Abstract
Rationale
Clitoria ternatea, commonly known as Aparajita, is used as Medhya rasayana in Ayurveda. The role of C. ternatea in experimental models of cognitive impairment is yet to be explored.
Objectives
The present study was designed to study the effect of aqueous and hydroalcoholic extracts of C. ternatea on biochemical and behavioral parameters related to cognitive impairment in in vitro and in vivo studies.
Methods
In vitro free radical scavenging and enzyme-inhibitory (cholinesterase, glycogen synthase kinase-3-β, rho kinase, prolyl endopeptidase, catechol-O-methyl transferase, and lipoxygenase) activities of aqueous and hydroalcoholic extracts of C. ternatea plant were evaluated. Based on in vitro results, hydroalcoholic extract of C. ternatea (100, 300, and 500 mg/kg, p.o.) was selected for evaluation in intracerebroventricularly injected streptozotocin (STZ)-induced cognitive impairment in male Wistar rats. Behavioral assessment was performed at baseline and on the 14th, 21st, and 28th days after STZ injection using elevated plus maze, passive avoidance, Morris water maze, and photoactometer. Oxidative stress parameters (malondialdehyde, reduced glutathione, nitric oxide levels, and superoxide dismutase activity), cholinesterase activity, and rho kinase (ROCK II) expression were studied in cerebral cortex and hippocampus of rats' brain at the end of the study.
Results
The hydroalcoholic extract possessed significantly more in vitro antioxidant and enzyme-inhibitory activities as compared to aqueous extract. The hydroalcoholic extract of C. ternatea prevented STZ-induced cognitive impairment dose dependently by reducing oxidative stress, cholinesterase activity, and ROCK II expression.
Conclusion
In vitro and in vivo results suggest the potential of hydroalcoholic extract of C. ternatea for treatment of cognitive deficit in neurological disorders.
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References
Agrawal R, Mishra B, Tyagi E, Nath C, Shukla R (2010) Effect of curcumin on brain insulin receptors and memory functions in STZ (ICV) induced dementia model of rat. Pharmacol Res 61:247–252
Ando S, Ohashi Y (1991) Longitudinal study on age-related changes of working and reference memory in the rat. Neurosci Lett 128:17–20
Auddy B, Ferreira M, Blasina F, Lafon L, Arredondo F, Dajas F, Tripathi PC, Seal T, Mukherjee B (2003) Screening of antioxidant activity of three Indian medicinal plants, traditionally used for the management of neurodegenerative diseases. J Ethnopharmacol 84:131–138
Awasthi H, Tota S, Hanif K, Nath C, Shukla R (2010) Protective effect of curcumin against intracerebral streptozotocin induced impairment in memory and cerebral blood flow. Life Sci 86:87–94
Blokland A, Jolles J (1994) Behavioral and biochemical effects of an ICV injection of streptozotocin in old Lewis rats. Pharmacol Biochem Behav 47:833–837
Chong ZZ, Li F, Maiese K (2005) Stress in the brain: novel cellular mechanisms of injury linked to Alzheimer's disease. Brain Res Rev 49:1–21
Daisy P, Santosh K, Rajathi M (2009) Antihyperglycemic and antihyperlipidemic effects of Clitoria ternatea Linn. in alloxan-induced diabetic rats. Afr J Microbiol Res 3:287–291
Dávalos A, Gómez-Cordovés C, Bartolomé B (2004) Extending applicability of the oxygen radical absorbance capacity (ORAC-fluorescein) assay. J Agric Food Chem 52:48–54
Di Matteo V, Esposito E (2003) Biochemical and therapeutic effects of antioxidants in the treatment of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Curr Drug Targets CNS Neurol Disord 2:95–107
Doody RS, Dunn JK, Clark CM, Farlow M, Foster NL, Liao T, Gonzales N, Lai E, Massman P (2001) Chronic donepezil treatment is associated with slowed cognitive decline in Alzheimer's disease. Dement Geriatr Cogn Disord 12:295–300
Ellis JM (2005) Cholinesterase inhibitors in the treatment of dementia. J Am Osteopath Assoc 105:145–158
Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77
Ellman G, Courtney D, Andres V (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95
Firuzi O, Zhuo J, Chinnici CM, Wisniewski T, Praticò D (2008) 5-Lipoxygenase gene disruption reduces amyloid-beta pathology in a mouse model of Alzheimer's disease. FASEB J 22:1169–1178
Geber M, Boutron-Ruault MC, Hercberg S, Riboli E, Scalbert A, Siess MH (2002) Food and cancer: state of the art about the protective effect of fruits and vegetables. Bull cancer 89:293–312
Glowinski J, Iversen LL (1966) Regional studies of catecholamines in the rat brain—I. The disposition of [3H] norepinephrine, [3H] dopamine and [3H] dopa in various regions of the brain. J Neurochem 13:655–670
Goodman Y, Steiner MR, Steiner SM, Mattson MP (1994) Nordihydroguaiaretic acid protects hippocampal neurons against amyloid beta-peptide toxicity, and attenuates free radical and calcium accumulation. Brain Res 654:171–176
Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Anal Biochem 126:131–138
Halliwell B, Gutteridge JMC (1999) Free radicals in biology and medicine, 3rd edn. Oxford University Press, Oxford
Hanish Singh JC, Alagarsamy V, Diwan PV, Sathesh Kumar S, Nisha JC, Narsimha Reddy Y (2011) Neuroprotective effect of Alpinia galanga (L.) fractions on Aβ(25–35) induced amnesia in mice. J Ethnopharmacol 138:85–91
Herholz K (2008) Acetylcholine esterase activity in mild cognitive impairment and Alzheimer's disease. Eur J Nucl Med Mol Imaging 35:S25–S29
Hou Y, Zhou L, Yang QD, Du XP, Li M, Yuan M, Zhou ZW (2012) Changes in hippocampal synapses and learning-memory abilities in a streptozotocin-treated rat model and intervention by using fasudil hydrochloride. Neuroscience 200:120–129
Huang L, He Z, Guo L, Wang H (2008) Improvement of cognitive deficit and neuronal damage in rats with chronic cerebral ischemia via relative long-term inhibition of rho-kinase. Cell Mol Neurobiol 28:757–768
Ishrat T, Khan MB, Hoda MN, Yousuf S, Ahmad M, Ansari MA, Ahmad AS, Islam F (2006) Coenzyme Q10 modulates cognitive impairment against intracerebro-ventricular infusion of streptozotocin in rats. Behav Brain Res 171:9–16
Jain NN, Ohal CC, Shroff SK, Bhutada RH, Somani RS, Kasture VS, Kasture SB (2003) Clitoria ternatea and the CNS. Pharmacol Biochem Behav 75:529–536
Jung HA, Min BS, Yokozawa T, Lee JH, Kim YS, Choi JS (2009) Anti-Alzheimer and antioxidant activities of Coptidis Rhizoma alkaloids. Biol Pharm Bull 32:1433–1438
Kamkaen N, Wilkinson JM (2009) The antioxidant activity of Clitoria ternatea flower petal and eye gel. Phytother Res 23:1624–1635
Kato A, Fukunari A, Yoko S, Tohru N (1997) Prevention of amyloid-like deposition by a selective prolyl endopeptidase inhibitor, Y-29794, in senescence-accelerated mouse. J Pharmacol Exp Ther 283:328–335
Kato T, Nakano T, Kojima K, Nagatsu T, Sakakibara S (1980) Changes in prolyl endopeptidase during maturation of rat brain and hydrolysis of substance P by the purified enzyme. J Neurochem 35:527–535
Kaur C, Kapoor HC (2002) Antioxidant activity and total phenolic content of some Asian vegetables. Int J Food Sci Tech 37:153–162
Kobayashi W, Miyase T, Sano M, Umehara K, Warashina T, Noguchi H (2002) Prolyl endopeptidase inhibitors from the roots of Lindera strychnifolia F. Vill. Biol Pharm Bull 25:1049–1052
Kooy NW, Royall JA, Ischiropoulos H, Beckman JS (1994) Peroxynitrite-mediated oxidation of dihydrorhodamine 123. Free Radic Biol Med 16:149–156
Kris-Etherton PM, Hecker KD, Bonanome A, Coval SM, Binkosi AE, Hilpert KF (2002) Bioactive compounds in foods: their role in the prevention of cardiovascular disease and cancer. Am J Med 113:71S–88S
Kurkela M, Siskonen A, Finel M, Tammela P, Taskinen J, Vuorela P (2004) Microplate screening assay to identify inhibitors of human catechol-O-methyltransferase. Anal Biochem 331:198–200
Lannert H, Hoyer S (1998) Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci 112:1199–1208
Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de la Monte SM (2006) Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer's disease. J Alzheimers Dis 9:13–33
Lee YJ, Choi DY, Han SB, Kim YH, Kim KH, Hwang BY, Kang JK, Lee BJ, Oh KW, Hong JT (2012) Inhibitory effect of ethanol extract of Magnolia officinalis on memory impairment and amyloidogenesis in a transgenic mouse model of Alzheimer's disease via regulating β-secretase activity. Phytother Res 26:1884–1892
Liu R, Liu IY, Bi X, Thompson RF, Doctrow SR, Malfroy B, Baudry M (2001) Reversal of age-related learning deficits and brain oxidative stress in mice with superoxide dismutase/catalase mimetics. Proc Natl Acad Sci USA 100:8526–8531
Mahdy K, Shaker O, Wafay H, Nassar Y, Hassan H, Hussein A (2012) Effect of some medicinal plant extracts on the oxidative stress status in Alzheimer's disease induced in rats. Eur Rev Med Pharmacol Sci 16:31–42
Marklund S, Marklund G (1974) Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 47:469–474
Masuda M, Tsunoda M, Imai K (2006) Low catechol-O-methyltransferase activity in the brain and blood pressure regulation. Biol Pharm Bull 29:202–205
Maxwell SRJ (1995) Prospects for the use of antioxidant therapies. Drugs 49:345–361
Mehla J, Pahuja M, Dethe SM, Agarwal A, Gupta YK (2012) Amelioration of intracerebroventricular streptozotocin induced cognitive impairment by Evolvulus alsinoides in rats: in vitro and in vivo evidence. Neurochem Int 61:1052–1064
Metodiewa D, Koska C (2000) Reactive oxygen species and reactive nitrogen species: relevance to cyto(neuro) toxic events and neurologic disorders. An overview. Neurotox Res 1:197–233
Moreira PI, Honda K, Liu Q, Alviev G, Oliveira CR, Santos MS, Zhu X, Smith MA, Perry G (2005) Alzheimer's disease and oxidative stress: the old problem remains unsolved. Curr Med Chem-CNS Agents 5:51–62
Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11:47–60
Mukherjee PK, Kumar V, Kumar NS, Heinrich M (2008) The Ayurvedic medicine Clitoria ternatea—from traditional use to scientific assessment. J Ethnopharmacol 120:291–301
Narahashi T, Moriguchi S, Zhao X, Marszalec W, Yeh JZ (2004) Mechanisms of action of cognitive enhancers on neuroreceptors. Biol Pharm Bull 27:1701–1716
Nitsch R, Hoyer S (1991) Local action of the diabetogenic drug, streptozotocin, on glucose and energy metabolism in rat brain cortex. Neurosci Lett 128:199–202
Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animals tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358
Patil AP, Patil VR (2011) Comparative evaluation of in vitro antioxidant activity of root of blue and white flowered varieties of Clitoria ternatea Linn. Int J Pharmacol 7:485–491
Portevin B, Benoist A, Remond G, Herve Y, Vincent M, Lepagnol J, De Nanteuil G (1996) New prolyl endopeptidase inhibitors: in vitro and in vivo activities of azabicyclo[2.2.2] octane, azabicyclo[2.2.1]heptane, and perhydroindole derivatives. J Med Chem 39:2379–2391
Rai KS, Murthy KD, Karanth KS, Nalini K, Rao MS, Srinivasan KK (2002) Clitoria ternatea root extract enhances acetylcholine content in rat hippocampus. Fitoterapia 73:685–689
Rai KS, Murthy KD, Karanth KS, Rao MS (2001) Clitoria ternatea (Linn) root extract treatment during growth spurt period enhances learning and memory in rats. Indian J Physiol Pharmacol 45:305–313
Reeta KH, Mehla J, Gupta YK (2009) Curcumin is protective against phenytoin-induced cognitive impairment and oxidative stress in rats. Brain Res 1301:52–60
Rodrigues L, Biasibetti R, Swarowsky A, Leite MC, Quincozes-Santos A, Quilfeldt JA, Achaval M, Gonçalves CA (2009) Hippocampal alterations in rats submitted to streptozotocin-induced dementia model are prevented by aminoguanidine. J Alzheimers Dis 17:193–202
Saini N, Singh D, Sandhir R (2012) Neuroprotective effects of Bacopa monnieri in experimental model of dementia. Neurochem Res 37:1928–1937
Salazar R, Pozos ME, Cordero P, Perez J, Salinas MC, Waksman N (2008) Determination of the antioxidant activity of plants from Northeast Mexico. Pharm Biol 46:166–170
Sehgal N, Gupta A, Valli RK, Joshi SD, Mills JT, Hamel E, Khanna P, Jain SC, Thakur SS, Ravindranath V (2012) Withania somnifera reverses Alzheimer's disease pathology by enhancing low-density lipoprotein receptor-related protein in liver. Proc Natl Acad Sci USA 109:3510–3515
Sharma M, Gupta YK (2001) Effect of chronic treatment of melatonin on learning, memory and oxidative deficiencies induced by intracerebroventricular streptozotocin in rats. Pharmacol Biochem Behav 70:325–331
Sharma M, Gupta YK (2003) Effect of alpha lipoic acid on intracerebroventricular streptozotocin model of cognitive impairment in rats. Eur Neuropsychopharmacol 13:241–247
Shinde UA, Kulkarni KR, Phadke AS, Nair AM, Mungantiwar AA, Dikshit VJ, Saraf MN (1999) Mast cell stabilizing and lipoxygenase inhibitory activity of Cedrus deodara (Roxb.) Loud. wood oil. Indian J Exp Biol 37:258–261
Shytle RD, Tan J, Bickford PC, Rezai-Zadeh K, Hou L, Zeng J, Sanberg PR, Sanberg CD, Alberte RS, Fink RC, Roschek B Jr (2012) Optimized turmeric extract reduces β-amyloid and phosphorylated tau protein burden in Alzheimer's transgenic mice. Curr Alzheimer Res 9:500–506
Singleton VL, Jr R (1965) Colorimetry of total phenolics with phosphomolybdic phosphotungstic acid reagents. Am J Enol Viticult 16:144–158
Solanki YB, Jain SM (2010) Antihyperlipidemic activity of Clitoria ternatea and Vigna mungo in rats. Pharm Biol 48:915–923
Sweet RA, Devlin B, Pollock BG, Sukonick DL, Kastango KB, Bacanu SA, Chowdari KV, DeKosky ST, Ferrell RE (2005) Catechol-O-methyl transferase haplotypes are associated with psychosis in Alzheimer's disease. Mol Psychiatry 10:1026–1036
Takashima A, Honda T, Yasutake K, Michel G, Murayama O, Murayama M, Ishiguro K, Yamaguchi H (1998) Activation of tau protein kinase I/glycogen synthase kinase-3beta by amyloid beta peptide (25–35) enhances phosphorylation of tau in hippocampal neurons. Neurosci Res 31:317–323
Taranalli AD, Cheeramkhuzhy TC (2000) Influence of Clitoria ternatea extracts on memory and central cholinergic activity in rats. Pharm Biol 38:51–56
Toide K, Iwamoto Y, Fujiwara T, Abe H (1995) JTP-4819, a novel PEP inhibitor with potential as cognitive enhancer. J Pharmacol Exp Ther 274:1370–1378
Tota S, Awasthi H, Kamat PK, Nath C, Hanif K (2010) Protective effect of quercetin against intracerebral streptozotocin induced reduction in cerebral blood flow and impairment of memory in mice. Behav Brain Res 209:73–79
Tota S, Kamat PK, Awasthi H, Singh N, Raghubir R, Nath C, Hanif K (2009) Candesartan improves memory decline in mice: involvement of AT1 receptors in memory deficit induced by intracerebral streptozotocin. Behav Brain Res 199:235–240
Tota S, Kamat PK, Saxena G, Hanif K, Najmi AK, Nath C (2012) Central angiotensin converting enzyme facilitates memory impairment in intracerebroventricular streptozotocin treated rats. Behav Brain Res 226:317–330
Tuppo EE, Arias HR (2005) The role of inflammation in Alzheimer's disease. Int J Biochem Cell Biol 37:289–305
Veerendra Kumar MH, Gupta YK (2003) Effect of Centella asiatica on cognition and oxidative stress in an intracerebroventricular streptozotocin model of Alzheimer's disease in rats. Clin Exp Pharmacol Physiol 30:336–342
Zhishen J, Mengcheng T, Jianming W (1999) The determination of flavonoid contents in mulberry and their scavenging effects on superoxide radicals. Food Chem 64:555–559
Zhou Y, Su Y, Li B, Liu F, Ryder JW, Wu X, Gonzalez-De Whitt PA, Gelfanova V, Hale JE, May PC, Paul SM, Ni B (2003) Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Abeta42 by inhibiting Rho. Science 302:1215–1217
Zhu BT, Wang P, Nagai M, Wen Y, Bai HW (2009) Inhibition of human catechol-O-methyltransferase (COMT)-mediated O-methylation of catechol estrogens by major polyphenolic components present in coffee. J Steroid Biochem Mol Biol 113:65–74
Acknowledgments
The authors are thankful to the Council of Scientific & Industrial Research, New Delhi, India, for providing financial assistance (9/6(434)/2011 EMR-I) to Jogender Mehla for carrying out this research work under the guidance of Prof. Y.K. Gupta.
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Mehla, J., Pahuja, M., Gupta, P. et al. Clitoria ternatea ameliorated the intracerebroventricularly injected streptozotocin induced cognitive impairment in rats: behavioral and biochemical evidence. Psychopharmacology 230, 589–605 (2013). https://doi.org/10.1007/s00213-013-3185-7
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DOI: https://doi.org/10.1007/s00213-013-3185-7