Flupirtine protects neurons against excitotoxic or ischemic damage and inhibits the increase in cytosolic Ca2+ concentration

Rupalla, Katrin; Cao, Weihong; Krieglstein, Josef

doi:10.1016/0014-2999(95)00570-6

Cited by 52 publications

(45 citation statements)

References 10 publications

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“…Also, it has been demonstrated, in our laboratory, that this drug inhibits the increase in the intracellular Ca 2+ concentration induced by stimulation of cultured neurones with glutamate (Rupalla et al, 1995). The aims of the present study were to investigate the possible modulation of inwardly rectifying K + currents by¯upirtine, as well as the corresponding second messenger system(s) by use of the wholecell con®guration of the patch-clamp technique.…”

Section: Introductionmentioning

confidence: 96%

“…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: Introductionmentioning

confidence: 96%

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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“…1 Neuroprotective properties of flupirtine have been previously demonstrated in models of cerebral ischemia. 2,3 In human brain slices a reduction of tumor necrosis factor-related apoptosis-inducing-ligandinduced neurodegeneration was described for this analgesic compound. 4 As one of the mechanisms underlying its neuroprotective properties, an up-regulation of the anti-apoptotic protein Bcl-2 was identified.…”

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confidence: 99%

Flupirtine as Neuroprotective Add-On Therapy in Autoimmune Optic Neuritis

Sättler

Williams

Neusch

et al. 2008

The American Journal of Pathology

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Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system that resultsin persistent impairment in young adults. During chronic progressive disease stages, there is a strong correlation between neurodegeneration and disability. Current therapies fail to prevent progression of neurological impairment during these disease stages. Flupirtine, a drug approved for oral use in patients suffering from chronic pain, was used in a rat model of autoimmune optic neuritis and significantly increased the survival of retinal ganglion cells, the neurons that form the axons of the optic nerve. When flupirtine was combined with interferon-␤, an established immunomodulatory therapy for MS, visual functions of the animals were improved during the acute phase of optic neuritis. Furthermore, flupirtine protected retinal ganglion cells from degeneration in a noninflammatory animal model of optic nerve transection. Although flupirtine was shown previously to increase neuronal survival by Bcl-2 up-regulation, this mechanism does not appear to play a role in flupirtine-mediated protection of retinal ganglion cells either in vitro or in vivo. Instead, we showed through patch-clamp investigations that the activation of inwardly rectifying potassium channels is involved in flupirtine-mediated neuroprotection. Considering the few side effects reported in patients who receive long-term flupirtine treatment for chronic pain, our results indicate that this drug is an interesting candidate for further evaluation of its neuroprotective potential in MS.

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“…In addition flupirtine acts anti-apoptotically on neurons against the deleterious effect caused by HIV-1 gp120. Furthermore, the neuroprotective effect of flupirtine has been proven in animal models of cerebral and retinal ischemia (Osborne et al, 1996;Rupalla et al, 1995;Block et al, 1995). Therefore, the results presented strongly suggest that flupirtine is a promising drug to treat not only (i) neurodegenerative disorders in general and AIDS-associated encephalopathia in particular but also (ii) induced apoptotic death of lymphocytes in AIDS patients.…”

Section: Discussionmentioning

confidence: 85%

“…It acts like an N-methyl-D-aspartate (NMDA) receptor antagonist but until now no binding at this receptor has been identified (Osborne et al, 1994;Schwarz et al, 1994;Osborne et al, 1996). Moreover, it was found that flupirtine enhances basal levels of ATP (Osborne et al, 1996) and reduces the NMDA-induced intracellular Ca 2+ increase in vitro (Rupalla et al, 1995). In addition, flupirtine acts neuroprotectively at doses of 1 ± 10 mg/kg in animal models of focal cerebral ischemia (mouse) (Rupalla et al, 1995) and global cerebral ischemia (rat) (Block et al, 1995) as well as of ischemia (rat, rabbit) Osborne et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Flupirtine protects both neuronal cells and lymphocytes against induced apoptosis in vitro: Implications for treatment of AIDS patients

Müller

Dobmeyer

et al. 1997

Cell Death Differ

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In the present study we demonstrate that flupirtine, an already clinically used, centrally acting, non-opiate analgesic agent, protects rat cortical neurons against HIV-gp120 induced apoptotic cell death. The drug was active at concentrations between 1 and 10 mg/ml. Furthermore we show inhibition of in vitro induced apoptosis in human blood mononuclear cells, using flupirtine. Induced apoptosis in peripheral blood mononuclear cells from healthy individuals and HIV-1 infected patients was reduced to approximately 50% after in vitro preincubation with flupirtine at concentrations between 0.1 and 10 mg/ml. The anti-apoptotic effect of flupirtine was restricted to CD3 + lymphocytes and in particular to CD4 + cells. Flupirtine does not affect uninduced apoptosis in human lymphocytes in vitro. The selective potential of flupirtine to reduce apoptosis without influencing uninduced apoptosis may qualify this compound as a potential drug in the therapy of HIV-1 infected patients.

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Flupirtine protects neurons against excitotoxic or ischemic damage and inhibits the increase in cytosolic Ca2+ concentration

Cited by 52 publications

References 10 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

Flupirtine as Neuroprotective Add-On Therapy in Autoimmune Optic Neuritis

Flupirtine protects both neuronal cells and lymphocytes against induced apoptosis in vitro: Implications for treatment of AIDS patients

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