Effects of Gastrodin on Analgesia and Inhibition of Ferroptosis

Abstract Background: Gastrodin possesses low toxicity and a broad range of pharmacological activities and exhibits beneficial effects in neurological diseases. This study investigated the effects of gastrodin (GAS) on analgesic, anti-inflammatory, anxiolytic and inhibition of ferroptosis. Materials and Methods: The chronic inflammatory pain model of C57BL/6J mice was established by hindpaw injection of complete Freund’s adjuvant (CFA). After GAS treatment, Thermal hyperalgesia test, Mechanical allodynia test, Elevated plus-maze (EPMT) and Open-field test (OFT) were performed to assess the behavioral changes of pain and anxiety. mRNAs of FTHI, GPX4, HO-1 and PTGS2 were measured by RT-qPCR. Results: In CFA-injected C57BL/6 mice, we found that the mechanical and thermal pain threshold was increased with treatment of GAS. In EPMT, the number of entries in open arms and retention times of open arms were increased by GAS. In the OFT, the time spent in the central area was also increased. Furthermore, GAS enhanced mRNA expressions of FTHI, GPX4 and H0-1, as well as decreased the expression of PTGS2 in a dose-dependent manner. Conclusion: GAS is effective in the treatment of mice chronic inflammatory pain and anxiety-like behaviors. It maybe exhibit potential neuroprotective effects through inhibition of ferroptosis.

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Apamin Enhances Neurite Outgrowth and Regeneration after Laceration Injury in Cortical Neurons

Toxins ◽

10.3390/toxins13090603 ◽

2021 ◽

Vol 13 (9) ◽

pp. 603

Author(s):

Hyunseong Kim ◽

Jin Young Hong ◽

Junseon Lee ◽

Wan-Jin Jeon ◽

In-Hyuk Ha

Keyword(s):

Phospholipase A2 ◽

Neurite Outgrowth ◽

Cortical Neurons ◽

Neurological Diseases ◽

Minor Component ◽

Underlying Mechanism ◽

Bee Venom ◽

Dependent Manner ◽

Neuroprotective Effects ◽

Wide Range

Apamin is a minor component of bee venom and is a polypeptide with 18 amino acid residues. Although apamin is considered a neurotoxic compound that blocks the potassium channel, its neuroprotective effects on neurons have been recently reported. However, there is little information about the underlying mechanism and very little is known regarding the toxicological characterization of other compounds in bee venom. Here, cultured mature cortical neurons were treated with bee venom components, including apamin, phospholipase A2, and the main component, melittin. Melittin and phospholipase A2 from bee venom caused a neurotoxic effect in dose-dependent manner, but apamin did not induce neurotoxicity in mature cortical neurons in doses of up to 10 µg/mL. Next, 1 and 10 µg/mL of apamin were applied to cultivate mature cortical neurons. Apamin accelerated neurite outgrowth and axon regeneration after laceration injury. Furthermore, apamin induced the upregulation of brain-derived neurotrophic factor and neurotrophin nerve growth factor, as well as regeneration-associated gene expression in mature cortical neurons. Due to its neurotherapeutic effects, apamin may be a promising candidate for the treatment of a wide range of neurological diseases.

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Chronic inflammatory pain drives alcohol drinking in a sex-dependent manner for C57BL/6J mice

Alcohol ◽

10.1016/j.alcohol.2018.10.002 ◽

2019 ◽

Vol 77 ◽

pp. 135-145 ◽

Cited By ~ 13

Author(s):

Waylin Yu ◽

Lara S. Hwa ◽

Viren H. Makhijani ◽

Joyce Besheer ◽

Thomas L. Kash

Keyword(s):

Alcohol Drinking ◽

Inflammatory Pain ◽

Dependent Manner ◽

Chronic Inflammatory Pain

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Analgesic Effect of Moxibustion with Different Temperature on Inflammatory and Neuropathic Pain Mice: A Comparative Study

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/4373182 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Wei Zhou ◽

Ruxue Lei ◽

Chuanyi Zuo ◽

Yunqing Yue ◽

Qin Luo ◽

...

Keyword(s):

Neuropathic Pain ◽

Inflammatory Pain ◽

Analgesic Effect ◽

Mechanical Allodynia ◽

Thermal Hyperalgesia ◽

Spared Nerve Injury ◽

Chronic Neuropathic Pain ◽

Chronic Inflammatory Pain ◽

Significant Difference ◽

Different Temperatures

The aim of this study was to determine whether variation of temperature during moxibustion would generate division of analgesic effect. The moxibustion with different temperatures (37°C, 42°C, 47°C, and 52°C) was applied to ST36 acupoint for 30 minutes in chronic inflammatory or neuropathic pain mice. The analgesic effect was evaluated by thermal hyperalgesia test in chronic inflammatory pain and by mechanical allodynia in neuropathic pain, respectively. The results indicated that interventions of moxibustion with different temperature caused different analgesic effect on either chronic inflammatory induced by injection of complete Freund’s adjuvant (CFA) or neuropathic pain induced by spared nerve injury (SNI). In chronic inflammatory pain, different moxibustion temperature generated different intensity of analgesic effect: the higher the better. In chronic neuropathic pain, stronger analgesic effect was found in moxibustion with temperature 47°C or 52°C other than 37°C and 42°C. However, there is no significant difference displayed between moxibustion temperatures 47°C and 52°C or 37°C and 42°C. It implies that the temperature should be taken into account for moxibustion treatment to chronic inflammatory or neuropathic pain.

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Neuroprotective Effects of Euonymus alatus Extract on Scopolamine-Induced Memory Deficits in Mice

Antioxidants ◽

10.3390/antiox9050449 ◽

2020 ◽

Vol 9 (5) ◽

pp. 449 ◽

Cited By ~ 1

Author(s):

Yunju Woo ◽

Ji Sun Lim ◽

Jisun Oh ◽

Jeong Soon Lee ◽

Jong-Sang Kim

Keyword(s):

Antioxidant Enzyme ◽

Neurotrophic Factor ◽

Ethanolic Extract ◽

Heme Oxygenase 1 ◽

Dependent Manner ◽

Leaf Extracts ◽

Behavioral Impairment ◽

Neuroprotective Effects ◽

Euonymus Alatus ◽

Beneficial Effects

Euonymus alatus is considered to elicit various beneficial effects against cancer, hyperglycemia, menstrual discomfort, diabetic complications, and detoxification. The young leaves of this plant are exploited as food and also utilized for traditional medicine in East Asian countries, including Korea and China. Our preliminary study demonstrated that ethanolic extract from the Euonymus alatus leaf (EAE) exhibited the strongest antioxidant enzyme-inducing activity among more than 100 kinds of edible tree leaf extracts. This study investigated whether EAE could attenuate the cognitive deficits caused by oxidative stress in mice. Oral intubation of EAE at 100 mg/kg bw or higher resulted in significant improvements to the memory and behavioral impairment induced via i.p. injection of scopolamine. Furthermore, EAE enhanced the expression levels of hippocampal neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor in mice, activated the Nrf2, and the downstream heme oxygenase-1 (HO-1) a quintessential antioxidant enzyme. As rutin (quercetin-3-O-rutinose) was abundantly present in EAE and free quercetin was able to induce defensive antioxidant enzymes in an Nrf2-dependent manner, our findings suggested that quercetin derived from rutin via the intestinal microflora played a significant role in the protection of the mouse hippocampus from scopolamine-induced damage through BDNF-mediated Nrf2 activation, thereby dampening cognitive decline.

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Far Infrared Emitted by Bioceramics Reduces Mechanical and Thermal Hyperalgesia in an Animal Model of Chronic Inflammatory Pain

The Journal of Alternative and Complementary Medicine ◽

10.1089/acm.2014.5083.abstract ◽

2014 ◽

Vol 20 (5) ◽

pp. A33-A33

Author(s):

Aline A. Emer ◽

Francisco Jose Cidral-Filho ◽

Fernanda Madeira ◽

Bruna L. Turnes ◽

Daniel F. Martins

Keyword(s):

Animal Model ◽

Inflammatory Pain ◽

Thermal Hyperalgesia ◽

Far Infrared ◽

Chronic Inflammatory Pain

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Effects and Mechanisms of Electroacupuncture on Chronic Inflammatory Pain and Depression Comorbidity in Mice

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/4951591 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Hung-Yu Huang ◽

Hsien-Yin Liao ◽

Yi-Wen Lin

Keyword(s):

Chronic Pain ◽

Signaling Pathway ◽

Inflammatory Pain ◽

Thermal Hyperalgesia ◽

Chronic Inflammatory Pain ◽

Calcium Calmodulin Dependent ◽

Successful Induction ◽

Dependent Protein ◽

The Brain ◽

Depression Disorder

Comorbidity of chronic pain and major depression disorder (MDD) are common diseases. However, the mechanisms of electroacupuncture (EA) and the responses of N-methyl-D-aspartate receptors in the brain remain unclear. Three injections of complete Freund's adjuvant (CFA) were administered to induce chronic inflammatory pain (CIP). EA was then performed once every other day from days 14 to 28. Behavior tests of chronic pain and depression were evaluated to make sure of the successful induction of comorbidity. We used Western blotting to analyze brain tissue from the prefrontal cortex (PFC), hippocampus, and hypothalamus for levels of phosphorylated N-methyl-D-aspartate receptor subunit 1 (pNR1), NR1, pNR2B, NR2B, and calcium/calmodulin-dependent protein kinase type II alpha isoform (pCaMKIIα). The mechanical hyperalgesia, thermal hyperalgesia, and depression were observed in the CIP group. Furthermore, decreased levels of N-methyl-D-aspartate receptors (NMDARs) were also noted. Not Sham EA but EA reversed chronic pain and depression as well as the decreased levels of NMDA in the signaling pathway. The CFA injections successfully induced a significant comorbidity model. EA treated the comorbidity by upregulating the NMDA signaling pathway in the PFC, hippocampus, and hypothalamus. Our results indicated significant mechanisms of comorbidity of chronic pain and MDD and EA-analgesia that involves the regulation of the NMDAR signaling pathway. These findings may be relevant to the evaluation and treatment of comorbidity of chronic pain and MDD.

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Reduced GABAergic transmission in the ventrobasal thalamus contributes to thermal hyperalgesia in chronic inflammatory pain

Scientific Reports ◽

10.1038/srep41439 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 7

Author(s):

Chan Zhang ◽

Rong-Xiang Chen ◽

Yu Zhang ◽

Jie Wang ◽

Feng-Yu Liu ◽

...

Keyword(s):

Inflammatory Pain ◽

Thermal Hyperalgesia ◽

Thalamic Reticular Nucleus ◽

Reticular Nucleus ◽

Patch Clamp Recording ◽

Gabaergic Transmission ◽

Chronic Inflammatory Pain ◽

Whole Cell Patch Clamp ◽

Ventrobasal Thalamus

Abstract The ventrobasal (VB) thalamus is innervated by GABAergic afferents from the thalamic reticular nucleus (TRN) and participates in nociception. But how the TRN-VB pathway regulates pain is not fully understood. In the present study, we reported decreased extracellular GABA levels in the VB of rats with CFA-induced chronic inflammatory pain, measured by microdialysis with HPLC analysis. In vitro whole-cell patch-clamp recording showed decreased amplitudes of tonic currents, increased frequencies of mIPSCs, and increased paired-pulse ratios in thalamic slices from chronic inflammatory rats (7 days). Microinjection of the GABAAR agonist muscimol and optogenetic activation of the TRN-VB pathway relieved thermal hyperalgesia in chronic inflammatory pain. By contrast, microinjecting the extrasynaptic GABAAR agonist THIP or selective knockout of synaptic GABAAR γ2 subunits aggravated thermal hyperalgesia in the chronic stage of inflammatory pain. Our findings indicate that reduced GABAergic transmission in the VB contributes to thermal hyperalgesia in chronic inflammatory pain, which could be a synaptic target for pharmacotherapy.

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Role of Transient Receptor Potential Vanilloid 1 in Electroacupuncture Analgesia on Chronic Inflammatory Pain in Mice

BioMed Research International ◽

10.1155/2017/5068347 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8 ◽

Cited By ~ 8

Author(s):

Jun Yang ◽

Ching-Liang Hsieh ◽

Yi-Wen Lin

Keyword(s):

Inflammatory Pain ◽

Transient Receptor Potential ◽

Tissue Injury ◽

Thermal Hyperalgesia ◽

Receptor Potential ◽

Transient Receptor Potential Vanilloid ◽

Expression Levels ◽

Chronic Inflammatory Pain ◽

Cytokines And Chemokines ◽

Transient Receptor

Chronic inflammatory pain may result from peripheral tissue injury or inflammation, increasing the release of protons, histamines, adenosine triphosphate, and several proinflammatory cytokines and chemokines. Transient receptor potential vanilloid 1 (TRPV1) is known to be involved in acute to subacute neuropathic and inflammatory pain; however, its exact mechanisms in chronic inflammatory pain are not elucidated. Our results showed that EA significantly reduced chronic mechanical and thermal hyperalgesia in the chronic inflammatory pain model. Chronic mechanical and thermal hyperalgesia were also abolished in TRPV1−/− mice. TRPV1 increased in the dorsal root ganglion (DRG) and spinal cord (SC) at 3 weeks after CFA injection. The expression levels of downstream molecules such as pPKA, pPI3K, and pPKC increased, as did those of pERK, pp38, and pJNK. Transcription factors (pCREB and pNFκB) and nociceptive ion channels (Nav1.7 and Nav1.8) were involved in this process. Inflammatory mediators such as GFAP, S100B, and RAGE were also involved. The expression levels of these molecules were reduced in EA and TRPV1−/− mice but not in the sham EA group. Our data provided evidence to support the clinical use of EA for treating chronic inflammatory pain.

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Prolactin regulates TRPV1, TRPA1, and TRPM8 in sensory neurons in a sex-dependent manner: Contribution of prolactin receptor to inflammatory pain

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00187.2013 ◽

2013 ◽

Vol 305 (9) ◽

pp. E1154-E1164 ◽

Cited By ~ 39

Author(s):

Mayur J. Patil ◽

Shivani B. Ruparel ◽

Michael A. Henry ◽

Armen N. Akopian

Keyword(s):

Sensory Neurons ◽

Inflammatory Pain ◽

Transient Receptor Potential ◽

Trp Channels ◽

Inflammatory Responses ◽

Thermal Hyperalgesia ◽

Female Rats ◽

Mrna Levels ◽

Dependent Manner ◽

Male And Female Rats

Prolactin (PRL) is a hormone produced in the anterior pituitary but also synthesized extrapituitary where it can influence diverse cellular processes, including inflammatory responses. Females experience greater pain in certain inflammatory conditions, but the contribution of the PRL system to sex-dependent inflammatory pain is unknown. We found that PRL regulates transient receptor potential (TRP) channels in a sex-dependent manner in sensory neurons. At >20 ng/ml, PRL sensitizes TRPV1 in female, but not male, neurons. This effect is mediated by PRL receptor (PRL-R). Likewise, TRPA1 and TRPM8 were sensitized by 100 ng/ml PRL only in female neurons. We showed that complete Freund adjuvant (CFA) upregulated PRL levels in the inflamed paw of both male and female rats, but levels were higher in females. In contrast, CFA did not change mRNA levels of long and short PRL-R in the dorsal root ganglion or spinal cord. Analysis of PRL and PRL-R knockout (KO) mice demonstrated that basal responses to cold stimuli were only altered in females, and with no significant effects on heat and mechanical responses in both sexes. CFA-induced heat and cold hyperalgesia were not changed in PRL and PRL-R KO compared with wild-type (WT) males, whereas significant reduction of heat and cold post-CFA hyperalgesia was detected in PRL and PRL-R KO females. Attenuation of CFA-induced mechanical allodynia was observed in both PRL and PRL-R KO females and males. Thermal hyperalgesia in PRL KO females was restored by administration of PRL into hindpaws. Overall, we demonstrate a sex-dependent regulation of peripheral inflammatory hyperalgesia by the PRL system.

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Intravenous administration of triptonide attenuates CFA-induced pain hypersensitivity through inhibiting AKT signaling pathway in mice

10.21203/rs.2.19974/v1 ◽

2020 ◽

Author(s):

Yue-Juan Ling ◽

Ting-Yu Ding ◽

Yong-Jing Gao ◽

Bao-Chun Jiang

Keyword(s):

Inflammatory Cytokines ◽

Inflammatory Pain ◽

Mechanical Allodynia ◽

Interleukin 1 ◽

Thermal Hyperalgesia ◽

Paw Edema ◽

Akt Inhibitor ◽

Pain Hypersensitivity ◽

Chronic Inflammatory Pain ◽

Pro Inflammatory Cytokines

Abstract Background: Triptonide (TPN) is a major component of Tripterygium wilfordii Hook.f., and reportedly has anti-inflammatory and neuroprotective effects. Recent studies have demonstrated that the phosphatidylinositol 3-kinase (PI3K)/AKT pathway plays an important role in the pathogenesis of inflammatory pain. Here we investigated the anti-nociceptive effect of systemic treatment with TPN on mouse models of chronic inflammatory pain and explored possible mechanisms. Results: Unilateral hind paw injection of complete Freund’s adjuvant (CFA) induced paw edema and persistent pain hypersensitivity. Intravenous treatment with TPN attenuated CFA-induced paw edema, mechanical allodynia, and thermal hyperalgesia. Western blotting and immunofluorescence results showed that CFA induced AKT activation in the dorsal root ganglion (DRG) neurons, which was inhibited by TPN treatment. Furthermore, TPN treatment inhibited mRNA increase of proinflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin 1 beta (IL-1β), and Interleukin 6 (IL-6)] induced by CFA. Finally, pretreatment with AKT inhibitor, AKT inhibitor Ⅳ, attenuated CFA-induced mechanical allodynia and thermal hyperalgesia, and decreased the mRNA expression of pro-inflammatory cytokines. Conclusions: These data indicate that TPN attenuates CFA-induced pain potentially via inhibiting AKT-mediated pro-inflammatory cytokines production in DRG. TPN may be used for the treatment of chronic inflammatory pain.

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