Molecular Neurobiology

, Volume 52, Issue 3, pp 1093–1105 | Cite as

Withania somnifera Improves Ischemic Stroke Outcomes by Attenuating PARP1-AIF-Mediated Caspase-Independent Apoptosis

  • Aparna Raghavan
  • Zahoor A. Shah


Withania somnifera (WS), popularly known as “Ashwagandha” has been used for centuries as a nerve tonic. Its protective effect has been elucidated in many neurodegenerative pathologies, although there is a paucity of data regarding its effects in ischemic stroke. We examined the neuroprotective properties of an aqueous extract of WS in both pre- and poststroke treatment regimens in a mouse model of permanent distal middle cerebral artery occlusion (pMCAO). WS (200 mg/kg) improved functional recovery and significantly reduced the infarct volume in mice, when compared to those treated with vehicle, in both paradigms. We investigated the protective mechanism/s induced by WS using brain cortices by testing its ability to modulate the expression of key proteins in the ischemic-apoptotic cascade. The Western blots and immunofluorescence analyses of mice cortices revealed that WS upregulated the expression of hemeoxygenase 1 (HO1) and attenuated the expression of the proapoptotic protein poly (ADP-ribose) polymerase-1 (PARP1) via the PARP1-AIF pathway, thus preventing the nuclear translocation of apoptosis-inducing factor (AIF), and subsequent apoptosis. Semaphorin-3A (Sema3A) expression was reduced in WS-treated group, whereas Wnt, pGSK3β, and pCRMP2 expression levels were virtually unaltered. These results indicate the interplay of antioxidant-antiapoptic pathways and the possible involvement of angiogenesis in the protective mechanism of WS while emphasizing the noninvolvement of one of the prime pathways of neurogenesis. Our results suggest that WS could be a potential prophylactic as well as a therapeutic agent aiding stroke repair, and that part of its mechanism could be attributed to its antiapoptotic and antioxidant properties.


AIF Hemeoxygenase 1 Ischemic stroke PARP1 AIF Withania somnifera 



This work was supported partly by a grant from the National Institutes of Health—(R00AT004197) and start-up funds from the University of Toledo to ZAS.


  1. 1.
    Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Soliman EZ, Sorlie PD, Sotoodehnia N, Turan TN, Virani SS, Wong ND, Woo D, Turner MB (2012) Heart disease and stroke statistics–2012 update: a report from the American Heart Association. Circulation 125:e2–e220CrossRefPubMedGoogle Scholar
  2. 2.
    Zivin JA (2009) Acute stroke therapy with tissue plasminogen activator (tPA) since it was approved by the U.S. Food and Drug Administration (FDA). Ann Neurol 66:6–10CrossRefPubMedGoogle Scholar
  3. 3.
    Barreto G, White RE, Ouyang Y, Xu L, Giffard RG (2011) Astrocytes: targets for neuroprotection in stroke. Cent Nerv Syst Agents Med Chem 11:164–173CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Wermuth CG (2004) Multitargeted drugs: the end of the “one-target-one-disease” philosophy? Drug Discov Today 9:826–827CrossRefPubMedGoogle Scholar
  5. 5.
    Adams JD Jr, Yang J, Mishra LC, Singh BB (2002) Effects of ashwagandha in a rat model of stroke. Altern Ther Health Med 8:18–19PubMedGoogle Scholar
  6. 6.
    Rathore P, Dohare P, Varma S, Ray A, Sharma U, Jagannathan NR, Ray M (2008) Curcuma oil: reduces early accumulation of oxidative product and is anti-apoptogenic in transient focal ischemia in rat brain. Neurochem Res 33:1672–1682CrossRefPubMedGoogle Scholar
  7. 7.
    Shah ZA, Nada SE, Dore S (2011) Heme oxygenase 1, beneficial role in permanent ischemic stroke and in Gingko biloba (EGb 761) neuroprotection. Neuroscience 180:248–255CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Zhu J, Jiang Y, Wu L, Lu T, Xu G, Liu X (2012) Suppression of local inflammation contributes to the neuroprotective effect of ginsenoside Rb1 in rats with cerebral ischemia. Neuroscience 202:342–351CrossRefPubMedGoogle Scholar
  9. 9.
    Kulkarni SK, Dhir A (2008) Withania somnifera: an Indian ginseng. Prog Neuropsychopharmacol Biol Psychiatry 32:1093–1105CrossRefPubMedGoogle Scholar
  10. 10.
    Kumar S, Seal CJ, Howes MJ, Kite GC, Okello EJ (2010) In vitro protective effects of Withania somnifera (L.) dunal root extract against hydrogen peroxide and beta-amyloid(1-42)-induced cytotoxicity in differentiated PC12 cells. Phytother Res 24:1567–1574CrossRefPubMedGoogle Scholar
  11. 11.
    Russo A, Izzo AA, Cardile V, Borrelli F, Vanella A (2001) Indian medicinal plants as antiradicals and DNA cleavage protectors. Phytomedicine 8:125–132CrossRefPubMedGoogle Scholar
  12. 12.
    Kumar S, Harris RJ, Seal CJ, Okello EJ (2012) An aqueous extract of Withania somnifera root inhibits amyloid beta fibril formation in vitro. Phytother Res 26:113–117CrossRefPubMedGoogle Scholar
  13. 13.
    Choudhary MI, Nawaz SA, Ul-Haq Z, Lodhi MA, Ghayur MN, Jalil S, Riaz N, Yousuf S, Malik A, Gilani AH, Ur-Rahman A (2005) Withanolides, a new class of natural cholinesterase inhibitors with calcium antagonistic properties. Biochem Biophys Res Commun 334:276–287CrossRefPubMedGoogle Scholar
  14. 14.
    Ahmad M, Saleem S, Ahmad AS, Ansari MA, Yousuf S, Hoda MN, Islam F (2005) Neuroprotective effects of Withania somnifera on 6-hydroxydopamine induced Parkinsonism in rats. Hum Exp Toxicol 24:137–147CrossRefPubMedGoogle Scholar
  15. 15.
    Sankar SR, Manivasagam T, Krishnamurti A, Ramanathan M (2007) The neuroprotective effect of Withania somnifera root extract in MPTP-intoxicated mice: an analysis of behavioral and biochemical variables. Cell Mol Biol Lett 12:473–481CrossRefPubMedGoogle Scholar
  16. 16.
    Kumar P, Kumar A (2009) Possible neuroprotective effect of Withania somnifera root extract against 3-nitropropionic acid-induced behavioral, biochemical, and mitochondrial dysfunction in an animal model of Huntington’s disease. J Med Food 12:591–600CrossRefPubMedGoogle Scholar
  17. 17.
    Naidu PS, Singh A, Kulkarni SK (2006) Effect of Withania somnifera root extract on reserpine-induced orofacial dyskinesia and cognitive dysfunction. Phytother Res 20:140–146CrossRefPubMedGoogle Scholar
  18. 18.
    Tohda C, Joyashiki E (2009) Sominone enhances neurite outgrowth and spatial memory mediated by the neurotrophic factor receptor, RET. Br J Pharmacol 157:1427–1440CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Mohanty IR, Arya DS, Gupta SK (2008) Withania somnifera provides cardioprotection and attenuates ischemia-reperfusion induced apoptosis. Clin Nutr 27:635–642CrossRefPubMedGoogle Scholar
  20. 20.
    Chaudhary G, Sharma U, Jagannathan NR, Gupta YK (2003) Evaluation of Withania somnifera in a middle cerebral artery occlusion model of stroke in rats. Clin Exp Pharmacol Physiol 30:399–404CrossRefPubMedGoogle Scholar
  21. 21.
    Kataria H, Wadhwa R, Kaul SC, Kaur G (2012) Water extract from the leaves of Withania somnifera protect RA differentiated C6 and IMR-32 cells against glutamate-induced excitotoxicity. PLoS One 7:e37080CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Margaill I, Plotkine M, Lerouet D (2005) Antioxidant strategies in the treatment of stroke. Free Radic Biol Med 39:429–443CrossRefPubMedGoogle Scholar
  23. 23.
    Aztatzi-Santillan E, Nares-Lopez FE, Marquez-Valadez B, Aguilera P, Chanez-Cardenas ME (2010) The protective role of heme oxygenase-1 in cerebral ischemia. Cent Nerv Syst Agents Med Chem 10:310–316CrossRefPubMedGoogle Scholar
  24. 24.
    Li X, Klaus JA, Zhang J, Xu Z, Kibler KK, Andrabi SA, Rao K, Yang ZJ, Dawson TM, Dawson VL, Koehler RC (2010) Contributions of poly(ADP-ribose) polymerase-1 and -2 to nuclear translocation of apoptosis-inducing factor and injury from focal cerebral ischemia. J Neurochem 113:1012–1022CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Kim YT, Hur EM, Snider WD, Zhou FQ (2011) Role of GSK3 signaling in neuronal morphogenesis. Front Mol Neurosci 4:48PubMedPubMedCentralGoogle Scholar
  26. 26.
    Wu D, Pan W (2010) GSK3: a multifaceted kinase in Wnt signaling. Trends Biochem Sci 35:161–168CrossRefPubMedGoogle Scholar
  27. 27.
    Joyal JS, Sitaras N, Binet F, Rivera JC, Stahl A, Zaniolo K, Shao Z, Polosa A, Zhu T, Hamel D, Djavari M, Kunik D, Honore JC, Picard E, Zabeida A, Varma DR, Hickson G, Mancini J, Klagsbrun M, Costantino S, Beausejour C, Lachapelle P, Smith LE, Chemtob S, Sapieha P (2011) Ischemic neurons prevent vascular regeneration of neural tissue by secreting semaphorin 3A. Blood 117:6024–6035CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Bacigaluppi M, Comi G, Hermann DM (2010) Animal models of ischemic stroke. Part two: modeling cerebral ischemia. Open Neurol J 4:34–38PubMedPubMedCentralGoogle Scholar
  29. 29.
    Freireich EJ, Gehan EA, Rall DP, Schmidt LH, Skipper HE (1966) Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemother Rep Part 1(50):219–244Google Scholar
  30. 30.
    Jennions MD, Moller AP (2003) A survey of the statistical power of research in behavioral ecology and animal behavior. Behav Ecol 14:438–445CrossRefGoogle Scholar
  31. 31.
    Parihar MS, Chaudhary M, Shetty R, Hemnani T (2004) Susceptibility of hippocampus and cerebral cortex to oxidative damage in streptozotocin treated mice: prevention by extracts of Withania somnifera and Aloe vera. J Clin Neurosci: Off J Neurosurg Soc Australas 11:397–402CrossRefGoogle Scholar
  32. 32.
    Love S (1999) Oxidative stress in brain ischemia. Brain Pathol 9:119–131CrossRefPubMedGoogle Scholar
  33. 33.
    Dore S (2002) Decreased activity of the antioxidant heme oxygenase enzyme: implications in ischemia and in Alzheimer’s disease. Free Radic Biol Med 32:1276–1282CrossRefPubMedGoogle Scholar
  34. 34.
    Dulak J, Deshane J, Jozkowicz A, Agarwal A (2008) Heme oxygenase-1 and carbon monoxide in vascular pathobiology: focus on angiogenesis. Circulation 117:231–241CrossRefPubMedGoogle Scholar
  35. 35.
    Al-Owais MM, Scragg JL, Dallas ML, Boycott HE, Warburton P, Chakrabarty A, Boyle JP, Peers C (2012) Carbon monoxide mediates the anti-apoptotic effects of heme oxygenase-1 in medulloblastoma DAOY cells via K + channel inhibition. J Biol Chem 287:24754–24764CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Otterbein LE, Bach FH, Alam J, Soares M, Tao Lu H, Wysk M, Davis RJ, Flavell RA, Choi AM (2000) Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med 6:422–428CrossRefPubMedGoogle Scholar
  37. 37.
    Nakka VP, Gusain A, Mehta SL, Raghubir R (2008) Molecular mechanisms of apoptosis in cerebral ischemia: multiple neuroprotective opportunities. Mol Neurobiol 37:7–38CrossRefPubMedGoogle Scholar
  38. 38.
    Broughton BR, Reutens DC, Sobey CG (2009) Apoptotic mechanisms after cerebral ischemia. Stroke 40:e331–e339CrossRefPubMedGoogle Scholar
  39. 39.
    Broker LE, Kruyt FA, Giaccone G (2005) Cell death independent of caspases: a review. Clin Cancer Res 11:3155–3162CrossRefPubMedGoogle Scholar
  40. 40.
    Cande C, Cohen I, Daugas E, Ravagnan L, Larochette N, Zamzami N, Kroemer G (2002) Apoptosis-inducing factor (AIF): a novel caspase-independent death effector released from mitochondria. Biochimie 84:215–222CrossRefPubMedGoogle Scholar
  41. 41.
    Cregan SP, Fortin A, MacLaurin JG, Callaghan SM, Cecconi F, Yu SW, Dawson TM, Dawson VL, Park DS, Kroemer G, Slack RS (2002) Apoptosis-inducing factor is involved in the regulation of caspase-independent neuronal cell death. J Cell Biol 158:507–517CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Shih CM, Wu JS, Ko WC, Wang LF, Wei YH, Liang HF, Chen YC, Chen CT (2003) Mitochondria-mediated caspase-independent apoptosis induced by cadmium in normal human lung cells. J Cell Biochem 89:335–347CrossRefPubMedGoogle Scholar
  43. 43.
    Plesnila N, Zhu C, Culmsee C, Groger M, Moskowitz MA, Blomgren K (2004) Nuclear translocation of apoptosis-inducing factor after focal cerebral ischemia. J Cereb Blood Flow Metab 24:458–466CrossRefPubMedGoogle Scholar
  44. 44.
    Zhu C, Qiu L, Wang X, Hallin U, Cande C, Kroemer G, Hagberg H, Blomgren K (2003) Involvement of apoptosis-inducing factor in neuronal death after hypoxia-ischemia in the neonatal rat brain. J Neurochem 86:306–317CrossRefPubMedGoogle Scholar
  45. 45.
    Chaitanya GV, Babu PP (2008) Multiple apoptogenic proteins are involved in the nuclear translocation of apoptosis inducing factor during transient focal cerebral ischemia in rat. Brain Res 1246:178–190CrossRefPubMedGoogle Scholar
  46. 46.
    Cao G, Xing J, Xiao X, Liou AK, Gao Y, Yin XM, Clark RS, Graham SH, Chen J (2007) Critical role of calpain I in mitochondrial release of apoptosis-inducing factor in ischemic neuronal injury. J Neurosci 27:9278–9293CrossRefPubMedGoogle Scholar
  47. 47.
    Abd Elmageed ZY, Naura AS, Errami Y, Zerfaoui M (2012) The poly(ADP-ribose) polymerases (PARPs): new roles in intracellular transport. Cell Signal 24:1–8CrossRefPubMedGoogle Scholar
  48. 48.
    Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ, Poirier GG, Dawson TM, Dawson VL (2002) Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 297:259–263CrossRefPubMedGoogle Scholar
  49. 49.
    Chiarugi A (2002) Poly(ADP-ribose) polymerase: killer or conspirator? The ‘suicide hypothesis’ revisited. Trends Pharmacol Sci 23:122–129CrossRefPubMedGoogle Scholar
  50. 50.
    Carmichael ST (2008) Themes and strategies for studying the biology of stroke recovery in the poststroke epoch. Stroke 39:1380–1388CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Font MA, Arboix A, Krupinski J (2010) Angiogenesis, neurogenesis and neuroplasticity in ischemic stroke. Curr Cardiol Rev 6:238–244CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Gangaraju S, Sultan K, Whitehead SN, Nilchi L, Slinn J, Li X, Hou ST (2013) Cerebral endothelial expression of Robo1 affects brain infiltration of polymorphonuclear neutrophils during mouse stroke recovery. Neurobiol Dis 54:24–31CrossRefPubMedGoogle Scholar
  53. 53.
    Hou ST, Keklikian A, Slinn J, O’Hare M, Jiang SX, Aylsworth A (2008) Sustained up-regulation of semaphorin 3A, neuropilin1, and doublecortin expression in ischemic mouse brain during long-term recovery. Biochem Biophys Res Commun 367:109–115CrossRefPubMedGoogle Scholar
  54. 54.
    Soleman S, Filippov MA, Dityatev A, Fawcett JW (2013) Targeting the neural extracellular matrix in neurological disorders. Neuroscience 253:194–213CrossRefPubMedGoogle Scholar
  55. 55.
    Kolodkin AL, Matthes DJ, Goodman CS (1993) The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell 75:1389–1399CrossRefPubMedGoogle Scholar
  56. 56.
    Luo Y, Raible D, Raper JA (1993) Collapsin: a protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell 75:217–227CrossRefPubMedGoogle Scholar
  57. 57.
    Pekcec A, Yigitkanli K, Jung JE, Pallast S, Xing C, Antipenko A, Minchenko M, Nikolov DB, Holman TR, Lo EH, van Leyen K (2013) Following experimental stroke, the recovering brain is vulnerable to lipoxygenase-dependent semaphorin signaling. FASEB J 27:437–445CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Acevedo LM, Barillas S, Weis SM, Gothert JR, Cheresh DA (2008) Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor. Blood 111:2674–2680CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Nada SE, Tulsulkar J, Shah ZA (2013) Heme oxygenase 1-mediated neurogenesis is enhanced by ginkgo biloba (EGb 761(R)) after permanent ischemic stroke in mice. Mol Neurobiol 49(2):945–56CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Song H, Ming G, He Z, Lehmann M, McKerracher L, Tessier-Lavigne M, Poo M (1998) Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. Science 281:1515–1518CrossRefPubMedGoogle Scholar
  61. 61.
    Suchting S, Bicknell R, Eichmann A (2006) Neuronal clues to vascular guidance. Exp Cell Res 312:668–675CrossRefPubMedGoogle Scholar
  62. 62.
    Ohab JJ, Fleming S, Blesch A, Carmichael ST (2006) A neurovascular niche for neurogenesis after stroke. J Neurosci 26:13007–13016CrossRefPubMedGoogle Scholar
  63. 63.
    Shruster A, Ben-Zur T, Melamed E, Offen D (2012) Wnt signaling enhances neurogenesis and improves neurological function after focal ischemic injury. PLoS One 7:e40843CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Hirabayashi Y, Itoh Y, Tabata H, Nakajima K, Akiyama T, Masuyama N, Gotoh Y (2004) The Wnt/beta-catenin pathway directs neuronal differentiation of cortical neural precursor cells. Development 131:2791–2801CrossRefPubMedGoogle Scholar
  65. 65.
    Ho KS, Scott MP (2002) Sonic hedgehog in the nervous system: functions, modifications and mechanisms. Curr Opin Neurobiol 12:57–63CrossRefPubMedGoogle Scholar
  66. 66.
    Galvez-Contreras AY, Gonzalez-Castaneda RE, Luquin S, Gonzalez-Perez O (2012) Role of fibroblast growth factor receptors in astrocytic stem cells. Curr Signal Transduct Ther 7:81–86CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Shimojo H, Ohtsuka T, Kageyama R (2011) Dynamic expression of notch signaling genes in neural stem/progenitor cells. Front Neurosci 5:78CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Rosso SB, Inestrosa NC (2013) WNT signaling in neuronal maturation and synaptogenesis. Front Cell Neurosci 7:103CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Oliva CA, Vargas JY, Inestrosa NC (2013) Wnts in adult brain: from synaptic plasticity to cognitive deficiencies. Front Cell Neurosci 7:224CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Toledo EM, Colombres M, Inestrosa NC (2008) Wnt signaling in neuroprotection and stem cell differentiation. Prog Neurobiol 86:281–296CrossRefPubMedGoogle Scholar
  71. 71.
    Varela-Nallar L, Inestrosa NC (2013) Wnt signaling in the regulation of adult hippocampal neurogenesis. Front Cell Neurosci 7:100CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Xing Y, Zhang X, Zhao K, Cui L, Wang L, Dong L, Li Y, Liu Z, Wang C, Zhang X, Zhu C, Qiao H, Ji Y, Cao X (2012) Beneficial effects of sulindac in focal cerebral ischemia: a positive role in Wnt/beta-catenin pathway. Brain Res 1482:71–80CrossRefPubMedGoogle Scholar
  73. 73.
    Hur EM, Zhou FQ (2010) GSK3 signalling in neural development. Nat Rev Neurosci 11:539–551CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Veeman MT, Axelrod JD, Moon RT (2003) A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling. Dev Cell 5:367–377CrossRefPubMedGoogle Scholar
  75. 75.
    Grumolato L, Liu G, Mong P, Mudbhary R, Biswas R, Arroyave R, Vijayakumar S, Economides AN, Aaronson SA (2010) Canonical and noncanonical Wnts use a common mechanism to activate completely unrelated coreceptors. Genes Dev 24:2517–2530CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Lu Q, Harris VA, Sun X, Hou Y, Black SM (2013) Ca(2)(+)/calmodulin-dependent protein kinase II contributes to hypoxic ischemic cell death in neonatal hippocampal slice cultures. PLoS One 8:e70750CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Repici M, Centeno C, Tomasi S, Forloni G, Bonny C, Vercelli A, Borsello T (2007) Time-course of c-Jun N-terminal kinase activation after cerebral ischemia and effect of D-JNKI1 on c-Jun and caspase-3 activation. Neuroscience 150:40–49CrossRefPubMedGoogle Scholar
  78. 78.
    Schlessinger K, Hall A, Tolwinski N (2009) Wnt signaling pathways meet Rho GTPases. Genes Dev 23:265–277CrossRefPubMedGoogle Scholar
  79. 79.
    Arimura N, Menager C, Kawano Y, Yoshimura T, Kawabata S, Hattori A, Fukata Y, Amano M, Goshima Y, Inagaki M, Morone N, Usukura J, Kaibuchi K (2005) Phosphorylation by Rho kinase regulates CRMP-2 activity in growth cones. Mol Cell Biol 25:9973–9984CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Hou ST, Jiang SX, Aylsworth A, Ferguson G, Slinn J, Hu H, Leung T, Kappler J, Kaibuchi K (2009) CaMKII phosphorylates collapsin response mediator protein 2 and modulates axonal damage during glutamate excitotoxicity. J Neurochem 111:870–881CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical SciencesUniversity of ToledoToledoUSA

Personalised recommendations