DP-b99 is a membrane-activated chelator of zinc and calcium ions, recently proposed as a therapeutic agent. Matrix metalloproteinases (MMPs) are zinc-dependent extracellularly operating proteases that might contribute to synaptic plasticity, learning and memory under physiological conditions. In excessive amounts these enzymes contribute to a number of neuronal pathologies ranging from the stroke to neurodegeneration and epileptogenesis. In the present study, we report that DP-b99 delays onset and severity of PTZ-induced seizures in mice, as well as displays neuroprotective effect on kainate excitotoxicity in hippocampal organotypic slices and furthermore blocks morphological reorganization of the dendritic spines evoked by a major neuronal MMP, MMP-9. Taken together, our findings suggest that DP-b99 may inhibit neuronal plasticity driven by MMPs, in particular MMP-9, and thus may be considered as a therapeutic agent under conditions of aberrant plasticity, such as those subserving epileptogenesis.
References
[1]
Angel A, Bar A, Horovitz T, Taler G, Krakovsky M, et al. (2002) Metal ion chelation in neurodegenerative disorders. Drug Develop Res 300–309.
[2]
Diener HC, Schneider D, Lampl Y, Bornstein NM, Kozak A, et al. (2008) DP-b99, a membrane-activated metal ion chelator, as neuroprotective therapy in ischemic stroke. Stroke 39: 1774–1778. doi: 10.1161/strokeaha.107.506378
[3]
Rosenberg G, Bornstein N, Diener HC, Gorelick PB, Shuaib A, et al. (2011) The Membrane-Activated Chelator Stroke Intervention (MACSI) Trial of DP-b99 in acute ischemic stroke: a randomized, double-blind, placebo-controlled, multinational pivotal phase III study. Int J Stroke 6: 362–367. doi: 10.1111/j.1747-4949.2011.00608.x
[4]
Lees KR, Bornstein N, Diener HC, Gorelick PB, Rosenberg G, et al. (2013) Results of Membrane-Activated Chelator Stroke Intervention randomized trial of DP-b99 in acute ischemic stroke. Stroke 44: 580–584. doi: 10.1161/strokeaha.111.000013
[5]
Barkalifa R, Hershfinkel M, Friedman JE, Kozak A, Sekler I (2009) The lipophilic zinc chelator DP-b99 prevents zinc induced neuronal death. Eur J Pharmacol 618: 15–21. doi: 10.1016/j.ejphar.2009.07.019
[6]
Choi DW, Koh JY (1998) Zinc and brain injury. Annu Rev Neurosci 21: 347–375. doi: 10.1146/annurev.neuro.21.1.347
[7]
Weiss JH, Sensi SL, Koh JY (2000) Zn(2+): a novel ionic mediator of neural injury in brain disease. Trends Pharmacol Sci 21: 395–401. doi: 10.1016/s0165-6147(00)01541-8
[8]
Friedman J, Rosenberg G, Kozak A (2010) DP-b99, a multi-faceted approach in the teratment of acute ischemic stroke: focus on MMP-9. International Journal of Stroke Vol. 5 suppl. 2141.
[9]
Friedman J, Rosenberg G, Kozak A (2010) DP-b99, a multi-faceted approach in the treatment of acute ischemic stroke: focus on TNF-a converting enzyme (TACE) and calpain. International Journal of Stroke Vol. 5 suppl. 2142.
[10]
Vincenti MP, Brinckerhoff CE (2002) Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: integration of complex signaling pathways for the recruitment of gene-specific transcription factors. Arthritis Res 4: 157–164.
[11]
Rivera S, Khrestchatisky M, Kaczmarek L, Rosenberg GA, Jaworski DM (2010) Metzincin proteases and their inhibitors: foes or friends in nervous system physiology? J Neurosci 30: 15337–15357. doi: 10.1523/jneurosci.3467-10.2010
[12]
Nagase H, Visse R, Murphy G (2006) Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69: 562–573. doi: 10.1016/j.cardiores.2005.12.002
[13]
Szklarczyk A, Lapinska J, Rylski M, McKay RD, Kaczmarek L (2002) Matrix metalloproteinase-9 undergoes expression and activation during dendritic remodeling in adult hippocampus. J Neurosci 22: 920–930.
[14]
Meighan SE, Meighan PC, Choudhury P, Davis CJ, Olson ML, et al. (2006) Effects of extracellular matrix-degrading proteases matrix metalloproteinases 3 and 9 on spatial learning and synaptic plasticity. J Neurochem 96: 1227–1241. doi: 10.1111/j.1471-4159.2005.03565.x
[15]
Nagy V, Bozdagi O, Matynia A, Balcerzyk M, Okulski P, et al. (2006) Matrix metalloproteinase-9 is required for hippocampal late-phase long-term potentiation and memory. J Neurosci 26: 1923–1934. doi: 10.1523/jneurosci.4359-05.2006
[16]
Okulski P, Jay TM, Jaworski J, Duniec K, Dzwonek J, et al. (2007) TIMP-1 abolishes MMP-9-dependent long-lasting long-term potentiation in the prefrontal cortex. Biol Psychiatry 62: 359–362. doi: 10.1016/j.biopsych.2006.09.012
[17]
Huntley GW, Elste AM, Patil SB, Bozdagi O, Benson DL, et al. (2012) Synaptic loss and retention of different classic cadherins with LTP-associated synaptic structural remodeling in vivo. Hippocampus 22: 17–28. doi: 10.1002/hipo.20859
[18]
Wilczynski GM, Konopacki FA, Wilczek E, Lasiecka Z, Gorlewicz A, et al. (2008) Important role of matrix metalloproteinase 9 in epileptogenesis. J Cell Biol 180: 1021–1035. doi: 10.1083/jcb.200708213
[19]
Mizoguchi H, Nakade J, Tachibana M, Ibi D, Someya E, et al. (2011) Matrix metalloproteinase-9 contributes to kindled seizure development in pentylenetetrazole-treated mice by converting pro-BDNF to mature BDNF in the hippocampus. J Neurosci 31: 12963–12971. doi: 10.1523/jneurosci.3118-11.2011
[20]
Morimoto K, Fahnestock M, Racine RJ (2004) Kindling and status epilepticus models of epilepsy: rewiring the brain. Prog Neurobiol 73: 1–60. doi: 10.1016/j.pneurobio.2004.03.009
[21]
Racine RJ (1972) Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 32: 281–294. doi: 10.1016/0013-4694(72)90177-0
[22]
Palmiter RD, Cole TB, Quaife CJ, Findley SD (1996) ZnT-3, a putative transporter of zinc into synaptic vesicles. Proc Natl Acad Sci U S A 93: 14934–14939. doi: 10.1073/pnas.93.25.14934
[23]
Bagri A, Cheng HJ, Yaron A, Pleasure SJ, Tessier-Lavigne M (2003) Stereotyped pruning of long hippocampal axon branches triggered by retraction inducers of the semaphorin family. Cell 113: 285–299. doi: 10.1016/s0092-8674(03)00267-8
[24]
Michaluk P, Kolodziej L, Mioduszewska B, Wilczynski GM, Dzwonek J, et al. (2007) Beta-dystroglycan as a target for MMP-9, in response to enhanced neuronal activity. J Biol Chem 282: 16036–16041. doi: 10.1074/jbc.m700641200
[25]
Jourquin J, Tremblay E, Decanis N, Charton G, Hanessian S, et al. (2003) Neuronal activity-dependent increase of net matrix metalloproteinase activity is associated with MMP-9 neurotoxicity after kainate. Eur J Neurosci 18: 1507–1517. doi: 10.1046/j.1460-9568.2003.02876.x
[26]
Chaturvedi M, Figiel I, Sreedhar B, Kaczmarek L (2012) Neuroprotection from tissue inhibitor of metalloproteinase-1 and its nanoparticles. Neurochem Int 61: 1065–1071. doi: 10.1016/j.neuint.2012.07.023
[27]
Michaluk P, Wawrzyniak M, Alot P, Szczot M, Wyrembek P, et al. (2011) Influence of matrix metalloproteinase MMP-9 on dendritic spine morphology. J Cell Sci 124: 3369–3380. doi: 10.1242/jcs.090852
[28]
Ruszczycki B, Szepesi Z, Wilczynski GM, Bijata M, Kalita K, et al. (2012) Sampling issues in quantitative analysis of dendritic spines morphology. BMC Bioinformatics 13: 213. doi: 10.1186/1471-2105-13-213
[29]
Knapska E, Lioudyno V, Kiryk A, Mikosz M, Gorkiewicz T, et al. (2013) Reward learning requires activity of matrix metalloproteinase-9 in the central amygdala. J Neurosci 33: 14591–14600. doi: 10.1523/jneurosci.5239-12.2013
[30]
Mioduszewska B, Jaworski J, Szklarczyk AW, Klejman A, Kaczmarek L (2008) Inducible cAMP early repressor (ICER)-evoked delayed neuronal death in the organotypic hippocampal culture. J Neurosci Res 86: 61–70. doi: 10.1002/jnr.21469
[31]
Rosenberg G, Angel I, Kozak A (2005) Clinical pharmacology of DP-b99 in healthy volunteers: first administration to humans. Br J Clin Pharmacol 60: 7–16. doi: 10.1111/j.1365-2125.2005.02378.x
[32]
Agrawal S, Anderson P, Durbeej M, van Rooijen N, Ivars F, et al. (2006) Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. J Exp Med 203: 1007–1019. doi: 10.1084/jem.20051342
[33]
Wang J, Tsirka SE (2005) Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage. Brain 128: 1622–1633. doi: 10.1093/brain/awh489
[34]
Zagulska-Szymczak S, Filipkowski RK, Kaczmarek L (2001) Kainate-induced genes in the hippocampus: lessons from expression patterns. Neurochem Int 38: 485–501. doi: 10.1016/s0197-0186(00)00101-7
[35]
Mello LE, Cavalheiro EA, Tan AM, Kupfer WR, Pretorius JK, et al. (1993) Circuit mechanisms of seizures in the pilocarpine model of chronic epilepsy: cell loss and mossy fiber sprouting. Epilepsia 34: 985–995. doi: 10.1111/j.1528-1157.1993.tb02123.x
[36]
Okazaki MM, Evenson DA, Nadler JV (1995) Hippocampal mossy fiber sprouting and synapse formation after status epilepticus in rats: visualization after retrograde transport of biocytin. J Comp Neurol 352: 515–534. doi: 10.1002/cne.903520404
[37]
Buckmaster PS, Zhang GF, Yamawaki R (2002) Axon sprouting in a model of temporal lobe epilepsy creates a predominantly excitatory feedback circuit. J Neurosci 22: 6650–6658.
[38]
Wang XB, Bozdagi O, Nikitczuk JS, Zhai ZW, Zhou Q, et al. (2008) Extracellular proteolysis by matrix metalloproteinase-9 drives dendritic spine enlargement and long-term potentiation coordinately. Proc Natl Acad Sci U S A 105: 19520–19525. doi: 10.1073/pnas.0807248105
[39]
Conant K, Wang Y, Szklarczyk A, Dudak A, Mattson MP, et al. (2010) Matrix metalloproteinase-dependent shedding of intercellular adhesion molecule-5 occurs with long-term potentiation. Neuroscience 166: 508–521. doi: 10.1016/j.neuroscience.2009.12.061
[40]
Tian L, Stefanidakis M, Ning L, Van Lint P, Nyman-Huttunen H, et al. (2007) Activation of NMDA receptors promotes dendritic spine development through MMP-mediated ICAM-5 cleavage. J Cell Biol 178: 687–700. doi: 10.1083/jcb.200612097
[41]
Dziembowska M, Wlodarczyk J (2012) MMP9: a novel function in synaptic plasticity. Int J Biochem Cell Biol 44: 709–713. doi: 10.1016/j.biocel.2012.01.023
[42]
Wiera G, Wozniak G, Bajor M, Kaczmarek L, Mozrzymas JW (2013) Maintenance of long-term potentiation in hippocampal mossy fiber-CA3 pathway requires fine-tuned MMP-9 proteolytic activity. Hippocampus 23: 529–543. doi: 10.1002/hipo.22112
[43]
Bilousova TV, Dansie L, Ngo M, Aye J, Charles JR, et al. (2009) Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model. J Med Genet 46: 94–102. doi: 10.1136/jmg.2008.061796
[44]
Vezzani A, Balosso S, Ravizza T (2008) The role of cytokines in the pathophysiology of epilepsy. Brain Behav Immun 22: 797–803. doi: 10.1016/j.bbi.2008.03.009
[45]
Walker L, Sills GJ (2012) Inflammation and epilepsy: the foundations for a new therapeutic approach in epilepsy? Epilepsy Curr 12: 8–12. doi: 10.5698/1535-7511-12.1.8
[46]
Vezzani A, Moneta D, Conti M, Richichi C, Ravizza T, et al. (2000) Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice. Proc Natl Acad Sci U S A 97: 11534–11539. doi: 10.1073/pnas.190206797
[47]
Zhou L, Yan C, Gieling RG, Kida Y, Garner W, et al. (2009) Tumor necrosis factor-alpha induced expression of matrix metalloproteinase-9 through p21-activated kinase-1. BMC Immunol 10: 15. doi: 10.1186/1471-2172-10-15
