Neurochemical Research最新文献

Cerebral microhemorrhages (CMHs) contribute to cognitive decline and motor deficits. Inhibiting A1 astrocyte polarization can attenuate brain injury and promote recovery after experimental intracerebral hemorrhage. Despite RIP1 is a known mediator of neurological impairment in hemorrhage models, it is not known whether it regulates astrocytic phenotypic switching to influence CMH progression. Here, a mouse model of hypertension-induced CMHs was established by co-administration of Ang II and L-NAME. Following hypertension induction, daily neurological assessments showed progressively declining scores, indicating ongoing CMH development. RIP1 silencing delayed CMH onset, reduced cumulative incidence, and alleviated hypertension-induced deficits including gait abnormalities, impaired spatial learning and memory, blood-brain barrier (BBB) dysfunction, and A1 astrocyte polarization. In vitro, primary mouse astrocytes were exposed to hemoglobin to simulate the microhemorrhagic microenvironment. RIP1 silencing attenuated hemoglobin-induced A1 polarization and promoted a shift toward the A2 phenotype. Furthermore, RIP1 knockdown counteracted the detrimental effects of A1-polarized astrocytes on endothelial function, as evidenced by improved endothelial cell proliferation, migration, and tube formation. Mechanistically, RIP1 knockdown facilitated the transition from A1 to A2 astrocytic phenotype by activating autophagy and suppressing the NF-κB-NLRP3 inflammasome pathway, thereby mitigating hypertension-induced BBB disruption following CMHs. In conclusion, RIP1 silencing alleviates BBB disruption following hypertension-induced CMHs by promoting autophagy-mediated A2 astrocyte polarization.

Post-traumatic stress disorder (PTSD) is a chronic psychiatric condition linked with abnormal fear responses, oxidative imbalance, inflammation, and neuronal injury. The present work examined the protective effects of morin hydrate (MH), a natural flavonoid known for its antioxidant and neuroprotective properties, in a stress–re-stress (SRS) rat model of PTSD. Male Wistar rats were exposed to repeated stress cues and then treated with vehicle, paroxetine (10 mg/kg, p.o.), or MH (15 and 30 mg/kg, p.o.). Behavioral outcomes were assessed using fear conditioning, elevated plus maze, open field, Y-maze, novel object recognition, forced swim, and sucrose preference tests. Animals exposed to SRS developed pronounced fear retention, anxiety-like and depressive behaviors, and cognitive impairment. Treatment with MH, especially at 30 mg/kg, improved exploratory activity, reduced immobility, and enhanced memory performance. Biochemical studies showed reduced lipid peroxidation and restoration of glutathione, superoxide dismutase, and catalase. MH also lowered pro-inflammatory cytokines (TNF-α, IL-1β) and increased hippocampal brain-derived neurotrophic factor (BDNF). Histological analysis confirmed preservation of neuronal density in CA1 and CA2 regions of the hippocampus. In summary, MH produced behavioral, biochemical, and structural improvements in the SRS model, suggesting its value as a natural therapeutic candidate for PTSD.

Brain aging involves progressive disruption of tissue homeostasis and susceptibility to neurodegenerative disorders. Within this context, astrocytes are key determinants of region-specific physiology, given their roles in metabolic support, synapse regulation, proteostasis, neuroinflammation, and blood-brain barrier maintenance. Aging is accompanied by broad transcriptional and functional remodeling in astrocytes, leading to the emergence of distinct cellular states that cannot be defined by classical morphological criteria alone. This review discusses how aging modifies astrocyte identities toward reactive and senescence-like states. We summarize core features of astrocyte senescence, including altered secretory signaling, impaired neuronal support, and changes in mitochondrial and proteostatic pathways, while integrating recent single-cell and regionally transcriptomic studies that delineate multiple reactive states associated with aging and pathological contexts. We further address evidence that reactivity and senescence are not mutually exclusive endpoints, but may coexist, arise sequentially, or partially overlap depending on timing, brain region, biological sex, and pathological insults. Finally, we define key open questions and experimental priorities required to establish the temporal and causal relationships among astrocyte states. We argue that resolving these issues is essential for advancing therapeutic strategies that specifically target defined astrocyte phenotypes, rather than nonspecifically suppressing astrocyte activity, in aging and neurodegenerative diseases.

Brain edema is a major contributor to secondary injury following intracerebral hemorrhage (ICH). Neurochemical disturbances, including disruption of blood-brain barrier (BBB) tight junctions and altered aquaporin-4 (AQP4) polarization, are central to post-hemorrhagic fluid imbalance. However, their association with glymphatic dysfunction and tissue-level alterations remains incompletely understood. A rat model of ICH was established and treated with glibenclamide. BBB integrity, glymphatic function, and AQP4 polarization were systematically evaluated using molecular, histological, and tracer-based approaches. Brain edema and perihematomal tissue mechanical properties were assessed. ICH was associated with marked disruption of BBB integrity, characterized by reduced tight junction protein expression and increased permeability, along with impaired AQP4 polarization and diminished glymphatic influx and clearance. These coordinated neurochemical alterations were accompanied by secondary changes in cerebrospinal fluid composition, brain water accumulation, and tissue mechanical properties. Glibenclamide treatment was associated with preservation of tight junction protein expression, restoration of AQP4 polarization, and improved glymphatic transport dynamics, accompanied by attenuation of edema formation and partial normalization of perihematomal tissue mechanics. Functional performance was correspondingly improved in treated animals. These findings indicate that experimental ICH was accompanied by coordinated changes in BBB integrity, AQP4 polarization, and fluid transport dynamics. Glibenclamide treatment was associated with parallel improvements across molecular, physiological, and functional domains. Collectively, the data highlight a coordinated pattern of neurovascular and fluid homeostasis alterations that may be involved in edema progression after hemorrhagic injury.

Alzheimer’s disease (AD) is characterized by glutamatergic dysregulation and excitotoxicity, largely associated with impaired activity of the excitatory amino acid transporter 2 (EAAT2). Downregulation of EAAT2 results in glutamate accumulation, N-Methyl-D-Aspartate (NMDA) receptor overactivation, and neuronal injury. Crocin (Cr), a carotenoid compound extracted from saffron (Crocus sativus), exhibits potent antioxidant and neuroprotective properties, particularly in experimental models of neurodegeneration. Forty-eight adult male rats were divided into six groups: control (saline), crocin (50 mg/kg), scopolamine (3 mg/kg for 7 days), scopolamine followed by memantine (M) (20 mg/kg), scopolamine followed by crocin, and scopolamine followed by both memantine and crocin. This study aimed to evaluate the therapeutic potential of crocin, alone and in combination with memantine, in a scopolamine-induced rat model of Alzheimer’s disease, with a focus on EAAT2 modulation. Scopolamine administration significantly elevated glutamate, NMDAR and p-tau levels while reducing p-Akt, GABA and EAAT2 levels, accompanied by marked hippocampal neurodegeneration. In contrast, crocin treatment, either alone or in combination with memantine, restored neurotransmitter balance, downregulated NMDAR, upregulated EAAT2, increased p-Akt expression level and reduced tau phosphorylation. Histological analysis further confirmed notable structural recovery of hippocampal neurons.

This study (a) used the forced swim test in a rat model of Parkinson’s disease (PD) to characterise the antidepressant-like effect of hydroxytyrosol (Hty) against 1-methyl-4-phenylpyridinium (MPP⁺) and (b), studied dopamine and serotonin levels in the striatum. Rats were intravenously administered 1.5 mg/kg Hty via the tail vein 5 min before an intra-striatal infusion of 10 µg MPP⁺; control animals received saline. After 6 days, locomotor activity was assessed in an open-field test and antidepressant-like effects were tested using the forced swim test. On day 6, all the animals received apomorphine (1 mg/kg, s.c.) and ipsilateral rotations were recorded for an hour before sacrifice and removal of striatal tissues for dopamine and serotonin quantification. Neither MPP⁺ injection nor Hty altered locomotor activity. Hty pretreatment significantly reduced immobility time, increased climbing time in the forced swim test, and diminished the number of ipsilateral rotations induced by apomorphine in rats treated with MPP⁺. These effects were consistent with an increase in dopamine and serotonin levels. These results show that Hty had antidepressant-like activity in the forced swim test in the rat MPP⁺ model and protected against MPP⁺ neurotoxicity, suggesting its potential utility in the treatment of neurodegenerative diseases such as PD and depression.

Epilepsy is a central nervous system disease characterized by the sudden onset of seizures, loss of consciousness, or confusion. In recent years, many non-intravenous routes of administration of benzodiazepines have been developed for seizure control, with intranasal administration being an attractive route of choice. However, for such a route of administration, there is a lack of evidence on the choice of the epilepsy drug. This study aims to compare the intranasal formulations of three first-line drugs for seizure control, namely midazolam, diazepam, and lorazepam, via an ideal intranasal treatment. A pilocarpine-induced seizure model in mice was used to compare drug efficacy. The three drugs were administered intranasally to 36 C57 mice at a single dose of 1 mg/kg, followed by inducing the seizures via intraperitoneal injection of pilocarpine. The subsequent seizure scores were observed for either 10–100 min. After sacrificing the mice at 10/100 minutes post-dosing, whole brain tissue and plasma were collected to analyze the drug concentrations as well as brain-to-plasma concentration ratios. In addition, effects of these intranasally delivered drugs on neuroinflammation-associated molecules were monitored and compared via the mRNA levels and/or protein expression of GABARα1, TNF-α, and IL-1β in the cortex and hippocampus. Additionally, drug bindings to plasma and brain tissue obtained using the ultrafiltration method were compared, and drug binding affinities towards the GABA_A receptor, as determined via the computer docking technique, were also compared. Among the three tested drugs, our results suggested that intranasal diazepam, with the highest brain-to-plasma ratio, was the best in seizure control at 10 min. Although all three drugs showed good stability, similar brain binding and receptor binding affinity, diazepam demonstrated the greatest efficacy in reducing TNF-α mRNA and protein levels, and lowest plasma protein binding, which could contribute to its higher brain-to-plasma ratio and better acute epilepsy control compared to the other two drugs. Our pilot in vivo experiments in the pilocarpine-induced mice seizure model for the first time demonstrated that intranasally administered benzodiazepines are effective for seizure control at the early stage, with intranasally delivered diazepam being the most potent one.

Spinal cord injury (SCI) initiates a devastating vicious cycle characterized by the secondary degeneration of motor neurons in the spinal cord and progressive denervation atrophy in the skeletal muscle they innervate. While the hormone 17β-estradiol (E2) has recognized neuroprotective properties, its capacity to simultaneously halt the distinct degenerative pathways in both the nervous and muscular systems, remains largely unexplored. This study elucidates a novel, dual mechanism through which E2 coordinately protects the entire motor unit. It was first established that a direct myoprotective role exists for E2 in vitro, demonstrating its ability to attenuate IFN-γ-induced upregulation of reactive oxygen species, the critical atrophy ligands MuRF1 and MAFbx in L6 myoblasts. In a contusion SCI model in male rats, we have demonstrated that E2 treatment comprehensively suppressed post-injury proteolytic and apoptotic signaling in skeletal muscle, thus normalizing the Bax: Bcl-2 and calpain: calpastatin ratios and reducing the expression of MAFbx and MuRF1. Mechanistically, this anti-atrophic effect was driven by the inhibition of NF-κB nuclear translocation in muscle tissue. Furthermore, E2 functionally preserved the neuromuscular junction, reducing the expression of MuRF1 and the denervation marker acetylcholinesterase while restoring presynaptic cholineacetyltransferase. Most significantly, our study demonstrated that focal delivery of a sustained-release E2 formulation directly to the site of the injured spinal cord activated the canonical Wnt/β-catenin pro-survival pathway, as evidenced by the stabilization of β-catenin and AKT proteins and a marked increase in the survival of β-catenin-positive motor neurons. Our findings reveal that E2 therapy confers comprehensive protection after SCI by operating on two fronts: it directly blocks NF-κB-driven proteolysis in skeletal muscle while concurrently activating Wnt/β-catenin signaling to promote motor neuron survival. This coordinated, dual-arm mechanism underscores the significant therapeutic potential of targeted E2 delivery to disrupt the self-perpetuating cycle of neuromuscular degeneration following spinal cord injury in male rats.

VCAN-AS1 is a novel long non-coding RNA that participates in diverse disease processes, but the mechanism of its action in cerebral infarction secondary epilepsy (CISE) is unclear. The potential action mechanism of VCAN-AS1 in CISE was explored by this study. VCAN-AS1 and its downstream targets, namely miR-885-3p and Netrin G1 (NTNG1), were screened by the GEO, LncRNASNP2, and miRDB databases. The epileptic mouse and cell models were constructed using pilocarpine and the Mg²⁺-free medium, respectively. ELISA kits or RT-qPCR was used for the measurement of TNF-α/IL-1/IL-6 levels. The levels of Fe²⁺, GSH, and ROS were detected by the specific biochemical kits. GPX4 expression was analyzed by RT-qPCR. Dual-luciferase reporter assay was used to detect the interactions between miR-885-3p and VCAN-AS1 or NTNG1. Meanwhile, the expression levels of VCAN-AS1, miR-885-3p, and NTNG1 were detected by RT-qPCR. Elevated serum levels of VCAN-AS1 were observed in patients with CISE, and silencing of VCAN-AS1 attenuated inflammation and ferroptosis in epilepsy-associated neurons and the hippocampus of epileptic mice. VCAN-AS1 negatively regulated miR-885-3p which subsequently repressed NTNG1 expression. Up-regulation of miR-885-3p inhibited inflammation and ferroptosis in epileptic mouse and cell models, and overexpression of NTNG1 reversed these effects of miR-885-3p. The suppression of VCAN-AS1 expression mitigated neuronal inflammation and ferroptosis in epileptic conditions by targeting the miR-885-3p/NTNG1 regulatory axis, which may be an important molecular mechanism of CISE.

Synthetic glucocorticoids, such as dexamethasone, are widely used in therapy; however, their administration at high doses may be associated with effects on the central nervous system, particularly on neurotransmitter systems, yet the molecular mechanisms underlying these phenomena remain poorly understood. In this study, we investigated the effects of a single intraperitoneal administration of dexamethasone (8 mg/kg) on the metabolism of key monoamines and the expression of their metabolic enzymes in various rat brain regions (striatum, hippocampus, and prefrontal cortex) using high-performance liquid chromatography and real-time quantitative reverse transcription polymerase chain reaction. We found that dexamethasone exerts a pronounced, region-specific impact on neurotransmitter systems. In the striatum, dexamethasone increased dopamine and serotonin levels while simultaneously reducing their catabolism, which was associated with decreased messenger ribonucleic acid expression of monoamine oxidase A, monoamine oxidase B, tryptophan hydroxylase and increased expression of tyrosine hydroxylase. In the hippocampus, dexamethasone elevated serotonin levels and reduced its turnover despite an increase in monoamine oxidase A messenger ribonucleic acid expression, suggesting the potential involvement of post-transcriptional regulation or alternative metabolic pathways. In the prefrontal cortex, dexamethasone induced a reduction in norepinephrine levels, accompanied by a decrease in monoamine oxidase A and catechol-O-methyltransferase messenger ribonucleic acid expression. This study highlights the importance of considering region-specific cerebral effects of glucocorticoids for the development of personalized therapeutic and neuroprotective strategies, including the potential use of dexamethasone in conditions such as Parkinson’s disease due to its ability to elevate striatal dopamine levels.