A large proportion of grafted striatal neurons die, and mechanisms by which they succumb may involve excitotoxicity and oxidative stress. We investigated the effects of pretreatment of the graft tissue with the N-methyl-D-aspartate (NMDA) receptor antagonist (+)dizocilpine hydrogen maleate (MK-801) and lipid peroxidation inhibitor lazaroid U-83836E on the survival of transplanted striatal neurons. Neither compound increased the survival of grafts, suggesting that NMDA-related excitotoxicity or oxidative stress may not be primary mediators of cell death in striatal grafts.
BealM. F.Mitochondria, free radicals, and neurodegeneration.Curr. Opin. Neurobiol.6: 661–666; 1996.
2.
BarthA.; BarthL.; MorrisonR. S.; NewellD. W.bFGF enhances the protective effects of MK-801 against ischemic neuronal injury in vitro.Neuroreport7: 1461–1464; 1996.
3.
BrundinP.; KarlssonJ.; EmgårdM.; Kaminski SchierleG. S.; HanssonO.; PetersénÅ.; CastilhoR. F.Improving the survival of grafted dopaminergic neurons: A review over current approaches.Cell Transplant. (in press).
4.
BuchanA. M.Do NMDA antagonists protect against cerebral ischemia: Are clinical trials warranted? Cerebrovasc.Brain Metab. Rev.2: 1–26; 1990.
5.
ColwellC. S.; CepedaC.; CrawfordC.; LevineM. S.Postnatal development of glutamate receptor-mediated responses in the neostriatum.Dev. Neurosci.20: 154–163; 1998.
6.
CoyleJ. T.; PuttfarckenP.Oxidative stress, glutamate, and neurodegenerative disorders.Science262: 689–695; 1993.
7.
EmgårdM.; KarlssonJ.; HanssonO.; BrundinP.Patterns of cells death and dopaminergic neuron survival in intrastriatal nigral grafts.Exp. Neurol. (in press).
8.
FreeseA.; DiFigliaM.; KoroshetzW. J.; BealM. F.; MartinJ. B.Characterization and mechanism of glutamate neurotoxicity in primary striatal cultures.Brain Res.521: 254–264; 1990.
9.
FrickerR. A.; TorresE. M.; DunnettS. B.The effects of donor stage on the survival and function of embryonic striatal grafts in the adult rat brain. I. Morphological characteristics.Neuroscience79: 695–710; 1997.
10.
FrickerR. A.; TorresE. M.; HumeS. P.; MyersR.; Opacka-JuffreyJ.; AshworthS.; BrooksD. J.; DunnettS. B.The effects of donor stage on the survival and function of embryonic striatal grafts in the adult rat brain. II. Correlation between positron emission tomography and reaching behaviour.Neuroscience79: 711–721; 1997.
11.
FrodlE. M.; NakaoN.; BrundinP.Lazaroids improve the survival of rat fetal dopaminergic neurons in vitro.Neuroreport5: 2393–2396; 1994.
12.
Grasbon-FrodlE. M.; AnderssonA.; BrundinP.Lazaroid treatment prevents death of cultured rat embryonic mesencephalic neurons following glutathione depletion.J. Neurochem.67: 1653–1660; 1996.
13.
Grasbon-FrodlE. M.; NakaoN.; BrundinP.Lazaroids improve the survival of embryonic mesencephalic donor tissue stored at 4°C and subsequently used for cultures or intracerebral transplantation.Brain Res. Bull.39: 341–347; 1996.
14.
Grasbon-FrodlE. M.; BrundinP.Mesencephalic neuron death induced by congeners of nitrogen monoxide is prevented by the lazaroid U-83836E.Exp. Brain Res.113: 138–143; 1997.
15.
GraybielA. M.; LiuF-C.; DunnettS. B.Intrastriatal grafts derived from fetal striatal primordia. I. Phenotypy and modular organization.J. Neurosci.9: 3250–3271; 1989.
16.
GundersenH. J. G.; BaggerP.; BendstenT. F.; EvansS. M.; KorbuL.; MarcussenN.; MøllerA.; NielsenK.; NyengardJ. R.; PakkenbergB.; SørensenF. B.; VesterbyA.; WestM. J.The new stereological tools: Dissector, fractionator, nucleator and point-sampled intercepts and their use in pathological research and diagnosis.Acta Pathol. Microbiol. Immunol. Scand.96: 857–881; 1988.
17.
HallE. D.Lipid antioxidant neuroprotectants for acute and chronic neurodegenerative disorders. In: BärP. R.; BealM. F., eds. Neuroprotection in CNS diseases.New York: Marcel Dekker Inc;1997: 161–181.
IsacsonO.; DunnettS. B.; BjörklundA.Graft-induced behavioral recovery in an animal model of Huntington's disease.Proc. Natl. Acad. Sci. USA83: 2728–2732; 1986.
20.
JinD. H.; JungY. W.; HamS. H.; KoB. H.; MoonI. S.Developmental expression, subcellular localization, and tyrosine phosphorylation of NR2A and NR2B in the rat brain Mol.Cells7: 64–71; 1997.
21.
KarlssonJ.; EmgårdM.; RosenbladC.; BrundinP.Treatment with the spin-trap agent alpha-phenyl-N-tert-butyl nitrone does not enhance the survival of embryonic or adult dopamine neurons.Brain Res.805: 155–168; 1998.
22.
KarlssonJ.; LoveR. M.; ClarkeD. J.; BrundinP.Effects of anaesthetics and lazaroid U-83836E on survival of transplanted rat dopaminergic neurones.Brain Res.821: 546–550; 1999.
23.
KielhoffG.; ErdöS. L.Parallel development of excitotoxic vulnerability to N-methyl-D-aspartate and kainate in dispersed cultures of the rat cerebral cortex.Neuroscience43: 35–40; 1991.
24.
LuccaE.; AngerettiN.; ForloniG.Influence of cell culture conditions on the protective effect of antioxidants against β-amyloid toxicity: Studies with lazaroids.Brain Res.764: 293–298; 1997.
25.
MonyerH.; HartleyD. M.; ChoiD. W.21-aminosteroids attenuate excitotoxic neuronal injury in cortical cell cultures.Neuron5: 121–126; 1990.
26.
MonyerH.; BurnashevN.; LaurieD. J.; SakmannB.; SeeburgP. H.Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.Neuron12: 529–540; 1994.
27.
MytilineouC.; RadcliffeP.; LeonardiE. K.; WernerP.; OlanowC. W.L-deprenyl protects mesencephalic dopamine neurons from glutamate receptor-mediated toxicity in vitro.J. Neurochem.68: 33–39; 1997.
28.
NakaoN.; FrodlE. M.; DuanW-M.; WidnerH.; BrundinP.Lazaroids improve the survival of grafted rat embryonic dopamine neurons.Proc. Natl. Acad. Sci. USA91: 12408–12412; 1994.
29.
NakaoN.; Grasbon-FrodlE. M.; WidnerH.; BrundinP.Antioxidant treatment protects striatal neurons against excitotoxic insults.Neuroscience73: 185–200; 1996.
30.
NakaoN.; Grasbon-FrodlE. M.; WidnerH.; BrundinP.DARPP-32-rich zones in grafts of lateral ganglionic eminence govern the extent of functional recovery in skilled paw-reaching in an animal model of Huntington's disease.Neuroscience74: 959–970; 1996.
31.
NakaoN.; BrundinP.Effects of α-phenyl-tert-butyl nitrone on neuronal survival and motor function following intrastriatal injections of quinolinic or 3-nitropropionic acid.Neuroscience76: 749–761; 1997.
32.
NakaoN.; BrundinP.The glutamate synapse as a therapeutical target: Molecular organization and pathology of the glutamate synapse. In: OttersenO. P.; LangmoenI. A.; GjerstadL., eds. Neurodegeneration and glutamate induced oxidative stress.Amsterdam: Elsevier;1998: 245–263.
33.
NellgårdB.; WielochT.Cerebral protection by AMPA- and NMDA-receptor antagonists administered after severe insulin-induced hypoglycemia.Exp. Brain Res.92: 259–266; 1992.
34.
OhmoriT.; HirashimaY.; KurimotoM.; EndoS.; TakakuA.In vitro hypoxia of cortical and hippocampal CA1 neurons: Glutamate, nitric oxide, and platelet activating factor participate in the mechanism of selective neural death in CA1 neurons.Brain Res.743: 109–115; 1996.
35.
OlanowC. W.A radical hypothesis for neurodegeneration.Trends Neurosci.16: 439–444; 1993.
36.
OthbergA.; KeepM.; BrundinP.; LindvallO.Tirilazad mesylate improves the survival of rat and human embryonic mesencephalic neurons in vitro.Exp. Neurol. 147: 498-502; 1997. [Erratum in Exp. Neurol.154: 260; 1998.
37.
SchierleG. S.; KarlssonJ.; BrundinP.MK-801 does not enhance dopaminergic cell survival in embryonic nigral grafts.Neuroreport9: 1313–1316; 1998.
38.
SchierleG. S.; BrundinP.Excitotoxicity plays a role in the death of tyrosine hydroxylase-immunopositive nigral neurons cultured in serum-free medium.Exp. Neurol.157: 338–348; 1999.
39.
ShengM.; CummingsJ.; RoldanL. A.; JanY. N.; JanL. Y.Changing subunit composition of heteromeric NMDA receptors during development of rat cortex.Nature368: 144–147; 1994.
40.
SparapaniM.; Dall'OlioR.; GandolfiO.; CianiE.; ContestabileA.Neurotoxicity of polyamines and pharmacological neuroprotection in cultures of rat cerebellar granule cells.Exp. Neurol.148: 157–166; 1997.
41.
SuredaF. X.; GabrielC.; PubillD.; PallàsM.; EscubedoE.; CamarasaJ.; CaminsA.Effects of U-83836E on glutamate-induced neurotoxicity in dissociated rat cerebellar granule cells.Toxicol. Appl. Pharmacol.156: 1–5; 1999.
42.
VornovJ. J.; ParkJ.; ThomasA. G.Regional vulnerability to endogenous and exogenous oxidative stress in organotypic hippocampal culture.Exp. Neurol.149: 109–122; 1998.
43.
WattsC.; DunnettS. B.Towards a protocol for the preparation and delivery of striatal tissue for clinical trials of transplantation in Huntington's disease.Cell Transplant. (in press).