The triaminopyridine flupirtine prevents cell death in rat cortical cells induced by N-methyl-d-aspartate and gp120 of HIV-1

Perovic, Sanja; Schleger, Claudia; Pergande, G.; Iskrić, Sonja; Ushijima, Hiroshi; Rytik, Peter G.; Müller, Wernér E.G.

doi:10.1016/0922-4106(94)90006-x

Cited by 53 publications

(22 citation statements)

References 34 publications

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“…Recently, it has been suggested that¯upirtine acts like an NMDA-antagonist (Perovic et al, 1994). But no relevant af®nity of¯upirtine to the known binding sites of the NMDA receptor was observed (Osborne et al, 1996) and the NMDAinduced currents were not reduced by this drug in cultured hippocampal neurones or cortical neurones of the rat.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, previous studies have shown that¯upirtine also exhibits neuroprotective activity in focal cerebral ischaemia in mice (Rupalla et al, 1995) and reduces apoptosis induced by N-methyl-D-aspartate (NMDA), gp 120 of HIV, prion protein fragment or lead acetate (Perovic et al, 1994; as well as necrosis induced by glutamate or NMDA (Rupalla et al, 1995;MuÈ ller, personal communication). Neuronal cultures treated with¯upirtine showed a higher viability compared with untreated control cultures (Perovic et al, 1994).…”

Section: Introductionmentioning

confidence: 98%

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Influence of flupirtine on a G‐protein coupled inwardly rectifying potassium current in hippocampal neurones

Jakob

Krieglstein

1997

British J Pharmacology

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1 Previous studies have shown that¯upirtine, a centrally acting, non-opioid analgesic agent, also exhibits neuroprotective activity in focal cerebral ischaemia in mice and reduces apoptosis induced by NMDA, gp 120 of HIV, prior protein fragment or lead acetate as well as necrosis induced by glutamate or NMDA in cell culture. To study the potential mechanism of the neuroprotective action of¯upirtine, we investigated whether¯upirtine is able to modulate potassium or NMDA-induced currents in rat cultured hippocampal neurones by use of the whole-cell con®guration of the patch-clamp technique. 2 We demonstrated that 1 mM¯upirtine activated an inwardly rectifying potassium current (K ir ) in hippocampal neurones (DI=739+18 pA at 7130 mV; n=10). This e ect was dose-dependent (EC 50 =0.6 mM). The reversal potential for K ir was in agreement with the potassium equilibrium potential predicted from the Nernst equation showing that K ir was predominantly carried by K + . Furthermore, the induced current was blocked completely by Ba 2+ (1 mM), an e ect typical for K ir . 3 The activation of K ir by¯upirtine was largely prevented by pretreatment of the cells with pertussis toxin (PTX) indicating the involvement of a PTX-sensitive G-protein in the transduction mechanism (DI=73+6 pA at 7130 mV; n=8). Inclusion of cyclic AMP in the intracellular solution completely abolished the activation of K ir (n=7). 4 The selective a 2 -adrenoceptor antagonist SKF-86466 (10 mM), the selective 5-HT 1A antagonist NAN 190 as well as the selective GABA B antagonist 2-hydroxysaclofen (10 mM) failed to block the¯upirtine e ect on the inward recti®er. 5 Flupirtine (1 mM) could not change the current induced by 50 mM NMDA. 6 These results show that in cultured hippocampal neurones¯upirtine activates an inwardly rectifying potassium current and that a PTX-sensitive G-protein is involved in the transduction mechanism.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Influence of flupirtine on a G‐protein coupled inwardly rectifying potassium current in hippocampal neurones

Jakob

Krieglstein

1997

British J Pharmacology

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“…Indirect antagonism of excitatory NMDA receptor has recently discussed as possible mechanism of action. [16][17][18][19][20] Flupirtine and some other anticonvulsant drugs showsanticonvulsant action by GABA mediated inhibition. This is a possible explanation for potentiation of anticonvulsant action of benzodiazepines by flupirtine.…”

Section: Discussion:-mentioning

confidence: 99%

Effect of flupirtine on seizure activity and its interactions with antiepileptic drugs in rats.

Dudhe¹,

Badwaik²,

Bhore³

2017

IJAR

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“…Rat primary cortical cells were prepared from the brains of 18-day-old Wistar rat embryos as described previously (Perovic et al, 1994. Brie¯y, after isolation cerebral hemispheres were placed into Hank's balanced salt solution (Biochrom) without Ca 2+ and Mg 2+ .…”

Section: Neuronal Cellsmentioning

confidence: 99%

“…At present, only a few drugs are known which may protect animals against PrP Sc infection and suppress PrP Sc -induced neurotoxicity: (i) polyanio-nic glycans, including pentosan sulfate and dextran sulfate, have been shown to prolong the incubation period and to inhibit PrP Sc formation in rodents (Diringer and Ehlers, 1991), most likely by reducing of the amount of PrP C on the cell surface through enhanced endocytosis of PrP C (Shyng et al, 1995); (ii) the polyene macrolide antibiotic, amphotericin B (Pocchiari et al, 1989), and its derivative, MS-8209 (Adjou et al, 1995), also cause a prolongation of the incubation period of PrP Sc -infected mice; (iii) the accumulation of PrP Sc could also be blocked by Congo red (Caughey and Race, 1992) and (iv) the anthracycline 4'-iodo-4'-deoxy-doxorubicin, which bind to amyloid ®brils (Tagliavini et al, 1997); (v) the neutotoxic effect displayed by PrP Sc was found to be prevented by antagonists of NMDA receptor channels, such as memantine and MK-801 Perovic et al, 1995;Brown et al, 1996); and (vi) the triaminopyridine¯upirtine, a clinically used non-opiod analgesic drug, was found to display in vitro a strong cytoprotective effect on neurons treated with PrP Sc or its toxic fragment, PrP 106 ± 126 (Perovic et al, 1994. This drug enhances the level of the antiapoptotic protein Bcl-2 and normalizes the level of intracellular glutathione (Perovic et al, 1996.…”

Section: Introductionmentioning

confidence: 99%

Suppression of PrP^Sc- and HIV-1 gp120 induced neuronal cell death by sulfated colominic acid

Ushijima¹,

Perovic²,

Leuck³

et al. 1999

J Neurovirol

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The scrapie prion protein (PrP Sc ) has been shown to induce apoptosis of rat cortical neurons in vitro. Here we demonstrate that the toxic effect displayed by PrP Sc can be blocked by sulfated colominic acid (polymer of N-acetylneuraminic acid). This compound acts neuroprotectively at a concentration of 50.3 mg/ml when preincubated with the neurons or PrP Sc . Rat cortical cells also undergo apoptosis after incubation with the HIV-1 coat protein gp120 in vitro. This effect was abolished also by sulfated colominic acid when preincubated with the cells or gp120. Addition of 0.3 mg/ml of compound resulted in an increase in cell viability by about 1.6 ± 1.9-fold compared to cultures incubated for 18 h with 30 ng/ml of PrP Sc or 20 ng/ml of gp120 alone (containing about 40% viable cells). Sulfated colominic acid does not act as antagonist of NMDA receptor channels at concentrations of up to 3 mg/ml when co-administered with 100 mg/ml of NMDA. It displayed a strong cytoprotective effect on human T lymphoblastoid CEM cells exposed to HIV-1; a 50% protection occurred after preincubation of the cells with 0.43 mg/ml of compound. At the same concentration, the compound caused an inhibition of HIV-1-induced syncytium formation. Sulfated colominic acid may be a promising compound for treatment of dementia caused by PrP Sc and HIV-1 infections.

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The triaminopyridine flupirtine prevents cell death in rat cortical cells induced by N-methyl-d-aspartate and gp120 of HIV-1

Cited by 53 publications

References 34 publications

Influence of flupirtine on a G‐protein coupled inwardly rectifying potassium current in hippocampal neurones

Influence of flupirtine on a G‐protein coupled inwardly rectifying potassium current in hippocampal neurones

Effect of flupirtine on seizure activity and its interactions with antiepileptic drugs in rats.

Suppression of PrP^Sc- and HIV-1 gp120 induced neuronal cell death by sulfated colominic acid

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The triaminopyridine flupirtine prevents cell death in rat cortical cells induced by N-methyl-d-aspartate and gp120 of HIV-1

Cited by 53 publications

References 34 publications

Influence of flupirtine on a G‐protein coupled inwardly rectifying potassium current in hippocampal neurones

Influence of flupirtine on a G‐protein coupled inwardly rectifying potassium current in hippocampal neurones

Effect of flupirtine on seizure activity and its interactions with antiepileptic drugs in rats.

Suppression of PrPSc- and HIV-1 gp120 induced neuronal cell death by sulfated colominic acid

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Suppression of PrP^Sc- and HIV-1 gp120 induced neuronal cell death by sulfated colominic acid