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1

Cell type specific uptake and clearance of wita-amyloid peptides

100%
Kuszczyk M., Sadowski
Acta Neurobiologiae Experimentalis
|
2009
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tom 69
|
nr 3
Aggregation of β-amyloid peptides (Aβs) into toxic oligomers, amyloid fi brils, and its deposition in senile plaques initiate the neurodegenerative cascade of Alzheimer`s disease. Intraneuronal accumulation of Aβs starts prior to the appearance of senile plaques, and contributes to neurodegeneration by affecting protein traffi cking, mitochondrial metabolism, tau phosphorylation, and synaptic plasticity. The aim of this study was to compare the uptake and clearance of Aβs by various cell lines. SK-N-SH neuroblastoma cells rapidly metabolized Aβ clearing 40 μM of Aβ40 from the medium within 48 h. Pulse-uptake experiment demonstrated that Aβ40 was totally metabolized inside SK-NSH cells within 6 h. Presence of apolipoprotein E4 accelerated the Aβ40 uptake. In comparison, primary hippocampal neurons internalized only small fraction of Aβ40 present in the medium but showed notable intraneuronal Aβ40 accumulation. In pulseuptake experiment, intraneuronal presence of Aβ40 monomers and oligomers could be demonstrated after 24 h. Accumulation of Aβ40 by hippocampal neurons affected cell viability and membrane integrity as determined by MTT and LDH release assays, respectively. Our results demonstrate that neuroblastoma cells internalize and metabolize Aβ40 more effi ciently than primary hippocampal neurons. Therefore, under conditions of elevated Aβ level, hippocampal neurons are susceptible to Aβ accumulation and intraneuronal oligomerization what leads to downstream toxic effects.
2

NMDA receptor antagonists MK-801 and memantine induce tolerance to oxygen and glucose deprivation in primary cultures of rat cerebellar granule cells

81%
Slomka M., Kuszczyk M., Lazarewicz J. W., Makarewicz D.
Acta Neurobiologiae Experimentalis
|
2014
|
tom 74
|
nr 4
Preconditioning is an experimental strategy for reducing ischemic brain damage. There are reports that brief exposure of neurons to NMDA-receptor antagonists may be an adequate preconditioning stressor. We studied effects of preconditioning of the cerebellar granule cells (CGC) in primary culture by 30-minute exposure to NMDA receptor antagonists 0.5 ^M MK-801 or 5 ^M memantine. CGC were challenged with oxygen and glucose deprivation (OGD) or excitotoxic glutamate and cell viability was tested 24 h later using calcein/ethidium homodimer-1 staining. We studied glutamate-induced increases in 45Ca uptake and in the intracellular Ca2+ level assessed with the fluorescent probe fluo-3. The number of living cells in OGD-treated cultures decreased by 42%. Preconditioning with MK-801 or memantine 24 h earlier reduced cell death to 8% and 30% and 48 h earlier to 27% and 33%, respectively. Pretreatment with MK-801 followed by the standard MK-801 wash out was slightly cytoprotective in a glutamate excitotoxicity test performed immediately; the protection increased significantly 24 h after preconditioning. In both cases the extensive wash out of MK-801 after preconditioning resulted in loss of cytoprotection. The increase in the intracellular Ca2+ level evoked by glutamate was decreased 24 h after preconditioning and even halved in the neuronal cultures 48 h after preconditioning with MK-801 and memantine. Glutamate-induced 45Ca uptake in these cells was decreased by 18%, irrespective of the time laps after preconditioning. These results demonstrate that preconditioning of CGC with NMDA receptor antagonists induces prolonged tolerance to OGD, which is accompanied by the reduction of glutamate-evoked calcium fluxes. The causal relationship between these effects may be suggested.
3

NMDA receptor antagonists - a novel approach at the phenomenon of neuroprotection

71%
Makarewicz D., Duszczyk M., Kuszczyk M., Lazarkiewicz J., Salinska E.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
nr S
Alternative methods of the therapy in the brain ischemia such as preconditioning seem more interesting because of the lack of the clinical applicable effective pharmacological neuroprotection. The role of NMDA receptor activation in triggering of this phenomenon was suggested, but it is not clear. Our recent in vitro studies (Kuszczyk et al. 2010) disclosed tolerance to the excitotoxic challenge by preconditioning with different NMDA receptor antagonists including MK-801 and memantine. The aim of the present study was to check if NMDA receptor antagonism induces also brain tolerance in vivo in different models of experimental brain ischemia. They included hypoxia-ischemia (H-I) in 7-dayold rats and 3-min global forebrain ischemia of Mongolian gerbils. In the neonatal rats exposure to 7% O2 in N2 was used for hypoxic preconditioning (H-P) as a positive control, while for pharmacological preconditioning two NMDA receptor antagonists MK-801 (3 mg/kg) and memantine (5 mg/kg) were injected i.p. Gerbils were pretreated with MK-801. The animals were preconditioned 24, 48, 72 and 96 hours before the insults, and the brain damage or deficit of CA1 pyramidal neurons was evaluated two weeks later. Our results demonstrated that MK-801 administered in all studied time points almost completely reduced brain damage compared to the H-I group, while H-P and preconditioning with memantine were less effective. In gerbils MK-801 was effective only 24 h before global ischemia. These data demonstrate for the first time ischemic tolerance induced by MK-801 and memantine preconditioning in vivo. Known neuroprotective effects of the NMDA receptor antagonists in various models of brain ischemia may be partially ascribed to induced tolerance. We consider a role of mild oxidative stress and enhanced production of trophic factors in its mechanisms. Supported by the MNiSW grant #0664/B/ P01/2010/38.
4

Neuroprotective effects of 1MeTIQ in vitro involve induced tolerance to excitotoxicity

71%
Kuszczyk M., Slomka W., Antkiewicz-Michaluk L., Salinska E., Lazarewicz J. W.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
nr 1
1,2,3,4,-Tetrahydroisochinolines (TIQ) are endogenous substances present in brain in low concentrations. Several TIQ derivatives are neurotoxic producing a Parkinson’s syndrome. In turn 1-methyl-1- ,2,3,4,-tetrahydroisochinoline (1MeTIQ) was found to reduce neuronal death in various models of neurotoxicity. Our previous results revealed that 1MeTIQ reduces excitotoxicity in the primary culture of rat cerebellar granule cells, inhibits glutamate evoked 45Ca accumulation in neurons and suppresses [3H]MK-801 binding to rat cortical membranes. Thus we hypothesized that this compound may be attributed to NMDA receptor antagonists. To verify this supposition, in the present study we compared the neuroprotective potential of 1MeTIQ with the established uncompetitive NMDA receptor antagonists MK-801 and memantine. The primary cultures of rat cerebellar granule neurons were briefly exposed to glutamate, and the substances tested were either co-applied with the excitotoxin or we tested their ability to induce tolerance to glutamate by pre- or post-conditioning. Consequently, 100, 250 or 500 µM 1MeTIQ, 0.5 µM MK-801 or 5 µM memantine were applied for 30 min either together with glutamate, 24 or 48 h before (pre-conditioning), or 0.5 h, 1 h and 3 h after (post-conditioning) exposure to 100 µM or 250 µM glutamate. Our results demonstrated that MK-801, memantine and 1MeTIQ induce an almost complete neuroprotection when co-applied with glutamate. Similar effects of 1MeTIQ and of the established NMDA receptor antagonists were observed in the pre-treatment experiments, even with 48 h lag between application of tested substances and the excitotoxic challenge. In the post-treatment experiments, MK-801 and memantine as well as 500 µM 1MeTIQ applied up to 3 h after brief exposition to glutamate significantly decreased the excitotoxic lesion, while 1MeTIQ in lower concentrations was ineffective. Thus, we demonstrated that 1MeTIQ acts as a weak NMDA receptor antagonist. The new finding of this study is that 1MeTIQ like MK-801 or memantine is neuroprotective when administered before and after exposure to glutamate. We suggest that 1MeTIQ induces long-lasting tolerance of cultured neurons to the excitotoxic insults, and consequently that the mechanism of neuroprotective effects of 1MeTIQ observed under various experimental conditions may be partially attributed to tolerance developing after pre- or post-treatment of neurons with this substance. The studies were supported by Polish MNiSW grant no. N N401 066438
5

Neuroprotective potential of 1-methyl-1,2,3,4,-tetrahydroisochinoline in brain ischemia: role of NMDA receptor antagonism

61%
Duszczyk M., Kuszczyk M., Makarewicz D., Salinska E., Antkiewicz-Michaluk L., Lazarewicz J. W.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
nr 1
Various endogenous teterahydroisochinoline derivatives present in the mammalian brain have been considered as neurotoxic substances. However 1-methyl-1,2,3,4-tetrahydroisochinoline (1MeTIQ) is known for its mild neuroprotective potential of the unclear mechanism. On the one hand 1MeTIQ exhibits anti-dopaminergic activity and reduces the neurotoxic effects of MPTP and rotenone, decreasing also the behavioral effects of MK-801 in rats in vivo. On the other hand the results of our previous study demonstrated that 1MeTIQ in vitro prevents glutamate-induced excitotoxicity in cultured neurons suggesting that this effect may be ascribed to its inhibitory effect on NMDA receptors. It is well known that the antagonists of NMDA receptors provide neuroprotection in brain ischemia, however the anti ischemic properties of 1MeTIQ were not tested previously. The aim of our present study was to verify in vitro putative antagonistic effects of 1MeTIQ on the NMDA receptors and to evaluate its neuroprotective potential in the animal models of brain ischemia. The receptor binding experiments using membranous fractions isolated from the rat brain cortex confirmed that 1MeTIQ in high micro molar concentrations inhibits in a concentration-dependent manner the specific binding of [3H] MK-801, while the binding of [3H]glutamate remains unaffected. The hypothesis that 1MeTIQ may be attributed to NMDA receptor antagonists acting as channel blockers was also supported by the results of experiments utilizing primary cultures of rat cerebellar granule cells submitted to acute NMDA and glutamate excitotoxicity. Under these conditions 1MeTIQ applied at high micro molar concentrations provided a pronounced neuroprotection and significantly inhibited generation of the calcium signal. The in vivo ischemic experiments demonstrated that application of 1MeTIQ in the dose of 50 mg/kg 30 min before the insult in the model of global forebrain ischemia in Mongolian gerbils or its repeated application in the same dose after hypoxia-ischemia in the rat model of perinatal asphyxia provided significant neuroprotection. In the gerbils treated with 1MeTIQ we observed the morphological and behavioral symptoms of neuroprotection and the postischemic hypothermia characteristic for medication of brain ischemia with the NMDA receptor antagonists. Collectively these data offer new arguments confirming the hypothesis that 1MeTIQ acts as a weak uncompetitive antagonist of NMDA receptors, providing the neuroprotection under various excitotoxic and ischemic conditions both in vitro and in vivo.
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