The authors thank Dr. R. E. Williams of this institute for providing the Ac-FKKSFKL-NH2 PKC substrate, D. Song for technical support, and B. Chakravarthy and Y. Wang for constructive discussions. This investigation was supported in part by the Astra/Canada Neuroprotection Network research collaboration jointly funded by the National Research Council Canada and Astra Arcus and grant ST2715 of the Heart and Stroke Foundation of Ontario.

  • 1
    Aderem A. (1992) The MARCKS brothers : a family of protein kinase C substrates.Cell 71,713716.
  • 2
    Altar C.A., Boylan C.B., Fritsche M., Jones B.E., Jackson C., Wiegand S.J., Lindsay R.M., Hyman C. (1994) Efficacy of brain-derived neurotrophic factor and neurotrophin-3 on neurochemical and behavioral deficits associated with partial nigrostriatal dopamine lesions.J. Neurochem. 63,10211032.
  • 3
    Ballarin M., Ernfors P., Lindefors N., Persson H. (1991) Hippocampal damage and kainic acid injection induce a rapid increase in mRNA for BDNF and NGF in the rat brain.Exp. Neurol. 114,3543.
  • 4
    Beck T., Lindholm D., Castren E., Wree A. (1994) Brain-derived neurotrophic factor protects against ischemic cell damage in rat hippocampus.J. Cereb. Blood Flow Metab. 14,689692.
  • 5
    Blackshear P.J. (1993) The MARCKS family of cellular protein kinase C substrates.J. Biol. Chem. 268,15011504.
  • 6
    Blumberg P.M., Acs G., Acs P., Areces L.B., Kazanietz M.G., Lewin N.E., Szallasi Z. (1995) Protein kinase C in cell signaling : strategies for the development of selective inhibitors.Agents Actions Suppl. 47,87100.
  • 7
    Busto R., Globus M.Y., Neary J.T., Ginsberg M.D. (1994) Regional alterations of protein kinase C activity following transient cerebral ischemia : effects of intraischemic brain temperature modulation.J. Neurochem. 63 10951103.
  • 8
    Cardell M. & Wieloch T. (1993) Time course of the translocation and inhibition of protein kinase C during complete cerebral ischemia in the rat.J. Neurochem. 61,13081314.
  • 9
    Cardell M., Bingren H., Wieloch T., Zivin J., Saitoh T. (1990) Protein kinase C is translocated to cell membranes during cerebral ischemia.Neurosci. Lett. 119,228232.
  • 10
    Chakravarthy B.R., Bussey A., Whitfield J.F., Sikorska M., Williams R.E., Durkin J.P. (1991) The direct measurement of protein kinase C (PKC) activity in isolated membranes using a selective peptide substrate.Anal. Biochem. 196,144150.
  • 11
    Chakravarthy B.R., Whitfield J.F., Durkin J.P. (1994) Inactive membrane protein kinase Cs : a possible target for receptor signalling.Biochem. J. 304,809816.
  • 12
    Chakravarthy B.R., Wong J., Durkin J.P. (1995) Evidence that the modulation of membrane-associated protein kinase C activity by an endogenous inhibitor plays a role in N1E-115 murine neuroblastoma cell differentiation.J. Neurochem. 65,15691579.
  • 13
    Chakravarthy B., Wang J., Tremblay R., Atkinson T., Wang F., Li L., Buchan A., Durkin J.P. (1998) Comparison of the changes in protein kinase C induced by glutamate in primary cortical neurons by in vivo cerebral ischemia.Cell. Signal. 10,291295.
  • 14
    Cheng B. & Mattson M.P. (1994) NT-3 and BDNF protect CNS neurons against metabolic/excitotoxic insults.Brain Res. 640,5667.
  • 15
    Comelli M.C., Seren M.S., Guidolin D., Manev R.M., Favaron M., Rimland J.M., Canella R., Negro A., Manev H. (1992) Photochemical stroke and brain-derived neurotrophic factor (BDNF) mRNA expression.Neuroreport 3,473476.
  • 16
    Crumrine R.C., Dubyak G., LaManna J.C. (1990) Decreased protein kinase C activity during cerebral ischemia and after reperfusion in the adult rat.J. Neurochem. 55,20012007.
  • 17
    Cui Q. & Harvey A.R. (1995) At least two mechanisms are involved in the death of retinal ganglion cells following target ablation in neonatal rats.J. Neurosci. 15,81438155.
  • 18
    Cunningham M.E., Stephens R.M., Kaplan D.R., Greene L.A. (1997) Autophosphorylation of activation loop tyrosines regulates signaling by the TRK nerve growth factor receptor.J. Biol. Chem. 272,1095710967.
  • 19
    Dessi F., Charriaut-Marlangue C., Ben-Ari Y. (1992) Anisomycin and cycloheximide protect cerebellar neurons in culture from anoxia.Brain Res. 581,323326.
  • 20
    Dichter M.A. (1978) Rat cortical neurons in cell culture : culture methods, cell morphology, electrophysiology, and synapse formation.Brain Res. 149,279293.
  • 21
    Domańska-Janik K. & Zalewska T. (1992) Effect of brain ischemia on protein kinase C.J. Neurochem. 58,14321439.
  • 22
    Durkin J.P., Tremblay R., Buchan A., Blosser J., Chakravarthy B., Mealing G., Morley P., Song D. (1996) An early loss in membrane protein kinase C activity precedes the excitatory amino acid-induced death of primary cortical neurons.J. Neurochem. 66,951962.
  • 23
    Durkin J.P., Tremblay R., Chakravarthy B., Mealing G., Morley P., Small D., Song D. (1997) Evidence that the early loss of membrane protein kinase C is a necessary step in the excitatory amino acid-induced death of primary cortical neurons.J. Neurochem. 68,14001412.
  • 24
    Ernfors P., Bengzon J., Kokaia Z., Persson H., Lindvall O. (1991) Increased levels of messenger RNAs for neurotrophic factors in the brain during kindling epileptogenesis.Neuron 7,165176.
  • 25
    Freese A., Finklestein S.P., DiFiglia M. (1992) Basic fibroblast growth factor protects striatal neurons in vitro from NMDA-receptor mediated excitotoxicity.Brain Res. 575,351355.
  • 26
    Furukawa K., Estus S., Fu W., Mark R.J., Mattson M.P. (1997) Neuroprotective action of cycloheximide involves induction of bcl-2 and antioxidant pathways.J. Cell Biol. 136,11371149.
  • 27
    Gordge P.C. & Ryves W.J. (1994) Inhibitors of protein kinase C.Cell. Signal. 6,871882.
  • 28
    Hannun Y.A., Loomis C.R., Bell R.M. (1985) Activation of protein kinase C by Triton X-100 mixed micelles containing diacylglycerol and phosphatidylserine.J. Biol. Chem. 260,1003910043.
  • 29
    Heemskerk F.M., Chen H.C., Huang F.L. (1993) Protein kinase C phosphorylates Ser152, Ser156 and Ser163 but not Ser160 of MARCKS in rat brain.Biochem. Biophys. Res. Commun. 190,236241.DOI: 10.1006/bbrc.1993.1036
  • 30
    Isackson P.J., Huntsman M.M., Murray K.D., Gall C.M. (1991) BDNF mRNA expression is increased in adult rat forebrain after limbic seizures : temporal patterns of induction distant from NGF.Neuron 6,937948.
  • 31
    Jarvis C.R., Xiong Z.G., Plant J.R., Churchill D., Lu W.Y., MacVicar B.A., MacDonald J.F. (1997) Neurotrophin modulation of NMDA receptors in cultured murine and isolated rat neurons.J. Neurophysiol. 78,23632371.
  • 32
    Jian Z., Nonaka I., Hattori S., Nakamura S. (1996) Activation of Ras and protection from apoptotic cell death by BDNF in PC12 cells expressing TrkB.Cell. Signal. 8,365370.
  • 33
    Kaplan D.R. & Miller F.D. (1997) Signal transduction by the neurotrophin receptors.Curr. Opin. Cell Biol. 9,213221.
  • 34
    Kato H., Kanellopoulos G.K., Matsuo S., Wu Y.J., Jacquin M.F., Hsu C.Y., Choi D.W., Kouchoukos N.T. (1997) Protection of rat spinal cord from ischemia with dextrorphan and cycloheximide : effects on necrosis and apoptosis.J. Thorac. Cardiovasc. Surg. 114,609618.
  • 35
    Kikkawa U., Takai Y., Minakuchi R., Inohara S., Nishizuki Y. (1982) Calcium-activated, phospholipid-dependent protein kinase from rat brain. Subcellular distribution, purification, and properties.J. Biol. Chem. 257,1334113348.
    Kishimoto A. (1990) Limited proteolysis of protein kinase C by calpain, its possible implication.Adv. Second Messenger Phospho-protein Res. 24,472477.
  • 37
    Klein R., Nanduri V., Jing S.A., Lamballe F., Tapley P., Bryant S., Cordon-Cardo C., Jones K.R., Reichardt L.F., Barcacid M. (1991) The trkB tyrosine protein kinase is a receptor for brain-derived neurotrophic factor and neurotrophin-3.Cell 66,395403.
  • 38
    Kokaia Z., Othberg A., Kokaia M., Lindvall O. (1994) BDNF makes cultured dentate granule cells more resistant to hypoglycaemic damage.Neuroreport 5,12411244.
  • 39
    Kokaia Z., Zhao Q., Kokaia M., Elmer E., Metsis M., Smith M.L., Siesjo B.K., Lindvall O. (1995) Regulation of brain-derived neurotrophic factor gene expression after transient middle cerebral artery occlusion with and without brain damage.Exp. Neurol. 136,7388.
  • 40
    Koketsu N., Berlove D.J., Moskowitz M.A., Kowall N.W., Caday C.G., Finklestein S.P. (1994) Pretreatment with intraventricular basic fibroblast growth factor decreases infarct size following focal cerebral ischemia in rats.Ann. Neurol. 35,451457.
  • 41
    Lewin G.R. & Barde Y.A. (1996) Physiology of the neurotrophins.Annu. Rev. Neurosci. 19,289317.
  • 42
    Lindefors N., Ballarin M., Ernfors P., Falkenberg T., Persson H. (1992) Stimulation of glutamate receptors increases expression of brain-derived neurotrophic factor mRNA in rat hippocampus.Ann. NY Acad. Sci. 648,296299.
  • 43
    Lindholm D., Dechant G., Heisenberg C.P., Thoenen H. (1993) Brain-derived neurotrophic factor is a survival factor for cultured rat cerebellar granule neurons and protects them against glutamate-induced neurotoxicity.Eur. J. Neurosci. 5,14551464.
  • 44
    Louis J.C., Magal E., Brixi A., Steinberg R., Yavin E., Vincedon G. (1991) Reduction of protein kinase C activity in the adult rat brain following transient forebrain ischemia.Brain Res. 541,171174.
  • 45
    Mattson M.P., Murrain M., Guthrie P.B., Kater S.B. (1989) Fibroblast growth factor and glutamate : opposing roles in the generation and degeneration of hippocampal neuroarchitecture.J. Neurosci. 9,37283740.
  • 46
    Mudo G., Persson H., Timmusk T., Funakoshi H., Bindoni M., Belluardo N. (1993) Increased expression of trkB and trkC messenger RNAs in the rat forebrain after focal mechanical injury.Neuroscience 57,901912.
  • 47
    Nozaki K., Finklestein S.P., Beal M.F. (1993) Delayed administration of basic fibroblast growth factor protects against N-methyl-d-aspartate neurotoxicity in neonatal rats. Eur. J. Pharmacol. 232,295297.
  • 48
    Pang L., Sawada T., Decker S.J., Saltiel A.R. (1995) Inhibition of MAP kinase kinase blocks the differentiation of PC-12 cells induced by nerve growth factor.J. Biol. Chem. 270,1358513588.
  • 49
    Robinson P.J., Liu J.P., Chen W., Wenzel T. (1993) Activation of protein kinase C in vitro and in intact cells or synaptosomes determined by acetic acid extraction of MARCKS.Anal. Biochem. 210,172178.DOI: 10.1006/abio.1993.1169
  • 50
    Schreiber S.S., Tocco G., Najm I., Thompson R.F., Baudry M. (1993) Cycloheximide prevents kainate-induced neuronal death and c-fos expression in adult rat brain.J. Mol. Neurosci. 4,149159.
  • 51
    Segal R. & Greenberg M.E. (1996) Intracellular signalling pathways activated by neurotrophic factors.Annu. Rev. Neurosci. 19,463489.
  • 52
    Senger D.L. & Campenot R.B. (1997) Rapid retrograde tyrosine phosphorylation of trkA and other proteins in rat sympathetic neurons in compartmented cultures.J. Cell Biol. 138,411421.
  • 53
    Shimohama S., Tamura Y., Akaike A., Tsukahara T., Ohara O., Watanabe S., Kimura J. (1993) Brain-derived neurotrophic factor pretreatment exerts a partially protective effect against glutamate-induced neurotoxicity in cultured rat cortical neurons.Neurosci. Lett. 164,5558.
  • 54
    Small D.L., Monette R., Chakravarthy B., Durkin J., Barbe G., Mealing G., Morley P., Buchan A.M. (1996) Mechanisms of 1S, 3R-ACPD-induced neuroprotection in rat hippocampal slices subjected to oxygen and glucose deprivation. Neuropharmacology 35,10371048.
  • 55
    Small D.L., Murray C.L., Mealing G.A.R., Poulter M.O., Buchan A.M., Morley P. (1998) Brain derived neurotrophic factor induction of N-methyl-d-aspartate receptor subunit NR2A expression in cultured rat cortical neurons. Neurosci. Lett. 252,211214.
  • 56
    Spina M.B., Squinto S.P., Miller J., Lindsay R.M., Hyman C. (1992) Brain-derived neurotrophic factor protects dopamine neurons against 6-hydroxydopamine and N-methyl-4-phenylpyridinium ion toxicity : involvement of the glutathione system. J. Neurochem. 59,99106.
  • 57
    Stephens R.M., Loeb D.M., Copeland T.D., Pawson T., Greene L.A., Kaplan D.R. (1994) Trk receptors use redundant signal transduction pathways involving SHC and PLC-gamma 1 to mediate NGF responses.Neuron 12,691705.
  • 58
    Williams R.E., Chakravarthy B.R., Sikorska M., Whitfield J.F., Durkin J.P. (1991) A protein kinase C substrate peptide derived from MARCKS protein inChemistry, Structure and Biology (River J. and Smilli J. A., eds), pp. 903927. ESCOM, Amsterdam.
  • 59
    Yamashita K., Wiessner C., Lindholm D., Thoenen H., Hossmann K.A. (1997) Post-occlusion treatment with BDNF reduces infarct size in a model of permanent occlusion of the middle cerebral artery in rat.Metab. Brain Dis. 12,271280.
  • 60
    Yu O. & Chuang D.M. (1997) Neurotrophin protection against toxicity induced by low potassium and nitroprusside in cultured cerebellar granule neurons.J. Neurochem. 68,6877.
  • 61
    Zirrgiebel U., Ohga Y., Carter B., Berninger B., Inagaki N., Thoenen H., Lindholm D. (1995) Characterization of TrkB receptor-mediated signaling pathways in rat cerebellar granule neurons : involvement of protein kinase C in neuronal survival.J. Neurochem. 65,22412250.