Plant Natural Product Puerarin Ameliorates Depressive Behaviors and Chronic Pain in Mice with Spared Nerve Injury (SNI)
- 752 Downloads
Simultaneous relief of the pain from body and brain remains an ongoing challenge. The aim of the present study was to clarify whether plant-derived isoflavone puerarin could ameliorate comorbid depression and pain. We investigated the effects of puerarin on depressive-like behaviors and neuropathic pain in C57BL/6 N mice with spared nerve injury (SNI). After SNI surgery, mice were allowed to recover spontaneously for 7 days and subsequently treated with puerarin, anti-depressant citalopram, and analgesic ibuprofen, alone or in combination, for 8 or 14 days. Forced swim test and tail suspension test were used to assess depressive-like behaviors, whereas von Frey filament test was used to estimate the sensitivity to the mechanical stimulation. Our results suggested that puerarin effectively ameliorated depression and pain in SNI mice although citalopram exhibited anti-depressant activity. In contrast, ibuprofen showed lesser activities against SNI-induced depression and pain. Further mechanistic studies revealed the uniqueness of puerarin as follows: (1) puerarin did not recover SNI-induced depletion of reduced glutathione and loss of superoxide dismutase (SOD), whereas citalopram and ibuprofen showed somewhat antioxidant activities; (2) puerarin markedly promoted the activation of CREB pathway although puerarin and citalopram activated ERK pathway to the same extent; (3) puerarin rapidly and persistently induced brain-derived neurotrophic factor (BDNF) expression whereas citalopram only induced BDNF expression after a prolonged stimulation. Collectively, these results suggest that puerarin may ameliorate the SNI-induced depression and pain via activating ERK, CREB, and BDNF pathways. Puerarin may serve as new lead compound for the development of novel therapeutics for depression and pain comorbidity.
KeywordsDepression Pain Puerarin BDNF Spared nerve injury
This work was supported by General Research Fund (GRF) (HKU 775812 M) from the Research Grants Council of Hong Kong and the Seed Funding for Basic Research Programme, The University of Hong Kong.
Compliance with Ethical Standard
Conflict of Interest
The authors declare that they have no competing interests.
- 1.Licinio J, Wong ML (1999) The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection. Mol Psychiatry 4:317–327CrossRefPubMedGoogle Scholar
- 8.Powell TR, Schalkwyk LC, Heffernan AL, Breen G, Lawrence T, Price T, Farmer AE, Aitchison KJ et al (2013) Tumor necrosis factor and its targets in the inflammatory cytokine pathway are identified as putative transcriptomic biomarkers for escitalopram response. Eur Neuropsychopharmacol 23:1105–1114CrossRefPubMedGoogle Scholar
- 9.Alboni S, Benatti C, Capone G, Corsini D, Caggia F, Tascedda F, Mendlewicz J, Brunello N (2010) Time-dependent effects of escitalopram on brain derived neurotrophic factor (BDNF) and neuroplasticity related targets in the central nervous system of rats. Eur J Pharmacol 643:180–187CrossRefPubMedGoogle Scholar
- 12.Leuchter AF, Husain MM, Cook IA, Trivedi MH, Wisniewski SR, Gilmer WS, Luther JF, Fava M et al (2010) Painful physical symptoms and treatment outcome in major depressive disorder: a STAR*D (Sequenced Treatment Alternatives to Relieve Depression) report. Psychol Med 40:239–251CrossRefPubMedGoogle Scholar
- 18.Zhao J, Cheng YY, Fan W, Yang CB, Ye SF, Cui W, Wei W, Lao LX et al (2015) Botanical drug puerarin coordinates with nerve growth factor in the regulation of neuronal survival and neuritogenesis via activating ERK1/2 and PI3K/Akt signaling pathways in the neurite extension process. CNS Neurosci Ther 21:61–70CrossRefPubMedGoogle Scholar
- 23.Zhao J, Cheng Y, Yang C, Lau S, Lao L, Shuai B, Cai J, Rong J (2015) Botanical drug puerarin attenuates 6-hydroxydopamine (6-OHDA)-induced neurotoxicity via upregulating mitochondrial enzyme arginase-2. Mol Neurobiol. [Epub ahead of print]Google Scholar
- 24.Richner M, Bjerrum OJ, Nykjaer A, Vaegter CB (2011) The spared nerve injury (SNI) model of induced mechanical allodynia in mice. J Vis Exp (54):3092. doi: 10.3791/3092
- 25.Gai BM, Bortolatto CF, Bruning CA, Zborowski VA, Stein AL, Zeni G, Nogueira CW (2014) Depression-related behavior and mechanical allodynia are blocked by 3-(4-fluorophenylselenyl)-2,5-diphenylselenophene in a mouse model of neuropathic pain induced by partial sciatic nerve ligation. Neuropharmacology 79:580–589CrossRefPubMedGoogle Scholar
- 35.Numakawa T, Richards M, Nakajima S, Adachi N, Furuta M, Odaka H, Kunugi H (2014) The role of brain-derived neurotrophic factor in comorbid depression: possible linkage with steroid hormones, cytokines, and nutrition. Front Psychol 5:136Google Scholar
- 37.Ishikawa K, Yasuda S, Fukuhara K, Iwanaga Y, Ida Y, Ishikawa J, Yamagata H, Ono M et al (2014) 4-Methylcatechol prevents derangements of brain-derived neurotrophic factor and TrkB-related signaling in anterior cingulate cortex in chronic pain with depression-like behavior. Neuroreport 25:226–232CrossRefPubMedGoogle Scholar
- 40.Liu Y, Lan N, Ren J, Wu Y, Wang ST, Huang XF, Yu Y (2015) Orientin improves depression-like behavior and BDNF in chronic stressed mice. Mol Nutr Food Res 59(6):1130–42Google Scholar
- 45.Matsuoka Y, Yang J (2012) Selective inhibition of extracellular signal-regulated kinases 1/2 blocks nerve growth factor to brain-derived neurotrophic factor signaling and suppresses the development of and reverses already established pain behavior in rats. Neuroscience 206:224–236CrossRefPubMedPubMedCentralGoogle Scholar
- 50.Mlyniec K, Budziszewska B, Holst B, Ostachowicz B, Nowak G (2015) GPR39 (zinc receptor) knockout mice exhibit depression-like behavior and CREB/BDNF down-regulation in the hippocampus. Int J Neuropsychopharmacol 18(3):1–8Google Scholar