Echinacoside ameliorates post-stroke depression by activating BDNF signaling through modulation of Nrf2 acetylation.

BACKGROUND: Post-stroke depression (PSD) affects approximately one-third of stroke survivors, leading to adverse outcomes in rehabilitation, reduced quality of life, and increased mortality rates. Despite these implications, the underlying causes of PSD remain unclear, posing challenges for prevention and treatment. Echinacoside (ECH), a natural compound with known neuroprotective and antidepressant properties, holds significant therapeutic potential for PSD. However, the precise mechanism of its action remains unknown. PURPOSE: To unravel the specific mechanism through which ECH alleviates PSD by exploring the intricate interplay between ECH and Nrf2, as well as its impact on the BDNF/TrkB signaling axis. STUDY DESIGN AND METHODS: A rat PSD model was established though middle cerebral artery occlusion coupled with chronic unpredictable mild stress, followed by ECH treatment. The rats' depressive state was evaluated using the sucrose preference test and force swimming test. Brain damage was assessed through TTC staining, Nissl staining, and TUNEL assay. The multifaceted mechanism of ECH in PSD was investigated using immunofluorescence, immunohistochemistry, RT-qPCR, dual-luciferase assay, and western blotting. Additionally, the interaction between ECH and Nrf2 was explored through molecular docking and microscale thermophoresis. RESULTS: Our findings unveiled a novel facet of ECH action, demonstrating its unique ability to upregulate Nrf2 through acetylation within the hippocampus of PSD-affected rats (p < 0.05). Moreover, ECH showcased its distinctive potential by enhancing BDNF transcriptional activity, activating the BDNF/TrkB signaling axis, and orchestrating a comprehensive response against oxidative stress and apoptosis, thereby alleviating PSD symptoms in rats (p < 0.05). CONCLUSIONS: This study not only provides insights into the pivotal role of Nrf2 in mediating the BDNF/TrkB axis activation by ECH but also highlights the novelty of ECH's mechanism in addressing PSD. The elucidation of these unique aspects positions ECH as a groundbreaking candidate for further exploration and development in the realm of PSD intervention.

Morroniside improves the symptoms of post-stroke depression in mice through the BDNF signaling pathway mediated by MiR-409-3p.

BACKGROUND: Post-stroke depression (PSD) is a common psychiatric symptom after a stroke. Morroniside, an iridoid glycoside found in Cornus officinalis, has garnered significant attention for its potential to alleviate symptoms associated with depression. PURPOSE: This study aims to highlight the potential use of morroniside in the treatment of PSD and elucidate the underlying molecular mechanisms. METHODS: To establish a reliable PSD model, male C57BL/6 mice were subjected to brief MCAO in conjunction with CUMS. Post-morroniside administration, neuronal viability, and hippocampal cell apoptosis were evaluated by Nissl staining and TUNEL detection, respectively. Depression-like behaviors were evaluated using SPT, TST, and FST. The Longa score and cylinder test were used to evaluate the effect of morroniside on motor function. Furthermore, to investigate the underlying molecular mechanisms, bioinformatic analysis and the dual luciferase assay were performed to investigate the MiR-409-3p-BDNF interaction. In addition, subsequent to MiR-409-3p overexpression via AAV virus, we assessed mRNA expression and protein levels of key components within the BDNF/TrkB signaling pathway using RT-qPCR, immunohistochemistry, and western blot analysis. RESULTS: The observed decrease in apoptosis and amelioration of depression-like behaviors strongly indicate the potential of morroniside as a therapeutic agent for PSD. Furthermore, the upregulation of key proteins within the BDNF/TrkB signaling pathway in the cortex suggests that morroniside activates this pathway. Through bioinformatics analysis, MiR-409-3p was identified and found to bind to the BDNF gene, resulting in the inhibition of BDNF expression. Importantly, we demonstrate that morroniside mitigates this inhibitory effect of MiR-409-3p on BDNF, thereby facilitating the activation of the BDNF/TrkB signaling pathway. CONCLUSION: The findings suggest that morroniside demonstrates the ability to improve PSD symptoms through the BDNF/TrkB signaling pathway mediated by MiR-409-3p. These results emphasize the importance of the BDNF signaling pathway in improving PSD symptoms and provide a possible mechanism for morroniside to treat PSD.

Effect of electroacupuncture on the pathomorphology of the sciatic nerve and the sensitization of P2X3 receptors in the dorsal root ganglion in rats with chronic constrictive injury.

OBJECTIVE: To explore the effect of electroacupuncture (EA) on the pathomorphology of the sciatic nerve and the role of P2X3 receptors in EA analgesia. METHODS: The chronic constriction injury (CCI) model was adopted in this study. A total of 32 rats were randomly divided into four groups: sham CCI, CCI, CCI plus contralateral EA (CCI + conEA) and CCI plus ipsilateral EA (CCI + ipsEA). Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were measured. EA began at day 7 after the CCI operation and was applied to the Zusanli (ST 36) and Yanglingquan acupoints (GB 34). At day 14, the pathomorphologic changes of the operated sciatic nerve were demonstrated by hematoxylin and eosin staining. In addition, dorsal root ganglion (DRG) neurons isolated from rats were examined by electrophysiological recording to determine if the P2X3 receptor agonists, adenosine 5'-triphosphate disodium (ATP) and α,ß-methylen-ATP (α,ß-meATP) evoked inward currents. RESULTS: Pain thresholds in the CCI group were obviously decreased post CCI surgery (P<0.01). In the EA groups, thermal and mechanical threshold values were increased after the last EA treatment (P<0.05, P<0.01). There was no significant difference in light microscopic examination among the four groups (P>0.05). Current amplitude after application of ATP and α,ß-meATP in DRG neurons were much larger in the CCI group compared to those obtained in sham CCI (P<0.05). ATP and α, ß-meATP invoked amplitudes in the CCI + EA groups were reduced. There was no signififi cant difference between the CCI + conEA group and the CCI + ipsEA group (P>0.05). CONCLUSION: EA analgesia may be mediated by decreasing the response of P2X3 receptors to the agonists ATP and α,ß-meATP in the DRG of rats with CCI. No pathological changes of the sciatic nerve of rats were observed after EA treatment.

[Characteristics of anatomical structures and clinical significance of lumbar Jiaji (EX-B 2) points].

OBJECTIVE: To observe the anatomical structure of Jiaji (EX-B 2) points at the level of lower lumbar region so as to provide evidence for the insertion angle and depth. METHODS: Thirty spine samples of male adults were adopted, and perpendicular insertion of the needle was applied at 3 locations including 1 cun, 0.5 cun and 0.3 cun lateral to the lower border of the spinous process of the lumbar vertebra. The needles were fixed at the local region. Structures and the adjacent major blood vessels and nerves were observed during the anatomy. RESULTS: When the needle was inserted perpendicularly at the point 1 cun lateral to the lower border of the spinous process of the lumber vertebra with the insertion depth of (35.77 +/- 5.86) mm, the zygapophyseal joints, the adjacent osteo-fibrous canal and osteo-fibrous aperture were touched by the tip of the needle, and the medial ramus of dorsal primary ramus of spinal nerve and concomitant vessels were stimulated. Then, needles were inserted perpendicularly 0.5 cun and 0.3 cun lateral to the lower border of the spinous process of the lumber vertebra with the insertion depth of (32.89 +/- 4.79)mm for both. When needle was inserted 0.5 cun lateral, the medial ramus of dorsal primary ramus of spinal nerve and the concomitant vessels were touched by the tip of the needle at where they across the lamina periosteum and erector spinae. When needle was inserted 0.3 cun lateral, the body of the needle reached the terminal branches of the medial ramus of dorsal primary ramus of spinal nerve and the concomitant vessels through the deep paraspinal muscles and the thoracolumbar fascia. CONCLUSION: The medial ramus of dorsal primary ramus of lumbar spinal nerve and concomitant vessels distributed at the region 1 cun, 0.5 cun and 0.3 cun beside the lower border of each lumbar spinous process. Therefore, the location of Jiaji (EX-B 2) points can be considered in the region from 0.3 cun to 1 cun beside the lower border of each spinous process.

Analgesic effect of electroacupuncture on chronic neuropathic pain mediated by P2X3 receptors in rat dorsal root ganglion neurons.

Adenosine 5'-triphosphate disodium (ATP) gated P2X receptors, especially the subtype P2X(3), play a key role in transmission of pain signals in neuropathic pain, ATP has been documented to play a significant role in the progression of pain signals, suggesting that control of these pathways through electroacupuncture (EA) is potentially an effective treatment for chronic neuropathic pain. EA has been accepted to effectively manage chronic pain by applying the stimulating current to acupoints through acupuncture needles. To determine the significance of EA on neuropathic pain mediated by P2X(3) receptors in the dorsal root ganglion (DRG) neurons, mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were recorded, and the expression of P2X(3) receptors in the DRG neurons was assessed by immunohistochemistry (IHC) and in situ hybridization (ISH). In addition, the currents which were evoked in DRG neurons isolated from rats following chronic constriction injury (CCI) by the P2X(3) receptors agonists i.e. ATP and α,ß-methylen-ATP (α,ß-meATP) were examined through the experimental use of whole cell patch clamp recording. The present study demonstrates that EA treatment can increase the MWT and TWL values and decrease the expression of P2X(3) receptors in DRG neurons in CCI rats. Simultaneously, EA treatment attenuates the ATP and α,ß-meATP evoked currents. EA may be expected to induce an apparent induce analgesic effect by decreasing expression and inhibiting P2X(3) receptors in DRG neurons of CCI rats. There is a similar effect on analgesic effect between rats with contralateral EA and those with ipsilateral EA.