Acute carbon monoxide (CO) poisoning is a common poisoning disease that commonly occurs after occupational and daily exposure to CO. Delayed encephalopathy after acute CO poisoning (DEACMP) occurs in 20% to 40% of all CO-poisoned patients due to the harmful effect of CO on the central nervous system (CNS)
[1]. With a disability rate of 78% and a fatality rate of 31%, DEACMP significantly impacts the quality of life for CO-poisoned patients
[2]. Therefore, identifying strategies to reduce CNS damage, promote the repair of injured nerves, and improve nerve function is crucial for treating DEACMP, which is also a popular topic in acute CO poisoning research.
The toxic effect of CO on the CNS is defined not only as damage to neurons in the cerebral cortex, globus pallidus, hippocampus, and other regions
[3] but also damage to the myelin sheath enveloping axons
[4]. Oligodendrocytes form myelin sheaths in the CNS. The myelin sheath is essential for neuronal action potentials and axonal trophic support
[5]. Furthermore, oligodendrocytes produce neuroprotective and trophic factors that maintain axon integrity and neuron survival
[6]. Disruption of myelin sheaths after CNS injury can cause the production of large amounts of nerve growth inhibitors
[7], thus hindering the regeneration of nerve axons and the survival of residual neurons. Therefore, the survival of neurons is closely related to that of oligodendrocytes. Previous study
[8] has shown that CO-induced apoptosis of neuronal cells and oligodendrocytes is an essential mechanism underlying CNS injury in CO-poisoned patients.
Long noncoding RNAs (lncRNAs) are biologically active transcripts with lengths of at least 200 nucleotides
[9]. LncRNAs cannot be translated but play vital roles in molecular, cellular, and biological events, mainly by regulating the expression levels of related proteins. Microarray analysis
[10] of lncRNAs expression patterns in different human tissues reveals that up to 40% of tissue-specific lncRNAs are expressed in the CNS. Changes in the expression of lncRNAs have been implicated in neurodevelopmental disorders (autism spectrum disorders, intellectual disability), brain damage, and neurodegenerative diseases
[11-12]. Small nuclear RNA host gene 15 (
SNHG15) is a lncRNA that was recently discovered. In a recent study
[13] on ischemic encephalopathy, lncRNA
SNHG15 expression is significantly increased after cerebral ischemia-reperfusion. Knockdown of lncRNA
SNHG15 effectively reduces oxidative stress in brain tissues, inhibits neural cell apoptosis, and promotes injury repair
[14-17]. However, the role of lncRNA
SNHG15 in CO-induced CNS injury remains unknown.
Leucine-rich repeat and immunoglobulin-like domain-containing protein 1 (LINGO-1) is a transmembrane protein specifically expressed on neurons and oligodendrocytes of the CNS
[18]. LINGO-1 performs many different biological functions, including negative regulation of myelination and neurite outgrowth during normal brain development
[19]. LINGO-1 protein expression level is also upregulated in CNS disease animal models
[20-21], inhibiting not only neuron and oligodendrocyte survival but also oligodendrocyte differentiation, axonal regeneration, and axonal myelin sheath function recovery
[19, 22]. In addition, blocking LINGO-1 promotes myelination, axonal regeneration, neuronal survival, and functional recovery in animal models of multiple sclerosis, Parkinson’s disease, and spinal cord injury
[18].
Retinoic acid (RA), a metabolic intermediate of vitamin A, plays a complex regulatory role in cell apoptosis in different diseases
[23]. RA synthesis increases after CNS injury
[24]. By interacting with numerous cytokines, RA plays a neuroprotective role in inhibiting apoptosis, promoting neuronal survival, and stimulating axonal regeneration
[24-25].
Our group
[26] has previously demonstrated that RA can improve the cognitive function in DEACMP rats, with an effect related to the decreased protein expression level of LINGO-1. However, the role of LINGO-1 in RA alleviating neurological damage caused by DEACMP and its key upstream and downstream molecules remain unknown. After extensive preliminary exploration, we found that lncRNA
SNHG15 seemed to have a close relationship with LINGO-1 during this process. Therefore, this study aims to determine whether lncRNA
SNHG15 and LINGO-1 are essential molecules involved in the mechanism by which RA mitigates neuronal and oligodendrocyte injury in mice induced by CO poisoning, and to explore the possible signaling pathway that is involved in this process.
1 Materials and methods
1.1 Ethics statements
This study was approved by the Medical Ethics Committee of Xiangya Hospital, Central South University (No. 201703221).
1.2 Cell culture
Mouse hippocampal neuronal cell line (HT22) and mouse primary oligodendrocytes (Pricella, China) were cultured in Dulbecco’s modified eagle medium (DMEM; Gibco, USA) supplemented with 10% fetal bovine serum (FBS; GIBCO, USA), 100 U/mL penicillin (GIBCO, USA), and 100 μg/mL streptomycin (GIBCO, USA). The primary mouse oligodendrocytes were isolated and purified as previously described
[27]. 1% B-27 supplement (Thermo Fisher Scientific, USA) was used to stimulate oligodendrocyte proliferation. The cells were maintained at 37 ℃ in a humidified atmosphere of 95% air and 5% CO
2.
1.3 CO-poisoned cell models
The cellular model of CO poisoning was established in a hermetic chamber, as described in a previous study
[8]. HT22 cells and primary oligodendrocytes were exposed to 1 000 ppm CO (Changsha Zhanyuan Gas Co. Ltd., China) for 6 h. A CO sensor (Edkors Co., Ltd., China) was used to monitor the CO concentrations. RA (Changsha Boyi Co., Ltd., China) was dissolved in dimethyl sulfoxide (DMSO) to prepare a 10 mmol/L stock solution and diluted in the culture medium to the indicated concentrations. After removal from the CO environment, the cells were treated with RA at different concentrations (5, 10, and 20 μmol/L), and the medium containing RA was refreshed every 24 h for 48 to 72 h until the end of the observation period.
1.4 Lentivirus transduction
Lentivirus vectors carrying targeting short hairpin RNA (shRNA) or over-expression RNA (oeRNA) were synthesized by Shanghai GenePharma Co., Ltd. (China), including negative control (NC), shRNA (sh-NC), NC oeRNA (oe-NC), LINGO-1 shRNA (sh-LINGO-1), LINGO-1 oeRNA (oe-LINGO-1), SNHG15 shRNA (sh-SNHG15), and SNHG15 oeRNA (oe-SNHG15). When HT22 cells reached 70% confluence, cells (3×105) were transduced with one of the following using Lipofectamine 3000 (Invitrogen, USA) in accordance with the manufacturer’s instructions: sh-NC, sh-LINGO-1, sh-SNHG15, oe-NC, oe-LINGO-1,or oe-SNHG15 for 48 h. For the cell models: 48 h after virus injection, CO treatment was applied for 30 min, and then the medium containing RA was refreshed every 24 h until the end of the observation period. For the animal models: after confirming successful establishment of the DEACMP mouse model, lentivirus was injected. The mouse hippocampal tissues were collected for observation and subsequent experiments 1 month post-injection.
1.5 Cell viability assay
Cells were seeded at a density of 2 000 cells/well in 96-well plates. After 24 to 72 h of treatment, cell vitality was assessed with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The absorbance of the culture medium was quantified at a wavelength of 450 nm using a microplate reader (Bio-Tek ELX 800, USA). All experiments were performed in triplicate and repeated independently 3 times.
1.6 Flow cytometry
After treatment for 48 h, by Annexin V/propidium iodide (PI) staining assay, apoptosis in HT22 cells and primary oligodendrocytes were determined via flow cytometry according to the manufacturer’s instructions (BD Pharmingen, USA). Flow cytometry data were plotted and analyzed on the fluorescence-activated cell sorting system (BD Biosciences, USA) within 1 h after staining. The percentage of cells in each quadrant was calculated using FlowJo V10 software (BD Biosciences, USA).
The apoptosis rate was calculated with the following formula: Apoptosis rate=percentage of cells in Q2 quadrant (Annexin V-positive and PI-positive cells)+percentage of cells in Q3 quadrant (Annexin V-positive and PI-negative cells).
1.7 Animals
A total of 24 healthy adult male Kunming mice (body weight 20 to 30 g, age 5 to 6 weeks), free of specific pathogens, were obtained from the Hunan SJA Laboratory Animal Co., Ltd. (China). The animals were housed at the Department of Laboratory Animals, Central South University, with a 12-hour light/dark cycle and ambient temperature maintained between 21 ℃ and 22 ℃.
1.8 DEACMP mouse model
After 1 week of adaptive feeding, basic water maze training was performed as described in our previous study
[24]. The 24 mice were randomly divided into 4 groups using the table of random numbers (
n=6 in each group): the sham group, the DEACMP group, the DEACMP + sh-
SNHG15 group (transfected with 2 μL 5×10
8 TU/mL
sh-SNHG15, Geneharma Co., Ltd., China), and the DEACMP+sh-
LINGO-1 group (transfected with 2 μL 5×10
8 TU/mL sh-
LINGO-1, Geneharma Co., Ltd., China). Every 6 mice in the same group were housed in the same cage. The method used to establish the animal model was adapted from a previous report
[28]. Mice were exposed to inhale 1 000 ppm CO gas for 40 min in the transparent box, and followed by 3 000 ppm CO gas for a further 20 min
[24]. The mice were removed from the box to regain consciousness in fresh air after they had lost consciousness. Similar to our previous study
[24], the mice in the sham group were placed in the aforementioned transparent box containing normal air without CO gas and maintained there for the same duration as the mice in the other 3 groups. Carboxyhemoglobin quantification and the water maze test were essential for evaluating the successful establishment of the DEACMP model as described in previous research
[26]. For the DEACMP+sh-
SNHG15 group or the DEACMP+sh-
LINGO-1 group, mice were injected with sh-
SNHG15 or sh-
LINGO-1 via the lateral ventricle, while the mice of sham group or the DEACMP group were given the same amount of solvent. The methods used for mouse anesthesia, brain tissue fixation, and mouse left hippocampal tissues sample collection were performed as previously described
[26]. Among the 24 mice, one mouse in the DEACMP group died of CO poisoning, and one mouse in the DEACMP+sh-
SNHG15 group did not exhibit signs of successful model establishment.
1.9 Real-time fluorescence quantitative PCR
The expression levels of
LINGO-1 and
SNHG15 RNA were analyzed by real-time fluorescence quantitative PCR (RT-qPCR). Total RNA was extracted with TRIzol reagent (Thermo Fisher Scientific, USA) and was reverse transcribed into complementary DNA using a reverse transcription kit (Wuhan Servicebio Technology Co., Ltd., China)
[26]. SYBR green-based RT-qPCR was used to quantify the RNA expression levels of
LINGO-1 and
SNHG15. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as an endogenous control. The specific primers for
GAPDH,
LINGO-1, and
SNHG15 were listed in
Table 1. The target gene expression was normalized against the expression of
GAPDH using the 2
-ΔΔCt method.
1.10 Western blotting
Cells or brain samples were lysed with lysis buffer [pH 6.8, including 50 mmol/L Tris, 2% sodium dodecylsulfate (SDS), 10% glycerol, 5% β-mercaptoethanol, and 1% protease inhibitor cocktail]. The protein concentrations of all the cell and brain samples were normalized. The proteins were separated via SDS-polyacrylamide gel electrophoresis (8%-12% polyacrylamide) and transferred to polyvinylidene fluoride (PVDF) membranes as previously reported
[29]. Membranes were blocked with 5% nonfat dry milk in Tris-buffered saline with 0.1% Tween-20 (TBST) for 1 h at room temperature. PVDF membranes were incubated overnight at 4 ℃ with the following primary antibodies: Rabbit anti-brain-derived neurotrophic factor (BDNF) (1꞉1 000 dilution, Abcam, UK), rabbit anti-LINGO-1 (1 µg/mL, Abcam, UK), rabbit anti-tyrosine kinase receptor B (TrkB) (1꞉5 000 dilution, Abcam, UK), rabbit anti-myelin basic protein (MBP) (1꞉1 000 dilution, Abcam, UK), rabbit anti-nerve growth factor (NGF) (1꞉1 000 dilution, Abcam, UK), rabbit anti-neurotrophin-3 (NT-3) (1 µg/mL, Abcam, UK), and rabbit anti-GAPDH (1꞉10 000 dilution, Abcam, UK). Horseradish peroxidase (HRP)-conjugated secondary anti-rabbit (1꞉1 000 dilution, Cell Signaling Technology, USA) was then added and incubated for 1 h. The proteins of interest were visualized using enhanced chemiluminescence (Thermo Fisher Scientific, USA). The intensity value of the protein bands were analyzed with ImageJ software (National Institutes of Health, Bethesda, MD, USA) and presented as a ratio to GADPH intensity.
1.11 Hematoxylin and eosin staining
Mouse left hippocampal CA1 tissues were prepared into 5 to 8 μm thick paraffin sections. The procedure involved dewaxing, hydrating, staining with hematoxylin and eosin (Wuhan Servicebio Technology Co., Ltd., China), washing, dehydrating, and treating with xylene to induce transparency in accordance with the manufacturer’s instructions. The pathological changes of stained hippocampal sections were checked using an optical microscope (Carl Zeiss AG, Germany) under 100× magnification.
1.12 Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay
The extent of apoptosis in mouse left hippocampal CA1 tissues was determined by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. The tissue sections were stained using the Click-iTTM TUNEL colorimetric immunohistochemistry staining (IHC) detection kit (Thermo Fisher Scientific, USA) according to the manufacturer’s instructions. Apoptotic and necrotic cells were stained with a 3,3’- diaminobenzidine (DAB) reaction mixture. Apoptotic cell nucleus were stained brown. Five different fields of view were randomly selected from each slice under a microscope (400× magnification) to analyze the stained tissues.
1.13 Statistical analysis
Numerical results were expressed as the mean±standard deviations, and graphs were generated using GraphPad Prism version 7.0. All data in this study were analyzed using SPSS software (Version 22). Numerical data satisfied normal distribution and homogeneity of variance. Statistical significance was evaluated using one-way analysis of variance (ANOVA), and repeated-measures ANOVA was used to analyze the MTT assay results. P<0.05 is considered statistically significant.
2 Results
2.1 Effects of RA on CO-induced injury in HT22 cells and primary oligodendrocytes
The MTT assay and flow cytometry results (
Figure 1) showed that cell viability of HT22 cells and primary oligodendrocytes both significantly decreased after CO exposure (both
P<0.05). Both 10 and 20 μmol/L RA dramatically reversed the effect of CO on cell viability of HT22 cells and primary oligodendrocytes (all
P<0.05). After CO exposure, the apoptosis rates were significantly increased both in HT22 cells and primary oligodendrocytes (both
P<0.05). Treatment with 10 or 20 μmol/L RA significantly reduced CO-induced apoptosis in HT22 cells and primary oligodendrocytes (all
P<0.05).
2.2 Effects of RA on the expression of <italic>SNHG15</italic>, <italic>LINGO-1</italic>, and BDNF/TrkB pathway-related proteins
The RT-qPCR results (
Figure 2A) showed that CO induced the up-regulation of lncRNA
SNHG15 and
LINGO-1 in HT22 cells and primary oligodendrocytes (all
P<0.01). RA at 10 or 20 μmol/L significantly down-regulated CO-induced high expression of
SNHG15 and
LINGO-1 in both HT22 cells and primary oligodendrocytes (all
P<0.05). Western blotting (
Figure 2B) revealed that 10 or 20 μmol/L RA potently reversed CO-induced up-regulation of LINGO-1 protein expression in HT22 cells and primary oligodendrocytes (all
P<0.05), which was consistent with the results of RT-qPCR. Interestingly, the expression of neuroprotective proteins BDNF and TrkB were significantly decreased after CO exposure and rebounded after RA administration at concentrations of 10 or 20 μmol/L in HT22 cells and primary oligodendrocytes (all
P<0.05).
2.3 RA alleviated CO-induced cell apoptosis by regulating <italic>SNHG15</italic> and <italic>LINGO-1</italic>
After transduction of oe-
SNHG15 or oe-
LINGO-1 in HT22 cells and primary oligodendrocytes, the expression of
SNHG15 in the CO+RA+oe-
SNHG15 group was at least 5 times than that in the CO+RA+oe-NC group. A similar result was obtained when
LINGO-1 was overexpressed (all
P<0.01,
Figure 3A). The results demonstrated that
SNHG15 or
LINGO-1 was successfully overexpressed in both HT22 cells and primary oligodendrocytes. Furthermore, the overexpression of
SNHG15 or
LINGO-1 significantly reduced cell viability and promoted apoptosis in both HT22 cells and primary oligodendrocytes. This effect counteracted the beneficial role of RA in improving cell viability and reducing apoptosis after CO poisoning (all
P<0.05, Figure
3B and
3C). Moreover, overexpression of
SNHG15 or
LINGO-1 diminished the RA-induced upregulation of BDNF and TrkB protein expression (all
P<0.05,
Figure 3D). While overexpression of
LINGO-1 had no effect on the expression of
SNHG15 (
P>0.05,
Figure 3A), the overexpression of
SNHG15 increased the expression of
LINGO-1 (
P<0.01
Figure 3A), indicating that
SNHG15 may regulate the expression of
LINGO-1 at the transcriptional level and
SNHG15 and
LINGO-1 could be involved in the neuroprotective effect of RA after CO injury.
2.4 Knockdown of <italic>SNHG15</italic> or <italic>LINGO-1</italic> improved CO-induced cell apoptosis
After HT22 cells and primary oligodendrocytes were transduced with sh-
SNHG15 or sh-
LINGO-1, knockdown of
SNHG15 reduced
SNHG15 RNA expression by 70% to 80% in the 2 cell types. Similarly, knockdown of
LINGO-1 decreased
LINGO-1 RNA expression by 70% to 85% (all
P<0.01,
Figure 4A) and protein expression by 50% to 55% in both cell types (all
P<0.05,
Figure 4D). Furthermore, knockdown of
SNHG15 down-regulated
LINGO-1 at both the transcription and the translation levels (all
P<0.05, Figure
4A and
4D). Interestingly, knockdown of either
SNHG15 or
LINGO-1 promoted cell proliferation, inhibited cell apoptosis, and up-regulated BDNF/TrkB protein expression in both HT22 cells and primary oligodendrocytes (all
P<0.05, Figure
4B-
4D).
2.5 Knockdown of <italic>SNHG15</italic> or <italic>LINGO-1</italic> alleviated cerebral injury in DEACMP model mice
Knockdown of
SNHG15 decreased its RNA expression by approximately 80% (
P<0.001,
Figure 5A). Knockdown of
LINGO-1 led to a reduction in
LINGO-1 RNA expression by 65% at the transcription level and 50% at translation level (both
P<0.05, Figure
5A and
5B). These results confirmed the successful establishment of lncRNA
SNHG15 and
LINGO-1 knockdown model in DEACMP mice.
In the DEACMP mouse model, neuronal morphology was severely disrupted,characterized by deeply stained nucleus, evident pyknosis, and concentrated cytoplasm and nuclei. Knockdown of either
SNHG15 or
LINGO-1 partially ameliorated these neuronal morphological changes (
Figure 6A). Furthermore, compared with the sham group, the number of apoptotic cells in the hippocampus increased significantly in the DEACMP model mice. In contrast, the knockdown of
SNHG15 or
LINGO-1 decreased the number of apoptotic cells in the hippocampus of the DEACMP model mice (
Figure 6B).
This study also investigated the mechanism by which lncRNA
SNHG15 and
LINGO-1 alleviated cerebral injury in the DEACMP model mice (Figure
5A and
5B). The expression levels of
SNHG15 and
LINGO-1 were significantly up-regulated in the DEACMP model mice (all
P<0.05). Knockdown of
SNHG15 down-regulated the expression of
LINGO-1 (
P<0.05), while knockdown of
LINGO-1 did not affect the expression of
SNHG15 (
P>0.05). Additionally, the expression of the neurotrophic factors (including MBP, NG, NT-3, BDNF, and TrkB) was significantly up-regulated after knockdown of
SNHG15 or
LINGO-1 in the DEACMP model mice.
3 Discussion
This study confirmed that RA alleviated the CO-induced apoptosis of hippocampal neurons and oligodendrocytes, thereby mitigating CNS injury and providing neuroprotection. LncRNA SNHG15 and LINGO-1 were identified as essential molecules in the RA-mediated inhibition of neuronal apoptosis and were closely related to the BDNF/TrkB pathway.
LncRNA
SNHG15 regulated the expression of
LINGO-1 at both transcription and translation levels, while
LINGO-1 could not effectively regulate the expression of lncRNA
SNHG15 in HT22 hippocampal neurons and primary oligodendrocytes. Similar results have been confirmed in animal experiments. In addition, previous studies
[9, 30-31] have reported that lncRNAs can function as enhancer, antisense, or cis/trans-acting nuclear lncRNAs and modulate protein expression posttranslationally. Both
SNHG15 and
LINGO-1 have been reported
[15, 32] to be involved in cerebral injury and repair in different contexts, suggesting that they may interact. In summary, this study confirmed that inhibition of the lncRNA
SNHG15/
LINGO-1 axis was an essential mechanism through which RA protected hippocampal neurons and primary oligodendrocytes from CO-induced injury. However, the specific interactions and regulatory mechanisms between lncRNA
SNHG15 and
LINGO-1 still need to be further explored.
As one of the most widely studied and characterized neurotrophic factors, BDNF binds to TrkB and plays a vital role in maintaining normal brain function. Binding with BDNF induces TrkB dimerization and autophosphorylation of tyrosine residues within its intracellular domain
[33]. Phosphorylated TrkB then activates the downstream phospholipase C-γ (PLCγ) signaling pathway
[34], protein kinase B (Akt) signaling pathway
[35], extracellular regulated protein kinases 1/2 (ERK1/2) signaling pathway
[36], cAMP response element-binding protein (CREB) signaling pathway
[37] and guanosine triphosphatases (GTPases). Ultimately, the BDNF/TrkB pathway inhibits cell apoptosis, promotes neuronal survival and enhances neuronal dendritic growth, branching and synaptic plasticity
[38-40]. In both clinical and pre-clinical research, BDNF/TrkB signaling improves learning, memory, and cognitive function
[41-42], the primary deficits observed in DEACMP. In this study, RA, lncRNA
SNHG15, and
LINGO-1 altered the expression levels of BDNF and TrkB, suggesting that the BDNF/TrkB signaling pathway is involved in repairing CO-induced cerebral injury, inhibiting cell apoptosis and promoting the survival of neurons and oligodendrocytes. Among the downstream signals of the BDNF/TrkB, the ERK1/2 signaling pathway may be critically important in the pathophysiology of CO neurotoxicity. Although CO poisoning can lead to CNS damage, it is undeniable that physiological doses of CO have neuroprotective effects
[43]. Coincidentally, BDNF-activated ERK also presents a dual neuroprotective and neurotoxic effect according to the kinetics and the stimuli
[44]. This may provide a step forward in explaining the paradoxical effect of CO on CNS.
In this study, the lncRNA
SNHG15/
LINGO-1 axis was found to be a potent negative regulator of the BDNF/TrkB pathway. Similar to our findings, it has been found that blocking LINGO-1 or activating the BDNF/TrkB pathway in a chronic cerebral hypoperfusion model can improve cognitive function, reduce cerebral white matter lesions, and confer neuroprotection
[45]. LINGO-1 can regulate the BDNF/TrkB pathway in multiple processes. It has been demonstrated that the LINGO-1 antibody increases BDNF expression in the mouse corpus callosum to improve remyelination
[22]. LINGO-1 in the cytoplasm can promote phosphorylation-activated TrkB internalization and mediate TrkB degradation through the lysosomal pathway
[46]. In addition, LINGO-1 has been shown to form a complex with TrkB to inhibit its phosphorylation and activation
[47] and block BDNF/TrkB signaling transduction.
This study showed that the lncRNA SNHG15/LINGO-1/BDNF/TrkB axis was involved in the pathogenesis of DEACMP and represented an important mechanism through which RA alleviated CO-induced cerebral injury. These findings provided a conceptual framework for optimising clinical management of DEACMP and established an experimental foundation for elucidating its molecular mechanisms. Future experiments will further explore the effect of the lncRNA SNHG15/LINGO-1/BDNF/TrkB axis on cognitive and behavioral changes, axonal regeneration, and demyelination changes in DEACMP model mice.
Due to the limited research base and time, the present study only reported a preliminary evidence of the effect of the lncRNA
SNHG15/
LINGO-1/BDNF/TrkB axis on alleviating cell apoptosis in the CNS after CO poisoning, and the mode of interaction among these molecules is unknown. In addition, the BDNF/TrkB pathway has been shown to suppress cell apoptosis in the CNS via multiple mechanisms, including modulation of glutamate signaling and neurotoxicity, reduction of oxidative damage, regulation of cell cycle-related gene expression, and promotion of neuronal growth, as reported in other disease models
[48]. However, the primary mechanism through which the BDNF/TrkB axis inhibits cell apoptosis in DEACMP still needs further exploration.
RA up-regulates the neuroprotective BDNF/TrkB pathway by inhibiting the expression of lncRNA SNHG15 and LINGO-1. LncRNA SNHG15/LINGO-1/BDNF/TrkB axis is an essential molecular mechanism through which RA functions in the treatment of DEACMP. These findings may help provide an experimental basis for further elucidating the pathogenic mechanism underlying DEACMP and identifying novel treatment modalities.
the Natural Science Foundation of Hunan Province(2021JJ31089)
the Scientific Research Project of Health Commission of Hunan Province(202203104548)
,
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