabolic coordination in ALS: A core effector of NRF2-directed therapy.
Yang Y, Yang Y, Zhang X … +7 more , Ma H, Ji S, Zou F, Yu X, Du G, Zhu X, Tian J
Neuropharmacology · 2026 Aug · PMID 41903869 · Publisher ↗
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, muscle weakness, and respiratory failure, with dysregulated energy metabolism and oxidative stress...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, muscle weakness, and respiratory failure, with dysregulated energy metabolism and oxidative stress representing core pathological features. Epidemiological studies indicate geographical variations in incidence, and recent multi-omics evidence identifies a hypermetabolic state and mitochondrial dysfunction as key drivers of disease progression. The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), which regulates antioxidant response and metabolism, represents a promising therapeutic target; however, the exploration of specific activators remains insufficient. This study evaluated the efficacy and mechanism of a novel KEAP1-NRF2 activator, MKL01351, in SOD1 G93A transgenic mice and NSC-34 motor neuron-like ALS models. Behavioral analyses demonstrated that MKL01351 significantly delayed disease onset, improved motor coordination in the rotarod and hanging tests, and extended survival. The compound alleviated oxidative stress by reducing malondialdehyde (MDA) levels and restoring the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, while also ameliorating the energy deficit by modulating glycolytic and mitochondrial functions, as confirmed by Seahorse analysis. Mechanistic investigations revealed that MKL01351 activated the NRF2 pathway, upregulating downstream targets such as NQO1 and HO-1, and specifically enhanced the expression of malic enzyme 1 (ME1). Loss-of-function experiments confirmed that ME1 knockdown abolished the protective effects, indicating that the NRF2-ME1 axis is a central hub for the synergistic regulation of metabolic and oxidative homeostasis. In conclusion, MKL01351 concurrently ameliorates oxidative stress and metabolic dysregulation via the NRF2-ME1 signaling pathway, offering a novel neuroprotective strategy for ALS treatment.
Ciprofloxacin exposure impairs neurogenesis and E/I balance in human cortical organoids.
Liu H, Jiang L, Bu Q … +18 more , Sun M, Zhao Y, He Y, Zhou Y, Han S, Dai Y, Zhang D, Li H, Wang L, Xiao Y, Qin F, Chen Y, Liu C, Qin M, Wang H, Tian J, Zhao Y, Cen X
Neuropharmacology · 2026 Jul · PMID 41895646 · Publisher ↗
Ciprofloxacin (CPFX) is a widely used broad-spectrum fluoroquinolone antibiotic. Although its neurotoxic potential in the mature brain has been recognized, its impact on the developing human nervous system remains largel...
Ciprofloxacin (CPFX) is a widely used broad-spectrum fluoroquinolone antibiotic. Although its neurotoxic potential in the mature brain has been recognized, its impact on the developing human nervous system remains largely unexplored. Given that the developing brain exhibits heightened vulnerability to environmental and pharmacological insults, we investigated the developmental neurotoxicity of CPFX using human cortical organoids (hCOs) that recapitulate key features of early cortical development. In this study, chronic low-dose CPFX exposure over two weeks induces significant mitochondrial dysfunction, characterized by excessive ROS production and decreased mitochondrial membrane potential (MMP). These mitochondrial impairments were accompanied by alterations in cortical development and disruptions in GABAergic network formation. Mechanistically, CPFX exposure significantly downregulated Forkhead box G1 (FOXG1) expression in hCOs. Molecular docking simulations suggested an interaction of CPFX with the functional domain of FOXG1. Furthermore, FOXG1 knockdown in primary mouse neurons mimicked CPFX-induced mitochondrial hyperactivity and metabolic dysregulation. Microelectrode array analyses revealed aberrant neuronal firing patterns consistent with an epileptiform phenotype. Importantly, aspirin significantly alleviated CPFX-induced mitochondrial dysfunction, restored ATP and ROS levels, and stabilized neuronal electrophysiological activity in primary neurons, underscoring its potential as a therapeutic intervention. Overall, CPFX induces a broad neuropathological phenotype and impair both mitochondrial function and neurogenesis in hCOs, potentially through a mechanism mediated by FOXG1 disruption. These findings offer novel insights into CPFX-induced neurotoxicity and imply FOXG1 as a promising intervention target.
Acute ethanol inhibits asynchronous glutamate release from mouse basolateral amygdala synapses.
Parrish BP, McCool BA
Neuropharmacology · 2026 Jul · PMID 41895645 · Full text
Acute ethanol modulates an incredibly diverse number of neurotransmitter receptors and intracellular pathways. Presynaptic modulation by acute ethanol has been identified at some GABAergic synapses; but descriptions of a...
Acute ethanol modulates an incredibly diverse number of neurotransmitter receptors and intracellular pathways. Presynaptic modulation by acute ethanol has been identified at some GABAergic synapses; but descriptions of acute ethanol regulation of presynaptic glutamatergic function are sparse. Recent reports suggest that acute ethanol can inhibit glutamatergic synaptic responses arising from recycling vesicles during tetanic stimulation of Stria terminalis inputs onto basolateral amygdala (BLA) principal neurons. This finding gives rise to the hypothesis that acute ethanol may modulate actively priming synaptic vesicles in glutamate synapses. To test this, we used whole cell patch clamp recordings in BLA principal neurons and measured the effects of acute ethanol on asynchronous synaptic transmission. We found Stria teminalis inputs express EGTA-sensitive asynchronous synaptic glutamatergic responses produced from both increased presynaptic activation and experimental elevation of presynaptic calcium using partial substitution of extracellular Na with Li. Under both conditions, asynchronous events were acutely inhibited by ethanol in a concentration-dependent fashion. Ethanol inhibition of asynchronous glutamate release was present in DBA/2J Stria terminalis synapses but absent when measuring inputs in C57BL/6J mice. EGTA, which robustly suppresses expression of asynchronous release, also occluded ethanol modulation under both conditions. Surprisingly, EGTA did not alter the expression or occlude ethanol modulation of synaptic responses arising from recycling vesicles. Our findings demonstrate a unique acute effect of ethanol on asynchronous glutamate vesicle priming pathways.
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