Top

Published in:

01-06-2020 | Original Paper

Harpagophytum procumbens Extract Ameliorates Allodynia and Modulates Oxidative and Antioxidant Stress Pathways in a Rat Model of Spinal Cord Injury

Authors: Garrett Ungerer, Jiankun Cui, Tina Ndam, Mikeala Bekemeier, Hailong Song, Runting Li, Heather R. Siedhoff, Bo Yang, Michael K. Appenteng, C. Michael Greenlief, Dennis K. Miller, Grace Y. Sun, William R. Folk, Zezong Gu

Published in: NeuroMolecular Medicine | Issue 2/2020

Abstract

Spinal cord injury (SCI) is a deliberating disorder with impairments in locomotor deficits and incapacitating sensory abnormalities. Harpagophytum procumbens (Hp) is a botanical widely used for treating inflammation and pain related to various inflammatory and musculoskeletal conditions. Using a modified rodent contusion model of SCI, we explored the effects of this botanical on locomotor function and responses to mechanical stimuli, and examined possible neurochemical changes associated with SCI-induced allodynia. Following spinal cord contusion at T10 level, Hp (300 mg/kg, p.o.) or vehicle (water) was administered daily starting 24 h post-surgery, and behavioral measurements made every-other day until sacrifice (Day 21). Hp treatment markedly ameliorated the contusion-induced decrease in locomotor function and increased sensitivity to mechanical stimuli. Determination of Iba1 expression in spinal cord tissues indicated microglial infiltration starting 3 days post-injury. SCI results in increased levels of 4-hydroxynonenal, an oxidative stress product and proalgesic, which was diminished at 7 days by treatment with Hp. SCI also enhanced antioxidant heme oxygenase-1 (HO-1) expression. Concurrent studies of cultured murine BV-2 microglial cells revealed that Hp suppressed oxidative/nitrosative stress and inflammatory responses, including production of nitric oxide and reactive oxygen species, phosphorylation of cytosolic phospholipases A₂, and upregulation of the antioxidative stress pathway involving the nuclear factor erythroid 2-related factor 2 and HO-1. These results support the use of Hp for management of allodynia by providing resilience against the neuroinflammation and pain associated with SCI and other neuropathological conditions.

Abdelouahab, N., & Heard, C. (2008). Effect of the major glycosides of Harpagophytum procumbens (Devil’s Claw) on epidermal cyclooxygenase-2 (COX-2) in vitro. Journal of Natural Products,71(5), 746–749.CrossRef

Ajit, D., Simonyi, A., Li, R., Chen, Z., Hannink, M., Fritsche, K. L., et al. (2016). Phytochemicals and botanical extracts regulate NF-kappaB and Nrf2/ARE reporter activities in DI TNC1 astrocytes. Neurochemistry International,97, 49–56. https://doi.org/10.1016/j.neuint.2016.05.004.CrossRefPubMedPubMedCentral

Anthonymuthu, T. S., Kenny, E. M., & Bayir, H. (2016). Therapies targeting lipid peroxidation in traumatic brain injury. Brain Research,1640(Pt A), 57–76. https://doi.org/10.1016/j.brainres.2016.02.006.CrossRefPubMedPubMedCentral

Baastrup, C., & Finnerup, N. B. (2012). Pain in spinal cord injury. Pain Management,2(1), 87–94. https://doi.org/10.2217/pmt.11.70.CrossRefPubMed

Basso, D. M., Beattie, M. S., & Bresnahan, J. C. (2002). Descending systems contributing to locomotor recovery after mild or moderate spinal cord injury in rats: Experimental evidence and a review of literature. Restorative Neurology and Neuroscience,20(5), 189–218.PubMed

Chuang, D. Y., Chan, M. H., Zong, Y., Sheng, W., He, Y., Jiang, J. H., et al. (2013). Magnolia polyphenols attenuate oxidative and inflammatory responses in neurons and microglial cells. Journal of Neuroinflammation,10, 15. https://doi.org/10.1186/1742-2094-10-15.CrossRefPubMedPubMedCentral

Chuang, D. Y., Cui, J., Simonyi, A., Engel, V. A., Chen, S., Fritsche, K. L., et al. (2014). Dietary Sutherlandia and elderberry mitigate cerebral ischemia-induced neuronal damage and attenuate p47phox and phospho-ERK1/2 expression in microglial cells. ASN Neuro. https://doi.org/10.1177/1759091414554946.CrossRefPubMedPubMedCentral

Chuang, D. Y., Simonyi, A., Cui, J., Lubahn, D. B., Gu, Z., & Sun, G. Y. (2016). Botanical polyphenols mitigate microglial activation and microglia-induced neurotoxicity: Role of cytosolic phospholipase A2. NeuroMolecular Medicine,18(3), 415–425. https://doi.org/10.1007/s12017-016-8419-5.CrossRefPubMed

Chuang, D. Y., Simonyi, A., Kotzbauer, P. T., Gu, Z., & Sun, G. Y. (2015). Cytosolic phospholipase A2 plays a crucial role in ROS/NO signaling during microglial activation through the lipoxygenase pathway. Journal of Neuroinflammation,12, 199. https://doi.org/10.1186/s12974-015-0419-0.CrossRefPubMedPubMedCentral

Csala, M., Kardon, T., Legeza, B., Lizak, B., Mandl, J., Margittai, E., et al. (2015). On the role of 4-hydroxynonenal in health and disease. Biochimica et Biophysica Acta,1852(5), 826–838. https://doi.org/10.1016/j.bbadis.2015.01.015.CrossRefPubMed

Dai, W., Wang, X., Teng, H., Li, C., Wang, B., & Wang, J. (2019). Celastrol inhibits microglial pyroptosis and attenuates inflammatory reaction in acute spinal cord injury rats. International Immunopharmacology,66, 215–223. https://doi.org/10.1016/j.intimp.2018.11.029.CrossRefPubMed

D’Angelo, R., Morreale, A., Donadio, V., Boriani, S., Maraldi, N., Plazzi, G., et al. (2013). Neuropathic pain following spinal cord injury: What we know about mechanisms, assessment and management. European Review for Medical and Pharmacological Sciences,17(23), 3257–3261.PubMed

De Logu, F., Nassini, R., Materazzi, S., Carvalho Goncalves, M., Nosi, D., Rossi Degl’Innocenti, D., et al. (2017). Schwann cell TRPA1 mediates neuroinflammation that sustains macrophage-dependent neuropathic pain in mice. Nature Communications,8(1), 1887. https://doi.org/10.1038/s41467-017-01739-2.CrossRefPubMedPubMedCentral

Diaz, A. F., Polo, S., Gallardo, N., Leanez, S., & Pol, O. (2019). Analgesic and antidepressant effects of Oltipraz on neuropathic pain in mice by modulating microglial activation. Journal of Clinical Medicine,8(6), 1. https://doi.org/10.3390/jcm8060890.CrossRef

Fiebich, B. L., Munoz, E., Rose, T., Weiss, G., & McGregor, G. P. (2012). Molecular targets of the antiinflammatory Harpagophytum procumbens (devil’s claw): Inhibition of TNFalpha and COX-2 gene expression by preventing activation of AP-1. Phytotherapy Research,26(6), 806–811. https://doi.org/10.1002/ptr.3636.CrossRefPubMed

Finnerup, N. B. (2013). Pain in patients with spinal cord injury. Pain,154(Suppl 1), S71–S76. https://doi.org/10.1016/j.pain.2012.12.007.CrossRefPubMed

Gaskell, H., Derry, S., Stannard, C., & Moore, R. A. (2016). Oxycodone for neuropathic pain in adults. Cochrane Database of Systematic Reviews,7, CD010692. https://doi.org/10.1002/14651858.cd010692.pub3.CrossRefPubMed

Georgiev, M. I., Ivanovska, N., Alipieva, K., Dimitrova, P., & Verpoorte, R. (2013). Harpagoside: From Kalahari Desert to pharmacy shelf. Phytochemistry,92, 8–15.CrossRef

Gosselin, R. D., Suter, M. R., Ji, R. R., & Decosterd, I. (2010). Glial cells and chronic pain. Neuroscientist,16(5), 519–531. https://doi.org/10.1177/1073858409360822.CrossRefPubMedPubMedCentral

Grace, P. M., Gaudet, A. D., Staikopoulos, V., Maier, S. F., Hutchinson, M. R., Salvemini, D., et al. (2016). Nitroxidative signaling mechanisms in pathological pain. Trends in Neurosciences,39(12), 862–879. https://doi.org/10.1016/j.tins.2016.10.003.CrossRefPubMedPubMedCentral

Hackel, D., Pflucke, D., Neumann, A., Viebahn, J., Mousa, S., Wischmeyer, E., et al. (2013). The connection of monocytes and reactive oxygen species in pain. PLoS ONE,8(5), e63564. https://doi.org/10.1371/journal.pone.0063564.CrossRefPubMedPubMedCentral

Huang, T. H., Tran, V. H., Duke, R. K., Tan, S., Chrubasik, S., Roufogalis, B. D., et al. (2006). Harpagoside suppresses lipopolysaccharide-induced iNOS and COX-2 expression through inhibition of NF-kappa B activation. Journal of Ethnopharmacology,104(1–2), 149–155. https://doi.org/10.1016/j.jep.2005.08.055.CrossRefPubMed

Jensen, T. S., Baron, R., Haanpaa, M., Kalso, E., Loeser, J. D., Rice, A. S., et al. (2011). A new definition of neuropathic pain. Pain,152(10), 2204–2205. https://doi.org/10.1016/j.pain.2011.06.017.CrossRefPubMed

Jensen, M. P., Kuehn, C. M., Amtmann, D., & Cardenas, D. D. (2007). Symptom burden in persons with spinal cord injury. Archives of Physical Medicine and Rehabilitation,88(5), 638–645. https://doi.org/10.1016/j.apmr.2007.02.002.CrossRefPubMedPubMedCentral

Jia, Z., Zhu, H., Li, J., Wang, X., Misra, H., & Li, Y. (2012). Oxidative stress in spinal cord injury and antioxidant-based intervention. Spinal Cord,50(4), 264–274. https://doi.org/10.1038/sc.2011.111.CrossRefPubMed

Kartha, S., Weisshaar, C. L., Philips, B. H., & Winkelstein, B. A. (2018). Pre-treatment with Meloxicam prevents the spinal inflammation and oxidative stress in DRG neurons that accompany painful cervical radiculopathy. Neuroscience,388, 393–404. https://doi.org/10.1016/j.neuroscience.2018.07.054.CrossRefPubMedPubMedCentral

Kaszkin, M., Beck, K. F., Koch, E., Erdelmeier, C., Kusch, S., Pfeilschifter, J., et al. (2004). Downregulation of iNOS expression in rat mesangial cells by special extracts of Harpagophytum procumbens derives from harpagoside-dependent and independent effects. Phytomedicine,11(7–8), 585–595. https://doi.org/10.1016/j.phymed.2004.02.003.CrossRefPubMed

Krishna, V., Andrews, H., Jin, X., Yu, J., Varma, A., Wen, X., et al. (2013). A contusion model of severe spinal cord injury in rats. Journal of Visualized Experiments. https://doi.org/10.3791/50111.CrossRefPubMed

Kwon, B. K., Okon, E., Hillyer, J., Mann, C., Baptiste, D., Weaver, L. C., et al. (2011). A systematic review of non-invasive pharmacologic neuroprotective treatments for acute spinal cord injury. Journal of Neurotrauma,28(8), 1545–1588. https://doi.org/10.1089/neu.2009.1149.CrossRefPubMedPubMedCentral

Lee, B. B., Cripps, R. A., Fitzharris, M., & Wing, P. C. (2014). The global map for traumatic spinal cord injury epidemiology: Update 2011, global incidence rate. Spinal Cord,52(2), 110–116. https://doi.org/10.1038/sc.2012.158.CrossRefPubMed

Li, W., Jiang, D., Li, Q., Yao, S., Sun, X., Yang, Y., et al. (2016). Lipopolysaccharide-induced preconditioning protects against traumatic spinal cord injury by upregulating Nrf2 expression in rats. Life Sciences,162, 14–20. https://doi.org/10.1016/j.lfs.2016.08.008.CrossRefPubMed

Lim, D. W., Kim, J. G., Han, D., & Kim, Y. T. (2014). Analgesic effect of Harpagophytum procumbens on postoperative and neuropathic pain in rats. Molecules,19(1), 1060–1068. https://doi.org/10.3390/molecules19011060.CrossRefPubMedPubMedCentral

Liu, N. K., Byers, J. S., Lam, T., Lu, Q. B., Sengelaub, D. R., & Xu, X. M. (2014a). Inhibition of cPLA2 has neuroprotective effects on motoneuron and muscle atrophy following spinal cord injury. Journal of Neurotrauma. https://doi.org/10.1089/neu.2014.3690.CrossRefPubMedPubMedCentral

Liu, N. K., Deng, L. X., Zhang, Y. P., Lu, Q. B., Wang, X. F., Hu, J. G., et al. (2014b). Cytosolic phospholipase A2 protein as a novel therapeutic target for spinal cord injury (Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t). Annals of Neurology,75(5), 644–658. https://doi.org/10.1002/ana.24134.CrossRefPubMedPubMedCentral

Lv, R., Du, L., Zhang, L., & Zhang, Z. (2019). Polydatin attenuates spinal cord injury in rats by inhibiting oxidative stress and microglia apoptosis via Nrf2/HO-1 pathway. Life Sciences,217, 119–127. https://doi.org/10.1016/j.lfs.2018.11.053.CrossRefPubMed

Ma, L., Liu, H., Chen, G., Chen, M., Wang, L., Zhang, X., et al. (2018). Sulfasalazine attenuates chronic constriction injury-induced neuroinflammation and mechanical hypersensitivity in rats. Neuroscience Letters,683, 174–180. https://doi.org/10.1016/j.neulet.2018.07.042.CrossRefPubMed

Mao, L., Wang, H., Wang, X., Liao, H., & Zhao, X. (2011). Transcription factor Nrf2 protects the spinal cord from inflammation produced by spinal cord injury. Journal of Surgical Research,170(1), e105–e115. https://doi.org/10.1016/j.jss.2011.05.049.CrossRefPubMed

Mncwangi, N., Chen, W., Vermaak, I., Viljoen, A. M., & Gericke, N. (2012). Devil’s Claw-a review of the ethnobotany, phytochemistry and biological activity of Harpagophytum procumbens. Journal of Ethnopharmacology,143(3), 755–771. https://doi.org/10.1016/j.jep.2012.08.013.CrossRefPubMed

Oehler, B., Kistner, K., Martin, C., Schiller, J., Mayer, R., Mohammadi, M., et al. (2017). Inflammatory pain control by blocking oxidized phospholipid-mediated TRP channel activation. Scientific Reports,7(1), 5447. https://doi.org/10.1038/s41598-017-05348-3.CrossRefPubMedPubMedCentral

Parenti, C., Arico, G., Chiechio, S., Di Benedetto, G., Parenti, R., & Scoto, G. M. (2015). Involvement of the heme-oxygenase pathway in the antiallodynic and antihyperalgesic activity of Harpagophytum procumbens in rats. Molecules,20(9), 16758–16769. https://doi.org/10.3390/molecules200916758.CrossRefPubMedPubMedCentral

Qu, Z., Meng, F., Zhou, H., Li, J., Wang, Q., Wei, F., et al. (2014). NitroDIGE analysis reveals inhibition of protein S-nitrosylation by epigallocatechin gallates in lipopolysaccharide-stimulated microglial cells. Journal of Neuroinflammation,11, 17. https://doi.org/10.1186/1742-2094-11-17.CrossRefPubMedPubMedCentral

Quintans, J. S., Antoniolli, A. R., Almeida, J. R., Santana-Filho, V. J., & Quintans-Junior, L. J. (2014). Natural products evaluated in neuropathic pain models—A systematic review. Basic & Clinical Pharmacology & Toxicology,114(6), 442–450. https://doi.org/10.1111/bcpt.12178.CrossRef

Rahbardar, M. G., Amin, B., Mehri, S., Mirnajafi-Zadeh, S. J., & Hosseinzadeh, H. (2018). Rosmarinic acid attenuates development and existing pain in a rat model of neuropathic pain: An evidence of anti-oxidative and anti-inflammatory effects. Phytomedicine,40, 59–67. https://doi.org/10.1016/j.phymed.2018.01.001.CrossRefPubMed

Rahimi-Movaghar, V., Sayyah, M. K., Akbari, H., Khorramirouz, R., Rasouli, M. R., Moradi-Lakeh, M., et al. (2013). Epidemiology of traumatic spinal cord injury in developing countries: A systematic review. Neuroepidemiology,41(2), 65–85. https://doi.org/10.1159/000350710.CrossRefPubMed

Rao, P., & Knaus, E. E. (2008). Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): Cyclooxygenase (COX) inhibition and beyond. Journal of Pharmacy and Pharmaceutical Sciences,11(2), 81s–110s.CrossRef

Raoof, R., Willemen, H., & Eijkelkamp, N. (2018). Divergent roles of immune cells and their mediators in pain. Rheumatology (Oxford),57(3), 429–440. https://doi.org/10.1093/rheumatology/kex308.CrossRef

Riego, G., Redondo, A., Leanez, S., & Pol, O. (2018). Mechanism implicated in the anti-allodynic and anti-hyperalgesic effects induced by the activation of heme oxygenase 1/carbon monoxide signaling pathway in the central nervous system of mice with neuropathic pain. Biochemical Pharmacology,148, 52–63. https://doi.org/10.1016/j.bcp.2017.12.007.CrossRefPubMed

Shen, S., Yu, S., Binek, J., Chalimoniuk, M., Zhang, X., Lo, S. C., et al. (2005). Distinct signaling pathways for induction of type II NOS by IFNgamma and LPS in BV-2 microglial cells. Neurochemistry International,47(4), 298–307. https://doi.org/10.1016/j.neuint.2005.03.007.CrossRefPubMed

Sheng, W., Zong, Y., Mohammad, A., Ajit, D., Cui, J., Han, D., et al. (2011). Pro-inflammatory cytokines and lipopolysaccharide induce changes in cell morphology, and upregulation of ERK1/2, iNOS and sPLA(2)-IIA expression in astrocytes and microglia. Journal of Neuroinflammation,8, 121. https://doi.org/10.1186/1742-2094-8-121.CrossRefPubMedPubMedCentral

Song, H., Lu, Y., Qu, Z., Mossine, V. V., Martin, M. B., Hou, J., et al. (2016). Effects of aged garlic extract and FruArg on gene expression and signaling pathways in lipopolysaccharide-activated microglial cells. Scientific Reports,6, 35323. https://doi.org/10.1038/srep35323.CrossRefPubMedPubMedCentral

Sun, G. Y., Chen, Z., Jasmer, K. J., Chuang, D. Y., Gu, Z., Hannink, M., et al. (2015). Quercetin attenuates inflammatory responses in BV-2 microglial cells: Role of MAPKs on the Nrf2 pathway and induction of heme oxygenase-1. PLoS ONE,10(10), e0141509. https://doi.org/10.1371/journal.pone.0141509.CrossRefPubMedPubMedCentral

Sun, G. Y., Chuang, D. Y., Zong, Y., Jiang, J., Lee, J. C., Gu, Z., et al. (2014). Role of cytosolic phospholipase A2 in oxidative and inflammatory signaling pathways in different cell types in the central nervous system. Molecular Neurobiology,50(1), 6–14. https://doi.org/10.1007/s12035-014-8662-4.CrossRefPubMedPubMedCentral

Sun, G. Y., Simonyi, A., Fritsche, K. L., Chuang, D. Y., Hannink, M., Gu, Z., et al. (2018). Docosahexaenoic acid (DHA): An essential nutrient and a nutraceutical for brain health and diseases. Prostaglandins Leukotrienes and Essential Fatty Acids,136, 3–13. https://doi.org/10.1016/j.plefa.2017.03.006.CrossRef

Tator, C. H., & Fehlings, M. G. (1991). Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. Journal of Neurosurgery,75(1), 15–26. https://doi.org/10.3171/jns.1991.75.1.0015.CrossRefPubMed

Visavadiya, N. P., Patel, S. P., VanRooyen, J. L., Sullivan, P. G., & Rabchevsky, A. G. (2016). Cellular and subcellular oxidative stress parameters following severe spinal cord injury. Redox Biology,8, 59–67. https://doi.org/10.1016/j.redox.2015.12.011.CrossRefPubMed

Vlachojannis, J., Roufogalis, B. D., & Chrubasik, S. (2008). Systematic review on the safety of Harpagophytum preparations for osteoarthritic and low back pain. Phytotherapy Research,22(2), 149–152. https://doi.org/10.1002/ptr.2314.CrossRefPubMed

Widerstrom-Noga, E. (2012). Multidimensional clinical pain phenotypes after spinal cord injury. Pain Management,2(5), 467–478. https://doi.org/10.2217/pmt.12.44.CrossRefPubMed

Yadav, R. K., Singh, M., Roy, S., Ansari, M. N., Saeedan, A. S., & Kaithwas, G. (2018). Modulation of oxidative stress response by flaxseed oil: Role of lipid peroxidation and underlying mechanisms. Prostaglandins & Other Lipid Mediators,135, 21–26. https://doi.org/10.1016/j.prostaglandins.2018.02.003.CrossRef

Yang, B., Fritsche, K. L., Beversdorf, D. Q., Gu, Z., Lee, J. C., Folk, W. R., et al. (2019a). Yin-Yang mechanisms regulating lipid peroxidation of docosahexaenoic acid and arachidonic acid in the central nervous system. Frontiers in Neurology,10, 642. https://doi.org/10.3389/fneur.2019.00642.CrossRefPubMedPubMedCentral

Yang, B., Li, R., Greenlief, C. M., Fritsche, K. L., Gu, Z., Cui, J., et al. (2018). Unveiling anti-oxidative and anti-inflammatory effects of docosahexaenoic acid and its lipid peroxidation product on lipopolysaccharide-stimulated BV-2 microglial cells. Journal of Neuroinflammation,15(1), 202. https://doi.org/10.1186/s12974-018-1232-3.CrossRefPubMedPubMedCentral

Yang, B., Li, R., Woo, T., Browning, J. D., Jr., Song, H., Gu, Z., et al. (2019b). Maternal dietary docosahexaenoic acid alters lipid peroxidation products and (n − 3)/(n − 6) fatty acid balance in offspring mice. Metabolites,9(3), 1. https://doi.org/10.3390/metabo9030040.CrossRef

Zhang, L., Feng, L., Jia, Q., Xu, J., Wang, R., Wang, Z., et al. (2011). Effects of beta-glucosidase hydrolyzed products of harpagide and harpagoside on cyclooxygenase-2 (COX-2) in vitro. Bioorganic & Medicinal Chemistry,19(16), 4882–4886. https://doi.org/10.1016/j.bmc.2011.06.069.CrossRef

Title: Harpagophytum procumbens Extract Ameliorates Allodynia and Modulates Oxidative and Antioxidant Stress Pathways in a Rat Model of Spinal Cord Injury
Authors: Garrett Ungerer
Jiankun Cui
Tina Ndam
Mikeala Bekemeier
Hailong Song
Runting Li
Heather R. Siedhoff
Bo Yang
Michael K. Appenteng
C. Michael Greenlief
Dennis K. Miller
Grace Y. Sun
William R. Folk
Zezong Gu
Publication date: 01-06-2020
Publisher: Springer US
Published in: NeuroMolecular Medicine / Issue 2/2020
Print ISSN: 1535-1084
Electronic ISSN: 1559-1174
DOI: https://doi.org/10.1007/s12017-019-08585-z

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Harpagophytum procumbens Extract Ameliorates Allodynia and Modulates Oxidative and Antioxidant Stress Pathways in a Rat Model of Spinal Cord Injury

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2020

Topiramate Reverses Physiological and Behavioral Alterations by Postoperative Cognitive Dysfunction in Rat Model Through Inhibiting TNF Signaling Pathway

Ultrastructural Characteristics of DHA-Induced Pyroptosis

ACE-Triggered Hypertension Incites Stroke: Genetic, Molecular, and Therapeutic Aspects

O-GlcNAcylation as a Therapeutic Target for Alzheimer’s Disease

Correction to: High‑Mobility Group Box‑1‑Induced Angiogenesis After Indirect Bypass Surgery in a Chronic Cerebral Hypoperfusion Model

Naringin Exhibits Neuroprotection Against Rotenone-Induced Neurotoxicity in Experimental Rodents