Skip to main content

Advertisement

SpringerLink
Log in

Licofelone attenuates MPTP-induced neuronal toxicity: behavioral, biochemical and cellular evidence

  • Research Article
  • Published:
Inflammopharmacology Aims and scope Submit manuscript

Abstract

Neuroinflammation and oxidative stress play critical role in the pathophysiology of neurodegenerative diseases including Parkinson’s disease (PD). Recent reports indicate the beneficial effect of anti-inflammatory drugs in attenuating the progression of PD. Therefore, the present study is aimed to evaluate the possible role of licofelone, a dual COX/LOX-inhibitor against MPTP-induced neurotoxicity in mice. Administration of MPTP (40 mg/kg in divided doses of four injections of 10 mg/kg, i.p. each at 1 h interval) significantly impaired locomotor activity and induced catatonia, oxidative damage (elevated levels of lipid peroxidation, superoxide anion and nitrite, and decreased levels of non-protein thiols) as compared with vehicle-treated animals. Biochemical studies revealed significant alterations in mitochondrial enzyme complex activities (decreased complex-I activity and mitochondrial viability) and increased levels of caspase-3 and NF-κB/p65 as compared to vehicle treated group. Licofelone (2.5, 5 or 10 mg/kg/day, p.o.) treatment for 7 days significantly improved locomotor activity, attenuated the severity of catatonia, oxidative damage and restored mitochondrial enzyme complex activity as compared to MPTP-treated group. Licofelone treatment also attenuated the expression of apoptotic factor (caspase-3) and transcription factor (NF-κB/p65) as compared to MPTP-treated group. The findings of the present study suggest that licofelone (dual inhibitor of COX and LOX) represents a new class of anti-inflammatory agent which may provide a novel therapeutic alternative for the treatment and management of PD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Agid Y (1991) Parkinson’s disease: pathophysiology. Lancet 337:1321–1324

    Article  CAS  PubMed  Google Scholar 

  • Aguirre JA, Leo G, Cueto R, Andbjer B, Naylor A, Medhurst AD et al (2008) The novel cyclooxygenase-2 inhibitor GW637185x protects against l-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine toxicity. Neuroreport 19:657–660

    Article  CAS  PubMed  Google Scholar 

  • Babior BM, Kipner RS, Cerutte JT (1973) Biological defense mechanism. The production by leukocytes of superoxide, a potential bacterial agent. J Clin Invest 52:741–744

    Article  CAS  PubMed  Google Scholar 

  • Bartels AL, Leenders KL (2007) Neuroinflammation in the pathophysiology of Parkinson’s disease: evidence from animal models to human in vivo studies with [11C]-PK11195 PET. Mov Disord 22:1852–1856

    Article  PubMed  Google Scholar 

  • Berman SB, Hastings TG (1999) Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria: implications for Parkinson’s disease. J Neurochem 73:1127–1137

    Article  CAS  PubMed  Google Scholar 

  • Bias P, Buchner A, Klesser B, Laufer S (2004) The gastrointestinal tolerability of the LOX/COX inhibitor, licofelone, is similar to placebo and superior to naproxen therapy in healthy volunteers: results from randomized, controlled trial. Am J Gastroenterol 99:611–618

    Article  CAS  PubMed  Google Scholar 

  • Bray MA, Ford-Hutchinson AW, Smith MJ (1981) Leukotriene B4: an inflammatory mediator in vivo. Prostaglandins 22:213–222

    Article  CAS  PubMed  Google Scholar 

  • Bredt DS, Snyder SH (1990) Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci USA 87:682–685

    Article  CAS  PubMed  Google Scholar 

  • Chalimoniuk M, Lukacova N, Marsala J, Langfort J (2006) Alterations of the expression and activity of midbrain nitric oxide synthase and soluble guanylyl cyclase in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice. Neuroscience 141:1033–1046

    Article  CAS  PubMed  Google Scholar 

  • Drechsel DA, Liang LP, Patel M (2007) 1-Methyl-4-phenylpyridinium-induced alterations of glutathione status in immortalized rat dopaminergic neurons. Toxicol Appl Pharmacol 220:341–348

    Article  CAS  PubMed  Google Scholar 

  • Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77

    Article  CAS  PubMed  Google Scholar 

  • Etminan M, Carleton BC, Samii A (2008) Non-steroidal anti-inflammatory drug use and the risk of Parkinson disease: a retrospective cohort study. J Clin Neurosci 15:576–577

    Article  CAS  PubMed  Google Scholar 

  • Feng ZH, Wang TG, Li DD, Fung P, Wilson BC, Liu B et al (2002) Cyclooxygenase-2-deficient mice are resistant to 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine-induced damage of dopaminergic neurons in the substantia nigra. Neurosci Lett 329:354–358

    Article  CAS  PubMed  Google Scholar 

  • Fiorucci S, Meli R, Bucci M, Cirino G (2001) Dual inhibitors of cyclooxygenase and 5-lipoxygenase. A new avenue in anti-inflammatory therapy. Biochem Pharmacol 62:1433–1438

    Article  CAS  PubMed  Google Scholar 

  • Gornall AG, Bardawill CJ, David MM (1949) Determination of serum proteins by means of the biuret reaction. J Biol Chem 177:751–766

    CAS  PubMed  Google Scholar 

  • Gupta A, Dhir A, Kumar A, Kulkarni SK (2009) Protective effect of cyclooxygenase (COX)-inhibitors against drug-induced catatonia and MPTP-induced striatal lesions in rats. Pharmacol Biochem Behav 94:219–226

    Article  CAS  PubMed  Google Scholar 

  • Gupta A, Dhir A, Kumar A, Kulkarni SK (2010) Effect of preferential cyclooxygenase-2 (COX-2)-inhibitor against 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced striatal lesions in rats: behavioral, biochemical and histological evidences. Indian J Exp Biol 48:577–585

    CAS  PubMed  Google Scholar 

  • Halliwell B (1992) Reactive oxygen species and the central nervous system. J Neurochem 59:1609–1623

    Article  CAS  PubMed  Google Scholar 

  • Hastings TG (1995) Enzymatic oxidation of dopamine: the role of prostaglandin H synthase. J Neurochem 64:919–924

    Article  CAS  PubMed  Google Scholar 

  • Hirsch EC, Breidert T, Rousselet E, Hunot S, Hartmann A, Michel PP (2003) The role of glial reaction and inflammation in Parkinson’s disease. Ann N Y Acad Sci 991:214–228

    Article  CAS  PubMed  Google Scholar 

  • Hunter RL, Dragicevic N, Seifert K, Choi DY, Liu M, Kim HC et al (2007) Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system. J Neurochem 100:1375–1386

    Article  CAS  PubMed  Google Scholar 

  • Kalonia H, Kumar P, Kumar A, Nehru B (2009) Effect of caffeic acid and rofecoxib and their combination against intrastriatal quinolinic acid induced oxidative damage, mitochondrial and histological alterations in rats. Inflammopharmacol 17:211–219

    Google Scholar 

  • Kim YS, Joh TH (2006) Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson’s disease. Exp Mol Med 38:333–347

    CAS  PubMed  Google Scholar 

  • King TE, Howard RL (1967) Preparations and properties of soluble NADH dehydrogenases from cardiac muscle. Methods Enzymol 10:275–284

    Article  CAS  Google Scholar 

  • Knott C, Stern G, Wilkin GP (2000) Inflammatory regulators in Parkinson’s disease: iNOS, lipocortin-1, and cyclooxygenases-1 and -2. Mol Cell Neurosci 16:724–739

    Article  CAS  PubMed  Google Scholar 

  • Kulkarni SK, Singh VP (2007) Licofelone—a novel analgesic and anti-inflammatory agent. Curr Top Med Chem 7:251–263

    Article  CAS  PubMed  Google Scholar 

  • Laufer S, Tries S, Augustin J, Dannhardt G (1994) Pharmacological profile of a new pyrrolizine derivative inhibiting the enzymes cyclo-oxygenase and 5-lipoxygenase. Arzneimittelforschung 44:629–636

    CAS  PubMed  Google Scholar 

  • Lewis RA, Austen KF, Soberman RJ (1990) Leukotrienes and other products of the 5-lipoxygenase pathway. Biochemistry and relation to pathobiology in human diseases. N Engl J Med 323:645–655

    Article  CAS  PubMed  Google Scholar 

  • Li Z, Choi DY, Shin EJ, Hunter RL, Jin CH, Wie MB et al (2008) Phenidone protects the nigral dopaminergic neurons from LPS-induced neurotoxicity. Neurosci Lett 445:1–6

    Article  CAS  PubMed  Google Scholar 

  • Martel-Pelletier J, Lajeunesse D, Reboul P, Pelletier JP (2003) Therapeutic role of dual inhibitors of 5-LOX and COX, selective and non-selective non-steroidal anti-inflammatory drugs. Ann Rheum Dis 62:501–509

    Article  CAS  PubMed  Google Scholar 

  • Mosley RL, Benner EJ, Kadiu I, Thomas M, Boska MD, Hasan K et al (2006) Neuroinflammation, oxidative stress and the pathogenesis of Parkinson’s disease. Clin Neurosci Res 6:261–281

    Article  CAS  PubMed  Google Scholar 

  • Mosmann T (1983) Rapid colorimetric assay for cellular growth survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  CAS  PubMed  Google Scholar 

  • Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    Article  CAS  PubMed  Google Scholar 

  • Przedborski S, Jackson-Lewis V, Yokoyama R, Shibata T, Dawson VL, Dawson TM (1996) Role of neuronal nitric oxide in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity. Proc Natl Acad Sci USA 93:4565–4571

    Article  CAS  PubMed  Google Scholar 

  • Przybyłkowski A, Kurkowska-Jastrzebska I, Joniec I, Ciesielska A, Członkowska A (2004) Cyclooxygenases mRNA and protein expression in striata in the experimental mouse model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration to mouse. Brain Res 1019:144–151

    Article  PubMed  Google Scholar 

  • Raghavendra V, Agrewala JN, Kulkarni SK (2000) Melatonin reversal of lipopolysaccharide-induced thermal and behavioral hyperalgesia in mice. Eur J Pharmacol 395:15–21

    Article  CAS  PubMed  Google Scholar 

  • Rainsford KD (2007) Anti-inflammatory drugs in the 21st century. Subcell Biochem 42:3–27

    Article  CAS  PubMed  Google Scholar 

  • Singh A, Kulkarni SK (2002) Role of adenosine in drug-induced catatonia. Indian J Exp Biol 40:882–888

    CAS  PubMed  Google Scholar 

  • Singh VP, Patil CS, Kulkarni SK (2005) Effect of licofelone against NSAIDs-induced gastrointestinal ulceration and inflammation. Indian J Exp Biol 43:247–253

    CAS  PubMed  Google Scholar 

  • Singh VP, Patil CS, Kulkarni SK (2006) Anti-inflammatory effect of licofelone against various inflammatory challenges. Fundam Clin Pharmacol 20:65–71

    Article  CAS  PubMed  Google Scholar 

  • Slivka A, Cohen G (1985) Hydroxyl radical attack on dopamine. J Biol Chem 260:15466–15472

    CAS  PubMed  Google Scholar 

  • Smeyne RJ, Jackson-Lewis V (2005) The MPTP model of Parkinson’s disease. Brain Res Mol Brain Res 134:57–66

    Article  CAS  PubMed  Google Scholar 

  • Spina MB, Cohen G (1989) Dopamine turnover and glutathione oxidation: implications for Parkinson disease. Proc Natl Acad Sci USA 86:1398–1400

    Article  CAS  PubMed  Google Scholar 

  • Sriram K, Miller DB, O’Callaghan P (2006) Minocycline attenuates microglial activation but fails to mitigate striatal dopaminergic neurotoxicity: role of tumor necrosis factor-alpha. J Neurochem 96:706–718

    Article  CAS  PubMed  Google Scholar 

  • Teismann P, Tieu K, Choi DK, Wu DC, Naini A, Hunot S, Vila M, Jackson-Lewis V, Przedborski S (2003) Cyclooxygenase-2 is instrumental in Parkinson’s disease neurodegeneration. Proc Natl Acad Sci USA 100:5473–5478

    Article  CAS  PubMed  Google Scholar 

  • Theodore S, Cao S, McLean PJ, Standaert DG (2008) Targeted overexpression of human alphasynuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease. J Neuropathol Exp Neurol 67:1149–1158

    Article  CAS  PubMed  Google Scholar 

  • Tipton KF, Singer TP (1993) Advances in our understanding of the mechanisms of the neurotoxicity of MPTP and related compounds. J Neurochem 61:1191–1206

    Article  CAS  PubMed  Google Scholar 

  • Tries S, Laufer S (2001) The pharmacological profile of ML 3000: a new pyrrolizine derivative inhibiting the enzymes cyclooxygenase and 5-lipoxygenase. Inflammopharmacology 9:113–124

    Article  CAS  Google Scholar 

  • Tries S, Neupert W, Laufer S (2002) The mechanism of action of the new anti-inflammatory compound ML3000: inhibition of 5-LOX and COX-1/2. Inflamm Res 51:135–143

    Article  CAS  PubMed  Google Scholar 

  • Vila M, Przedborski S (2003) Targeting programmed cell death in neurodegenerative diseases. Nat Rev Neurosci 4:365–375

    Article  CAS  PubMed  Google Scholar 

  • Vila M, Ramonet D, Perier C (2008) Mitochondrial alterations in Parkinson’s disease: new clues. J Neurochem 107:317–328

    Article  CAS  PubMed  Google Scholar 

  • Wahner AD, Bronstein JM, Bordelon YM, Ritz B (2007) Nonsteroidal anti-inflammatory drugs may protect against Parkinson disease. Neurology 69:1836–1842

    Article  CAS  PubMed  Google Scholar 

  • Yokoyama H, Kuroiwa H, Yano R, Araki T (2008) Targeting reactive oxygen species, reactive nitrogen species and inflammation in MPTP neurotoxicity and Parkinson’s disease. Neurol Sci 29:293–301

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The study is supported by the research grant of Council of Scientific and Industrial Research (CSIR), New Delhi and Amit Gupta is a Senior Research Fellow under the project.

Author information

Authors and Affiliations

  1. Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Center of Advanced Study (UGC-CAS), Punjab University, Chandigarh, 160014, India

    Amit Gupta, Anil Kumar & S. K. Kulkarni

Authors
  1. Amit Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anil Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. K. Kulkarni
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. K. Kulkarni.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gupta, A., Kumar, A. & Kulkarni, S.K. Licofelone attenuates MPTP-induced neuronal toxicity: behavioral, biochemical and cellular evidence. Inflammopharmacol 18, 223–232 (2010). https://doi.org/10.1007/s10787-010-0052-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10787-010-0052-6

Keywords

Search

Navigation