title: Protective role of Ashwagandha leaf extract and its component withanone on scopolamine-induced changes in the brain and brain-derived cells.
abstract: BACKGROUND
  Scopolamine is a well-known cholinergic antagonist that causes amnesia in human and animal models. Scopolamine-induced amnesia in rodent models has been widely used to understand the molecular, biochemical, behavioral changes, and to delineate therapeutic targets of memory impairment. Although this has been linked to the decrease in central cholinergic neuronal activity following the blockade of muscarinic receptors, the underlying molecular and cellular mechanism(s) particularly the effect on neuroplasticity remains elusive. In the present study, we have investigated (i) the effects of scopolamine on the molecules involved in neuronal and glial plasticity both in vivo and in vitro and (ii) their recovery by alcoholic extract of Ashwagandha leaves (i-Extract).
  
  
  RESULTS
  As a drug model, scopolamine hydrobromide was administered intraperitoneally to mice and its effect on the brain function was determined by molecular analyses. The results showed that the scopolamine caused downregulation of the expression of BDNF and GFAP in dose and time dependent manner, and these effects were markedly attenuated in response to i-Extract treatment. Similar to our observations in animal model system, we found that the scopolamine induced cytotoxicity in IMR32 neuronal and C6 glioma cells. It was associated with downregulation of neuronal cell markers NF-H, MAP2, PSD-95, GAP-43 and glial cell marker GFAP and with upregulation of DNA damage--γH2AX and oxidative stress--ROS markers. Furthermore, these molecules showed recovery when cells were treated with i-Extract or its purified component, withanone.
  
  
  CONCLUSIONS
  Our study suggested that besides cholinergic blockade, scopolamine-induced memory loss may be associated with oxidative stress and Ashwagandha i-Extract, and withanone may serve as potential preventive and therapeutic agents for neurodegenerative disorders and hence warrant further molecular analyses.
authors.affiliation: Biochemistry and Molecular Biology Laboratory, Department of Zoology, Banaras Hindu University, Varanasi, India.
authors.forename: Arpita
authors.initials: A
authors.lastname: Konar
authors.forename: Navjot
authors.initials: N
authors.lastname: Shah
authors.forename: Rumani
authors.initials: R
authors.lastname: Singh
authors.forename: Nishant
authors.initials: N
authors.lastname: Saxena
authors.forename: Sunil C
authors.initials: SC
authors.lastname: Kaul
authors.forename: Renu
authors.initials: R
authors.lastname: Wadhwa
authors.forename: Mahendra K
authors.initials: MK
authors.lastname: Thakur
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology*; D018515:Plant Leaves / Q000737:chemistry*; D012601:Scopolamine / Q000633:toxicity*; D014315:Triterpenes / Q000494:pharmacology*; D032341:Withania / Q000737:chemistry*; D054358:Withanolides
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D010936:Plant Extracts; D014315:Triterpenes; D054358:Withanolides; C528900:glial fibrillary astrocytic protein, mouse; D012601:Scopolamine; C560597:withanone; C030693:Ashwagandha
references.citation: J Biol Chem. 2000 Sep 15;275(37):28929-36
references.pmid: 10852911
references.citation: Hum Mol Genet. 2010 Aug 15;19(16):3169-78
references.pmid: 20538881
references.citation: Life Sci. 2003 Jul 11;73(8):1007-16
references.pmid: 12818353
references.citation: Alcohol Clin Exp Res. 2009 Nov;33(11):1945-55
references.pmid: 19673741
references.citation: Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):8802-6
references.pmid: 8415610
references.citation: Neurobiol Learn Mem. 2008 Nov;90(4):596-603
references.pmid: 18707012
references.citation: Br J Pharmacol. 2005 Apr;144(7):961-71
references.pmid: 15711595
references.citation: J Neurosci Res. 2007 Feb 15;85(3):525-35
references.pmid: 17149751
references.citation: J Pharm Pharmacol. 2010 Feb;62(2):263-71
references.pmid: 20487207
references.citation: Curr Opin Neurobiol. 2007 Jun;17(3):325-30
references.pmid: 17419049
references.citation: Brain Res Mol Brain Res. 1999 Apr 6;67(1):124-36
references.pmid: 10101239
references.citation: N Engl J Med. 2005 Feb 17;352(7):692-9
references.pmid: 15716563
references.citation: Hippocampus. 2011 Sep;21(9):999-1009
references.pmid: 20865740
references.citation: Neurochem Res. 2009 Nov;34(11):1975-83
references.pmid: 19444606
references.citation: J Neurochem. 2002 Sep;82(5):1058-64
references.pmid: 12358753
references.citation: Br J Pharmacol. 2009 Aug;157(8):1427-40
references.pmid: 19594760
references.citation: Neuroscience. 2006 Oct 13;142(2):505-14
references.pmid: 16889901
references.citation: Pharmacol Biochem Behav. 2002 Nov;73(4):893-900
references.pmid: 12213536
references.citation: Neurosci Lett. 2004 Jul 1;364(2):63-6
references.pmid: 15196678
references.citation: Pharmacol Biochem Behav. 2009 Feb;91(4):554-9
references.pmid: 18930076
references.citation: Indian J Pharmacol. 2009 Aug;41(4):192-6
references.pmid: 20523872
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11024-31
references.pmid: 11572963
references.citation: Clin Cancer Res. 2007 Apr 1;13(7):2298-306
references.pmid: 17404115
references.citation: Chem Pharm Bull (Tokyo). 2004 Nov;52(11):1358-61
references.pmid: 15520512
references.citation: PLoS One. 2010 Oct 21;5(10):e13536
references.pmid: 20975835
references.citation: J Neurosci. 2008 Feb 6;28(6):1452-9
references.pmid: 18256266
references.citation: Learn Mem. 2004 Nov-Dec;11(6):727-31
references.pmid: 15537738
references.citation: Eur J Neurosci. 1994 Apr 1;6(4):587-96
references.pmid: 8025713
references.citation: J Nutr. 2004 Jul;134(7):1827-31
references.pmid: 15226476
references.citation: Mol Brain. 2009 Aug 13;2:27
references.pmid: 19674479
references.citation: Behav Brain Res. 1991 Aug 29;44(2):217-9
references.pmid: 1751013
references.citation: Horm Behav. 2009 Mar;55(3):454-64
references.pmid: 19101559
references.citation: J Pharmacol Sci. 2003 Apr;91(4):267-70
references.pmid: 12719654
references.citation: Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6245-7
references.pmid: 10841527
references.citation: Neuroscience. 2008 Aug 13;155(2):476-84
references.pmid: 18585439
references.citation: Neuroscience. 2003;120(4):941-50
references.pmid: 12927200
references.citation: Arch Neurol. 2002 Oct;59(10):1524-8
references.pmid: 12374489
references.citation: Neurochem Int. 1997 Feb;30(2):181-90
references.pmid: 9017665
references.citation: Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12683-8
references.pmid: 9770546
references.citation: Biotechniques. 1999 Feb;26(2):302-4, 306-7
references.pmid: 10023542
references.citation: J Neurochem. 2007 Sep;102(6):1978-1989
references.pmid: 17540011
references.citation: Psychopharmacology (Berl). 2009 Jan;202(1-3):165-72
references.pmid: 18695930
references.citation: J Neurosci. 2002 May 1;22(9):3454-62
references.pmid: 11978822
references.citation: Neuron. 1993 Mar;10(3):475-89
references.pmid: 8461137
references.citation: Cancer Sci. 2009 Sep;100(9):1740-7
references.pmid: 19575749
references.citation: J Neurosci. 1993 Sep;13(9):3818-26
references.pmid: 8366347