Multifunctional drug treatment in neurotrauma (original) (raw)
Summary
Although the concepts of secondary injury and neuroprotection after neurotrauma are experimentally well supported, clinical trials of neuroprotective agents in traumatic brain injury or spinal cord injury have been disappointing. Most strategies to date have used drugs directed toward a single pathophysiological mechanism that contributes to early necrotic cell death. Given these failures, recent research has increasingly focused on multifunctional (i.e., multipotential, pluripotential) agents that target multiple injury mechanisms, particularly those that occur later after the insult. Here we review two such approaches that show particular promise in experimental neurotrauma: cell cycle inhibitors and small cyclized peptides. Both show extended therapeutic windows for treatment and appear to share at least one important target.
Key Words: Neurotrauma, neuroprotection, treatment, cell cycle inhibitors, small cyclized peptides
References
- 1.Yakovlev AG, Faden AI. Mechanisms of neural cell death: implications for development of neuroprotective treatment strategies. NeuroRX. 2004;1:5–16. doi: 10.1602/neurorx.1.1.5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Faden AI, Stoica B. Neuroprotection: challenges and opportunities. Arch Neurol. 2007;64:794–800. doi: 10.1001/archneur.64.6.794. [DOI] [PubMed] [Google Scholar]
- 3.Faden AI. Neuroprotection and traumatic brain injury: theoretical option or realistic proposition. Curr Opin Neurol. 2002;15:707–712. doi: 10.1097/00019052-200212000-00008. [DOI] [PubMed] [Google Scholar]
- 4.Dumont RJ, Okonkwo DO, Verma S, et al. Acute spinal cord injury, part I: pathophysiologic mechanisms. Clin Neuropharmacol. 2001;24:254–264. doi: 10.1097/00002826-200109000-00002. [DOI] [PubMed] [Google Scholar]
- 5.Tator CH. Experimental and clinical studies of the pathophysiology and management of acute spinal cord injury. J Spinal Cord Med. 1996;19:206–214. doi: 10.1080/10790268.1996.11719436. [DOI] [PubMed] [Google Scholar]
- 6.Olney JW. Excitotoxin-mediated neuron death in youth and old age. Prog Brain Res. 1990;86:37–51. doi: 10.1016/S0079-6123(08)63165-9. [DOI] [PubMed] [Google Scholar]
- 7.Faden AI. Comparison of single and combination drug treatment strategies in experimental brain trauma. J Neurotrauma. 1993;10:91–100. doi: 10.1089/neu.1993.10.91. [DOI] [PubMed] [Google Scholar]
- 8.Faden AI, Jacobs TP, Holaday JW. Thyrotropin-releasing hormone improves neurologic recovery after spinal trauma in cats. N Engl J Med. 1981;305:1063–1067. doi: 10.1056/NEJM198110293051806. [DOI] [PubMed] [Google Scholar]
- 9.Faden AI, Jacobs TP, Smith MT. Thyrotropin-releasing hormone in experimental spinal injury: dose response and late treatment. Neurology. 1984;34:1280–1284. doi: 10.1212/wnl.34.10.1280. [DOI] [PubMed] [Google Scholar]
- 10.Faden AI, Yum SW, Lemke M, Vink R. Effects of TRH-analog treatment on tissue cations, phospholipids and energy metabolism after spinal cord injury. J Pharmacol Exp Ther. 1990;255:608–614. [PubMed] [Google Scholar]
- 11.Lux WE, Feuerstein G, Faden AI. Alteration of leukotriene D4 hypotension by thyrotropin releasing hormone. Nature. 1983;302:822–824. doi: 10.1038/302822a0. [DOI] [PubMed] [Google Scholar]
- 12.Feuerstein G, Lux WE, Ezra D, Hayes EC, Snyder F, Faden AI. Thyrotropin-releasing hormone blocks the hypotensive effects of platelet-activating factor in the unanesthetized guinea pig. J Cardiovasc Pharmacol. 1985;7:335–340. doi: 10.1097/00005344-198503000-00020. [DOI] [PubMed] [Google Scholar]
- 13.McIntosh TK, Vink R, Faden AI. An analogue of thyrotropin-releasing hormone improves outcome after brain injury: 31P-NMR studies. Am J Physiol. 1988;254:R785–792. doi: 10.1152/ajpregu.1988.254.5.R785. [DOI] [PubMed] [Google Scholar]
- 14.McIntosh TK, Vink R, Faden AI. Beneficial effect of the TRH analog CG-3703 on outcome and survival following traumatic brain injury in rats. Prog Clin Biol Res. 1988;264:415–420. [PubMed] [Google Scholar]
- 15.Faden AI. TRH analog YM-14673 improves outcome following traumatic brain and spinal cord injury in rats: dose-response studies. Brain Res. 1989;486:228–235. doi: 10.1016/0006-8993(89)90509-X. [DOI] [PubMed] [Google Scholar]
- 16.Faden AI, Fox GB, Fan L, et al. Novel TRH analog improves motor and cognitive recovery after traumatic brain injury in rodents. Am J Physiol. 1999;277:R1196–1204. doi: 10.1152/ajpregu.1999.277.4.R1196. [DOI] [PubMed] [Google Scholar]
- 17.Faden AI, Sacksen I, Noble LJ. Structure-activity relationships of TRH analogs in rat spinal cord injury. Brain Res. 1988;448:287–293. doi: 10.1016/0006-8993(88)91265-6. [DOI] [PubMed] [Google Scholar]
- 18.Wang GL, Zhu C. Effects of thyrotropin-releasing hormone on acute experimental traumatic head injury in cats. Chin Med J (Engl) 1991;104:939–944. [PubMed] [Google Scholar]
- 19.Tanaka K, Ogawa N, Asanuma M, Kondo Y. Thyrotropin releasing hormone prevents abnormalities of cortical acetylcholine and monoamines in mice following head injury. Regul Pept. 1997;70:173–178. doi: 10.1016/S0167-0115(97)01013-6. [DOI] [PubMed] [Google Scholar]
- 20.Arias MJ. Treatment of experimental spinal cord injury with TRH, naloxone, and dexamethasone. Surg Neurol. 1987;28:335–338. doi: 10.1016/0090-3019(87)90054-1. [DOI] [PubMed] [Google Scholar]
- 21.Behrmann DL, Bresnahan JC, Beattie MS. Modeling of acute spinal cord injury in the rat: neuroprotection and enhanced recovery with methylprednisolone, U-74006F and YM-14673. Exp Neurol. 1994;126:61–75. doi: 10.1006/exnr.1994.1042. [DOI] [PubMed] [Google Scholar]
- 22.Puniak MA, Freeman GM, Agresta CA, Van Newkirk L, Barone CA, Salzman SK. Comparison of a serotonin antagonist, opioid antagonist, and TRH analog for the acute treatment of experimental spinal trauma. J Neurotrauma. 1991;8:193–203. doi: 10.1089/neu.1991.8.193. [DOI] [PubMed] [Google Scholar]
- 23.Pitts LH, Ross A, Chase GA, Faden AI. Treatment with thyrotropin-releasing hormone (TRH) in patients with traumatic spinal cord injuries. J Neurotrauma. 1995;12:235–243. doi: 10.1089/neu.1995.12.235. [DOI] [PubMed] [Google Scholar]
- 24.Friedman TC, Wilk S. Delineation of a particulate thyrotropin-releasing hormone-degrading enzyme in rat brain by the use of specific inhibitors of prolyl endopeptidase and pyroglutamyl peptide hydrolase. J Neurochem. 1986;46:1231–1239. doi: 10.1111/j.1471-4159.1986.tb00643.x. [DOI] [PubMed] [Google Scholar]
- 25.Coggins PJ, McDermott JR, Snell CR, Gibson AM. Thyrotrophin releasing hormone degradation by rat synaptosomal peptidases: production of the metabolite His-Pro. Neuropeptides. 1987;10:147–156. doi: 10.1016/0143-4179(87)90016-3. [DOI] [PubMed] [Google Scholar]
- 26.Faden Knoblach SM, Movsesyan VA, Lea PMt, Cernak I. Novel neuroprotective tripeptides and dipeptides. Ann N Y Acad Sci. 2005;1053:472–481. doi: 10.1196/annals.1344.041. [DOI] [PubMed] [Google Scholar]
- 27.Faden AI, Labroo VM, Cohen LA. Imidazole-substituted analogues of TRH limit behavioral deficits after experimental brain trauma. J Neurotrauma. 1993;10:101–108. doi: 10.1089/neu.1993.10.101. [DOI] [PubMed] [Google Scholar]
- 28.Prasad C. Limited proteolysis and physiological regulation: an example from thyrotropin-releasing hormone metabolism. Thyroid. 1998;8:969–975. doi: 10.1089/thy.1998.8.969. [DOI] [PubMed] [Google Scholar]
- 29.Faden AI, Movsesyan VA, Knoblach SM, Ahmed F, Cernak I. Neuroprotective effects of novel small peptides in vitro and after brain injury. Neuropharmacology. 2005;49:410–424. doi: 10.1016/j.neuropharm.2005.04.001. [DOI] [PubMed] [Google Scholar]
- 30.Faden AI, Fox GB, Di X, et al. Neuroprotective and nootropic actions of a novel cyclized dipeptide after controlled cortical impact injury in mice. J Cereb Blood Flow Metab. 2003;23:355–363. doi: 10.1097/00004647-200303000-00010. [DOI] [PubMed] [Google Scholar]
- 31.Faden AI, Knoblach SM, Cernak I, et al. Novel diketopiperazine enhances motor and cognitive recovery after traumatic brain injury in rats and shows neuroprotection in vitro and in vivo. J Cereb Blood Flow Metab. 2003;23:342–354. doi: 10.1097/00004647-200303000-00009. [DOI] [PubMed] [Google Scholar]
- 32.Faden AI, Knoblach SM, Movsesyan VA, Cernak I. Novel small peptides with neuroprotective and nootropic properties. J Alzheimers Dis. 2004;6:S93–97. doi: 10.3233/jad-2004-6s603. [DOI] [PubMed] [Google Scholar]
- 33.Cernak I, Stoica B, Byrnes KR, Di Giovanni S, Faden AI. Role of the cell cycle in the pathobiology of central nervous system trauma. Cell Cycle. 2005;4:1286–1293. doi: 10.4161/cc.4.9.1996. [DOI] [PubMed] [Google Scholar]
- 34.Byrnes KR, Stoica BA, Fricke S, Di Giovanni S, Faden AI. Cell cycle activation contributes to post-mitotic cell death and secondary damage after spinal cord injury. Brain. 2007;130:2977–2992. doi: 10.1093/brain/awm179. [DOI] [PubMed] [Google Scholar]
- 35.Kitagawa M, Higashi H, Jung HK, et al. The consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2. Embo J. 1996;15:7060–7069. [PMC free article] [PubMed] [Google Scholar]
- 36.Sears RC, Nevins JR. Signaling networks that link cell proliferation and cell fate. J Biol Chem. 2002;277:11617–11620. doi: 10.1074/jbc.R100063200. [DOI] [PubMed] [Google Scholar]
- 37.Di Giovanni S, Knoblach SM, Brandoli C, Aden SA, Hoffman EP, Faden AI. Gene profiling in spinal cord injury shows role of cell cycle in neuronal death. Ann Neurol. 2003;53:454–468. doi: 10.1002/ana.10472. [DOI] [PubMed] [Google Scholar]
- 38.De Biase A, Knoblach SM, Di Giovanni S, et al. Gene expression profiling of experimental traumatic spinal cord injury as a function of distance from impact site and injury severity. Physiol Genomics. 2005;22:368–381. doi: 10.1152/physiolgenomics.00081.2005. [DOI] [PubMed] [Google Scholar]
- 39.Kangas A, Nicholson DW, Holtta E. Involvement of CPP32/ Caspase-3 in c-Myc-induced apoptosis. Oncogene. 1998;16:387–398. doi: 10.1038/sj.onc.1201779. [DOI] [PubMed] [Google Scholar]
- 40.Di Giovanni S, Movsesyan V, Ahmed F, et al. Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury. Proc Natl Acad Sci U S A. 2005;102:8333–8338. doi: 10.1073/pnas.0500989102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Strazza M, Luddi A, Brogi A, et al. Activation of cell cycle regulatory proteins in the apoptosis of terminally differentiated oligodendrocytes. Neurochem Res. 2004;29:923–931. doi: 10.1023/B:NERE.0000021236.32785.37. [DOI] [PubMed] [Google Scholar]
- 42.Giovanni A, Wirtz-Brugger F, Keramaris E, Slack R, Park DS. Involvement of cell cycle elements, cyclin-dependent kinases, pRb, and E2F × DP, in B-amyloid-induced neuronal death. J Biol Chem. 1999;274:19011–19016. doi: 10.1074/jbc.274.27.19011. [DOI] [PubMed] [Google Scholar]
- 43.Padmanabhan J, Park DS, Greene LA, Shelanski ML. Role of cell cycle regulatory proteins in cerebellar granule neuron apoptosis. J Neurosci. 1999;19:8747–8756. doi: 10.1523/JNEUROSCI.19-20-08747.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Otsuka Y, Tanaka T, Uchida D, et al. Roles of cyclin-dependent kinase 4 and p53 in neuronal cell death induced by doxorubicin on cerebellar granule neurons in mouse. Neurosci Lett. 2004;365:180–185. doi: 10.1016/j.neulet.2004.04.083. [DOI] [PubMed] [Google Scholar]
- 45.Kruman II, Wersto RP, Cardozo-Pelaez F, et al. Cell cycle activation linked to neuronal cell death initiated by DNA damage. Neuron. 2004;41:549–561. doi: 10.1016/S0896-6273(04)00017-0. [DOI] [PubMed] [Google Scholar]
- 46.Park DS, Morris EJ, Bremner R, et al. Involvement of retinoblastoma family members and E2F/DP complexes in the death of neurons evoked by DNA damage. J Neurosci. 2000;20:3104–3114. doi: 10.1523/JNEUROSCI.20-09-03104.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Park DS, Obeidat A, Giovanni A, Greene LA. Cell cycle regulators in neuronal death evoked by excitotoxic stress: implications for neurodegeneration and its treatment. Neurobiol Aging. 2000;21:771–781. doi: 10.1016/S0197-4580(00)00220-7. [DOI] [PubMed] [Google Scholar]
- 48.Park DS, Levine B, Ferrari G, Greene LA. Cyclin dependent kinase inhibitors and dominant negative cyclin dependent kinase 4 and 6 promote survival of NGF-deprived sympathetic neurons. J Neurosci. 1997;17:8975–8983. doi: 10.1523/JNEUROSCI.17-23-08975.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Wiessner C, Brink I, Lorenz P, Neumann-Haefelin T, Vogel P, Yamashita K. Cyclin D1 messenger RNA is induced in microglia rather than neurons following transient forebrain ischaemia. Neuroscience. 1996;72:947–958. doi: 10.1016/0306-4522(95)00601-X. [DOI] [PubMed] [Google Scholar]
- 50.Kato H, Takahashi A, Itoyama Y. Cell cycle protein expression in proliferating microglia and astrocytes following transient global cerebral ischemia in the rat. Brain Res Bull. 2003;60:215–221. doi: 10.1016/S0361-9230(03)00036-4. [DOI] [PubMed] [Google Scholar]
- 51.Shen A, Liu Y, Zhao J, et al. Temporal-spatial expressions of p27kip1 and its phosphorylation on Serine-10 after acute spinal cord injury in adult rat: implications for post-traumatic glial proliferation. Neurochem Int. 2008;52:1266–1275. doi: 10.1016/j.neuint.2008.01.011. [DOI] [PubMed] [Google Scholar]
- 52.Tanaka T, Tatsuno I, Noguchi Y, et al. Activation of cyclin-dependent kinase 2 (Cdk2) in growth-stimulated rat astrocytes. Geranylgeranylated Rho small GTPase(s) are essential for the induction of cyclin E gene expression. J Biol Chem. 1998;273:26772–26778. doi: 10.1074/jbc.273.41.26772. [DOI] [PubMed] [Google Scholar]
- 53.Lee SC, Liu W, Brosnan CF, Dickson DW. GM-CSF promotes proliferation of human fetal and adult microglia in primary cultures. Glia. 1994;12:309–318. doi: 10.1002/glia.440120407. [DOI] [PubMed] [Google Scholar]
- 54.Hoke A, Silver J. Heterogeneity among astrocytes in reactive gliosis. Perspect Dev Neurobiol. 1994;2:269–274. [PubMed] [Google Scholar]
- 55.Silver J, Miller JH. Regeneration beyond the glial scar. Nat Rev Neurosci. 2004;5:146–156. doi: 10.1038/nrn1326. [DOI] [PubMed] [Google Scholar]
- 56.Ridet JL, Malhotra SK, Privat A, Gage FH. Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci. 1997;20:570–577. doi: 10.1016/S0166-2236(97)01139-9. [DOI] [PubMed] [Google Scholar]
- 57.Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV. Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci. 2004;24:2143–2155. doi: 10.1523/JNEUROSCI.3547-03.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58.Raivich G, Jones LL, Werner A, Bluthmann H, Doetschmann T, Kreutzberg GW. Molecular signals for glial activation: pro- and anti-inflammatory cytokines in the injured brain. Acta Neurochir Suppl. 1999;73:21–30. doi: 10.1007/978-3-7091-6391-7_4. [DOI] [PubMed] [Google Scholar]
- 59.Benveniste EN. Inflammatory cytokines within the central nervous system: sources, function, and mechanism of action. Am J Physiol. 1992;263:C1–16. doi: 10.1152/ajpcell.1992.263.1.C1. [DOI] [PubMed] [Google Scholar]
- 60.Lynch NJ, Willis CL, Nolan CC, et al. Microglial activation and increased synthesis of complement component C1q precedes blood-brain barrier dysfunction in rats. Mol Immunol. 2004;40:709–716. doi: 10.1016/j.molimm.2003.08.009. [DOI] [PubMed] [Google Scholar]
- 61.Pawate S, Shen Q, Fan F, Bhat NR. Redox regulation of glial inflammatory response to lipopolysaccharide and interferongamma. J Neurosci Res. 2004;77:540–551. doi: 10.1002/jnr.20180. [DOI] [PubMed] [Google Scholar]
- 62.Wharton SB, Williams GH, Stoeber K, et al. Expression of Ki67, PCNA and the chromosome replication licensing protein Mcm2 in glial cells of the ageing human hippocampus increases with the burden of Alzheimer-type pathology. Neurosci Lett. 2005;383:33–38. doi: 10.1016/j.neulet.2005.04.019. [DOI] [PubMed] [Google Scholar]
- 63.Yang Y, Mufson EJ, Herrup K. Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer’s disease. J Neurosci. 2003;23:2557–2563. doi: 10.1523/JNEUROSCI.23-07-02557.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64.Yang Y, Geldmacher DS, Herrup K. DNA replication precedes neuronal cell death in Alzheimer’s disease. J Neurosci. 2001;21:2661–2668. doi: 10.1523/JNEUROSCI.21-08-02661.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 65.Gartner U, Bruckner MK, Krug S, Schmetsdorf S, Staufenbiel M, Arendt T. Amyloid deposition in APP23 mice is associated with the expression of cyclins in astrocytes but not in neurons. Acta Neuropathol. 2003;106:535–544. doi: 10.1007/s00401-003-0760-8. [DOI] [PubMed] [Google Scholar]
- 66.Newcomb EW. Flavopiridol: pleiotropic biological effects enhance its anti-cancer activity. Anticancer Drugs. 2004;15:411–419. doi: 10.1097/01.cad.0000127332.06439.47. [DOI] [PubMed] [Google Scholar]
- 67.Meijer L, Raymond E. Roscovitine and other purines as kinase inhibitors. From starfish oocytes to clinical trials. Acc Chem Res. 2003;36:417–425. doi: 10.1021/ar0201198. [DOI] [PubMed] [Google Scholar]
- 68.Dai Y, Grant S. Small molecule inhibitors targeting cyclin-dependent kinases as anticancer agents. Curr Oncol Rep. 2004;6:123–130. doi: 10.1007/s11912-004-0024-3. [DOI] [PubMed] [Google Scholar]
- 69.Swanton C. Cell-cycle targeted therapies. Lancet Oncol. 2004;5:27–36. doi: 10.1016/S1470-2045(03)01321-4. [DOI] [PubMed] [Google Scholar]
- 70.Abraham RT, Acquarone M, Andersen A, et al. Cellular effects of olomoucine, an inhibitor of cyclin-dependent kinases. Biol Cell. 1995;83:105–120. doi: 10.1016/0248-4900(96)81298-6. [DOI] [PubMed] [Google Scholar]
- 71.Bossenmeyer-Pourie C, Chihab R, Schroeder H, Daval JL. Transient hypoxia may lead to neuronal proliferation in the developing mammalian brain: from apoptosis to cell cycle completion. Neuroscience. 1999;91:221–231. doi: 10.1016/S0306-4522(98)00565-X. [DOI] [PubMed] [Google Scholar]
- 72.Jorda EG, Verdaguer E, Canudas AM, et al. Neuroprotective action of flavopiridol, a cyclin-dependent kinase inhibitor, in colchicine-induced apoptosis. Neuropharmacology. 2003;45:672–683. doi: 10.1016/S0028-3908(03)00204-1. [DOI] [PubMed] [Google Scholar]
- 73.Verdaguer E, Jimenez A, Canudas AM, et al. Inhibition of cell cycle pathway by flavopiridol promotes survival of cerebellar granule cells after an excitotoxic treatment. J Pharmacol Exp Ther. 2004;308:609–616. doi: 10.1124/jpet.103.057497. [DOI] [PubMed] [Google Scholar]
- 74.Hilton GD, Stoica BA, Byrnes KR, Faden AI. Roscovitine reduces neuronal loss, glial activation, and neurologic deficits after brain trauma. J Cereb Blood Flow Metab. 2008;28:1845–1859. doi: 10.1038/jcbfm.2008.75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 75.Tian DS, Yu ZY, Xie MJ, Bu BT, Witte OW, Wang W. Suppression of astroglial scar formation and enhanced axonal regeneration associated with functional recovery in a spinal cord injury rat model by the cell cycle inhibitor olomoucine. J Neurosci Res. 2006;84:1053–1063. doi: 10.1002/jnr.20999. [DOI] [PubMed] [Google Scholar]
- 76.Tian DS, Dong Q, Pan DJ, et al. Attenuation of astrogliosis by suppressing of microglial proliferation with the cell cycle inhibitor olomoucine in rat spinal cord injury model. Brain Res. 2007;1154:206–214. doi: 10.1016/j.brainres.2007.04.005. [DOI] [PubMed] [Google Scholar]
- 77.Rashidian J, Iyirhiaro G, Aleyasin H, et al. Multiple cyclin-dependent kinases signals are critical mediators of ischemia/hypoxic neuronal death in vitro and in vivo. Proc Natl Acad Sci U S A. 2005;102:14080–14085. doi: 10.1073/pnas.0500099102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 78.Wang F, Corbett D, Osuga H, et al. Inhibition of cyclin-dependent kinases improves CA1 neuronal survival and behavioral performance after global ischemia in the rat. J Cereb Blood Flow Metab. 2002;22:171–182. doi: 10.1097/00004647-200202000-00005. [DOI] [PubMed] [Google Scholar]
- 79.Osuga H, Osuga S, Wang F, et al. Cyclin-dependent kinases as a therapeutic target for stroke. Proc Natl Acad Sci U S A. 2000;97:10254–10259. doi: 10.1073/pnas.170144197. [DOI] [PMC free article] [PubMed] [Google Scholar]