Neurosci. Lett. [JOURNAL]
Sun
200 papers
Indoleamine 2,3-dioxygenase 1 (IDO1) promoted the activation of inflammatory response in the brain tissue of Alzheimer's disease mice by regulating NF-κB pathway.
Xu X, Wang Q, Wang L … +4 more , Cheng W, Li F, Liu H, Guo Y
Neurosci Lett · 2026 May · PMID 42162832 · Publisher ↗
OBJECTIVE: To investigate the regulatory mechanism of IDO1 on brain tissue damage in Alzheimer's disease (AD) mice. METHODS: APP/PS1 mice (AD model mice) and C57BL/6J mice were treated with IDO1 inhibitor 1-MT. Behaviora...
OBJECTIVE: To investigate the regulatory mechanism of IDO1 on brain tissue damage in Alzheimer's disease (AD) mice. METHODS: APP/PS1 mice (AD model mice) and C57BL/6J mice were treated with IDO1 inhibitor 1-MT. Behavioral changes were assessed using the open field test, and histopathological changes were analyzed using HE staining, Nissl staining, and transmission electron microscopy. TUNEL staining and immunofluorescence were used to detect cell apoptosis and the expression of IDO1 and GFAP, respectively. Metabolomics was analyzed using liquid chromatography-mass spectrometry. An in vitro AD cell model was established, and inflammatory factor levels were measured using ELISA/qPCR, while NF-κB pathway activation was assessed using WB. RESULTS: In vivo experiments showed that compared with the model group mice, 1-MT intervention improved behavioral abnormalities in AD mice, reduced hippocampal tissue damage, decreased neuronal apoptosis, and downregulated the expression of IDO1 and GFAP. In vitro experiments demonstrated that interfering with IDO1 could decrease the levels of IL-1β, TNF-α, and IL-6, reduce GFAP expression, and inhibit p65 phosphorylation. CONCLUSION: Interfering with IDO1 can inhibit the NF-κB pathway, reduce the release of inflammatory factors, and improve brain tissue damage in AD mice.
Perivascular macrophages lack cyclooxygenase-2 induction and do not mediate fever.
Maksimov V, Eskilsson A
Neurosci Lett · 2026 May · PMID 42134710 · Publisher ↗
Perivascular macrophages, immune cells located in the Virchow-Robin spaces that surround small arterioles, capillaries, and venules in the brain, have been suggested to produce prostaglandins upon immune stimulation and...
Perivascular macrophages, immune cells located in the Virchow-Robin spaces that surround small arterioles, capillaries, and venules in the brain, have been suggested to produce prostaglandins upon immune stimulation and influence centrally elicited disease symptoms such as fever. Here, we examined in mice the role of perivascular macrophages in the febrile response. Using a mouse line carrying a loxP-flanked transcriptional blocker upstream of the Ptgs2 gene, crossed with a Cx3cr1-Cre line, we sought to selectively express the prostaglandin-synthesizing enzyme cyclooxygenase-2 in Cx3cr1-expressing cells, including most perivascular macrophages as well as brain microglial cells. Whereas immune challenge by intravenous injection of lipopolysaccharide resulted in a febrile response in WT mice, StopfloxPtgs2 Cx3cr1-CreERT2 mice instead displayed profound hypothermia, similar to mice with whole-body deletion of cyclooxygenase-2. Real-time PCR analysis showed no or negligible levels of Ptgs2 transcript in the StopfloxPtgs2 Cx3cr1-CreERT2 mice, and immunohistochemistry showed no cyclooxygenase-2 immunoreactivity in perivascular macrophages or reporter gene expression indicative of cyclooxygenase-2 transcription. We conclude that perivascular macrophages do not produce appreciable amounts of cyclooxygenase-2 upon immune challenge, at least not in the mouse, and therefore do not contribute to the febrile response.
ZBP1 deficiency ameliorates the motor dysfunction following brachial plexus root avulsion in mice.
Tang L, Peng Y, Zhang Y … +4 more , Li W, Huang R, Chen S, Zhu J
Neurosci Lett · 2026 Jun · PMID 42119609 · Publisher ↗
Brachial plexus root avulsion (BPRA) is a devastating peripheral nerve injury that results in irreversible forelimb motor dysfunction, largely due to extensive motor neuron (MN) degeneration in the spinal ventral horn ac...
Brachial plexus root avulsion (BPRA) is a devastating peripheral nerve injury that results in irreversible forelimb motor dysfunction, largely due to extensive motor neuron (MN) degeneration in the spinal ventral horn accompanied by robust neuroinflammation. Z-DNA-binding protein 1 (ZBP1) has been implicated in inflammatory regulation and programmed cell death in several neurological disorders; however, its role in BPRA remains unclear. Here, we observed a marked upregulation of ZBP1 mRNA in the ipsilateral spinal ventral horn following BPRA. To examine the functional relevance of ZBP1 in BPRA pathology, ZBP1 knockout (KO) mice were subjected to BPRA followed by ventral root reimplantation. Behavioral assessments, histological analyses, and quantitative real-time PCR were performed to evaluate motor recovery, neuronal survival, and inflammatory responses. ZBP1 deficiency significantly improved forelimb motor function, increased MN survival, enhanced axonal remyelination, and attenuated biceps brachii muscle atrophy after BPRA. These beneficial effects were associated with reduced expression of pyroptosis-related and pro-inflammatory genes in the spinal ventral horn, suggesting an alleviation of the neuroinflammatory microenvironment. Collectively, these findings identify ZBP1 as a critical regulator of BPRA-induced MN degeneration and functional impairment, and indicate that targeting ZBP1 may represent a promising therapeutic strategy for improving neurological outcomes following brachial plexus injuries.
Unilateral damage to the entopeduncular nucleus causes dysfunction in skilled forelimb movement and hinders recovery in rats.
Sakai R, Kuroda K, Ryoke T … +3 more , Maegawa A, Murata K, Fukazawa Y
Neurosci Lett · 2026 Jun · PMID 42119608 · Publisher ↗
The entopeduncular nucleus (EPN) is an output nucleus of the basal ganglia and is suggested to play a critical role in motor control. This study aimed to clarify the impact of EPN damage on skilled motor function and its...
The entopeduncular nucleus (EPN) is an output nucleus of the basal ganglia and is suggested to play a critical role in motor control. This study aimed to clarify the impact of EPN damage on skilled motor function and its recovery. Unilateral EPN damage or intracerebral hemorrhage (ICH) was induced by stereotactic injection of kainic acid (KA) into the EPN or collagenase type Ⅳ into the internal capsule, respectively. Skilled motor function was assessed by the number of trials and success rates in a single-pellet reaching task from baseline to day 28. EPN damage was quantified by immunohistochemistry for NeuN or hematoxylin-eosin staining. KA-induced EPN damage reduced the number of trials by 100% in most rats (n = 5/8) on day 2, resulting in a significantly lower success rate compared to controls (P < 0.05). Trial reduction was transient in two rats but persisted through day 28 in three rats. Notably, success rates on day 28 positively correlated with the number of remaining NeuN-positive cells (P < 0.05). In the ICH model, most rats (n = 10/11) reduced trials on day 2, and half (n = 5/11) remained impaired on day 28. The success rates on day 28 were positively correlated with remaining EPN volume (P < 0.01), but not with total lesion volume. These findings demonstrated that unilateral EPN damage reduces voluntary reaching trials and impairs skilled motor function, indicating that EPN integrity is crucial for skilled motor control and may represent a critical predictor of motor prognosis after damage.
Developmental electrophysiological changes in mouse mesencephalic trigeminal neurons.
Toyoda H
Neurosci Lett · 2026 Jun · PMID 42105852 · Publisher ↗
This study examined the postnatal maturation of electrophysiological properties in mesencephalic trigeminal (MesV) neurons, focusing on firing patterns, intrinsic membrane properties, membrane resonance, and inward‑recti...
This study examined the postnatal maturation of electrophysiological properties in mesencephalic trigeminal (MesV) neurons, focusing on firing patterns, intrinsic membrane properties, membrane resonance, and inward‑rectifying currents. MesV neurons exhibited phasic, tonic, and stuttering firing modes, with phasic firing predominant at P7 and an increased proportion of tonic firing at P14 and P21, indicating progressive diversification of discharge behaviors during postnatal development. Resting membrane potential and spike threshold remained stable, whereas input resistance decreased and membrane charging kinetics changed, consistent with neuronal growth and reduced excitability. Membrane resonance matured with development, characterized by a decline in impedance and a marked increase in resonance frequency by P21, suggesting enhanced frequency selectivity. Inward rectification was also strengthened, as evidenced by faster sag responses, increased inward‑rectifying current density, depolarizing shifts in half‑maximal activation, and faster activation kinetics. Together, these findings demonstrate coordinated maturation of passive and active membrane properties in MesV neurons, supporting improved regulation of firing and integration of membrane inputs during postnatal development.
K-Cl cotransporter KCC2 is involved in long-term potentiation at trigeminal excitatory synapses.
Mujiwati, Youn DH
Neurosci Lett · 2026 Jun · PMID 42105851 · Publisher ↗
The K-Cl cotransporter (KCC)2 is critical for maintaining low intracellular chloride levels and ensuring hyperpolarizing GABAergic inhibition. While KCC2 dysfunction is well established in spinal mechanisms of chronic pa...
The K-Cl cotransporter (KCC)2 is critical for maintaining low intracellular chloride levels and ensuring hyperpolarizing GABAergic inhibition. While KCC2 dysfunction is well established in spinal mechanisms of chronic pain, its role in trigeminal synaptic plasticity remains unclear. This study investigated whether KCC2 activity is required for high-frequency stimulation (HFS)-induced long-term potentiation (LTP) and group I metabotropic glutamate receptor (mGluR)-mediated plasticity at excitatory synapses in ascending trigeminal pathways from the spinal trigeminal subnucleus caudalis (Vc) to the interpolaris (Vi) and oralis (Vo) regions. Using whole-cell voltage-clamp recordings in rat brainstem slices, HFS of the deep layer of Vc reliably induced robust LTP in Vi neurons under control conditions. However, bath application of furosemide, an inhibitor for non‑selective cation-chloride cotransporters including KCC2, significantly reduced the magnitude of HFS-induced LTP; LTP was maintained in five out of nine neurons, whereas four of nine neurons exhibited long-term depression (LTD). Furthermore, plasticity induced by 3,5-dihydroxyphenylglycine (DHPG), a group I mGluR agonist, showed a polarity reversal during KCC2 blockade in Vo neurons. Under control conditions, DHPG induced LTP in six out of ten neurons, whereas KCC2 blockade with VU0240551 predominantly induced DHPG-LTD in six of eleven neurons. In addition, HFS-induced suppression of GABAergic inhibitory responses in Vi neurons was significantly enhanced in the presence of furosemide, resulting in an increased magnitude of LTD. These findings indicate that acute KCC2 blockade alters both the magnitude and direction of synaptic plasticity in excitatory and inhibitory transmission within the spinal trigeminal nucleus.
The evaluation of HI-6 encapsulated in reconstituted lipid nanoparticles for central delivery and reactivation in soman-poisoned mice.
Zhuang T, Zhao J, Yang X … +3 more , Wang M, Nie Z, Zhang J
Neurosci Lett · 2026 Jun · PMID 42105850 · Publisher ↗
Nerve agents represent a significant hazard to human health and safety. Prompt reactivation of inhibited cholinesterase is imperative; however, the blood-brain barrier (BBB) impedes the delivery of cholinesterase reactiv...
Nerve agents represent a significant hazard to human health and safety. Prompt reactivation of inhibited cholinesterase is imperative; however, the blood-brain barrier (BBB) impedes the delivery of cholinesterase reactivators to the central nervous system (CNS). This study aimed to develop brain-targeted reconstituted lipid nanoparticles (rLNPs) loaded with HI-6 (rLNPs/HI-6), with the goal of enhancing CNS delivery and improving reactivation efficacy in soman-poisoned mice. In healthy mice, rLNPs/HI-6 significantly enhanced BBB permeability to (11.47 ± 1.62)% and blood-cerebrospinal fluid barrier (BCSFB) permeability to (24.46 ± 2.65)%. In soman-poisoned mice (70% LD), rLNPs/HI-6 further elevated BBB and BCSFB permeability to (22.95 ± 2.89)% and (41.12 ± 4.32)%. Importantly, rLNPs/HI-6 achieved a brain acetylcholinesterase (AChE) relative activity of (36.17 ± 1.95)%, which was 1.9-fold higher than that of free HI-6. These findings demonstrate that brain-derived rLNPs effectively enhance the CNS delivery efficiency of HI-6 and augment AChE reactivation efficacy by increasing BBB and BCSFB permeability, thereby offering a feasible strategy for central nervous system-targeted treatment of nerve agent poisoning.
Liraglutide alleviates postoperative cognitive impairment via NRF2/NLRP3 signal pathway in aged mice.
Sun H, Cheng X, Lei D … +5 more , Liu J, Jin Y, Wang C, Fei Y, Han C
Neurosci Lett · 2026 Jun · PMID 42102962 · Publisher ↗
Postoperative cognitive dysfunction (POCD) frequently occurs in elderly surgical patients, yet effective preventive strategies are lacking. This study investigated whether the GLP-1R agonist liraglutide (LIR) could allev...
Postoperative cognitive dysfunction (POCD) frequently occurs in elderly surgical patients, yet effective preventive strategies are lacking. This study investigated whether the GLP-1R agonist liraglutide (LIR) could alleviate POCD in aged mice and explored the underlying mechanisms. Aged mice underwent laparotomy combined with transient superior mesenteric artery occlusion-a clinically relevant intestinal ischemia-reperfusion model-under sevoflurane anesthesia, followed by 14 days of LIR treatment (300 μg/kg/day). LIR administration improved behavioral performance in the Y-maze and fear conditioning tests. It also decreased microglial activation, promoted an M2-like phenotype, and protected synaptic structures and protein levels. Molecular analysis showed that LIR activated the GLP-1R/NRF2 pathway, reduced reactive oxygen species (ROS) accumulation, and suppressed the expression of NLRP3 inflammasome components. The NRF2 inhibitor ML385 reversed these protective effects. Furthermore, depleting microglia with PLX5622 ameliorated surgery-induced cognitive deficits to near-baseline levels. In these depleted mice, LIR provided no additional cognitive or molecular benefits, suggesting highly overlapping, microglia-dependent mechanisms. These findings indicate that the GLP-1R/NRF2/NLRP3 signaling axis regulates the oxidative stress and inflammatory responses in POCD, highlighting LIR as a potential therapeutic option.
Tanshinone IIA, salvianic acid A, salvianolic acid B, and hydroxysafflor yellow A reduce cerebral injury via TGF-β1/Smad3 pathway.
Luo B, Zhang W, Zhang Y … +7 more , Lei Y, Xu Q, Li W, Yu J, Zhu X, Miao Q, Zhu H
Neurosci Lett · 2026 Jun · PMID 42102961 · Publisher ↗
Cerebral ischemia-reperfusion injury (CIRI) is a cerebrovascular disorder with high rates of incidence, disability, and death. It has been identified that Salvia miltiorrhiza and safflower have a protective effect in CIR...
Cerebral ischemia-reperfusion injury (CIRI) is a cerebrovascular disorder with high rates of incidence, disability, and death. It has been identified that Salvia miltiorrhiza and safflower have a protective effect in CIRI. However, the synergistic mechanisms of their multiple active components remain to be elucidated. In this study, we investigated the protective mechanisms of the combination of Tanshinone IIA, salvianic acid A, salvianolic acid B, and hydroxy safflower yellow A in CIRI, based on the TGF-β1/Smad3 signaling pathway. Sprague-Dawley (SD) rats were used to establish the rat middle cerebral artery occlusion/reperfusion (MCAO/R) model using the suture method. Drugs were administered intraperitoneally once daily for 7 consecutive days. Neurological function scores and the volume of brain infarction were evaluated using TTC staining, and the pathological changes in brain tissue were examined using Nissl staining. ELISA kits were used to detect the concentrations of IL-1β, IL-6, and ICAM-1 in serum. At the same time, RT-qPCR, Western blot, and immunohistochemistry were employed to evaluate the mRNA and protein expression of TGF-β1, Smad3, and IL-1β in brain tissue. Following treatment, particularly in the medium-dose group, our findings indicated that neurological deficits and cerebral infarct volume were significantly reduced. Nissl staining revealed improved neuronal morphology and survival in rats with MCAO/R. The levels of pro-inflammatory cytokines (IL-1β, IL-6, and ICAM-1) in serum were significantly decreased. Furthermore, TGF-β1 and Smad3 expression in rat brains were upregulated, while IL-1β expression was downregulated. Taken together, these results indicate that the combination of Tanshinone IIA, salvianic acid A, salvianolic acid B, and hydroxyl safflower yellow A may exhibit a neuroprotective effect on cerebral I/R injury in rats by activating the TGF-β1/Smad3 signaling pathway and subsequently inhibiting the inflammatory response.
Abscisic acid ameliorates cognitive deficits in an amyloid-β-induced mouse model of Alzheimer's disease associated with alterations in markers of neuroplasticity and neuroinflammation.
Shahsavari F, Rajizadeh MA, Pirmoradi Z … +4 more , Sabzalizadeh M, Kohlmeier KA, Soti M, Shabani M
Neurosci Lett · 2026 Jun · PMID 42097395 · Publisher ↗
Abscisic acid (ABA, CHO), a mammalian hormone, exhibits neuroprotective and anti-inflammatory properties. This study aimed to investigate the effects of ABA on the hippocampal-dependent processes: anxiety-, depression-li...
Abscisic acid (ABA, CHO), a mammalian hormone, exhibits neuroprotective and anti-inflammatory properties. This study aimed to investigate the effects of ABA on the hippocampal-dependent processes: anxiety-, depression-like behaviors and cognitive impairments as well as levels of factors involved in neuroplasticity and neuroinflammation in an amyloid-β (Aβ)-induced mouse model of Alzheimer's disease (AD). One week following intracerebroventricular (i.c.v.) injection of Aβ in male mice, ABA was administered i.c.v. at doses of 10 or 15 µg/µl for 7 consecutive days. Behavioral assessments were conducted using the novel object recognition, open field, elevated plus maze, tail suspension, Morris water maze, and passive avoidance tests. Hippocampal gene expression levels of brain-derived neurotrophic factor (BDNF), N-methyl-D-aspartate receptor (NMDAR), and nuclear factor-κB (NF-κB) were evaluated using real-time PCR. ABA treatment significantly attenuated anxiety-like behaviors and improved spatial, avoidance and recognition memory deficits induced by Aβ administration with more behavioral domains affected at the 15 µg/µl dose. ABA induced significant upregulation in the hippocampus of NMDAR and BDNF expression and marked suppression of NF-κB in the ABA (15 µg/µl)-treated Aβ group, which could have played a mechanistic role in improvements in behaviors controlled by this structure. Histological analysis demonstrated attenuation of neuronal degeneration and pyknosis in the hippocampal CA1 region following ABA intervention. Collectively, these findings suggest that ABA ameliorates anxiety-related behaviors and cognitive impairments in an experimental mouse model of AD, potentially through modulation of neuroinflammatory and neuroplasticity-related pathways.
Prolonged β-adrenergic stimulation reduces β2-adrenergic receptor levels and limits astrocytic responsiveness during early amyloid pathology.
Roy Choudhury R, Kushwaha S, Karunakaran S
Neurosci Lett · 2026 Jun · PMID 42097394 · Publisher ↗
Early Alzheimer's disease (AD) is associated with declining noradrenergic tone and early alterations in astrocytic regulation. β-adrenergic signaling links norepinephrine activity to extracellular signal-regulated kinase...
Early Alzheimer's disease (AD) is associated with declining noradrenergic tone and early alterations in astrocytic regulation. β-adrenergic signaling links norepinephrine activity to extracellular signal-regulated kinase (ERK) activation and astrocytic responses, but the effects of sustained adrenergic stimulation during early amyloid exposure remain unclear. In this study, wild-type (WT) and pre-plaque APPSwe/PSEN1dE9 (APP/PS1) mice received chronic oral isoproterenol (ISO) from postnatal day 26-47. Hippocampal adrenergic signaling and astrocytic responses were examined at 3 months of age. ISO exposure was associated with reduced β2-adrenergic receptor (β2AR) protein levels and increased β-arrestin-1 expression, consistent with receptor desensitization-associated signaling changes, while ERK phosphorylation remained detectable in both genotypes. WT mice showed increased glial fibrillary acidic protein (GFAP) expression, whereas APP/PS1 mice displayed attenuated molecular responses despite comparable ERK activation. Morphometric analysis revealed no clear evidence of robust astrocytic structural changes at the animal level. These findings indicate that sustained β-adrenergic stimulation is associated with reduced β2AR levels while downstream ERK signaling persists, suggesting that astrocytic responsiveness to adrenergic signaling may be constrained during early amyloid pathology.
Formalin-induced pain preferentially activates orexin neurons in male mice.
Fukasawa S, Mukae S, Matsuo A … +1 more , Kanaya M
Neurosci Lett · 2026 Jun · PMID 42097393 · Publisher ↗
Sex differences are well-documented across many functions of the orexin system; however, whether such differences extend to pain processing has been examined far less thoroughly. Therefore, we investigated whether males...
Sex differences are well-documented across many functions of the orexin system; however, whether such differences extend to pain processing has been examined far less thoroughly. Therefore, we investigated whether males and females differ in orexin system engagement during nociception, and whether any differences reflect structural organization or functional recruitment. Adult C57BL/6N mice of both sexes were used, with females tested during proestrus and metestrus. Formalin was injected into the hind paw, and c-Fos induction in lateral hypothalamic orexin neurons was quantified together with orexin A/B fiber density and orexin receptor OX1R/OX2R mRNA expression in the lumbar cord. Orexin A and B were fully colocalized, allowing orexin B to serve as a reliable marker. The total number of orexin-immunoreactive neurons did not differ between the sexes or across estrous stages, and spinal orexinergic innervation and OX1R/OX2R mRNA levels were comparable across groups. In contrast, formalin induced a significantly higher proportion of c-Fos-positive orexin neurons in males, indicating male-biased recruitment of orexin neurons during nociception, despite equivalent anatomical substrates. These findings suggest that sex differences in orexin involvement in nociception are not attributable to structural disparities in the number of orexin neurons, spinal projections, or receptor expression, but instead arise from sex- and context-dependent differences in the functional activation of orexin neurons in response to painful stimuli.
Metformin attenuates neurodegeneration in ICV-STZ-induced Alzheimer's model via antioxidant and anti-inflammatory mechanisms: implications for disease-modifying therapy.
Darzi M, Golchoobian R, Varzi HN … +1 more , Shanehbandpour Tabari F
Neurosci Lett · 2026 Jun · PMID 42067052 · Publisher ↗
Alzheimer's disease (AD) is the leading cause of dementia, accounting for over 60% of cases in older adults. Growing evidence suggests that metformin, a first-line antidiabetic drug, may have neuroprotective properties....
Alzheimer's disease (AD) is the leading cause of dementia, accounting for over 60% of cases in older adults. Growing evidence suggests that metformin, a first-line antidiabetic drug, may have neuroprotective properties. This study evaluated metformin's effects in a streptozotocin (STZ)-induced rat model of sporadic AD. Thirty-two male rats were divided into four groups (n = 8/group): Sham, STZ, Metformin, and Metformin + STZ. The AD model was established via bilateral intracerebroventricular STZ injections (3 mg/kg) on days 61 and 63, with metformin administered in drinking water (2 mg/mL) for 82 days. Metformin treatment significantly enhanced hippocampal catalase activity while reducing malondialdehyde (MDA) and total oxidative status (TOS) levels in both brain and serum. Notably, it selectively decreased hippocampal IL-1β without affecting serum levels, suggesting central-specific anti-inflammatory effects. These findings demonstrate metformin's dual antioxidant and anti-inflammatory actions in an AD model, supporting its potential as a disease-modifying therapy. The dissociation between central and peripheral IL-1β responses highlights the importance of blood-brain barrier considerations in AD treatment strategies.
Brain creatine, estradiol and neurocognitive complaints in perimenopausal women: an exploratory cross-sectional study.
Ostojic SM, Ostojic J
Neurosci Lett · 2026 Jun · PMID 42061673 · Publisher ↗
BACKGROUND: Menopause and the perimenopausal transition involve profound hormonal and metabolic changes that may impair brain function. Beyond structural alterations, reduced cerebral bioenergetics could underlie the cog...
BACKGROUND: Menopause and the perimenopausal transition involve profound hormonal and metabolic changes that may impair brain function. Beyond structural alterations, reduced cerebral bioenergetics could underlie the cognitive complaints often reported during this period. Because creatine serves as a key neuronal energy buffer and is influenced by estrogen, this study examined brain creatine concentrations in perimenopausal women and their associations with neurocognitive symptoms and serum estradiol. METHODS: Twelve healthy perimenopausal women (mean age 49.8 ± 5.4 years) experiencing irregular cycles and at least one perimenopausal symptom underwent multi-voxel 1H-magnetic resonance spectroscopy to quantify total brain creatine across bilateral frontal, precentral, and parietal gray- and white-matter regions and the thalamus. Serum estradiol was measured by ELISA, and symptom severity was rated on visual analog scales. Associations were assessed using Kendall's τ. RESULTS: Mean whole-brain creatine concentration (6.31 ± 0.98 mM) was significantly lower than reference values in younger adults (Z = -1.65, P = 0.049). Lower creatine levels in the thalamus, right precentral, and right parietal white matter correlated with greater concentration difficulties (τ = -0.38 to -0.51, P ≤ 0.049), while right frontal white-matter creatine positively correlated with headache severity (τ = 0.41, P = 0.034). Serum estradiol averaged 119.5 ± 109.5 pg/mL and was inversely associated with right parietal gray-matter creatine (τ = -0.37, P = 0.049). CONCLUSIONS: Perimenopausal women exhibited lower cerebral creatine than younger adults, with region-specific reductions linked to concentration difficulties and estradiol levels. These findings suggest that estrogen-related changes in brain bioenergetics may contribute to cognitive symptoms during the menopausal transition.
Effect of ADP on cumulative TRPV1 desensitization to capsaicin in rat DRG neurons.
Petrushenko O, Petrushenko M, Lukyanetz E
Neurosci Lett · 2026 May · PMID 42009289 · Publisher ↗
Transient receptor potential vanilloid 1 (TRPV1) channels play a key role in nociception and undergo Ca-dependent desensitization, which is closely linked to cellular metabolic state. In nociceptive dorsal root ganglion...
Transient receptor potential vanilloid 1 (TRPV1) channels play a key role in nociception and undergo Ca-dependent desensitization, which is closely linked to cellular metabolic state. In nociceptive dorsal root ganglion (DRG) neurons, TRPV1 channels are coexpressed with metabotropic purinergic receptors P2Y1, P2Y2, P2Y4, and P2Y6, among which ATP is an agonist for P2Y1. In this study, we examined the effect of ADP on reversal of TRPV1 desensitization in rat DRG neurons (P8-10; 1-2 days in vitro) using Fura-2 AM Ca imaging. Elevation of intracellular Ca with 50 mM KCl resulted in a significant reduction in capsaicin action (18.4 ± 4.0% of control), which is associated with rapid Ca-dependent inactivation of TRPV1 channels. This effect was reversible, with recovery observed within 10-15 min. Repeated application of capsaicin (100 nM, 10 s; 3-5 trials at 2-5 min intervals) resulted in a progressive reduction in capsaicin-induced Ca transients, consistent with cumulative TRPV1 desensitization. Application of adenosine-5'-diphosphate (ADP; 0.1 mM, 60 s) 10 min after repeated capsaicin stimulation was associated with a partial restoration of the subsequent capsaicin-induced Ca response. These data indicate that postponed purinergic signaling may counteract cumulative TRPV1 desensitization in DRG sensory neurons.
Pharmacological inhibition of calcium channel modulates NF-κB-NLRP3 inflammasome axis and alters post-stroke innate immunity.
Bhattacharya P, Saraf S, Karmarkar G … +6 more , Barik A, Ghosh B, Kumari A, Mukherjee U, Datta A, Malik DS
Neurosci Lett · 2026 May · PMID 42002094 · Publisher ↗
Ischemic stroke triggers a series of pathological processes where calcium overload and mitochondrial dysfunction are key mediators of neuronal damage. Mitochondria not only fail energetically under calcium excitotoxicity...
Ischemic stroke triggers a series of pathological processes where calcium overload and mitochondrial dysfunction are key mediators of neuronal damage. Mitochondria not only fail energetically under calcium excitotoxicity but also play a crucial role in alteration of innate immune response through the production of danger signals. Although innate immunity is responsible for post-stroke tissue repair, it is also involved in the amplification of neuroinflammation exacerbating neuronal injury. Indirect evidence suggests role of calcium overload in neuroinflammation, but direct mechanistic evidence is still unclear. Calcium channel inhibition may provide a promising strategy to unravel this relationship by elucidating whether calcium influx is a causal factor in immune activation. Our recent findings demonstrated that inhibiting calcium influx alleviates mitochondrial dysfunction by calcineurin and cardiolipin modulation. The present study is a further molecular expedition into the role of calcium signaling in exacerbating stroke outcomes through innate immune modulation. Stroke was induced in male Sprague Dawley rats via middle cerebral artery occlusion. Genes and proteins expression were then assessed for markers of innate immunity. Mitochondrial complex activity was measured following calcium channel inhibition. It was observed that inhibiting calcium channel altered the innate immunity associated gene and protein expression when compared to stroke. In addition, calcium channel inhibition restored mitochondrial complex activity compared to stroke. These observations offer direct evidence of the role of calcium signaling in modulation of innate immunity and related molecular mechanisms. Thus, calcium channel inhibition could be one of the potential future adjunctive therapies to improve post-stroke outcomes.
MiR-372-3p alleviates isoflurane-induced cognitive dysfunction by targeting STAT3 to mitigate neuroinflammation and oxidative stress.
Zhao M, Li T, Zhang Q … +1 more , Liu X
Neurosci Lett · 2026 Jun · PMID 41980675 · Publisher ↗
OBJECTIVE: Isoflurane (ISO), a common anesthetic, can impair learning and memory, especially in the elderly. This study aims to determine whether miR-372-3p modulates neurocognitive dysfunction resulting from isoflurane...
OBJECTIVE: Isoflurane (ISO), a common anesthetic, can impair learning and memory, especially in the elderly. This study aims to determine whether miR-372-3p modulates neurocognitive dysfunction resulting from isoflurane anesthesia in experimental rats. METHODS: SD rats were employed to construct the ISO treatment rat model. Spatial learning and memory were evaluated in rats using the Morris water maze (MWM). Hippocampal and microglial expression of miR-372-3p and STAT3 mRNA were quantified via qRT-PCR. ELISA assays detected pro-inflammatory cytokines, oxidative stress indicators, and Iba-1 levels in these tissues. The miR-372-3p/STAT3 regulatory axis was functionally validated through dual-luciferase reporter systems, RIP, and phenotypic rescue studies. RESULTS: ISO treatment induced significant cognitive impairment in rats, concomitant with a marked downregulation of miR-372-3p expression in the hippocampal tissue. These deficits, evidenced by impaired spatial memory in the Morris water maze test, were effectively alleviated by the administration of a miR-372-3p agomir. Mechanistically, ISO triggered neuroinflammation, oxidative stress, and microglial activation (elevated Iba1) both in vivo and in BV-2 microglial cells. These detrimental effects were significantly mitigated by miR-372-3p overexpression. MiR-372-3p bound to the 3'UTR of STAT3 and suppressed its expression. Crucially, the protective effects of miR-372-3p against ISO-induced were effectively reversed by STAT3 overexpression. CONCLUSION: miR-372-3p downregulation acts as a critical contributor to ISO-induced cognitive dysfunction. Mechanistically, miR-372-3p's protective effects relate to the regulation of STAT3 signaling, with in vitro data confirming direct targeting and functional interplay. These results highlight the potential therapeutic value of the miR-372-3p/STAT3 axis in mitigating anesthesia-related neurotoxicity.
Dysregulation of mRNAs and hub genes in Parkinson's disease within post mortem substantia Nigra: using three methods differential expression genes analysis.
Aung TL, Aung YW, Myint KS … +1 more , Shi X
Neurosci Lett · 2026 May · PMID 41980674 · Publisher ↗
This study employed an integrative bioinformatics approach to identify key molecular signatures in Parkinson's disease (PD) by analyzing substantia nigra transcriptomes from 22 PD patients and 22 healthy controls (HCs) a...
This study employed an integrative bioinformatics approach to identify key molecular signatures in Parkinson's disease (PD) by analyzing substantia nigra transcriptomes from 22 PD patients and 22 healthy controls (HCs) across three Gene Expression Omnibus (GEO) datasets. Using DESeq2, edgeR, and limma, we identified 85 consensuses differentially expressed mRNA (DEmRNAs) (23 up-regulated and 62 down-regulated), including key players in PD pathogenesis such as molecular chaperones (DNAJB1, HSPA1B/L), dopaminergic markers (TH, SLC6A3), and extracellular matrix components (COL5A1, LAMB1). Functional enrichment analyses revealed up-regulated pathways in PI3K-Akt signaling and extracellular matrix organization, while down-regulated genes were enriched in dopaminergic synapse and mitochondrial function pathways. Protein-protein interaction (PPI) network analysis identified 20 hub genes, with DNAJB1, TH, KCNJ6, and SLC6A3 emerging as central regulators. Notably, we discovered novel candidate's mRNAs alongside validated PD-associated genes, highlighting both degenerative processes and compensatory mechanisms. These findings provide a comprehensive molecular framework for PD pathogenesis, offering potential biomarkers and therapeutic targets for further investigation.
The exposure to the air pollutant fine particulate matter (PM) slightly enhances high-fat diet-induced anxiety-like behavior and impairs brain redox balance in female rats.
Costa-Beber LC, de Pelegrin Basso EG, Friske PT … +8 more , Dos Santos JB, Sulzbacher LM, Friske SN, Passos FR, Ludwig MS, Goettems-Fiorin PB, Rhoden CR, Heck TG
Neurosci Lett · 2026 May · PMID 41962857 · Publisher ↗
INTRODUCTION: Obesity is a major risk factor for mood disorders. Additionally, the pollutant fine particulate matter (PM) has effects on central nervous system (CNS) that demand elucidation. OBJECTIVE: To evaluate if PM...
INTRODUCTION: Obesity is a major risk factor for mood disorders. Additionally, the pollutant fine particulate matter (PM) has effects on central nervous system (CNS) that demand elucidation. OBJECTIVE: To evaluate if PM potentiates the neuropsychological and oxidative effects of obesity. METHODS: Female Wistar rats received high-fat (HFD) or standard diet ad libitum for 24 weeks and were daily exposed to 250 µg of PM or saline (50 µL), via intranasal instillation. In the last two days, animals underwent open field and elevated plus maze tests. Brain structures were collected for oxidative stress evaluation. RESULTS: HFD and PM had independent and cumulative effects on anxiety-like behaviors. HFD reduced exploration in the open field, whereas PM enhanced the time spent in the closed arms of the elevated plus maze. Additionally, animals exposed to pollution were more susceptible to the effects of diet in reducing rearing frequency, suggesting subtle cumulative effects. Obese rats exposed to PM presented higher lipoperoxidation in hippocampus. Conversely, HFD decreased lipoperoxidation and SOD defense in the cortex, while PM primarily affected the cerebellum's antioxidant defense. CONCLUSION: PM and obesity have independent effects, and their association increases vulnerability to each other's neurobehavioral and oxidative impacts.
Hemorphin LVV-H3 attenuates calcineurin activity and regulates cytokine levels in experimental Parkinson's disease.
Sarukhanyan F, Hunanyan O, Zakaryan H … +1 more , Knaryan V
Neurosci Lett · 2026 May · PMID 41946390 · Publisher ↗
Dysregulation of intracellular Ca levels and activation of the Ca/calmodulin-dependent phosphatase calcineurin (CaN) contribute to neurodegeneration and inflammatory responses associated with the Parkinson's disease (PD)...
Dysregulation of intracellular Ca levels and activation of the Ca/calmodulin-dependent phosphatase calcineurin (CaN) contribute to neurodegeneration and inflammatory responses associated with the Parkinson's disease (PD) pathogenesis. Hence, regulation of CaN activity may be beneficial in PD. Hemorphins, endogenous hemoglobin-derived peptides, play modulatory role in the brain and immune system in experimental pathologies. The effect of hemorphin LVV-H3 on CaN activity and proinflammatory cytokines (IL-2, TNFα) in the CNS (brain, spinal cord), peripheral tissues (thymus, spleen) and plasma was studied using a rotenone-induced PD model in rats. Rotenone was administered at 0.5 mg/kg (s.c.) for 40 days. Hemorphin LVV-H3 (1 mg/kg; i.p.) was administered in pretreatment and posttreatment regimens. To assess LVV-H3 effects on cytokines levels associated with CaN signaling, rats received the CaN inhibitor cyclosporine A (CsA; 5 mg/kg; i.p.) alone or combined with LVV-H3 in rotenone-injected rats. Chronic rotenone administration significantly increased CaN activity in the brain and spinal cord (by 76%), thymus (by 255%), spleen (by 45%), and plasma (by 59%) compared to controls. LVV-H3 posttreatment reduced CaN activity in these tissues. IL-2 and TNFα levels were altered differently by rotenone; for example, IL-2 increased and TNFα decreased in the brain. LVV-H3 pretreatment reversed these changes, decreasing IL-2 and increasing TNFα compared to rotenone-injected rats. Results indicate that LVV-H3-mediated cytokine regulation is partially, but not entirely mediated through CaN-dependent mechanisms. Modulation of CaN activity and cytokine levels suggests hemorphin as a potential regulatory agent against rotenone-induced changes in the CNS and peripheral tissues.
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