Evaluation of neuroprotective effect of flupirtine in brain of albino rats

Elango P, Darling Chellathai, Saravana Babu


Background: Flupirtine (FP) is found to antagonize both glutamate and N methyl, D aspartate (NMDA) and the current study was undertaken to elucidate a possible neuroprotective role of flupirtine against NMDA induced neurotoxicity in experimental rat model.

Methods: Excitotoxicty was produced in rat and it is counteracted by flupirtine. The animals were grouped as Group 1 (vehicle treated), Group 2 (received NMDA+vehicle), Group 3 (received FP+NMDA only), and Group 4 (received FP+vehicle) and were observed of animal behavior and oxidative stress biomarkers and also mRNA expression using reverse transcriptase-polymerase chain reaction (PCR PCR) was performed to determine the level of mRNA expression of acetyl cholinesterase (AChE) and muscarinic cholinergic receptor (MChR) in brain samples (hippocampus) of experimental animals.

Results: Depression effect induced by NMDA was reversed by flupirtine. Decrease in oxidative stress bio-markers associated with increase in the antioxidant enzyme activities in group 3 and 4 compared to group 1 and 2. Gene expression were up-regulated in group 2 compared to 1, 3 and 4. Flupritine treatment reversed these alterations.

Conclusions: This study represents the neuroprotective characteristics of flupiritne against the excitotoxicity induced by NMDA in an in vivo rat models.


Flupirtine, NMDA, Malondialdehyde, Glutathione, mRNA, AChE, MChR

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Nakanishi S. Molecular diversity of glutamate receptors and implications for brain function. Science. 1992;258(5082):597-603.

Siman R, Noszek JC. Excitatory amino acids activate calpain and induce structural protein breakdown in vivo. Neuron. 1988;1(4):279-87.

Xifro X, Garcia-Martinez JM, Del Toro D, Alberch J, Perez-Navarro E. Calcineurin is involved in the early activation of NMDA-mediated cell death in mutant huntingtin knock-in striatal cells. J Neurochem. 2008;105(5):1596-612.

Chang YC, Kim HW, Rapoport SI, Rao JS. Chronic NMDA administration increases neuroinflammatory markers in rat frontal cortex: cross-talk between excitotoxicity and neuroinflammation. Neurochem Res. 2008,33(11):2318-23.

Weichel O, Hilgert M, Chatterjee SS, Lehr M, Klein J. Bilobalide, a constituent of Ginkgo biloba, inhibits NMDA-induced phospholipase A2 activation and phospholipid breakdown in rat hippocampus. Naunyn Schmiedebergs Arch Pharmacol. 1999;360(6):609-15.

Rao JS, Ertley RN, Rapoport SI, Bazinet RP, Lee HJ. Chronic NMDA administration to rats up-regulates frontal cortex cytosolic phospholipase A2 and its transcription factor, activator protein-2. J Neurochem. 2007;102(6):1918-27.

Monaghan DT, Cotman CW. Distribution of N-methyl-D-aspar-tate-sensitive L-[3H]glutamate-binding sites in rat brain. J Neurosci 1985;5(11):2909-19.

Tilleux S, Hermans E. Neuroinflammation and regulation of glial glutamate uptake in neurological disorders. J Neurosci Res. 2007;85(10):2059-70.

Fang M, Li J, Tiu SC, Zhang L, Wang M, Yew DT: N-methyl-D- aspartate receptor and apoptosis in Alzheimer's disease and multiinfarct dementia. J Neurosci Res. 2005;81(2):269-74.

Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, et al. Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci. 2005;8(8):1051-8.

Hallett PJ, Dunah AW, Ravenscroft P, Zhou S, Bezard E, Crossman AR, Brotchie JM, Standaert DG. Alterations of striatal NMDA receptor subunits associated with the development of dyskinesia in the MPTP-lesioned primate model of Parkinson's disease. Neuropharmacology. 2005;48(4):503-16.

Young AB, Greenamyre JT, Hollingsworth Z, Albin R, D'Amato C,Shoulson I, Penney JB. NMDA receptor losses in putamen from patients with Huntington's disease. Science. 1988;241(4868):981-3.

Mueller HT, Meador-Woodruff JH. NR3A NMDA receptor subunit mRNA expression in schizophrenia, depression and bipolar disorder. Schizophr Res. 2004,71(2-3):361-70.

Basselin M, Chang L, Bell JM, Rapoport SI. Chronic lithium chloride administration attenuates brain NMDA receptor-initiated signaling via arachidonic acid in unanesthetized rats. Neuropsychopharmacology. 2006,31(8):1659-74.

Basselin M, Villacreses NE, Chen M, Bell JM, Rapoport SI. Chronic carbamazepine administration reduces N-methyl-D-aspartate receptor-initiated signaling via arachidonic acid in rat brain. Biol Psychiatry. 2007,62(8):934-43.

Clinton SM, Meador-Woodruff JH: Abnormalities of the NMDA receptor and associated intracellular molecules in the thalamus in schizophrenia and bipolar disorder. Neuropsychopharmacology. 2004;29(7):1353-62.

Labuyere J, Fuller TA, Olney JW, Price MT, Zorumski C, Clifford D. Phencyclidine and ketamine protect against kainic acid-induced seizure related damage. Soc Neurosci Abstr. 1986;12:344.

Boast CA, Gerhardt SC, Pastor G., Lehmann J, Etienne PE, Liebman, JM. The N-methyl-D-aspartate antagonist CGS19755 and CPP reduce ischemic brain damage in gerbils. Brain Res. 1988;442:345-8.

Gill R, Foster C, Woodruff GN. Systemic administration of MK-801 protects against ischemia-induced hippocampal neurodegeneration in the gerbil, J. Neurosci. 1987;7:3343-9.

McDonald JW, Silverstein FS, Johnston MV. MK-801 protects the neonatal brain from hypoxic-ischemic damage. Eur J Pharmacol. 1987;140:359-61.

Simon RP, Swan JH, Griffiths T, Meldrum BS. Blockade of N-methyl-D-aspartate receptors may protect against ischemic damage in the brain, Science. 1984;226:850-2.

Harish S, Bhuvana K, Bengalorkar GM, Kumar TN. Flupirtine: clinical pharmacology. J Anaesthesiol Clin Pharmacol. 2012;28(2):172-7.

Basselin M, Chang L, Bell JM, Rapoport SI. Chronic lithium chloride administration to unanesthetized rats attenuates brain dopamine D2-like receptor-initiated signaling via arachidonic acid. Neuropsychopharmacology. 2005;30(6):1064-75.

Ormandy GC, Song L, Jope RS. Analysis of the convulsant-potentiating effects of lithium in rats. Exp Neurol. 1991;111(3):356-61.

Varty GB, Morgan CA, Cohen-Williams ME, Coffin VL, Carey GJ. The gerbil elevated plus-maze i: behavioral characterization and pharmacological validation Neuropsychopharmacology. 2002;27:57-370.

Tsakiris S; Schulpis K; Marinou K, Behrakis P. Protective effect of L-cysteine and glutathione on the modulated sucking rat brain Na+, K+, ATPase and Mg2+-ATPase activities induced by the in vitro galactosaemia. Pharmacol Res. 2004;49:475-9.

Kakkar P, Das B, Viswanathan PNA. Modified spectrophotometric assay of superoxide dismutase. Ind. J Biochem Biophys. 1984;21:130-2.

Ohkawa H, Ohishi N, Yagi K. Assay of lipid peroxides in animal tissues by thio babituric acid reaction. Anal Biochem. 1979;95:351.

Moren MS, Desplerra JW, Mannervick B. Levels of glutathione, glutathione reductase and glutathione S transferase activity in rat liver and lung. Biochimica Biophysica Acta. 1979;585:67.

Allgaier C, Scheibler P, Müller D, Feuerstein TJ, Illes P. NMDA receptor characterization and subunit expression in rat cultured mesencephalic neurons. Br J Pharmacol. 1999;126(1):121-30.

Nagaraja H, Kumar P. Neuroprotective effect of Centella asiatica extract (CAE) on experimentally induced parkinsonism in aged Sprague-Dawley rats. J Toxicol Sci. 2010;35(1):41-7.

Obermeier K, Niebch G, Thiemer K. Pharmacokinetics and biotransformation of the analgesic flupirtine in the rat and dog. Arzneimittelforschung. 1985;35:60-7.

Hlavica P, Niebch G. Pharmacokinetics and biotransformation of the analgesic flupirtine in humans. Arzneimittelforschung. 1985;35:67-4.

Li C, Ni J, Wang Z, Li M, Gasparic M, Terhaag B, Uberall MA. Analgesic efficacy and tolerability of flupirtine vs. tramadol in patients with subacute low back pain: a double-blind multicentre trial. Curr Med Res Opin. 2008;24:3523-30.

Perovic S, Schröder HC, Pergande G, Ushijima H, Müller WE. Effect of flupirtine on Bcl-2 and glutathione level in neuronal cells treated in vitro with the prion protein fragment (PrP106-126). Exp Neurol. 1997;147:518-24.

Perovic S, Böhm M, Meesters E, Meinhardt A, Pergande G, Müller WE. Pharmacological intervention in age-associated brain disorders by Flupirtine: Alzheimer’s and prion diseases. Mech Ageing Dev. 1998;101:1-19.

Müller WE, Romero FJ, Perovic S, Pergande G, Pialoglou P. Protection of flupirtine on beta-amyloid-induced apoptosis in neuronal cells in vitro: prevention of amyloid-induced glutathione depletion. J Neurochem. 1997;68:2371-7.

Block F, Schwarz M, Sontag KH. Retinal ischemia induced by occlusion of both common carotid arteries in rats as demonstrated by electroretinography. Neurosci Lett. 1992;144:124-6.

Rupalla K, Cao W, Krieglstein J. Flupirtine protects neurons against excitotoxic or ischemic damage and inhibits the increase in cytosolic Ca2+ concentration. Eur J Pharmacol. 1995;294:469-73.

Sättler MB, Williams SK, Neusch C, Otto M, Pehlke JR, Bähr M, et al. Flupirtine as neuroprotective add-on therapy in autoimmune optic neuritis. Am J Pathol. 2008;173:1496-1507.

Panchanathan E, Ramanathan G, Lakkakula BV. Effect of flupirtine on the growth and viability of U373 malignant glioma cells. Cancer Biol Med. 2013;10:142-7.

Harish S, Bhuvana K, Bengalorkar GM, Kumar T. Flupirtine: clinical pharmacology. J Anaesthesiol Clin Pharmacol. 2012;28:172-7.