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Verapamil attenuates scopolamine induced cognitive deficits by averting oxidative stress and mitochondrial injury – A potential therapeutic agent for Alzheimer’s Disease

  • Saravanaraman PonneEmail author
  • Chinnadurai Raj Kumar
  • Rathanam Boopathy
Original Article
  • 52 Downloads

Abstract

Alzheimer’s disease (AD) is a multifactorial disorder where amyloid beta (Aβ) plaques, Ca2+ dysregulation, excessive oxidative stress, mitochondrial dysfunction and synaptic loss operate synergistically to bring about cholinergic deficits and dementia. New therapeutic interventions are gaining prominence as the morbidity and mortality of AD increases exponentially every year. Treating AD with antihypertensive drugs is thought to be a promising intervention; however, its mechanism of action of ameliorating AD needs further investigation. In this context, the present study explores the protective effect of verapamil, an antihypertensive agent of Ca2+ channel blocker (CCB) class against scopolamine-induced in vitro neurotoxicity and in vivo cognitive impairment. Supplementation of verapamil was found to attenuate oxidative stress by preventing mitochondrial injury, and augment the expression of genes involved in the cholinergic function (mACR1), synaptic plasticity (GAP43, SYP) and Ca2+-dependent memory-related genes (CREB1, CREBBP, BDNF). Further, verapamil treatment in mice attenuated the cognitive and behavioural deficits induced by scopolamine as measured by the elevated plus maze and passive avoidance test (P < 0.05). Thus, the present study demonstrates the neuroprotective effect of verapamil against the pathogenesis of AD such as oxidative stress, mitochondrial dysfunction and cognitive decline. These observations emphasize the importance of ‛Ca2+ dysregulation’ and ‛mitochondrial dysfunction’ theories in AD and recommends the supplementation of compounds that regulate Ca2+ homeostasis and mitochondrial function in susceptible AD individuals.

Keywords

Alzheimer’s disease Verapamil Mitochondria Acetylcholinesterase Cognition 

Abbreviations

Amyloid beta

DMEM

Dulbecco’s modified eagle medium

DMSO

Dimethyl sulfoxide

DNPH

2,4-dinitrophenylhydrazine

DTNB

5,5′-dithiobis-(2-nitrobenzoic acid)

EDTA

Ethylenediaminetetraacetic acid

FBS

Fetal bovine serum

GAPDH

Glyceraldehyde 3-phosphate dehydrogenase

HBSS

Hank’s balanced salt solution

Iso-OMPA

tetraisopropyl pyrophosphoramide

JC1

5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanine iodide

LTP

Long term potentiation

MTT

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NBT

Nitroblue tretazolium

PBS

Phosphate buffered saline

VOC

Voltage operated channel

Notes

Acknowledgements

We acknowledge the support from Dr. G. Ariharasivakumar (KMCH College of Pharmacy, Coimbatore, India) and R. Vadivelan (JSS College of Pharmacy, Ooty, India) for animal studies. The authors PS and RKC respectively acknowledge the research fellowships DST-INSPIRE and DST-PURSE, both provided by the Department of Science and Technology, New Delhi.

Compliance with ethical standards

Conflict of interest

The authors declared that no conflict of interest exists with respect to the authorship and publication of this article.

References

  1. Balon R, Ramesh C (1996) Calcium channel blockers for anxiety disorders? Ann Clin Psychiatry 8:215–220CrossRefGoogle Scholar
  2. Brodie C, Sampson SR (1991) Verapamil regulation of Na-K pump levels in rat skeletal myotubes: role of spontaneous activity and Na channels. J Neurosci Res 28:229–235.  https://doi.org/10.1002/jnr.490280210 CrossRefPubMedGoogle Scholar
  3. Chen G, Zou X, Watanabe H et al (2010) CREB binding protein is required for both short-term and long-term memory formation. J Neurosci 30:13066–13077.  https://doi.org/10.1523/JNEUROSCI.2378-10.2010 CrossRefPubMedPubMedCentralGoogle Scholar
  4. Chinopoulos C, Adam-Vizi V (2006) Calcium, mitochondria and oxidative stress in neuronal pathology. Novel aspects of an enduring theme. FEBS J 273:433–450.  https://doi.org/10.1111/j.1742-4658.2005.05103.x CrossRefPubMedGoogle Scholar
  5. Chintoh A, Fulton J, Koziel N et al (2003) Role of cholinergic receptors in locomotion induced by scopolamine and oxotremorine-M. Pharmacol Biochem Behav 76:53–61CrossRefGoogle Scholar
  6. Darwish I, Dessouky I (2015) Potential Neuroprotective Role of Verapamil in Experimentally- Induced Chronic Sciatic Nerve Constriction in Mice. Br J Med Med Res 8:781–789.  https://doi.org/10.9734/BJMMR/2015/17908 CrossRefGoogle Scholar
  7. Di Carlo M, Giacomazza D, Picone P et al (2012) Are oxidative stress and mitochondrial dysfunction the key players in the neurodegenerative diseases? Free Radic Res 46:1327–1338.  https://doi.org/10.3109/10715762.2012.714466 CrossRefPubMedGoogle Scholar
  8. Diadiushka GP (1979) Inhibitory effect of verapamil on the acetylcholinesterase activity of skeletal muscle sarcolemma. Biokhimiia 44:1912–1917PubMedGoogle Scholar
  9. Dickey CA, Loring JF, Montgomery J et al (2003) Selectively reduced expression of synaptic plasticity-related genes in amyloid precursor protein + presenilin-1 transgenic mice. J Neurosci 23(12):5219–5226.  https://doi.org/10.1523/JNEUROSCI.23-12-05219.2003 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Dubovsky SL, Franks RD, Allen S, Murphy J (1986) Calcium antagonists in mania: a double-blind study of verapamil. Psychiatry Res 18:309–320CrossRefGoogle Scholar
  11. Ellman GL, Courtney KD, Andres V, Feather-Stone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95CrossRefGoogle Scholar
  12. Finger S, Green L, Tarnoff ME et al (1990) Nimodipine enhances new learning after hippocampal damage. Exp Neurol 109:279–285CrossRefGoogle Scholar
  13. Fisher A, Pittel Z, Haring R et al (2003) M1 muscarinic agonists can modulate some of the hallmarks in Alzheimer’s disease: implications in future therapy. J Mol Neurosci 20:349–356.  https://doi.org/10.1385/JMN:20:3:349 CrossRefPubMedGoogle Scholar
  14. Flynn DD, Ferrari-DiLeo G, Mash DC, Levey AI (1995) Differential regulation of molecular subtypes of muscarinic receptors in Alzheimer’s disease. J Neurochem 64:1888–1891CrossRefGoogle Scholar
  15. Freir DB, Costello DA, Herron CE (2003) A beta 25-35-induced depression of long-term potentiation in area CA1 in vivo and in vitro is attenuated by verapamil. J Neurophysiol 89:3061–3069.  https://doi.org/10.1152/jn.00992.2002 CrossRefPubMedGoogle Scholar
  16. Fulga IG, Stroescu V (1997) Experimental research on the effect of calcium channel blockers nifedipine and verapamil on the anxiety in mice. Rom J Physiol 34:127–136PubMedGoogle Scholar
  17. Gurtu S, Seth S, Roychoudhary AK (1992) Evidence for verapamil-induced functional inhibition of noradrenergic neurotransmission in vivo. Naunyn Schmiedeberg's Arch Pharmacol 345:172–175CrossRefGoogle Scholar
  18. Haile M, Limson F, Gingrich K et al (2009) Nimodipine prevents transient cognitive dysfunction after moderate hypoxia in adult mice. J Neurosurg Anesthesiol 21:140–144.  https://doi.org/10.1097/ANA.0b013e3181920d28 CrossRefPubMedGoogle Scholar
  19. Höschl C (1991) Do calcium antagonists have a place in the treatment of mood disorders? Drugs 42:721–729.  https://doi.org/10.2165/00003495-199142050-00001 CrossRefPubMedGoogle Scholar
  20. Höschl C, Vacková J, Janda B (1992) Mood stabilizing effect of verapamil. Bratisl Lek Listy 93:208–209PubMedGoogle Scholar
  21. Hsieh M-T, Hsieh C-L, Lin L-W et al (2003) Differential gene expression of scopolamine-treated rat hippocampus-application of cDNA microarray technology. Life Sci 73:1007–1016CrossRefGoogle Scholar
  22. Ingole SR, Satyendra KR, Sharma SS (2008) Cognition Enhancers: Current Strategies and Future Perspectives. CRIPS 9:42–48Google Scholar
  23. Kalonia H, Kumar P, Kumar A (2011) Attenuation of proinflammatory cytokines and apoptotic process by verapamil and diltiazem against quinolinic acid induced Huntington like alterations in rats. Brain Res 1372:115–126.  https://doi.org/10.1016/j.brainres.2010.11.060 CrossRefPubMedGoogle Scholar
  24. Kedziora-Kornatowska K, Szram S, Kornatowski T et al (2002) The effect of verapamil on the antioxidant defence system in diabetic kidney. Clin Chim Acta 322:105–112CrossRefGoogle Scholar
  25. Kelley SR, Kamal TJ, Molitch ME (1996) Mechanism of verapamil calcium channel blockade-induced hyperprolactinemia. Am J Physiol 270:E96–100.  https://doi.org/10.1152/ajpendo.1996.270.1.E96
  26. Konar A, Shah N, Singh R et al (2011) Protective role of Ashwagandha leaf extract and its component withanone on scopolamine-induced changes in the brain and brain-derived cells. PLoS One 6:e27265.  https://doi.org/10.1371/journal.pone.0027265 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Konrad T, Beier K, Kusterer K et al (1997) The effect of verapamil on mitochondrial calcium content in normoxic, hypoxic and reoxygenated rat liver. Histochem J 29:309–315CrossRefGoogle Scholar
  28. Koo WS, Gengaro PE, Burke TJ, Schrier RW (1995) Verapamil attenuates calcium-induced mitochondrial swelling and respiratory dysfunction. J Pharmacol Exp Ther 273:206–212PubMedGoogle Scholar
  29. Kwon S-H, Lee H-K, Kim J-A et al (2010) Neuroprotective effects of chlorogenic acid on scopolamine-induced amnesia via anti-acetylcholinesterase and anti-oxidative activities in mice. Eur J Pharmacol 649:210–217.  https://doi.org/10.1016/j.ejphar.2010.09.001 CrossRefPubMedGoogle Scholar
  30. Lakhina V, Arey RN, Kaletsky R et al (2015) Genome-wide functional analysis of CREB/long-term memory-dependent transcription reveals distinct basal and memory gene expression programs. Neuron 85:330–345.  https://doi.org/10.1016/j.neuron.2014.12.029 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Lebois EP, Bridges TM, Lewis LM et al (2010) Discovery and characterization of novel subtype-selective allosteric agonists for the investigation of M(1) receptor function in the central nervous system. ACS Chem Neurosci 1:104–121.  https://doi.org/10.1021/cn900003h CrossRefPubMedGoogle Scholar
  32. Lee EH, Lin WR (1991) Nifedipine and verapamil block the memory-facilitating effect of corticotropin-releasing factor in rats. Life Sci 48:1333–1340CrossRefGoogle Scholar
  33. Levine RL, Garland D, Oliver CN et al (1990) Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol 186:464–478CrossRefGoogle Scholar
  34. Li N, Liu G (2010) The novel squamosamide derivative FLZ enhances BDNF/TrkB/CREB signaling and inhibits neuronal apoptosis in APP/PS1 mice. Acta Pharmacol Sin 31:265–272.  https://doi.org/10.1038/aps.2010.3 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795.  https://doi.org/10.1038/nature05292 CrossRefPubMedGoogle Scholar
  36. Liu Y, Lo Y-C, Qian L et al (2011) Verapamil protects dopaminergic neuron damage through a novel anti-inflammatory mechanism by inhibition of microglial activation. Neuropharmacology 60:373–380.  https://doi.org/10.1016/j.neuropharm.2010.10.002 CrossRefPubMedGoogle Scholar
  37. López-Arrieta JM, Birks J (2002) Nimodipine for primary degenerative, mixed and vascular dementia. Cochrane Database Syst Rev CD000147. doi:  https://doi.org/10.1002/14651858.CD000147
  38. Lovell MA, Abner E, Kryscio R et al (2015) Calcium Channel Blockers, Progression to Dementia, and Effects on Amyloid Beta Peptide Production. Oxidative Med Cell Longev 2015:787805.  https://doi.org/10.1155/2015/787805 CrossRefGoogle Scholar
  39. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275Google Scholar
  40. Mak IT, Weglicki WB (1990) Comparative antioxidant activities of propranolol, nifedipine, verapamil, and diltiazem against sarcolemmal membrane lipid peroxidation. Circ Res 66:1449–1452CrossRefGoogle Scholar
  41. Maniskas ME, Roberts JM, Aron I et al (2016) Stroke neuroprotection revisited: Intra-arterial verapamil is profoundly neuroprotective in experimental acute ischemic stroke. J Cereb Blood Flow Metab 36:721–730.  https://doi.org/10.1177/0271678X15608395 CrossRefPubMedGoogle Scholar
  42. Matesic DF, Lin RC (1994) Microtubule-associated protein 2 as an early indicator of ischemia-induced neurodegeneration in the gerbil forebrain. J Neurochem 63:1012–1020CrossRefGoogle Scholar
  43. Moron MS, Depierre JW, Mannervik B (1979) Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochim Biophys Acta 582:67–78CrossRefGoogle Scholar
  44. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63CrossRefGoogle Scholar
  45. O’Brien FE, O’Connor RM, Clarke G et al (2013) P-glycoprotein inhibition increases the brain distribution and antidepressant-like activity of escitalopram in rodents. Neuropsychopharmacology 38:2209–2219.  https://doi.org/10.1038/npp.2013.120 CrossRefPubMedPubMedCentralGoogle Scholar
  46. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358CrossRefGoogle Scholar
  47. Palit G, Kalsotra A, Kumar R et al (2001) Behavioural and anti-psychotic effects of Ca2+ channel blockers in rhesus monkey. Eur J Pharmacol 412:139–144CrossRefGoogle Scholar
  48. Pandareesh MD, Anand T (2013) Neuromodulatory propensity of Bacopa monniera against scopolamine-induced cytotoxicity in PC12 cells via down-regulation of AChE and up-regulation of BDNF and muscarnic-1 receptor expression. Cell Mol Neurobiol 33:875–884.  https://doi.org/10.1007/s10571-013-9952-5 CrossRefPubMedGoogle Scholar
  49. Pandya JD, Nukala VN, Sullivan PG (2013) Concentration dependent effect of calcium on brain mitochondrial bioenergetics and oxidative stress parameters. Front Neuroenerg 5:10.  https://doi.org/10.3389/fnene.2013.00010 CrossRefGoogle Scholar
  50. Pauwels PJ, Van Assouw HP, Peeters L, Leysen JE (1990) Neurotoxic action of veratridine in rat brain neuronal cultures: mechanism of neuroprotection by Ca++ antagonists nonselective for slow Ca++ channels. J Pharmacol Exp Ther 255:1117–1122PubMedGoogle Scholar
  51. Peng T-I, Jou M-J (2010) Oxidative stress caused by mitochondrial calcium overload. Ann N Y Acad Sci 1201:183–188.  https://doi.org/10.1111/j.1749-6632.2010.05634.x CrossRefPubMedGoogle Scholar
  52. Phillips HS, Hains JM, Armanini M et al (1991) BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer’s disease. Neuron 7:695–702CrossRefGoogle Scholar
  53. Poorheidari G, Pratt JA, Dehghani N (2002) Effects of low-dose scopolamine on locomotor activity: No dissociation between cognitive and non-effects. Neurosci Res Commun 31:165–174.  https://doi.org/10.1002/nrc.10049 CrossRefGoogle Scholar
  54. Popović M, Caballero-Bleda M, Popović N et al (1997a) Neuroprotective effect of chronic verapamil treatment on cognitive and noncognitive deficits in an experimental Alzheimer’s disease in rats. Int J Neurosci 92:79–93CrossRefGoogle Scholar
  55. Popović M, Caballero-Bleda M, Popović N et al (2006) Verapamil prevents, in a dose-dependent way, the loss of ChAT-immunoreactive neurons in the cerebral cortex following lesions of the rat nucleus basalis magnocellularis. Exp Brain Res 170:368–375.  https://doi.org/10.1007/s00221-005-0219-3 CrossRefPubMedGoogle Scholar
  56. Popović M, Popović N, Jovanova-Nesić K et al (1997b) Effect of physostigmine and verapamil on active avoidance in an experimental model of Alzheimer’s disease. Int J Neurosci 90:87–97CrossRefGoogle Scholar
  57. Pucilowski O (1992) Psychopharmacological properties of calcium channel inhibitors. Psychopharmacology 109:12–29CrossRefGoogle Scholar
  58. Pugazhenthi S, Wang M, Pham S et al (2011) Downregulation of CREB expression in Alzheimer’s brain and in Aβ-treated rat hippocampal neurons. Mol Neurodegener 6:60.  https://doi.org/10.1186/1750-1326-6-60 CrossRefPubMedPubMedCentralGoogle Scholar
  59. Quartermain D, deSoria VG, Kwan A (2001) Calcium channel antagonists enhance retention of passive avoidance and maze learning in mice. Neurobiol Learn Mem 75:77–90.  https://doi.org/10.1006/nlme.1999.3958 CrossRefPubMedGoogle Scholar
  60. Quartermain D, Garcia de Soria V (2001) The effects of calcium channel antagonists on short- and long-term retention in mice using spontaneous alternation behavior. Neurobiol Learn Mem 76:117–124.  https://doi.org/10.1006/nlme.2000.3981 CrossRefPubMedGoogle Scholar
  61. Rauer H, Grissmer S (1999) The effect of deep pore mutations on the action of phenylalkylamines on the Kv1.3 potassium channel. Br J Pharmacol 127:1065–1074.  https://doi.org/10.1038/sj.bjp.0702599 CrossRefPubMedPubMedCentralGoogle Scholar
  62. Reddy PH, Beal MF (2008) Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. Trends Mol Med 14:45–53.  https://doi.org/10.1016/j.molmed.2007.12.002
  63. Reddy PH, Mani G, Park BS et al (2005) Differential loss of synaptic proteins in Alzheimer’s disease: implications for synaptic dysfunction. J Alzheimers Dis 7:103–117 discussion 173-180CrossRefGoogle Scholar
  64. Ressler KJ, Nemeroff CB (2000) Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress Anxiety 12(Suppl 1):2–19.  https://doi.org/10.1002/1520-6394(2000)12:1+<2::AID-DA2>3.0.CO;2-4 CrossRefPubMedGoogle Scholar
  65. Saravanaraman P, Chinnadurai RK, Boopathy R (2014) Why calcium channel blockers could be an elite choice in the treatment of Alzheimer’s disease: a comprehensive review of evidences. Rev Neurosci 25:231–246.  https://doi.org/10.1515/revneuro-2013-0056 CrossRefPubMedGoogle Scholar
  66. Scott Bitner R (2012) Cyclic AMP response element-binding protein (CREB) phosphorylation: a mechanistic marker in the development of memory enhancing Alzheimer’s disease therapeutics. Biochem Pharmacol 83:705–714.  https://doi.org/10.1016/j.bcp.2011.11.009 CrossRefPubMedGoogle Scholar
  67. Shirey JK, Brady AE, Jones PJ et al (2009) A selective allosteric potentiator of the M1 muscarinic acetylcholine receptor increases activity of medial prefrontal cortical neurons and restores impairments in reversal learning. J Neurosci 29:14271–14286.  https://doi.org/10.1523/JNEUROSCI.3930-09.2009 CrossRefPubMedPubMedCentralGoogle Scholar
  68. Siegel HN, Lukas RJ (1986) Allosteric modification of alpha-bungarotoxin binding by the “calcium channel antagonist” verapamil. Brain Res 387:37–42PubMedGoogle Scholar
  69. Silva AJ, Kogan JH, Frankland PW, Kida S (1998) CREB and memory. Annu Rev Neurosci 21:127–148.  https://doi.org/10.1146/annurev.neuro.21.1.127 CrossRefPubMedGoogle Scholar
  70. Sitges M, Reyes A (1995) Effects of verapamil on the release of different neurotransmitters. J Neurosci Res 40:613–621.  https://doi.org/10.1002/jnr.490400506 CrossRefPubMedGoogle Scholar
  71. Soltani MH, Pichardo R, Song Z et al (2005) Microtubule-associated protein 2, a marker of neuronal differentiation, induces mitotic defects, inhibits growth of melanoma cells, and predicts metastatic potential of cutaneous melanoma. Am J Pathol 166:1841–1850.  https://doi.org/10.1016/S0002-9440(10)62493-5 CrossRefPubMedPubMedCentralGoogle Scholar
  72. Srere PA, Brazil H, Gonen L, Takahashi M (1963) The Citrate Condensing Enzyme of Pigeon Breast Muscle and Moth Flight Muscle. Acta Chem Scand (17 supl):129–134.  https://doi.org/10.3891/acta.chem.scand.17s-0129
  73. Taya K, Watanabe Y, Kobayashi H, Fujiwara M (2000) Nimodipine improves the disruption of spatial cognition induced by cerebral ischemia. Physiol Behav 70:19–25CrossRefGoogle Scholar
  74. Trofimiuk E, Holownia A, Braszko JJ (2010) Activation of CREB by St. John’s wort may diminish deletorious effects of aging on spatial memory. Arch Pharm Res 33:469–477.  https://doi.org/10.1007/s12272-010-0318-y CrossRefPubMedGoogle Scholar
  75. Tsuda K, Tsuda S, Goldstein M, Masuyama Y (1993) Effects of verapamil and diltiazem on dopamine release in the central nervous system of spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 20:641–645CrossRefGoogle Scholar
  76. Umukoro S, Ashorobi R, Essein E (2006) Anticonvulsant and Anxiolytic Effects of Calcium Channel Blockers in Mice. J Med Sci (Faisalabad) 6:1021–1024.  https://doi.org/10.3923/jms.2006.1021.1024 CrossRefGoogle Scholar
  77. Villard V, Espallergues J, Keller E et al (2011) Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma 1 (σ1) ligand ANAVEX2-73, a novel aminotetrahydrofuran derivative. J Psychopharmacol (Oxford) 25:1101–1117.  https://doi.org/10.1177/0269881110379286 CrossRefGoogle Scholar
  78. Waite M, Van Deenen LL, Ruigrok TJ, Elbers PF (1969) Relation of mitochondrial phospholipase A activity to mitochondrial swelling. J Lipid Res 10:599–608PubMedGoogle Scholar
  79. Wu D, Lu J, Zheng Y et al (2008) Purple sweet potato color repairs d-galactose-induced spatial learning and memory impairment by regulating the expression of synaptic proteins. Neurobiol Learn Mem 90:19–27.  https://doi.org/10.1016/j.nlm.2008.01.010 CrossRefPubMedGoogle Scholar
  80. Xiao J, Li S, Sui Y et al (2014) Lactobacillus casei-01 facilitates the ameliorative effects of proanthocyanidins extracted from lotus seedpod on learning and memory impairment in scopolamine-induced amnesia mice. PLoS One 9:e112773.  https://doi.org/10.1371/journal.pone.0112773 CrossRefPubMedPubMedCentralGoogle Scholar
  81. Yamada K, Nabeshima T (2003) Brain-derived neurotrophic factor/TrkB signaling in memory processes. J Pharmacol Sci 91:267–270CrossRefGoogle Scholar
  82. Zhang W, Wang GM, Wang PJ et al (2014) Effects of neural stem cells on synaptic proteins and memory in a mouse model of Alzheimer’s disease. J Neurosci Res 92:185–194.  https://doi.org/10.1002/jnr.23299 CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Biotechnology, School of Biotechnology and Genetic EngineeringBharathiar UniversityCoimbatoreIndia
  2. 2.Department of BiotechnologyPondicherry UniversityPuducherryIndia

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