Summary.
The neuroprotective potency of N-PEP-12, a novel, proprietary compound consisting of biopeptides and amino acids was investigated. Lesion models have been applied in neuronal cultures of embryonic chicken cortex, pre-treated with N-PEP-12 from the first day onwards. On day 8 in vitro neurons were lesioned and cell viability was measured 24 and 48 hours later. To simulate acute brain ischemia, cytotoxic hypoxia was induced by sodium cyanide or by iodoacetate and excitotoxicity by L-glutamate. Ionomycin for up to 48 hours induced calcium overload. The cytoskeleton was disrupted by addition of colchicine. N-PEP-12 shows dose-dependent neuroprotection in all different models. The effect size depends on the recovery time but also on the extent of the lesion. In cases of mild to moderate lesion pronounced dose-dependent effects could be demonstrated. This indicates that chronic exposure to N-PEP-12 is able to prevent neuronal cell death associated to conditions occurring during normal aging and neurological disorders like ischemic stroke, hypoxia, brain trauma, or AD.
Similar content being viewed by others
References
E Adamec M Mercken ML Beermann M Didier RA Nixon (1997) ArticleTitleAcute rise in the concentration of free cytoplasmic calcium leads to dephosphorylation of the microtubule-associated protein tau. Brain Res 757 93–101 Occurrence Handle10.1016/S0006-8993(97)00166-2 Occurrence Handle9200503
F Akai S Hiruma T Sato N Iwamoto M Fujimoto M Ioku S Hashimoto (1992) ArticleTitleNeurotrophic factor-like effect of FPF1070 on septal cholinergic neurons after transections of fimbria-fornix in the rat brain. Histol Histopathol 7 213–221 Occurrence Handle1515704
C Arias T Montiel R Quiroz-Báez L Massieu (2002) ArticleTitleβ-Amyloid neurotoxicity is exacerbated during glycolysis inhibition and mitochondrial impairment in the rat hippocampus in vivo and in isolated nerve terminals: implications for Alzheimer’s disease. Exp Neurol 176 163–174 Occurrence Handle10.1006/exnr.2002.7912 Occurrence Handle12093093
M Arundine M Tymianski (2003) ArticleTitleMolecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity. Cell Calcium 34 325–337 Occurrence Handle12909079
JS Bains CA Shaw (1997) ArticleTitleNeurodegenerative disorders in humans: the role of glutathione in oxidative stress-mediated neuronal death. Brain Res 25 335–358 Occurrence Handle10.1016/S0165-0173(97)00045-3
A Baskys MJ Wojtowicz (1994) ArticleTitleEffects of brain tissue hydrolysate on synaptic transmission in the hippocampus. Pharmacol Biochem Behav 49 1105–1197 Occurrence Handle10.1016/0091-3057(94)90272-0 Occurrence Handle7886083
JP Blass (2003) ArticleTitleCerebrometabolic abnormalities in Alzheimer’s disease. Neurol Res 25 556–566 Occurrence Handle10.1179/016164103101201995 Occurrence Handle14503009
RJ Boado D Wu M Windisch (1999) ArticleTitleIn vivo upregulation of the blood-brain barrier GLUT1 glucose transporter by brain-derived peptides. Neurosci Res 34 217–224 Occurrence Handle10.1016/S0168-0102(99)00056-5 Occurrence Handle10576544
E Braak K Griffing K Arai J Bohl H Bratzke H Braak (1999) ArticleTitleNeuropathology of Alzheimer’s disease: what is new since A. Alzheimer? Eur Arch Psy Clin N 249 14–22
GJ Brewer (1999) ArticleTitleRegeneration and proliferation of embryonic and adult rat hippocampal neurons in culture. Exp Neurol 159 237–247 Occurrence Handle10.1006/exnr.1999.7123 Occurrence Handle10486191
SR Bruckner G Perry S Estus (2003) ArticleTitle4-hydroxynonenal contributes to NGF withdrawal-induced neuronal apoptosis. J Neurochem 85 999–1005 Occurrence Handle12716431
M Brzyska D Elbaum (2003) ArticleTitleDysregulation of calcium in Alzheimer’s disease. Acta Neurobiol Exp 63 171–183
JK Callaway (2001) ArticleTitleInvestigation of AM-36: a novel neuroprotective agent. Clin Exp Pharmacol P 28 913–918 Occurrence Handle10.1046/j.1440-1681.2001.03547.x
G Cebers A Cebere S Liljequist (1998) ArticleTitleMetabolic inhibition potentiates AMPA-induced Ca2+ fluxes and neurotoxicity in rat cerebellar granule cells. Brain Res 779 194–204 Occurrence Handle10.1016/S0006-8993(97)01123-2 Occurrence Handle9473670
CC Chao EH Lee (1999) ArticleTitleNeuroprotective mechanism of glial cell line-derived neurotrophic factor on dopamine neurons: role of antioxidation. Neuropharmacology 38 913–916 Occurrence Handle10.1016/S0028-3908(99)00030-1 Occurrence Handle10465695
MB Collatz R Rudel H Brinkmeier (1997) ArticleTitleIntracellular calcium chelator BAPTA protects cells against toxic calcium overload but also alters physiological calcium responses. Cell Calcium 21 453–459 Occurrence Handle10.1016/S0143-4160(97)90056-7 Occurrence Handle9223681
M Cookson C Mead S Austwick V Pentreath (1995) ArticleTitleUse of the MTT assay for estimating toxicity in primary astrocyte and C6 glioma cell cultures. Toxicol in Vitro 9/1 39–48 Occurrence Handle10.1016/0887-2333(94)00193-X
AK Demetriades (2002) ArticleTitleFunctional neuroimaging in Alzheimer’s type dementia. J Neurol Sci 203 247–251 Occurrence Handle10.1016/S0022-510X(02)00299-X Occurrence Handle12417392
VW Dimlich M Nielsen (1992) ArticleTitleFacilitating postischemic reduction of cerebral lactate in rats. Stroke 23/8 1145–1152
MF Dubois R Hébert (2001) ArticleTitleThe incidence of vascular dementia in Canada: a comparison with Europe and East Asia. Neuroepidemiology 20 179–187 Occurrence Handle10.1159/000054785 Occurrence Handle11490164
J Emerit A Edeas F Bricaire (2004) ArticleTitleNeurodegenerative diseases and oxidative stress. Biomed Pharmacother 58 39–46 Occurrence Handle10.1016/j.biopha.2003.11.004 Occurrence Handle14739060
E Farkas PGM Luiten (2001) ArticleTitleCerebral microvascular pathology in aging and Alzheimer’s disease. Prog Neurobiol 64 575–611 Occurrence Handle10.1016/S0301-0082(00)00068-X Occurrence Handle11311463
T Fath J Eidenmüller R Brandt (2002) ArticleTitleTau-mediated cytotoxicity in a pseudohyperphosphorylation model of Alzheimer’s disease. J Neurosci 22 9733–9741 Occurrence Handle12427828
RA Floyd K Hensley (2002) ArticleTitleOxidative stress in brain aging – implications for therapeutics of neurodegenerative diseases. Neurobiol Aging 23 795–807 Occurrence Handle10.1016/S0197-4580(02)00019-2 Occurrence Handle12392783
F François MJ Godinho M Dragunow ML Grimes (2001) ArticleTitleA population of PC12 cells that is initiating apoptosis can be rescued by nerve growth factor. Mol Cell Neurosci 18 347–362 Occurrence Handle10.1006/mcne.2001.1035 Occurrence Handle11640893
Y Gilgun-Sherki Z Rosenbaum E Melamed D Offen (2002) ArticleTitleAntioxidant therapy in acute central nervous system injury: current state. Pharmacol Rev 54 271–284 Occurrence Handle10.1124/pr.54.2.271 Occurrence Handle12037143
DE Goll VF Thompson HQ Li W Wei JY Cong (2003) ArticleTitleThe calpain system. Physiol Rev 83 731–801 Occurrence Handle12843408
I Gozes DE Brenneman (2000) ArticleTitleA new concept in the pharmacology of neuroprotection. J Mol Neurosci 14 61–68 Occurrence Handle10.1385/JMN:14:1-2:061 Occurrence Handle10854037
ZH Guo MP Mattson (2000) ArticleTitleNeurotrophic factors protect cortical synaptic terminals against amyloid- and oxidative stress-induced impairment of glucose transport, glutamate transport and mitochondrial function. Cereb Cortex 10 50–57
M Hartbauer B Hutter-Paier G Skofitsch M Windisch (2001) ArticleTitleAntiapoptotic effects of the peptidergic drug Cerebrolysin on primary cultures of embryonic chick cortical neurons. J Neural Transm 108 459–473 Occurrence Handle10.1007/s007020170067 Occurrence Handle11475013
D Hicks V Heidinger S Mohand-Said J Sahel H Dreyfus (1998) ArticleTitleGrowth factors and gangliosides as neuroprotective agents in excitotoxicity acid ischemia. Gen Pharmacol 30 265–273 Occurrence Handle10.1016/S0306-3623(97)00356-X Occurrence Handle9510073
RR Hicks S Numan HS Dhillon MR Prasad KB Seroogy (1997) ArticleTitleAlterations in BDNF and NT-3 mRNAs in rat hippocampus after experimental brain trauma. Mol Brain Res 48 401–406 Occurrence Handle10.1016/S0169-328X(97)00158-7 Occurrence Handle9332737
L Hillered L Ernster B Siesjö (1984) ArticleTitleInfluence of in vitro lactic acidosis and hypercapnia on respiratory activity of isolated rat brain mitochondria. J Cerebr Blood Flow Met 4 430–437
S Hoyer (2003) ArticleTitleMemory function and brain glucose metabolism. Pharmacopsychiatry 36 S62–S67 Occurrence Handle10.1055/s-2003-40452 Occurrence Handle13130391
B Hutter-Paier E Steiner M Windisch (1998) ArticleTitleCerebrolysin protects isolated cortical neurons from neurodegeneration after brief histotoxic hypoxia. J Neural Transm [Suppl] 53 351–361
B Hutter-Paier E Grygar M Loibner G Skofitsch M Windisch (2000) ArticleTitleEffects of NaCN and ionomycin on neuronal viability and on the abundance of microtubule-associated proteins MAP1, MAP2, and tau in isolated chick cortical neurons. Cell Tissue Res 302 39–47 Occurrence Handle10.1007/s004410000258 Occurrence Handle11079714
J Jaboin CJ Kim DR Kaplan CJ Thiele (2002) ArticleTitleBrain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from chemotherapy-induced apoptosis via phosphatidylinositol 3′-kinase pathway. Cancer Res 62 6756–6763 Occurrence Handle12438277
K Katasura A Ekholm BS Asplund (1991) ArticleTitleExtracellular pH in the brain during ischemia: relationship to the severity of lactic acidosis. J Cereb Blood Flow Metab 11 597–599 Occurrence Handle1904880
T Kobayashi Y Mori (1998) ArticleTitleCa2+ channel antagonists and neuroprotection from cerebral ischemia. Eur J Pharmacol 363 1–15 Occurrence Handle10.1016/S0014-2999(98)00774-2 Occurrence Handle9877076
J Krieglstein (1997) ArticleTitleExcitotoxicity and neuroprotection. Eur J Pharm Sci 5 181–187 Occurrence Handle10.1016/S0928-0987(97)00276-5
T Kristian BK Siesjo (1998) ArticleTitleCalcium in ischemic cell death. Stroke 29 705–718 Occurrence Handle9506616
DA Le YQ Wu ZH Huang K Matsushita N Plesnila JC Augustinack BT Hyman JY Yuan K Kuida RA Flavell MA Moskowitz (2002) ArticleTitleCaspase activation and neuroprotection in caspase-3-deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation. Proc Natl Acad Sci USA 99 15188–15193 Occurrence Handle10.1073/pnas.232473399 Occurrence Handle12415117
EM Mandelkow E Mandelkow (1998) ArticleTitleTau in Alzheimer’s disease. Trends Cell Biol 8 425–427 Occurrence Handle10.1016/S0962-8924(98)01368-3 Occurrence Handle9854307
WR Markesbery (1999) ArticleTitleThe role of oxidative stress in Alzheimer disease. Arch Neurol 56 1449–1452 Occurrence Handle10.1001/archneur.56.12.1449 Occurrence Handle10593298
L Massieu N Gómez-Román T Montiel (2000) ArticleTitleIn vivo potentiation of glutamate-mediated neuronal damage after chronic administration of the glycolysis inhibitor iodoacetate. Exp Neurol 165 257–267 Occurrence Handle10.1006/exnr.2000.7481 Occurrence Handle10993686
MP Mattson W Duan WA Pedersen C Culmsee (2001) ArticleTitleNeurodegenerative disorders and ischemic brain diseases. Apoptosis 6 69–81 Occurrence Handle10.1023/A:1009676112184 Occurrence Handle11321043
PP Michel EC Hirsch Y Agid (2002) ArticleTitleParkinson’s disease: cell death mechanisms. Rev Neurol 158 S24–S32 Occurrence Handle12690661
SL Minger JW Geddes ML Holtz SD Craddock SW Whiteheart RG Siman LC Pettigrew (1998) ArticleTitleGlutamate receptor antagonists inhibit calpain-mediated cytoskeletal proteolysis in focal cerebral ischemia. Brain Res 810 181–199 Occurrence Handle10.1016/S0006-8993(98)00921-4 Occurrence Handle9813316
T Miyazawa K Matsumoto H Ohmichi H Katoh T Yamashima T Nakamura (1998) ArticleTitleProtection of hippocampal neurons from ischemia-induced delayed neuronal death by hepatocyte growth factor: a novel neurotrophic factor. J Cereb Blood Flow Metab 18 345–348 Occurrence Handle10.1097/00004647-199804000-00001 Occurrence Handle9538898
U Müller J Krieglstein (1995) ArticleTitleInhibitors of lipid peroxidation protect cultured neurons against cyanide-induced injury. Brain Res 678 265–268 Occurrence Handle10.1016/0006-8993(95)00196-W Occurrence Handle7620895
Y Nakagawa-Yagi DK Choi N Ogane S Shimada M Seya T Momoi T Ito Y Sakaki (2001) ArticleTitleDiscovery of a novel compound: insight into mechanisms for acrylamide-induced axonopathy and colchicine-induced apoptotic neuronal cell death. Brain Res 909 8–19 Occurrence Handle10.1016/S0006-8993(01)02608-7 Occurrence Handle11478917
JA Park JY Lee TA Sato JY Koh (2000) ArticleTitleCo-induction of p75(NTR) and p75(NTR)-associated death executor in neurons after zinc exposure in cortical culture or transient ischemia in the rat. J Neurosci 20 9096–9103 Occurrence Handle11124986
HF Poon V Calabrese G Scapagnini DA Butterfield (2004) ArticleTitleFree radicals: key to brain aging and heme oxygenase as a cellular response to oxidative stress. J Gerontol Ser A Biol Sci Med 59 478–493
K Prass U Dirnagl (1998) ArticleTitleGlutamate antagonists in therapy of stroke. Restor Neurol Neuros 13 3–10
JH Prehn J Krieglstein (1993) ArticleTitlePlatelet-activating factor antagonists reduce excitotoxic damage in cultured neurons from embryonic chick telencephalon and protect the rat hippocampus and neocortex from ischemic injury in vivo. J Neurosci Res 34 179–188 Occurrence Handle10.1002/jnr.490340205 Occurrence Handle8095559
JL Price AI Ko MJ Wade SK Tsou DW McKeel JC Morris (2001) ArticleTitleNeuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. Arch Neurol 58 1395–1402 Occurrence Handle10.1001/archneur.58.9.1395 Occurrence Handle11559310
R Raghupathi (2004) ArticleTitleCell death mechanisms following traumatic brain. Brain Pathol 14 215–222 Occurrence Handle15193035
K Reinprecht B Hutter-Paier K Crailsheim M Windisch (1998) ArticleTitleInfluence of BDNF and FCS on viability and programmed cell death (PCD) of developing cortical chicken neurons in vitro. J Neural Transm [Suppl] 53 373–384
KP Riley DA Snowdon WR Markesbery (2002) ArticleTitleAlzheimer’s neurofibrillary pathology and the spectrum of cognitive function: findings from the nun study. Ann Neurol 51 567–577 Occurrence Handle10.1002/ana.10161 Occurrence Handle12112102
J Rudolf (2002) ArticleTitleHydroxyethyl starch for hypervolemic hemodilution in patients with acute ischemic stroke: a randomized, placebo-controlled phase II safety study. Cerebrovasc Dis 14 33–41 Occurrence Handle10.1159/000063721 Occurrence Handle12097849
WR Schabitz S Schwab M Spranger W Hacke (1997) ArticleTitleIntraventricular brain-derived neurotrophic factor reduces infarct size after focal cerebral ischemia in rats. J Cerebr Blood Flow Metab 17 500–506
P Scheltens (2001) ArticleTitleStructural neuroimaging of Alzheimer’s disease and other dementias. Aging Clin Exp Res 13 203–209
PT Shah KW Yoon XM Xu LD Broder (1997) ArticleTitleApoptosis mediates cell death following traumatic injury in rat hippocampal neurons. Neuroscience 79 999–1004 Occurrence Handle10.1016/S0306-4522(97)00013-4 Occurrence Handle9219962
E Sigalov M Fridkin DE Brenneman I Gozes (2000) ArticleTitleVIP-related protection against iodoacetate toxicity in pheochromocytoma (PC12) cells. J Mol Neurosc 15 147–154 Occurrence Handle10.1385/JMN:15:3:147
PJLM Strijbos (1998) ArticleTitleNitric oxide in cerebral ischemic neurodegeneration and excitotoxicity. Crit Rev Neurobiol 12 223–243 Occurrence Handle9847056
CD Sturm WA Frisella K Yoon (1993) ArticleTitleAttenuation of potassium cyanide-mediated neuronal cell death by adenosine. J Neurosurg 79 111–115 Occurrence Handle8315447
AY Sun JH Cheng (1999) ArticleTitleNovel targets for therapeutic intervention against ischemic brain injury. Clin Neuropharmacol 22 164–171 Occurrence Handle10367181
DF Swaab (2003) ArticleTitleReactivation of atrophic neurons in Alzheimer’s disease. Neurol Res 25 652–660 Occurrence Handle10.1179/016164103101201959 Occurrence Handle14503020
M Torcia G DeChiara L Nencioni S Ammendola D Labardi M Lucibello P Rosini LNJL Marlier P Bonini P DelloSbarba AT Palamara N Zambrano T Russo E Garaci F Cozzolino (2001) ArticleTitleNerve growth factor inhibits apoptosis in memory B lymphocytes via inactivation of p38 MAPK, prevention of Bcl-2 phosphorylation, and cytochrome C release. J Biol Chem 276 39027–39036 Occurrence Handle10.1074/jbc.M102970200 Occurrence Handle11495898
MH Tuszynski (2000) ArticleTitleIntraparenchymal NGF infusions rescue degenerating cholinergic neurons. Cell Transplant 9 629–636 Occurrence Handle11144960
JC Vickers TC Dickson PA Adlard HL Saunders CE King G McCormack (2000) ArticleTitleThe cause of neuronal degeneration in Alzheimer’s disease. Prog Neurobiol 60 139–165 Occurrence Handle10.1016/S0301-0082(99)00023-4 Occurrence Handle10639052
JM Vongher CA Frye (1999) ArticleTitleProgesterone in conjunction with estradiol has neuroprotective effects in an animal model of neurodegeneration. Pharmacol Biochem Behav 64 777–785 Occurrence Handle10.1016/S0091-3057(99)00140-9 Occurrence Handle10593201
NG Wahlgren N Ahmed (2004) ArticleTitleNeuroprotection in cerebral ischaemia: facts and fancies – The need for new approaches. Cerebrovasc Dis 17 153–166 Occurrence Handle10.1159/000075784
L Wei SP Yu F Gottron BJ Snider GJ Zipfel DW Choi (2003) ArticleTitlePotassium channel blockers attenuate hypoxia- and ischemia-induced neuronal death in vitro and in vivo. Stroke 34 1281–1286 Occurrence Handle10.1161/01.STR.0000065828.18661.FE Occurrence Handle12677023
J Weis S Saxena M Evangelopoulos A Kruttgen (2003) ArticleTitleTrophic factors in neurodegenerative disorders. Iubmb Life 55 353–357 Occurrence Handle12938738
GJ Wells R Bihovsky (1998) ArticleTitleCalpain inhibitors as potential treatment for stroke and other neurodegenerative diseases: recent trends and developments. Expert Opin Ther Pat 8 1707–1727 Occurrence Handle10.1517/13543776.8.12.1707
L Williams (1995) ArticleTitleOxidative stress, age-related neurodegeneration, and the potential for neurotrophic treatment. Cerebrovasc Brain Met 7 55–73
T Yamashima Y Kohda K Tsuchiya T Ueno J Yamashita T Yoshioka E Kominami (1998) ArticleTitleInhibition of ischaemic hippocampal neuronal death in primates with cathepsin B inhibitor CA-074: a novel strategy for neuroprotection based on ‘calpain-cathepsin hypothesis’. Eur J Neurosci 10 1723–1733 Occurrence Handle10.1046/j.1460-9568.1998.00184.x Occurrence Handle9751144
WH Ying (1997) ArticleTitleDeleterious network: a testable pathogenetic concept of Alzheimer’s disease. Gerontology 43 242–253 Occurrence Handle9222753
JA Zivin (1997) ArticleTitleNeuroprotective therapies in stroke. Drugs 54 IssueID[Suppl 3] 83–89 Occurrence Handle9360855
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Windisch, M., Hutter-Paier, B., Grygar, E. et al. N-PEP-12 – a novel peptide compound that protects cortical neurons in culture against different age and disease associated lesions. J Neural Transm 112, 1331–1343 (2005). https://doi.org/10.1007/s00702-005-0283-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-005-0283-7