The CB1 Receptor-Mediated Endocannabinoid Signaling and NGF: The Novel Targets of Curcumin


Increasing interest has recently been attracted towards the identification of natural compounds including those with antidepressant properties. Curcumin has shown promising antidepressant effect, however, its molecular target(s) have not been well defined. Based on the interaction between the neurotrophins and endocannabinoid system as well as their contribution to the emotional reactivity and antidepressant action, here we show that 4-week treatment with curcumin, similar to the classical antidepressant amitriptyline, results in the sustained elevation of brain nerve growth factor (NGF) and endocannabinoids in dose-dependent and brain region-specific fashion. Pretreatment with cannabinoid CB1 receptor neutral antagonist AM4113, but not the CB2 antagonist SR144528, prevents the enhancement of brain NGF contents. AM4113 exerts no effect by itself. Our findings by presenting the CB1 receptor-mediated endocannabinoid signaling and NGF as novel targets for curcumin, suggest that more attention should be focused on the therapeutic potential of herbal medicines including curcumin.

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  1. 1.

    Riolo SA, Nguyen TA, Greden JF, King CA (2005) Prevalence of depression by race/ethnicity: findings from the national health and nutrition examination survey III. Am J Public Health 95(6):998–1000

    PubMed  Article  Google Scholar 

  2. 2.

    Ereshefsky L (2009) Drug-drug interactions with the use of psychotropic medications: questions and answers. CNS Spectr 14(8):1–8

    PubMed  Google Scholar 

  3. 3.

    Nemeroff CB (2007) The burden of severe depression: a review of diagnostic challenges and treatment alternatives. J Psychiatr Res 41:189–206

    PubMed  Article  Google Scholar 

  4. 4.

    van der Watt G, Laugharne J, Janca A (2008) Complementary and alternative medicine in the treatment of anxiety and depression. Curr Opin Psychiatry 21(1):37–42

    PubMed  Article  Google Scholar 

  5. 5.

    Zhou H, Beevers CS, Huang S (2011) The targets of curcumin. Curr Drug Targets 12:332–347

    PubMed  CAS  Google Scholar 

  6. 6.

    Chainani-Wu N (2003) Safety and anti-inflammatory activity of curcumin: a component of turmeric (curcuma longa). J Alternative Compl Med 9:161–168

    Article  Google Scholar 

  7. 7.

    Maheshwari RK, Singh AK, Gaddipati J, Smiral RC (2006) Multiple biological activities of curcumin: a short review. Life Sci 78:2081–2087

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Aggarwal BB, Harikumar KB (2009) Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol 41:40–59

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Xu Y, Ku BS, Yao HY, Lin YH, Ma X, Zhang YH et al (2005) The effects of curcumin on depressive-like behaviors in mice. Eur J Pharmacol 518:40–46

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Xu Y, Ku BS, Yao HY, Lin YH, Ma X, Zhang YH et al (2005) Antidepressant effects of curcumin in the forced swim test and olfactory bulbectomy models of depression in rats. Pharmacol Biochem Behav 82:200–206

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Kulkarni SK, Bhutani MK, Bishnoi M (2008) Antidepressant activity of curcumin: involvement of serotonin and dopamine system. Psychopharmacology (Berl) 201:435–442

    Article  CAS  Google Scholar 

  12. 12.

    Berton O, Nestler EJ (2006) New approaches to antidepressant drug discovery: Beyond monoamines. Nat Rev Neurosci 7:137–151

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Tanis KQ, Duman RS (2007) Intracellular signaling pathways pave roads to recovery for mood disorders. Ann Med 39:531–544

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Huang EJ, Reichardt LF (2001) Neurotrophins: roles in neuronal development and function. Ann Rev Neurosci 24:677–736

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Castren E, Voikar V, Rantamaki T (2007) Role of neurotrophic factors in depression. Curr Opin Pharmacol 7(1):18–21

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Shaltiel G, Chen G, Manji HK (2007) Neurotrophic signalling cascades in the pathophysiology and treatment of bipolar disorder. Curr Opin Pharmacol 7:22–26

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Adachi M, Barrot M, Autry AE, Theobald D, Monteggia LM (2008) Selective loss of brain-derived neurotrophic factor in the dentate gyrus attenuates antidepressant efficacy. Biol Psychiatry 63:642–649

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Xu Y, Ku B, Cui L, Li X, Barish PA, Foster TC et al (2007) Curcumin reverses impaired hippocampal neurogenesis and increases serotonin receptor 1A mRNA and brain derived neurotrophic factor expression in chronically stressed rats. Brain Res 1162:9–18

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Wang R, Li YB, Li YH, Xu Y, Wu H, Li XJ (2008) Curcumin protects against glutamate excitotoxicity in rat cerebral cortical neurons by increasing brain-derived neurotrophic factor level and activating TrkB. Brain Res 1210:84–91

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Ebendal T (1992) Function and evolution in the NGF family and its receptors. J Neurosci Res 32:461–470

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Lad SP, Neet KE, Mufson EJ (2003) Nerve growth factor: structure, function and therapeutic implications for Alzheimer’s disease. Curr Drug Targets CNS Neurol Disord 2:315–334

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Alleva E, Petruzzi S, Cirulli F, Aloe L (1996) NGF regulatory role in stress and coping of rodents and humans. Pharmacol Biochem Behav 54(1):65–72

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Jang SW, Liu X, Chan CB, Weinshenker D, Hall RA, Xiao G et al (2009) The antidepressant amitriptyline is a TrkA and TrkB receptor agonist that promotes TrkA/TrkB heterodimerization and has potent neurotrophic activity. Chem Biol 16:644–656

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Chadwick W, Mitchell N, Caroll J, Zhou Y, Park SS, Wang L et al (2011) Amitriptyline-mediated cognitive enhancement in aged 3 × Tg Alzheimer’s disease mice is associated with neurogenesis and neurotrophic activity. Plos One 6:e21660

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Viveros MP, Marco EM, File SE (2005) Endocannabinoid system and stress and anxiety responses. Pharmacol Biochem Behav 81(2):331–342

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Viveros MP, Marco EM, Liorente R, Lopez-Gallardo M (2007) Endocannabinoid system and synaptic plasticity: implication for emotional response. Neural Plast 2007:52908

    PubMed  Article  Google Scholar 

  27. 27.

    Bambico FR, Duranti A, Tontini A, Tarzia G, Gobbi G (2009) Endocannabinoids in the treatment of mood disorders: evidence from animal models. Curr Pharm Des 15(14):1623–1646

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Rodríguez-Gaztelumendi A, Rojo ML, Pazos A, Díaz A (2009) Altered CB1 receptor-signaling in prefrontal cortex from an animal model of depression is reversed by chronic fluoxetine. J Neurochem 108(6):1423–1433

    PubMed  Article  Google Scholar 

  29. 29.

    Williams EJ, Walsh FS, Doherty P (2003) The FGF receptor uses the endocannabinoid signaling system to couple to an axonal growth response. J Cell Biol 160:481–486

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Khaspekov LG, Brenz Verca MS, Frumkina LE, Hermann H, Marsicano G, Lutz B (2004) Involvement of brain-derived neurotrophic factor in cannabinoid receptor-dependent protection against excitotoxicity. Eur J Neurosci 19:1691–1698

    PubMed  Article  Google Scholar 

  31. 31.

    Ghoneim AI, Abdel-Naim AB, Khalifa AE, El-Denshary ES (2002) Protective effects of curcumin against ischaemia/reperfusion insult in rat forebrain. Pharmacol Res 46:273–279

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Li Yu-Cheng, Wang Fu-Meng, Pan Ying, Qiang Li-Qin, Cheng Guang, Zhang Wei-Yun et al (2009) Antidepressant-like effects of curcumin on serotonergic receptor-coupled AC-cAMP pathway in chronic unpredictable mild stress of rats. Prog Neuropsychopharmacol Biol Psychiatry 33(3):435–449

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    di Matteo V, di Mascio M, di Giovanni G, Esposito E (2000) Acute administration of amitriptyline and mianserin increases dopamine release in the rat nucleus accumbens: possible involvement of serotonin 2C receptors. Psychopharmacology (Berl) 150:45–51

    Article  Google Scholar 

  34. 34.

    Järbe TU, LeMay BJ, Olszewska T, Vemuri VK, Wood JT, Makriyannis A (2008) Intrinsic effects of AM4113, a putative neutral CB1 receptor selective antagonist, on open-field behaviours in rats. Pharmacol Biochem Behav 91(1):84–90

    PubMed  Article  Google Scholar 

  35. 35.

    Sink KS, McLaughlin PJ, Wood JA, Brown C, Fan P, Vemuri VK et al (2008) The novel cannabinoid CB (1) receptor neutral antagonist AM4113 suppresses food intake and food-reinforced behavior but does not induce signs of nausea in rats. Neuropsychopharmacology 33:946–955

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Abalo R, Cabezos PA, Vera G, Fernandez-pujol R, Martin MI (2010). The cannabinoid antagonist SR144528 enhances the acute effect of WIN 55,212-2 on gastrointestinal motility in the rat. Neurogastroenterol Motil 22(6): 694–e206

    Google Scholar 

  37. 37.

    Gwinn RP, Kondratyev A, Gale K (2002) Time-dependent increase in basic fibroblast growth factor protein in limbic regions following electroshock seizures. Neuroscience 114:403–409

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Vinay P, KhanMohammad M, Alvin T, Sahebarao PM (2004) Differential effects of typical and atypical antipsychotics on nerve growth factor and choline acetyltransferase expression in the cortex and nucleus basalis of rats. J Psychiat Res 38(5):521–529

    Article  Google Scholar 

  39. 39.

    Paxinos G, Watson C (1997) The Rat Brain in Stereotaxic Coordinates. Academic Press, San Diego

    Google Scholar 

  40. 40.

    Hoener MC, Hewitt E, Conner JM, Costello JW, Varon S (1996) Nerve growth factor (NGF) content in adult rat brain tissues is several-fold higher than generally reported and is largely associated with sedimentable fractions. Brain Res 728:47–56

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Hellweg R, Hock C, Hartung HD (1989) An improved rapid and highly sensitive enzyme immunoassay for nerve growth factor. Technique J Meth Cell Mol Biol 1:43–49

    Google Scholar 

  42. 42.

    Hellweg R, Thomas H, Arnswald A, von Richthofen S, Kay S, Fink H et al (2001) Serotonergic lesion of median raphe nucleus alters nerve growth factor content and vulnerability of cholinergic septohippocampal neurons in rat. Brain Res 907:100–108

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Hellweg R, Lang UE, Nagel M, Baumgartner A (2002) Subchronic treatment with lithium increases nerve growth factor content in distinct brain regions of adult rats. Mol Psychiatry 7:604–608

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein–dye binding. Anal Biochem 72:248–254

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    de Lago E, Petrosino S, Valenti M, Morera E, Ortega-Gutierrez S, Fernandez-Ruiz J et al (2005) Effect of repeated systemic administration of selective inhibitors of endocannabinoid inactivation on rat brain endocannabinoid levels. Biochem Pharmacol 70:446–452

    PubMed  Article  Google Scholar 

  46. 46.

    Koga D, Santa T, Fukushima T, Homma H, Imai K (1997) Liquid chromatographic-atmospheric pressure chemical ionization mass spectrometric determination of anandamide and its analogues in rat brain and peripheral tissues. J Chromatogr B Biomed Sci Appl 690:7–13

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Patel S, Rademacher DJ, Hillard CJ (2003) Differential regulation of the endocannabinoids anandamide and 2-Arachidonylglycerol within the limbic forebrain by dopamine receptor activity. J Pharmacol Exp Ther 306:880–888

    PubMed  Article  CAS  Google Scholar 

  48. 48.

    Hassanzadeh P, Hassanzadeh A (2010) Effects of different psychotropic agents on the central nerve growth factor protein. Iran J Basic Med Sci 13(1):202–209

    CAS  Google Scholar 

  49. 49.

    Yanpallewar SU, Fernandes K, Marathe SV, Vadodaria KC, Jhaveri D, Rommelfanger K et al (2010) α2-adrenoceptor blockade accelerates the neurogenic, neurotrophic, and behavioral effects of chronic antidepressant treatment. J Neurosci 30(3):1096–1109

    PubMed  Article  CAS  Google Scholar 

  50. 50.

    Cheng S, Ma M, Ma Y, Wang Z, Xu G, Liu X (2009) Combination therapy with intranasal NGF and electroacupuncture enhanced cell proliferation and survival in rats after stroke. Neurol Res 31(7):753–758

    PubMed  Article  Google Scholar 

  51. 51.

    Banasr M, Valentine GW, Li XY, Gourley SL, Taylor JR, Duman RS (2007) Chronic unpredictable stress decreases cell proliferation in the cerebral cortex of the adult rat. Biol Psychiatry 62(5):496–504

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Conner JM, Franks KM, Titterness AK, Russell K, Merrill DA, Christie BR et al (2009) NGF is essential for hippocampal plasticity and learning. J Neurosci 29(35):10883–10889

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    Winkler J, Ramirez GA, Thal LJ, Waite JJ (2000) Nerve growth factor (NGF) augments cortical and hippocampal cholinergic functioning after p75NGF receptor-mediated deafferentation but impairs inhibitory avoidance and induces fear-related behaviors. J Neurosci 20(2):834–844

    PubMed  CAS  Google Scholar 

  54. 54.

    Moises HC, Womble MD, Washburn MS, Williams LR (1995) Nerve growth factor facilitates cholinergic neurotransmission between nucleus basalis and the amygdala in rat: an electrophysiological analysis. J Neurosci 15(12):8131–8142

    PubMed  CAS  Google Scholar 

  55. 55.

    Miwa T, Moriizumi T, Horikawa I, Uramoto N, Ishimaru T, Nishimura T et al (2002) Role of nerve growth factor in the olfactory system. Microsc Res Tech 58(3):197–203

    PubMed  Article  CAS  Google Scholar 

  56. 56.

    Marsicano G, Lutz B (2006) Neuromodulatory functions of the endocannabinoid system. J Endocrinol Investig 29(3):27–46

    CAS  Google Scholar 

  57. 57.

    Hankoff LD, Peress NS (1981) Neuropathology of the brain stem in psychiatric disorders. Biol Psychiatry 16(10):945–952

    PubMed  CAS  Google Scholar 

  58. 58.

    Teiten MH, Eifes S, Dicato M, Diederich M (2010) Curcumin- The paradigm of a multi-target natural compound with applications in cancer prevention and treatment. Toxins 2:128–162

    PubMed  Article  CAS  Google Scholar 

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This work was supported by a grant from Shahid Beheshti University of Medical Sciences (SB587). The authors thank Ali Mahdavi, PhD, Department of immunology, Tarbiat Modarres University, Tehran, for technical assistance; and Nosrat Naderi, MD, FACG, Research Center for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, for helpful comments on the manuscript.

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Correspondence to Parichehr Hassanzadeh.

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Supplementary Figure 1: Brain regional levels of NGF are not altered following single injection of 100 mg kg−1 curcumin or 5 mg kg−1 amitriptyline. (A) NGF levels 24 h after the treatment, (B) NGF levels 48 h after the treatment, (C) NGF levels 72 h after the treatment. Data are expressed as mean ± SEM of n=6/group. Vehicles 1 and 2 are related to curcumin and amitriptyline, respectively. (TIFF 15 kb)

Supplementary Figure 2: Acute administration of 150 mg kg−1 curcumin or 10 mg kg−1 amitriptyline does not alter brain NGF levels. (A) NGF levels 24 h after the treatment, (B) NGF levels 48 h after the treatment, (C) NGF levels 72 h after the treatment. Data are expressed as mean ± SEM of n=6/group. (TIFF 15 kb)

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Hassanzadeh, P., Hassanzadeh, A. The CB1 Receptor-Mediated Endocannabinoid Signaling and NGF: The Novel Targets of Curcumin. Neurochem Res 37, 1112–1120 (2012).

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  • Curcumin
  • Amitriptyline
  • Endocannabinoid system
  • CB1 receptors
  • CB2 receptors
  • NGF
  • Brain
  • Rat