Cognitive Neurodynamics

, Volume 11, Issue 1, pp 35–49 | Cite as

Pterostilbene ameliorates intracerebroventricular streptozotocin induced memory decline in rats

  • Bhagyashree Naik
  • Abhijit Nirwane
  • Anuradha Majumdar
Research Article


There is strong evidence that mitochondrial dysfunction mediated oxidative stress results in aging and energy metabolism deficits thus playing a prime role in pathogenesis of Alzheimer’s disease, neuronal death and cognitive dysfunction. Evidences accrued in empirical studies suggest the antioxidant, anticancer and anti-inflammatory activities of the phytochemical pterostilbene (PTS). PTS also exhibits favourable pharmacokinetic attributes compared to other stilbenes. Hence, in the present study, we explored the neuroprotective role of PTS in ameliorating the intracerebroventricular administered streptozotocin (STZ) induced memory decline in rats. PTS at doses of 10, 30 and 50 mg/kg, was administered orally to STZ administered Sprague–Dawley (SD) rats. The learning and memory tests, Morris water maze test and novel object recognition test were performed which revealed improved cognition on PTS treatment. Further, there was an overall improvement in brain antioxidant parameters like elevated catalase and superoxide dismutase activities, GSH levels, lowered levels of nitrites, lipid peroxides and carbonylated proteins. There was improved cholinergic transmission as evident by decreased acetylcholinesterase activities. The action of ATPases (Na+ K+, Ca2+ and Mg2+) indicating the maintenance of cell membrane potential was also augmented. mRNA expression of battery of genes involved in cellular mitochondrial biogenesis and inflammation showed variations which extrapolate to hike in mitochondrial biogenesis and abated inflammation. The histological findings corroborated the effective role of PTS in countering STZ induced structural aberrations in brain.


Pterostilbene Streptozotocin Fenofibrate Brain Learning and memory Inflammation AChE ATPases Protein carbonylation PPARα PGC1α TNF-α IL-6 Rats 


  1. Abdalla B, Bisharat B, Abir M et al (2012) Traditional and modern medicine harmonizing the two approaches in the treatment of neurodegeneration (Alzheimer’s disease-AD). Complementary Therapies for the Contemporary Healthcare: Intech, pp 181–212Google Scholar
  2. Acharya JD, Ghaskadbi SS (2013) Protective effect of Pterostilbene against free radical mediated oxidative damage. Complement Altern Med 13:238CrossRefGoogle Scholar
  3. Aebi H, Scherz B, Ben-Yoseph Y et al (1975) Dissociation of erythrocyte catalase into subunits and their re-association. Experientia 31:397–399CrossRefPubMedGoogle Scholar
  4. Ahmed ME, Khan MM, Javed H et al (2013) Amelioration of cognitive impairment and neurodegeneration by catechin hydrate in rat model of streptozotocin-induced experimental dementia of Alzheimer’s type. Neurochem Int 62:492–501CrossRefGoogle Scholar
  5. Amenta F, Di Tullio MA, Tomassoni D (2002) The cholinergic approach for the treatment of vascular dementia: evidence from pre-clinical and clinical studies. Clin Exp Hypertens 24:697–713CrossRefPubMedGoogle Scholar
  6. Awasthi H, Tota S, Hanif K et al (2010) Protective effect of curcumin against intracerebral streptozotocin induced impairment in memory and cerebral blood flow. Life Sci 86:87–94CrossRefPubMedGoogle Scholar
  7. Bhaskaran S, Vishwaraman M (2009) process for obtaining purified Pterostilbene and methods of use thereof. US patent 20110144053 2009 July 30Google Scholar
  8. Buege JA, Aust SD (1978) Microsomal lipid peroxidation. Methods Enzymol 52:302–310CrossRefPubMedGoogle Scholar
  9. Carlini VP (2011) The object recognition task: a new proposal for the memory performance study. Intech. doi: 10.5772/14667 Google Scholar
  10. Castegna A, Drake J, Pocernich C et al (2003) Protein carbonyl levels—an assessment of protein oxidation. In: Hensley K, Floyd RA (eds) Methods in biological oxidative stress. Humana Press Inc., Totowa, NJ, pp 161–168CrossRefGoogle Scholar
  11. Castellani R, Hirai K, Aliev G et al (2002) Role of mitochondrial dysfunction in Alzheimer’s disease. J Neurosci Res 70:357–360CrossRefPubMedGoogle Scholar
  12. Chakravarthy MV, Zhu Y, López M et al (2007) Brain fatty acid synthase activates PPARα to maintain energy homeostasis. J Clin Invest 117:2539–2552CrossRefPubMedPubMedCentralGoogle Scholar
  13. Chang J, Rimando A, Pallas M et al (2012) Low-dose pterostilbene, but not resveratrol, is a potent neuromodulator in aging and Alzheimer’s disease. Neurobiol Aging 33:2062–2071CrossRefPubMedGoogle Scholar
  14. Chartier-Harlin MC, Crawford F, Hamandi K et al (1991) Screening for the β-amyloid precursor protein mutation (APP717: Val → Ile) in extended pedigrees with early onset Alzheimer’s disease. Neurosci Lett 129:134–135CrossRefPubMedGoogle Scholar
  15. Chew LJ, Takanohashi A, Bell M (2006) Microglia and inflammation: impact on developmental brain injuries. Ment Retard Dev Disabil Res Rev 12:105–112CrossRefPubMedGoogle Scholar
  16. Dalle-Donne I, Aldini G, Carini M et al (2006) Protein carbonylation, cellular dysfunction, and disease progression. J Cell Mol Med 10:389–406CrossRefPubMedGoogle Scholar
  17. Drolet G, Laforest S, Bédard PJ et al (2009) Progress in neuro-psychopharmacology & biological psychiatry. Elsevier: Amsterdam 33:1289–1586Google Scholar
  18. Duthey B (2013) Background paper 6.11: Alzheimer disease and other dementias. A public health approach to innovation. Accessed 8 Jun 2014
  19. Ellman GL, Courtney K, Andres V et al (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95CrossRefPubMedGoogle Scholar
  20. Farovik A, Dupont LM, Eichenbaum H (2010) Distinct roles for dorsal CA3 and CA1 in memory for sequential nonspatial events. Learn Mem 17:12–17CrossRefPubMedPubMedCentralGoogle Scholar
  21. Feige JN, Gelman L, Michalik L et al (2006) From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Prog Lipid Res 45:120–159CrossRefPubMedGoogle Scholar
  22. Fidaleo M, Fanelli F, Paola Ceru M et al (2014) Neuroprotective properties of peroxisome proliferator-activated receptor alpha (PPARα) and its lipid ligands. Curr Med Chem 21:2803–2821CrossRefPubMedGoogle Scholar
  23. Fiske CH, Subbarow Y (1925) The colorimetric determination of phosphorus. J Biol Chem 66:375–400Google Scholar
  24. Geula C (1998) Abnormalities of neural circuitry in Alzheimer’s disease Hippocampus and cortical cholinergic innervation. Neurol 51:S18–S29CrossRefGoogle Scholar
  25. Ghosh A, Jana M, Modi K et al (2015) Activation of peroxisome proliferator-activated receptor α induces lysosomal biogenesis in brain cells implications for lysosomal storage disorders. J Biol Chem 290:10309–10324CrossRefPubMedPubMedCentralGoogle Scholar
  26. Gibson G, Blass J (1976) Impaired synthesis of acetylcholine in brain accompanying mild hypoxia and hypoglycemia. J Neurochem 27:37–42CrossRefPubMedGoogle Scholar
  27. Greco SJ, Bryan KJ, Sarkar S et al (2010) Leptin reduces pathology and improves memory in a transgenic mouse model of Alzheimer’s disease. J Alzheimers Dis 19:1155PubMedPubMedCentralGoogle Scholar
  28. Green LC, Wagner DA, Glogowski J et al (1982) Analysis of nitrate, nitrite, and [15 N] nitrate in biological fluids. Anal Biochem 126:131–138CrossRefPubMedGoogle Scholar
  29. Grieb P (2015) Intracerebroventricular streptozotocin injections as a model of Alzheimer’s disease: in search of a relevant mechanism. Mol Neurobiol 53:1–12Google Scholar
  30. Grover J, Vats V, Yadav S (2005) Pterocarpus marsupium extract (Vijayasar) prevented the alteration in metabolic patterns induced in the normal rat by feeding an adequate diet containing fructose as sole carbohydrate. Diab Obes Metab 7:414–420CrossRefGoogle Scholar
  31. Harman D (1992) Free radical theory of aging. Mutat Res DNAging 275:257–266CrossRefGoogle Scholar
  32. Hartree EF (1972) Determination of protein: a modification of the Lowry method that gives a linear photometric response. Anal Biochem 48:422–427CrossRefPubMedGoogle Scholar
  33. Hjertén S, Pan H (1983) Purification and characterization of two forms of a low-affinity Ca 2 + -ATPase from erythrocyte membranes. BBA Biomembr 728:281–288CrossRefGoogle Scholar
  34. Hou Y, Xie G, Miao F et al (2014) Pterostilbene attenuates lipopolysaccharide-induced learning and memory impairment possibly via inhibiting microglia activation and protecting neuronal injury in mice. Prog Neuro Psychopharmacol Biol Psych 54:92–102CrossRefGoogle Scholar
  35. Ishrat T, Hoda MN, Khan MB et al (2009) Amelioration of cognitive deficits and neurodegeneration by curcumin in rat model of sporadic dementia of Alzheimer’s type (SDAT). Eur Neuropsychopharmacol 19:636–647CrossRefPubMedGoogle Scholar
  36. Javed H, Khan M, Ahmad A et al (2012) Rutin prevents cognitive impairments by ameliorating oxidative stress and neuroinflammation in rat model of sporadic dementia of Alzheimer type. Neurosci 210:340–352CrossRefGoogle Scholar
  37. Jollow D, Mitchell J, Zampaglione N et al (1974) Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3,4-bromobenzene oxide as the hepatotoxic metabolite. Pharmacol 11:151–169CrossRefGoogle Scholar
  38. Jones RW (2003) Have cholinergic therapies reached their clinical boundary in Alzheimer’s disease? Int J Geriatr Psychiatry 18:S7–S13CrossRefPubMedGoogle Scholar
  39. Joseph J, Fisher D, Bielinski D (2006) Blueberry extract alters oxidative stress-mediated signaling in COS-7 cells transfected with selectively vulnerable muscarinic receptor subtypes. J Alzheimers Dis 9:35–42PubMedGoogle Scholar
  40. Joseph JA, Rimando AM, Shukitt-Hale B (2008) Method to ameliorate oxidative stress and improve working memory via pterostilbene administration. US patent WO2009032870 A3Google Scholar
  41. Kapetanovic IM, Muzzio M, Huang Z et al (2011) Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats. Cancer Chemother Pharmacol 68:593–601CrossRefPubMedGoogle Scholar
  42. Karasawa J, Hashimoto K, Chaki S (2008) D-Serine and a glycine transporter inhibitor improve MK-801-induced cognitive deficits in a novel object recognition test in rats. Behav Brain Res 186:78–83CrossRefPubMedGoogle Scholar
  43. Kosaraju J, Madhunapantula SV, Chinni S et al (2014) Dipeptidyl peptidase-4 inhibition by Pterocarpus marsupium and Eugenia jambolana ameliorates streptozotocin induced Alzheimer’s disease. Behav Brain Res 267:55–65CrossRefPubMedGoogle Scholar
  44. Kuijpers W, Bonting S (1970) The cochlear potentials. Pflugers Archiv 320:348–358CrossRefPubMedGoogle Scholar
  45. 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 112:1199CrossRefPubMedGoogle Scholar
  46. Lester-Coll N, Rivera EJ, Soscia SJ et al (2006) Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer’s disease. J Alzheimers Dis 9:13–33PubMedGoogle Scholar
  47. Li L, Zhang ZF, Holscher C et al (2012) (Val 8) glucagon-like peptide-1 prevents tau hyperphosphorylation, impairment of spatial learning and ultra-structural cellular damage induced by streptozotocin in rat brains. Eur J Pharmacol 674:280–286CrossRefPubMedGoogle Scholar
  48. Manickam M, Ramanathan M, Farboodniay Jahromi M et al (1997) Antihyperglycemic activity of phenolics from Pterocarpus marsupium. J Nat Prod 60:609–610CrossRefPubMedGoogle Scholar
  49. Mariani E, Polidori M, Cherubini A et al (2005) Oxidative stress in brain aging, neurodegenerative and vascular diseases: an overview. J Chromatogr B 827:65–75CrossRefGoogle Scholar
  50. McFadden D (2013) A review of pterostilbene antioxidant activity and disease modification. Oxid Med Cell Longev 2013:1–15Google Scholar
  51. Mehla J, Pahuja M, Gupta P et al (2013) Clitoria ternatea ameliorated the intracerebroventricularly injected streptozotocin induced cognitive impairment in rats: behavioral and biochemical evidence. Psychopharmacol 230:589–605CrossRefGoogle Scholar
  52. Meraz Ríos MA, Toral Rios D, Franco Bocanegra D et al (2013) Inflammatory process in Alzheimer’s disease. Front Integr Neurosci 7:741–749CrossRefGoogle Scholar
  53. Misra HP, Fridovich I (1972) The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem 247:3170–3175PubMedGoogle Scholar
  54. Moreira PI, Duarte AI, Santos MS et al (2009) An integrative view of the role of oxidative stress, mitochondria and insulin in Alzheimer’s disease. J Alzheimers Dis 16:741PubMedGoogle Scholar
  55. Moreira PI, Carvalho C, Zhu X et al (2010) Mitochondrial dysfunction is a trigger of Alzheimer’s disease pathophysiology. Biochim Biophysica Acta Mol Basis Dis 1802:2–10CrossRefGoogle Scholar
  56. Moreno S, Cerù MP (2015) In search for novel strategies towards neuroprotection and neuroregeneration: is PPARα a promising therapeutic target? Neural Regen Res 10:1409CrossRefPubMedPubMedCentralGoogle Scholar
  57. Naderali EK, Ratcliffe SH, Dale MC (2009) Review: obesity and Alzheimer’s disease: a link between body weight and cognitive function in old age. Am J Alzheimers Dis Dementias 24:445–449CrossRefGoogle Scholar
  58. Ohnishi T, Suzuki T, Suzuki Y et al (1982) A comparative study of plasma membrane Mg2+-ATPase activities in normal, regenerating and malignant cells. Biochim Biophysica Acta Biomem 684:67–74CrossRefGoogle Scholar
  59. Ouk T, Gautier S, Pétrault M et al (2014) Effects of the PPAR-α agonist fenofibrate on acute and short-term consequences of brain ischemia. J Cereb Blood Flow Metab 34:542–551CrossRefPubMedPubMedCentralGoogle Scholar
  60. Pan MH, Chang YH, Tsai ML et al (2008) Pterostilbene suppressed lipopolysaccharide-induced up-expression of iNOS and COX-2 in murine macrophages. J Agri Food Chem 56:7502–7509CrossRefGoogle Scholar
  61. Pathan AR, Viswanad B, Sonkusare SK et al (2006) Chronic administration of pioglitazone attenuates intracerebroventricular streptozotocin induced-memory impairment in rats. Life Sci 79:2209–2216CrossRefPubMedGoogle Scholar
  62. Paxinos G, Ashwell KW, Tork I (2013) Atlas of the developing rat nervous system, 2nd edn. Academic, San DiegoGoogle Scholar
  63. Peixoto FP, Carrola J, Coimbra AM et al (2013) Oxidative stress responses and histological hepatic alterations in barbel, Barbus bocagei, from Vizela River, Portugal. Rev Int Contam Ambient 29:29–38Google Scholar
  64. Pinsky MR, Brochard L, Mancebo J et al (2006) Applied physiology in intensive care medicine. Springer, Berlin, pp 53–56CrossRefGoogle Scholar
  65. Prasad KN, Cole WC, Prasad KC (2002) Risk factors for Alzheimer’s disease: role of multiple antioxidants, non-steroidal anti-inflammatory and cholinergic agents alone or in combination in prevention and treatment. J Am Coll Nutr 21:506–522CrossRefPubMedGoogle Scholar
  66. Pyper SR, Viswakarma N, Yu S et al (2010) PPARα: energy combustion, hypolipidemia, inflammation and cancer. Nucl Recept Sig 8:1–21CrossRefGoogle Scholar
  67. Rai S, Kamat PK, Nath C et al (2014) Glial activation and post-synaptic neurotoxicity: the key events in streptozotocin (ICV) induced memory impairment in rats. Pharmacol Biochem Behav 117:104–117CrossRefPubMedGoogle Scholar
  68. Reddy PH (2006) Amyloid precursor protein-mediated free radicals and oxidative damage: implications for the development and progression of Alzheimer’s disease. J Neurochem 96:1–13CrossRefPubMedGoogle Scholar
  69. Remsberg CM, Yáñez JA, Ohgami Y et al (2008) Pharmacometrics of pterostilbene: preclinical pharmacokinetics and metabolism, anticancer, antiinflammatory, antioxidant and analgesic activity. Phytother Res 22:169–179CrossRefPubMedGoogle Scholar
  70. Rimando AM, Nagmani R, Feller DR et al (2005) Pterostilbene, a new agonist for the peroxisome proliferator-activated receptor α-isoform, lowers plasma lipoproteins and cholesterol in hypercholesterolemic hamsters. J Agri Food Chem 53:3403–3407CrossRefGoogle Scholar
  71. Rubin D, Rubin T (2009) Method and compositions for administering resveratrol and pterostilbene. EP patent WO2009089338 A2Google Scholar
  72. Saxena G, Singh SP, Pal R et al (2007) Gugulipid, an extract of Commiphora whighitii with lipid-lowering properties, has protective effects against streptozotocin-induced memory deficits in mice. Pharmacol Biochem Behav 86:797–805CrossRefPubMedGoogle Scholar
  73. Saxena G, Singh SP, Agrawal R et al (2008) Effect of donepezil and tacrine on oxidative stress in intracerebral streptozotocin-induced model of dementia in mice. Eur J Pharmacol 581:283–289CrossRefPubMedGoogle Scholar
  74. Saxena G, Bharti S, Kamat PK et al (2010) Melatonin alleviates memory deficits and neuronal degeneration induced by intracerebroventricular administration of streptozotocin in rats. Pharmacol Biochem Behav 94:397–403CrossRefPubMedGoogle Scholar
  75. Saxena G, Patro IK, Nath C (2011) ICV STZ induced impairment in memory and neuronal mitochondrial function: a protective role of nicotinic receptor. Behav Brain Res 224:50–57CrossRefPubMedGoogle Scholar
  76. Schmatz R, Mazzanti CM, Spanevello R et al (2009) Resveratrol prevents memory deficits and the increase in acetylcholinesterase activity in streptozotocin-induced diabetic rats. Eur J Pharmacol 610:42–48CrossRefPubMedGoogle Scholar
  77. Sharma M, Gupta Y (2001) Effect of chronic treatment of melatonin on learning, memory and oxidative deficiencies induced by intracerebroventricular streptozotocin in rats. Pharmacol Biochem Behav 70:325–331CrossRefPubMedGoogle Scholar
  78. Siddiqui MF, Levey A (1999) Cholinergic therapies in Alzheimer’s disease. Drugs Future 24:417–424CrossRefGoogle Scholar
  79. Sisodia SS, Kim SH, Thinakaran G (1999) Function and dysfunction of the presenilins. Am J Hum Genet 65:7–12CrossRefPubMedPubMedCentralGoogle Scholar
  80. Streck EL, Zugno AI, Tagliari B et al (2001) Inhibition of rat brain Na+, K+-ATPase activity induced by homocysteine is probably mediated by oxidative stress. Neurochem Res 26:1195–1200CrossRefPubMedGoogle Scholar
  81. Szkudelski T (2012) Streptozotocin–nicotinamide-induced diabetes in the rat. Characteristics of the experimental model. Exp Biol Med 237:481–490CrossRefGoogle Scholar
  82. Taglialatela G, Hogan D, Zhang WR et al (2009) Intermediate-and long-term recognition memory deficits in Tg2576 mice are reversed with acute calcineurin inhibition. Behav Brain Res 200:95–99CrossRefPubMedPubMedCentralGoogle Scholar
  83. Tota S, Kamat PK, Shukla R et al (2011) Improvement of brain energy metabolism and cholinergic functions contributes to the beneficial effects of silibinin against streptozotocin induced memory impairment. Behav Brain Res 221:207–215CrossRefPubMedGoogle Scholar
  84. Vauzour D (2012) Dietary polyphenols as modulators of brain functions: biological actions and molecular mechanisms underpinning their beneficial effects. Oxid Med Cell Longev 2012:1–16CrossRefGoogle Scholar
  85. Weinstock M, Kirschbaum SN, Lazarovici P et al (2001) Neuroprotective effects of novel cholinesterase inhibitors derived from rasagiline as potential anti-Alzheimer drugs. Ann N Y Acad Sci 939:148–161CrossRefPubMedGoogle Scholar
  86. White RF, Marans KS, Krengel M (2000) Psychological/behavioral symptoms in neurological disorders. In: Emergencies in mental health practice: evaluation and management, pp 312–331Google Scholar
  87. Xuan AG, Chen Y, Long DH et al (2014) PPARα agonist fenofibrate ameliorates learning and memory deficits in rats following global cerebral ischemia. Mol Neurobiol 52:1–9Google Scholar
  88. Yan LJ (2009) Analysis of oxidative modification of proteins. Curr Protoc Protein Sci. doi: 10.1002/0471140864.ps1404s55 Google Scholar
  89. Zeevalk GD, Bernard LP, Nicklas WJ (1998) Role of oxidative stress and the glutathione system in loss of dopamine neurons due to impairment of energy metabolism. J Neurochem 70:1421–1430CrossRefPubMedGoogle Scholar
  90. Zhang J-M et al (2007) Cytokines, inflammation and pain. Int Anesthesiol Clin 45(2):27–37CrossRefPubMedPubMedCentralGoogle Scholar
  91. Zhanga R, Xuea G, Wanga S et al (2012) Novel object recognition as a facile behavior test for evaluating drug effects in APP/PS1 Alzheimer’s disease mouse model. J Alzheimers Dis 31:801–812Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • Bhagyashree Naik
    • 1
  • Abhijit Nirwane
    • 1
  • Anuradha Majumdar
    • 1
  1. 1.Department of PharmacologyBombay College of PharmacyMumbaiIndia

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