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Endocannabinoid 2-Arachidonylglycerol Protects Primary Cultured Neurons Against LPS-Induced Impairments in Rat Caudate Nucleus

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Abstract

Inflammation plays a pivotal role in the pathogenesis of many diseases in the central nervous system. Caudate nucleus (CN), the largest nucleus in the brain, is also implicated in many neurological disorders. 2-Arachidonoylglycerol (2-AG), the most abundant endogenous cannabinoid and the true natural ligand for CB1 receptors, has been shown to exhibit neuroprotective effects through its anti-inflammatory action from proinflammatory stimuli in hippocampus. However, it is still not clear whether 2-AG is also able to protect CN neurons from proinflammation stimuli. In the present study, we discovered that 2-AG significantly protects CN neurons in culture against lipopolysaccharide (LPS)-induced inflammatory response. 2-AG is capable of suppressing elevation of LPS-induced cyclooxygenase-2 expression associated with ERK/p38MAPK/NF-κB signaling pathway in CB1 receptor-dependant manner in primary cultured CN neurons. Moreover, 2-AG inhibits LPS-induced increase in voltage-gated sodium channel currents and hyperpolarizing shift of activation curves through CB1 receptor-dependant pathway. Our study suggests the therapeutic potential of 2-AG for the treatment of some inflammation-induced neurological disorders and pain.

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References

  • Amir R, Argoff CE, Bennett GJ, Cummins TR, Durieux ME, Gerner P et al (2006) The role of sodium channels in chronic inflammatory and neuropathic pain. J Pain 7:S1–S29

    Article  CAS  PubMed  Google Scholar 

  • Aoki T, Narumiya S (2012) Prostaglandins and chronic inflammation. Trends Pharmacol Sci 33:304–311

    Article  CAS  PubMed  Google Scholar 

  • Araldi D, Ferrari LF, Lotufo CM, Vieira AS, Athié MC, Figueiredo JG et al (2013) Peripheral inflammatory hyperalgesia depends on the COX increase in the dorsal root ganglion. Proc Natl Acad Sci U S A 110:3603–3608

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Barnéoud P, Mazadier M, Miquet JM, Parmentier S, Dubédat P, Doble A et al (1996) Neuroprotective effects of riluzole on a model of Parkinson’s disease in the rat. Neuroscience 74:971–983

    Article  PubMed  Google Scholar 

  • Black JA, Liu S, Tanaka M, Cummins TR, Waxman SG (2004) Changes in the expression of tetrodotoxin-sensitive sodium channels within dorsal root ganglia neurons in inflammatory pain. Pain 108:237–247

    Article  CAS  PubMed  Google Scholar 

  • Brück A, Portin R, Lindell A, Laihinen A, Bergman J, Haaparanta M et al (2001) Positron emission tomography shows that impaired frontal lobe functioning in Parkinson’s disease is related to dopaminergic hypofunction in the caudate nucleus. Neurosci Lett 311:81–84

    Article  PubMed  Google Scholar 

  • Chang YH, Lee ST, Lin WW (2001) Effects of cannabinoids on LPS-stimulated inflammatory mediator release from macrophages: involvement of eicosanoids. J Cell Biochem 81:715–723

    Article  CAS  PubMed  Google Scholar 

  • Chen X, Zhang J, Chen C (2011) Endocannabinoid 2-arachidonoylglycerol protects neurons against β-amyloid insults. Neuroscience 178:159–168

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Docherty RJ, Farmer CE (2009) The pharmacology of voltage-gated sodium channels in sensory neurones. Handb Exp Pharmacol 194:519–561

    Article  CAS  PubMed  Google Scholar 

  • Duan Y, Zheng J, Nicholson RA (2008) Inhibition of [3H]batrachotoxinin A-20alpha-benzoate binding to sodium channels and sodium channel function by endocannabinoids. Neurochem Int 52:438–446

    Article  CAS  PubMed  Google Scholar 

  • Eljaschewitsch E, Witting A, Mawrin C, Lee T, Schmidt PM, Wolf S et al (2006) The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells. Neuron 49:67–79

    Article  CAS  PubMed  Google Scholar 

  • England S, Bevan S, Docherty RJ (1996) PGE2 modulates the tetrodotoxin-resistant sodium current in neonatal rat dorsal root ganglion neurones via the cyclic AMP-protein kinase A cascade. J Physiol 495:429–440

    CAS  PubMed Central  PubMed  Google Scholar 

  • Freund TF, Katona I, Piomelli D (2003) Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 83:1017–1066

    CAS  PubMed  Google Scholar 

  • Gold MS, Reichling DB, Shuster MJ, Levine JD (1996) Hyperalgesic agents increase a tetrodotoxin-resistant Na+ current in nociceptors. Proc Natl Acad Sci U S A 93:1108–1112

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hillard CJ (2000) Biochemistry and pharmacology of the endocannabinoids arachidonylethanolamide and 2-arachidonylglycerol. Prostaglandins Other Lipid Mediat 61:3–18

    Article  CAS  PubMed  Google Scholar 

  • Jain NK, Patil CS, Kulkarni SK, Singh A (2002) Modulatory role of cyclooxygenase inhibitors in aging- and scopolamine or lipopolysaccharide-induced cognitive dysfunction in mice. Behav Brain Res 133:369–376

    Article  CAS  PubMed  Google Scholar 

  • Jung GY, Lee JY, Rhim H, Oh TH, Yune TY (2013) An increase in voltage-gated sodium channel current elicits microglial activation followed inflammatory responses in vitro and in vivo after spinal cord injury. Glia 61:1807–1821

    PubMed  Google Scholar 

  • Ke Y, Song WW, Dong MM, Peng F, Yang HW (2013) Cyclooxgense-2 mediated antagonised effect of curcumin on LPS induced impairment of neurons in caudate nucleus. Lishizhen Med Mater Med Res 24:2590–2592

    CAS  Google Scholar 

  • Korotzer AR, Cotman CW (1992) Voltage-gated currents expressed by rat microglia in culture. Glia 6:81–88

    Article  CAS  PubMed  Google Scholar 

  • Kotz SA, Anwander A, Axer H, Knösche TR (2013) Beyond cytoarchitectonics: the internal and external connectivity structure of the caudate nucleus. PLoS One 8:e70141

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Luchicchi A, Pistis M (2012) Anandamide and 2-arachidonoylglycerol: pharmacological properties, functional features, and emerging specificities of the two major endocannabinoids. Mol Neurobiol 46:374–392

    Article  CAS  PubMed  Google Scholar 

  • Lynch AM, Walsh C, Delaney A, Nolan Y, Campbell VA, Lynch MA (2004) Lipopolysaccharide-induced increase in signalling in hippocampus is abrogated by IL-10—a role for IL-1 beta? J Neurochem 88:635–646

    Article  CAS  PubMed  Google Scholar 

  • Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR et al (1995) Identification of an endogenous 2-monoglyceride, present in canine gut that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90

    Article  CAS  PubMed  Google Scholar 

  • Okada Y, Imendra KG, Miyazaki T, Hotokezaka H, Fujiyama R, Zeredo JL et al (2005) Biophysical properties of voltage-gated Na+ channels in frog parathyroid cells and their modulation by cannabinoids. J Exp Biol 208:4747–4756

    Article  CAS  PubMed  Google Scholar 

  • Oz M (2006) Receptor-independent actions of cannabinoids on cell membranes: focus on endocannabinoids. Pharmacol Ther 111:114–144

    Article  CAS  PubMed  Google Scholar 

  • Panikashvili D, Simeonidou C, Ben-Shabat S, Hanus L, Breuer A, Mechoulam R et al (2001) An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 413:527–531

    Article  CAS  PubMed  Google Scholar 

  • Panikashvili D, Shein NA, Mechoulam R, Trembovler V, Kohen R, Alexandrovich A et al (2006) The endocannabinoid 2-AG protects the blood-brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines. Neurobiol Dis 22:257–264

    Article  CAS  PubMed  Google Scholar 

  • Peng F, LU YL, Yang HW (2012) Primary culture of neurons from caudate nucleus and study on the characteristics of ion channels. J Chin Med Univ 41:676–678

    Google Scholar 

  • Pertwee RG (2005) Pharmacological actions of cannabinoids. Handb Exp Pharmacol 168:1–51

    Article  CAS  PubMed  Google Scholar 

  • Pertwee RG (2010) Receptors and channels targeted by synthetic cannabinoid receptor agonists and antagonists. Curr Med Chem 17:1360–1381

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sprengelmeyer R, Canavan AG, Lange HW, Hömberg V (1995) Associative learning in degenerative neostriatal disorders: contrasts in explicit and implicit remembering between Parkinson’s and Huntington’s diseases. Mov Disord 10:51–65

    Article  CAS  PubMed  Google Scholar 

  • Sugiura T, Waku K (2002) Cannabinoid receptors and their endogenous ligands. J Biochem 132:7–12

    Article  CAS  PubMed  Google Scholar 

  • Sugiura T, Kishimoto S, Oka S, Gokoh M (2006) Biochemistry, pharmacology and physiology of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand. Prog Lipid Res 45:405–446

    Article  CAS  PubMed  Google Scholar 

  • Tanaka M, Cummins TR, Ishikawa K, Dib-Hajj SD, Black JA, Waxman SG (1998) SNS Na+ channel expression increases in dorsal root ganglion neurons in the carrageenan inflammatory pain model. Neuroreport 9:967–972

    Article  CAS  PubMed  Google Scholar 

  • Walter L, Stella N (2004) Cannabinoids and neuroinflammation. Br J Pharmacol 14:775–785

    Google Scholar 

  • Waxman SG, Cummins TR, Dib-Hajj S, Fjell J, Black JA (1999) Sodium channels, excitability of primary sensory neurons, and the molecular basis of pain. Muscle Nerve 22:1177–1187

    Article  CAS  PubMed  Google Scholar 

  • Williams AJ, Tortella FC (2002) Neuroprotective effects of the sodium channel blocker RS100642 and attenuation of ischemia-induced brain seizures in the rat. Brain Res 932:45–55

    Article  CAS  PubMed  Google Scholar 

  • Yang H, Chen C (2008) Cyclooxygenase-2 in synaptic signaling. Curr Pharm Des 14:1443–1451

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang J, Chen C (2008) Endocannabinoid 2-arachidonoylglycerol protects neurons by limiting COX-2 elevation. J Biol Chem 283:22601–22611

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zogopoulos P, Vasileiou I, Patsouris E, Theocharis S (2013) The neuroprotective role of 1endocannabinoids against chemical-induced injury and other adverse effects. J Appl Toxicol 33:246–264

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (no. 30970930).

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Correspondence to Hongwei Yang.

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Lu, Y., Peng, F., Dong, M. et al. Endocannabinoid 2-Arachidonylglycerol Protects Primary Cultured Neurons Against LPS-Induced Impairments in Rat Caudate Nucleus. J Mol Neurosci 54, 49–58 (2014). https://doi.org/10.1007/s12031-014-0246-2

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  • DOI: https://doi.org/10.1007/s12031-014-0246-2

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