A quantitative description of the adenosine and caffeine influence on the glutamatergic synaptic neurotransmission is presented. The analysis is based on a set of coupled mathematical models for a sequence of processes involved in the synaptic transmission, starting from the action potential at the presynaptic axonal terminal and up to the spike generation at the postsynaptic membrane. Adenosine and caffeine act via binding to the presynaptic adenosine receptors that results in the alteration of axon terminal calcium ion influx and, thereby, in the modulation of the efficiency of neurotransmitter release. Dynamics of the glutamate in the synaptic cleft were determined taking into account its release from the presynaptic vesicles with subsequent glutamate diffusion and reuptake. Maximal value of the glutamate concentration in the cleft is about 1.2 mM. The glutamate content elevation induces a spike at the postsynaptic neuron. The dependence of the synaptic transmission efficiency on the levels of adenosine and caffeine has been analyzed. The probability of the synaptic transmission is increased from 0.3 to about 0.5 when varying caffeine concentration from 0 to 200 µM. Transmission probability significantly depends on the number of the postsynaptic glutamate receptors.
Though the nucleus accumbens (NAc) is a key terminal region of the mesolimbic dopaminergic system, it is also innervated by noradrenergic inputs from the ventral medulla and contains intrinsic cholinergic neurons. However, the roles of α-adrenoceptors in regulating basal accumbal cholinergic activity remain unclear. This study employed in vivo microdialysis in unanesthetized rats to investigate the role of α1- and α2-adrenoceptors in modulating extracellular acetylcholine (ACh) levels in the NAc. Accumbal administration of the α2-agonist UK 14304 (30.0 and 300.0 pmol) and the α2-antagonist RX 821002 (0.6, 600.0, and 6000.0 pmol) dose-dependently decreased and increased accumbal ACh efflux, respectively. Neither compound (UK 14304: 300.0 pmol; RX 821002: 6000.0 pmol) affected basal accumbal dopamine levels. Co-administration of RX 821002 (0.6 pmol) blocked the UK 14304 (300.0 pmol)-induced reduction in ACh efflux, whereas UK 14304 (30.0 pmol) inhibited the RX 821002 (6000.0 pmol)-induced increase. Intraperitoneal administration of RX 821002 (1.0 mg/kg), but not UK 14304 (2.5 mg/kg), increased accumbal ACh efflux, which was inhibited by intra-accumbal infusion of UK 14304 (30.0 pmol). Neither the α1-agonist methoxamine (0.24 pmol) nor the α1-antagonist prazosin (6.0 pmol) altered accumbal ACh levels. Doses of drugs infused indicate the total amount (mol) during the 60-min infusion. These findings indicate that RX 821002 enhances ACh efflux in the NAc by blocking accumbal α2-adrenoceptor-mediated inhibition of ACh release. Given that reduced accumbal ACh levels have been implicated in cognitive impairment, systemic administration of α2-adrenoceptor antagonists should be investigated for their potential to improve such deficits in experimental models.
This study aimed to investigate the role and underlying mechanism of lncRNA MIAT in sevoflurane (Sev)-induced cognitive dysfunction in neonatal rats, thereby offering theoretical basis for clinical intervention. Seven-day-old Sprague-Dawley (SD) rats were chosen to construct a Sev-induced cognitive dysfunction model. Anxiety-like behavior and locomotor activity were assessed by the open field test (OFT), whereas cognitive function was evaluated using novel object recognition (NOR) test and Morris water maze (MWM) test. The expression levels of lncRNA MIAT, miR-15b-5p, and Ccnd1 were detected by RT-qPCR. The dual-luciferase reporter gene assay was carried out to validate the targeted binding relationships. Sev exposure led to a downregulation of lncRNA MIAT expression in rat hippocampus. lncRNA MIAT alleviated Sev-induced cognitive impairment, as manifested by increased central zone residence time in OFT, elevated recognition index (RI) in NOR test, shortened escape latency, increased platform crossings, and prolonged target quadrant residence time in MWM test. Mechanistically, lncRNA MIAT directly targeted miR-15b-5p and inhibited its expression. miR-15b-5p targeted Ccnd1 and suppressed its expression. Overexpression of miR-15b-5p or silencing of Ccnd1 reversed the neuroprotective effect of lncRNA MIAT. LncRNA MIAT ameliorates Sev-induced cognitive dysfunction in neonatal rats by sponging miR-15b-5p to upregulate Ccnd1 expression, which may serve as a potential target for preventing Sev-related neurotoxicity.
A complete human sleep consists of multiple states, each of which has its own unique and typical characteristics. A clear definition of these states lays a solid foundation for the study of related sleep disorders. However, there remain significant challenges in current research on human sleep. Focusing on the automatic staging of sleep states, this review is organized around the technical route, technical challenges, and future perspectives of sleep staging. First, 2044 records related to sleep staging were initially screened from the Web of Science Core Collection, and key methodological themes were identified through an initial screening. Second, more than 200 highly relevant studies were selected for review, and 174 of them were cited. Compared with previous surveys on automated sleep staging, in this paper, more attention is paid to the complete technical route, key technical challenges, data strategy, and future research trends. Special attention is given to the N1 stage, which represents the most challenging classification target due to both its inherent physiological ambiguity and low inter-scorer reliability under the current AASM framework. This review aims to provide a practically oriented and operationally actionable reference for researchers in the field.
Non-motor symptoms in Parkinson's disease (PD) may be influenced by the α4β2* subtype of nicotinic acetylcholine receptors (nAChRs) present in the hippocampus (HP) and subiculum (SUB). To continue efforts in positron emission tomography (PET) diagnostics for PD, autoradiographic [18F]nifene binding to α4β2* nAChR was quantitatively assessed in the HP-SUB of PD (n = 27; 14 males and 13 females) and cognitively normal (CN) (n = 32; 16 males and 16 females) cases. Anti-ubiquitin for Lewy body and anti-α-synuclein immunostaining on adjacent slices were analyzed in QuPath, and [18F]nifene binding was quantified in OptiQuant. The SUB had greater [18F]nifene binding (51%-85%) compared to HP in all cases. Significantly higher [18F]nifene binding (>250%; p < 0.0001) was seen in PD SUB and PD HP compared to CN in both males and females. The grey matter (GM) to white matter (WM) ratio in PD = 3.53, whereas CN = 1.33, a >150% increase in PD (p < 0.0001). Binding of [18F]nifene to GM was >250% greater than WM in PD for both male and female. Male CN exhibited an increase, whereas male PD exhibited a significant decrease in [18F]nifene binding with aging, whereas females did not exhibit significant differences. In summary, α4β2* nAChR measured by [18F]nifene is significantly upregulated in the PD HP and SUB. This increased [18F]nifene binding may be of diagnostic value using PET imaging.
In recent decades, the rate of aging has increased significantly worldwide. Since both cognitive and motor performance decline during aging, they are considered indicators of this stage of normal development. Successful, healthy aging-not associated with pathology-is accompanied by a decline in motor skills due to the underlying anatomical and functional organization of the motor cortex. Deep-layer V neurons are thought to be the relay that translates afferent information to this cortical region and the organizers of the output of information that generates motor activity. Basal dendritic arborization was studied using the Sholl method, along with dendritic spine density and the amounts of distinct spine types in medial segments of primary dendrites in deep pyramidal neurons of layer V of the motor cortex of young (3-4 months) and aged (22-24 months), male Sprague-Dawley rats. Significant reductions in dendritic arborization and spine density were observed in the aged animals. Each spine type-thin, mushroom, stubby, and wide-existed in lower numbers than in the young animals. Results suggest both a reduction in the integrative capacity of synaptic stimuli by pyramidal cells and a downregulation in the processing of excitatory information. These findings could underlie the decline in the acquisition and maintenance of motor skills during healthy aging.
Anorexia nervosa is a deadly eating disorder marked by extreme food restriction, compulsive exercise, and severe weight loss. In a prior study using the activity-based anorexia (ABA) animal model of anorexia nervosa, 30 mg/kg, but not 3 mg/kg, of ketamine reduced relapse vulnerability, measured as increased food intake, increased body weight (BW), and reduced excessive wheel running, though there were individual differences in responsiveness to treatment. This study investigated whether ketamine evoked sustained changes to AMPA receptors (AMPARs) at excitatory synapses of the prefrontal cortex (PFC), and whether they might correlate with individual differences in sustained behavioral improvements. Adolescent female mice that received 30 mg/kg (N = 8) or 3 mg/kg (N = 8) of ketamine underwent two cycles of ABA induction (ABA1 and ABA2), which included acclimation to a wheel preceding food restriction, with ABA2 modeling relapse. We analyzed the distributions of PFC AMPARs at synapses of pyramidal neurons (PNs) and of GABA interneurons (GABA-INs) using electron microscopy, with 10-nm immunogold to localize AMPARs. Increased AMPARs in the cytoplasm of PN synapses correlated with better BW retention during ABA2, as well as a reduction in excessive wheel running. Increased AMPARs in PN synapses' cytoplasm and GABA-INs synapses' postsynaptic density were associated with higher food intake during recovery. These correlations fit with a previous proposal that excitatory outflow from PFC to the GABA-INs in the dorsal raphe promotes feeding, while decreased excitatory outflow from PFC to dorsal medial striatum decreases hyperactivity during ABA, both of which contribute positively toward gain of resilience against ABA.
Propofol (PPF), a commonly employed clinical anesthetic, has elicited growing concern due to its associated neurotoxic effects. However, the functional role and mechanistic insights of microRNA-3909 (miR-3909) in PPF-induced neurotoxicity remain unexplored. This study sought to elucidate the expression of miR-3909 and its underlying molecular mechanisms in the context of PPF-induced neurotoxicity. An in vitro model of PPF neurotoxicity was established using SH-SY5Y cells (PPF-SH-SY5Y). Initial assessments via cell counting kit-8 (CCK-8) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) demonstrated that treatment with 50 µM PPF significantly reduced cell viability and downregulated miR-3909 expression. Subsequent functional assays revealed that overexpression of miR-3909 effectively alleviated PPF-induced neurotoxicity, as evidenced by enhanced cell viability, suppression of apoptosis, reduced lactate dehydrogenase (LDH) release, and decreased reactive oxygen species (ROS) levels. Mechanistic investigations, including a dual-luciferase reporter assay, validated that miR-3909 directly targets and negatively regulates the expression of polymerase I and transcript release factor (PTRF). Notably, PTRF was significantly upregulated in PPF-SH-SY5Y cells, and overexpression of PTRF substantially counteracted the neuroprotective effects mediated by miR-3909. Collectively, these findings indicate that miR-3909 alleviates propofol-induced neurotoxicity by targeting PTRF, thereby providing a potential therapeutic target for this condition.
To investigate the regulatory mechanism of BLACAT1 expression in sevoflurane (Sev)-induced neuronal cell injury.An in vitro model was created by treating microglial cell lines with 3% Sev. An in vivo model was created by administering 2.2% Sev gas inhalation to mice for three consecutive days. Learning and memory capacity was assessed using the Morris water maze test. Gene expression was detected via RT-qPCR, while cellular functional alterations were observed through CCK-8 assays and flow cytometry. ELISA monitored inflammatory cytokine levels, while assay kits assessed oxidative stress marker expression. Dual luciferase reporter assay and RNA immunoprecipitation validated gene-target relationships.Treatment with Sev increased BLACAT1 levels in microglia and mouse hippocampi, while reducing the expression of miR-361-3p. Transfection with si-BLACAT1 counteracted the inhibitory effects of Sev on cell proliferation while reducing inflammatory and oxidative stress levels. miR-361-3p was a downstream target of BLACAT1, with miR inhibitor counteracting si-BLACAT1's protective effects on damaged neurons. Furthermore, Sev treatment impaired learning and memory functions in the mouse hippocampus, as evidenced by prolonged escape latency and fewer platform crossings during the original platform phase.BLACAT1 participates in Sev-induced glial cell injury via miR-361-3p, leading to hippocampal cognitive dysfunction.
OBJECTIVE:This study aims to explore the role of ubiquitination in neuroinflammation and functional damage after stroke using multi-omics analysis, focusing on the pathways influenced by ubiquitination. METHODS:Gene expression data related to stroke were collected from the GEO database. Differentially expressed genes were identified using the "limma" package in R. GO and KEGG enrichment analyses were performed to identify significant pathways. Ubiquitination data were integrated with differential gene data to identify genes with ubiquitination sites, focusing on those that bind to E3 ligases. Network analysis was conducted to examine the interactions among ubiquitin-modified proteins, and protein-RNA correlations were analyzed using data from proteomic analysis. RESULTS:The analysis identified several inflammatory pathways significantly altered after stroke, including the NF-κB, TNF, and NOD-like receptor signaling pathways. A total of 113 genes with ubiquitination sites were found to be associated with E3 ligases and stroke-related genes. Among them, TRIM37 and TRIM25 emerged as key regulatory factors. Protein interaction network analysis revealed that ubiquitination modifications enhance neuroinflammation, leading to functional impairments. Post-translational modifications, indicated by higher protein stability, were observed in the proteins with the most ubiquitination sites, supporting their potential as therapeutic targets. DISCUSSION:The study identifies TRIM37 and TRIM25 as crucial regulators of neuroinflammation through ubiquitination after stroke. These findings suggest that ubiquitination plays a significant role in stroke pathology and could serve as therapeutic targets for stroke treatment.
The cerebellum contributes to motor, cognitive, and affective functions that progressively decline with aging. The search for effective therapies to delay age-related degeneration has become a focus of the scientific community. Resveratrol, a natural polyphenol, exhibits neuroprotective properties through antioxidant and anti-inflammatory actions in different models of brain injury and aging. Here, we evaluated the effects of resveratrol on fine motor performance, oxidative stress, glial reactivity, and Purkinje cell survival in the cerebellum of male Wistar rats treated for 6, 12, 18, or 24 months. Three-month-old rats were randomly assigned to receive either vehicle (drinking water) or resveratrol (10 mg/kg, orally, daily by gavage between 8:00 and 10:00 a.m.). Fine motor skills were assessed using the balance beam test. Rats treated with resveratrol for 18 or 24 months showed improved motor coordination and fewer slips compared with controls. Histological analysis revealed less cellular disorganization and greater preservation of Purkinje cells after 12, 18, and 24 months of treatment. Nissl staining confirmed that resveratrol attenuated neuronal disintegration and preserved cerebellar architecture. Moreover, resveratrol significantly reduced GFAP immunoreactivity at 12, 18, and 24 months, indicating decreased astrocytic activation and inflammation. In conclusion, chronic resveratrol treatment exerted neuroprotective effects in the cerebellum, improving fine motor performance and reducing glial reactivity. These findings support resveratrol as a potential strategy to mitigate motor decline, inflammation, and cerebellar neurodegeneration associated with aging.
The accumulation of tau tangles and Aβ plaques are prominent neuropathologies that characterize Alzheimer's disease (AD) and Down syndrome (DS). Continuous developments of PET tracers as biomarkers can be supported by autoradiography to validate effectiveness and accuracy of binding properties that elucidate the pathophysiology of DSAD and AD. This in vitro comparative study evaluates [125I]IPPI binding to tau and [125I]IBETA binding to Aβ plaques in the frontal cortex (FCX) and temporal cortex (TCX) of postmortem human brain slices of AD (n = 5), DSAD (n = 5), and cognitively normal (CN) (n = 5) cases. With anti-tau and anti-Aβ immunostains confirming the presence of tau and Aβ plaques, [125I]IPPI and [125I]IBETA binding in autoradiographic images were significantly higher in DSAD and AD gray matter (GM) compared to CN. When comparing DSAD with AD, FCX and TCX GM binding was similar throughout DSAD and AD, except in FCX GM where there was 48% more [125I]IPPI binding in DSAD than AD. In vitro drug inhibition studies revealed that [125I]IPPI binding was significantly inhibited with increasing harmine concentrations (IC50 = 115 nM) in DSAD FCX and TCX, but KuFal194, a DYRK1A drug, minimally inhibited [125I]IPPI binding in the same cases. The GM/white matter ratios for DSAD ([125I]IPPI = 4.1, [125I]IBETA = 2.9) and AD ([125I]IPPI = 4.2, [125I]IBETA = 2.6) were significantly greater than CN ([125I]IPPI = 1.3, [125I]IBETA = 1.2). A positive correlation between [125I]IPPI and [125I]IBETA binding suggests a synergistic relationship between tau and Aβ plaque in DSAD and AD pathology. This study demonstrates that [125I]IPPI and [125I]IBETA may serve as novel radiotracers in both DSAD and AD to continue diagnostic investigations.
The cerebellin (CBLN) family includes CBLN1, CBLN2, CBLN3, and CBLN4, which are important secreted glycoproteins that play roles in synaptogenesis and the maintenance and plasticity of synapses across various regions of the central nervous system (CNS). Generally known for their implications in cerebellar parallel fiber-Purkinje cell synapses, CBLNs also play a comprehensive role in synaptic regulation in the CNS. By forming trans-synaptic complexes with postsynaptic glutamate delta receptors (GluDs) and presynaptic neurexins (NRXNs), CBLNs significantly impact the synaptic specificity and potency. Each CBLN protein has its own expression signature and function. Current research points to a key role for CBLN1 in forming excitatory synapses, especially in the cerebellum, while CBLN2 is reported to regulate inhibitory synaptic transmission and serotonergic circuits. In addition, CBLN3 regulates synaptic stability and is associated with many neurodevelopmental problems. Apart from its role in the regulation of inhibitory synapse formation, CBLN4 is also linked to many neurodegenerative disorders. Dysfunction of pathways associated with CBLN signaling has been linked to several neuropsychiatric and neurological disorders, such as ataxia and schizophrenia. This review article compares existing data on the structure, expression, and functional properties of CBLN proteins, their roles in synapse organization, and their potential as therapeutic targets for neurological disease.
Sevoflurane may trigger neuroinflammation, thereby leading to cognitive dysfunction. This study aimed to investigate the mechanism of microRNA-101b-3p (miR-101b-3p) in sevoflurane-induced hippocampal neurodegeneration. In this study, 48 male C57BL/6 mice were procured to establish an animal model of cognitive dysfunction. The expression of miR-101b-3p and thioredoxin-interacting protein (TXNIP) was quantified using real-time quantitative polymerase chain reaction (RT-qPCR), and their targeting relationship was validated through a dual-luciferase reporter assay. The Morris water maze test was employed to assess the cognitive ability of mice. The concentrations of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in hippocampal tissues were measured via enzyme-linked immunosorbent assay (ELISA). A detection kit was utilized to evaluate the activity of superoxide dismutase (SOD), malondialdehyde (MDA) content, and reactive oxygen species (ROS) levels. Bcl-2-associated X protein (Bax) and B-cell lymphoma 2 (Bcl-2) proteins were determined by Western blotting. Sevoflurane treatment not only reduced the expression of miR-101b-3p but also concurrently increased the expression of TXNIP. Overexpression of miR-101b-3p was capable of suppressing TXNIP expression and alleviating sevoflurane-induced cognitive dysfunction, inflammatory response, and oxidative stress. Conversely, overexpression of TXNIP reversed these protective effects. Moreover, sevoflurane exposure may induce apoptosis, as indicated by elevated Bax and reduced Bcl-2 expression. However, overexpression of miR-101b-3p inhibited apoptosis, and this effect was counteracted by TXNIP supplementation. Overexpression of miR-101b-3p suppressed the expression of TXNIP, thereby attenuating the inflammatory response and oxidative stress and mitigating sevoflurane-induced cognitive dysfunction.
In recent years, global life expectancy has risen significantly, leading to a marked increase in the elderly population. Aging disproportionately affects the brain, resulting in cognitive decline and increased susceptibility to neurodegenerative diseases. This vulnerability is largely due to the high metabolic activity of neural tissue and its sensitivity to reactive oxygen species (ROS). Consequently, oxidative and inflammatory processes are key contributors to cellular damage and age-related cognitive deficits. These oxidative processes may act as primary drivers of neuronal damage during aging. Recent evidence suggests that phenolic compounds may play a crucial role in neuroprotective strategies. Among these, gallic acid (GA) has garnered attention due to its potent antioxidant and anti-inflammatory properties, which enhance neuronal resilience in animal models. However, the effects of GA on hippocampal neurodegeneration during aging remain unclear. In this study, we evaluated the impact of GA on learning, memory, redox balance, neuroinflammation, apoptosis, and synaptic plasticity in the hippocampus (Hp) of aged rats. Male rats aged 18 months received a daily dose of GA (20 mg/kg) for 60 days. GA treatment significantly improved short- and long-term recognition memory. In the Hp, ROS, tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and lipid peroxidation were reduced, while superoxide dismutase (SOD) and catalase (CAT) activities increased. GA administration also decreased caspase-3 expression. Collectively, these findings indicate that GA enhances antioxidant and anti-inflammatory defenses, thereby mitigating hippocampal damage and supporting its potential as a promising therapeutic strategy to prevent or reduce neurodegenerative disorders associated with aging.
Low-dose ketamine is an efficacious antidepressant for treatment-resistant unipolar and bipolar depressed patients. Major depressive disorder patients receiving a single infusion report elevated mood within 2 h, and ketamine's antidepressant effects have been observed as long as 7 days posttreatment. In light of this remarkable observation, efforts have been undertaken to "reverse-translate" ketamine's effects to understand its mechanism of action. Major advances have been achieved in understanding the molecular, cellular, and circuit-level changes that are initiated by low-dose ketamine. Although enhancement of protein synthesis clearly plays a role, the field lacks a comprehensive understanding of the protein synthesis program initiated after ketamine treatment. Here, using ribosome-bound mRNA footprinting and deep sequencing (RiboSeq), we uncovered a genome-wide set of actively translated mRNAs (the translatome) in medial prefrontal cortex after an acute antidepressant-like dose of ketamine. Gene Ontology analysis confirmed that initiation of protein synthesis is a defining feature of antidepressant-dose ketamine in mice, and Gene Set Enrichment Analysis pointed to a role for GPCR signaling, metabolism, vascularization, and structural plasticity in ketamine's effects. One gene, VIPR2, whose protein product VPAC2 acts as a GPCR for the neuropeptide vasoactive intestinal peptide, was characterized in the cortex and identified as a potential novel target for antidepressant action. We demonstrate that VPAC2's functional expression in medial prefrontal cortex is limited to somatostatin-positive neurons and that in vivo dosing of a VPAC2 agonist elicits complex effects on prefrontal cortical pyramidal neurons, bidirectionally modulating their activity and disrupting the structure of coordinated neural activity. Finally, we show that VPAC2 agonism is sufficient to drive an antidepressant response, confirming the validity of our approach to targeted drug development.
This study aims to investigate the role of long noncoding RNA RMRP in diabetic peripheral neuropathy (DPN) and its potential mechanisms. We used high glucose (HG) treatment on Schwann cells (SCs) and established a DPN rat model to study the role of RMRP in DPN. RT-qPCR was employed to assess the levels of RMRP and miR-3142. The targeting relationship between RMRP and miR-3142 was verified through dual-luciferase reporter assays, RIP assays, and RNA pull-down experiments. CCK-8 assays and flow cytometry were used to evaluate cell proliferation and apoptosis. The von Frey test and thermal stimulus apparatus measured the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) in rats. In addition, the motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV) of the rats were assessed. RMRP was abnormally expressed in both HG-treated SCs and DPN rats. Inhibition of RMRP significantly alleviated the reduction in SCs proliferation and the increase in apoptosis induced by HG, while also reducing oxidative stress and neuroinflammation levels. In DPN rats, inhibition of RMRP improved MWT and TWL and enhanced nerve conduction velocity, whereas inhibition of miR-3142 diminished the protective effects of si-RMRP. Inhibiting RMRP can relieve DPN-related oxidative stress and cell inflammation, as well as reduce pain hypersensitivity and the decline in nerve conduction velocity in rats by upregulating miR-3142.
BACKGROUND:Isoflurane is an inhalational anesthetic widely used in clinical practice. However, its potential neurotoxic mechanisms have not been fully elucidated. Recent studies have found that miR-3099-5p is stably expressed in the brain and is closely associated with neural injury, neurodevelopment, and stem cell differentiation. METHOD:This study utilized an isoflurane-treated SD rat model to assess the effects of isoflurane on the spatial learning and memory capabilities of the rats through the Morris water maze experiment system. ELISA technology was employed to measure the levels of inflammatory factors, while the thiobarbituric acid reactive substance method and WST-1/NBT colorimetric method were used to determine oxidative stress indicators. Furthermore, qRT-PCR technology was applied to detect gene expression levels, and the regulatory relationships between target genes were further examined through dual-luciferase reporter gene assays. RESULT:Exposure to isoflurane can lead to cognitive dysfunction in rats, accompanied by an upregulation of miR-3099-5p expression. Additionally, inhibiting miR-3099-5p not only significantly improves these cognitive deficits but also attenuates the isoflurane-induced inflammatory response of microglia and oxidative stress, with the mechanism being through direct targeting and inhibition of AQP4 expression. CONCLUSION:miR-3099-5p mediates isoflurane-induced neurotoxicity via AQP4 regulation. Its inhibition alleviates cognitive impairment and neuroinflammation, providing a novel therapeutic target for anesthesia-related neural damage and potential neuroprotective drug development.
Postherpetic neuralgia (PHN) is a form of neuropathic pain that has significant detrimental effects. This study seeks to explore the potential association between miR-138-5p and PHN. A PHN model was established by infecting rats with the varicella-zoster virus. Following this, the expression level of miR-138-5p in spinal cord was quantified using RT-qPCR. To further investigate its role, miR-138-5p levels were modulated through the intrathecal administration of a lentivirus. The abnormal pain sensitivity in the rats was assessed utilizing the paw withdrawal threshold (PWT). Additionally, the levels of glial fibrillary acidic protein (GFAP) and pro-inflammatory cytokines (IL-1β and TNF-α) in spinal cord were measured by RT-qPCR or enzyme-linked immunosorbent assay (ELISA). Dual-luciferase reporter assay was used to verify the binding relationship between miR-138-5p and ROCK2. miR-138-5p is downregulated in the spinal cord tissue of PHN rats. Notably, the overexpression of miR-138-5p significantly enhances the PWT in PHN rats. Furthermore, the elevation of miR-138-5p markedly mitigates the abnormal increase of GFAP and pro-inflammatory factors. Mechanistically, ROCK2 has been identified as a downstream target of miR-138-5p. During the onset of PHN, ROCK2 is persistently upregulated, whereas the overexpression of miR-138-5p effectively inhibits this increase. Interestingly, the concurrent overexpression of miR-138-5p and ROCK2 can counteract the enhancement in PWT engendered solely by the upregulation of miR-138-5p, alongside the reduction in levels of GFAP, IL-1β, and IL-6. miR-138-5p plays a crucial role in modulating the development of PHN. In the context of PHN, miR-138-5p inhibits spinal cord inflammation and hyperalgesia by suppressing ROCK2.
