Disease relevance of Flupirtine

• Flupirtine may be useful as a drug capable of halting the progression of neurodegenerative diseases caused by dysregulated apoptosis [1].
• 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 microg/ml [2].
• In some instances, flupirtine was injected into the eye before ischemia [3].
• Thus, flupirtine may be adequate for the treatment of the neuronal loss in Alzheimer's disease (where A beta accumulates in senile plaques) and probably other neurological diseases such as amyotrophic lateral sclerosis [4].
• This decrease in GSH level was strongly blocked by flupirtine under incubation conditions that reduce cell toxicity [5].

Psychiatry related information on Flupirtine

• Lorazepam and higher doses of flupirtine produced increases in subject-rated liking, ARCI MBG scale scores, and sedative-like effects including impaired psychomotor performance [6].
• Due to its favourable pharmacokinetic profile, Flupirtine is considered to be a promising drug to prevent neuronal death in Creutzfeldt-Jakob disease (CJD) and other neurodegenerative disorders occurring with age, e.g. Alzheimer's disease [7].
• We now report that in monoamine depleted rats (pretreated with reserpine, 5 mg/kg, and alpha-methyl-para-tyrosine, 250 mg/ kg i.p.) flupirtine dose-dependently (1-20 mg/kg i.p.) suppressed rigidity, measured as tonic EMG activity in the gastrocnemius muscle, but had no effect on akinesia, measured as locomotor activity [8].
• Flupirtine dose-dependently increased pain threshold in the electrostimulated pain test in mice [9].
• In contrast to buprenorphine, codeine and tramadol, flupirtine caused no decrease in body weight and no other withdrawal symptoms [10].

High impact information on Flupirtine

• Flupirtine also prevents the death of CLN3- and CLN2-deficient postmitotic hNT neurons at the mitochondrial level [1].
• Flupirtine blocks apoptosis in batten patient lymphoblasts and in human postmitotic CLN3- and CLN2-deficient neurons [1].
• 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 [2].
• 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 [2].
• The anti-apoptotic effect of flupirtine was restricted to CD3+ lymphocytes and in particular to CD4+ cells [2].

Chemical compound and disease context of Flupirtine

• Injection of flupirtine into the vitreous humor during ischemia enhanced the uptake of serotonin [3].
• 1. Previous studies have shown that flupirtine, 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 [11].
• Since retigabine and flupirtine are well tolerated in humans, the present finding of pronounced antidystonic efficacy in the dt (sz) mutant suggests that neuronal K(v)7 channel activators are interesting candidates for the treatment of dystonia-associated dyskinesias and probably of other types of dystonias [12].
• Clinical trial of flupirtine maleate in patients with migraine [13].
• In vitro studies on primary neurons demonstrate that Flupirtine (Katadolon) at a concentration of 1 microg/ml, significantly reduces the neurotoxic (apoptotic) effect displayed by A beta25-35, a segment of the amyloid beta-protein precursor the etiologic agent of Alzheimer's disease [14].

Biological context of Flupirtine

• Furthermore we show inhibition of in vitro induced apoptosis in human blood mononuclear cells, using flupirtine [2].
• Flupirtine (10-20 microM), an M-current activator, caused a 3-14 mV leftward shift in the current-voltage relationship and also led to a hyperpolarization of resting membrane potential [15].
• Flupirtine reduces formation of reactive oxygen species in retinal dissociates and causes changes in various oncogene products in RPE cultures, which may explain its action in preventing apoptosis induced by ischemia [16].
• A beta25-35-induced DNA fragmentation could be abolished by preincubation of the cells with 1 microg/ml flupirtine [4].
• Protection of mitochondrial integrity from oxidative stress by the triaminopyridine derivative flupirtine [17].

Anatomical context of Flupirtine

• In comparison with opiate drugs, flupirtine appears to produce fewer central nervous system effects, no respiratory or cardiovascular depression, and no overt tolerance or physical dependence on prolonged administration [18].
• Induction of apoptosis in cultured human retinal pigment epithelial cells is counteracted by flupirtine [16].
• PURPOSE: The aim of the study was to determine whether flupirtine can counteract the induction of apoptosis in cultured retinal pigment epithelium (RPE) cells [16].
• At supra-physiological flupirtine concentrations of 20 nmol mg(-1) mitochondrial protein and above, the mitochondrial calcium concentrations were indistinguishable from those in untreated mitochondria [19].
• Since flupirtine has no action on known receptor sites we have investigated the effect of this drug on mitochondrial membrane potential, and the changes in intramitochondrial calcium concentration in particular [19].

Associations of Flupirtine with other chemical compounds

• Moreover, melatonin and flupirtine counteracted iron-ascorbate-induced ROS formation and decreased the ratio of mRNA for ICH-1L and ICH-1S [20].
• Inclusion of flupirtine (flupirtine gluconate, 100 microM) or 10% fetal calf serum in the medium prevented ischemia-induced apoptosis occurring after 72 hours [16].
• Interestingly, retigabine (0.01-10 microM) and flupirtine (0.01-10 microM) dose-dependently prevented DG neuronal death induced by SW, with IC50 s of 0.4 microM and 0.7 microM, respectively [21].
• In conclusion, the preservation of the Ca(2+) buffer capacity of mitochondria and of the ANT activity against oxidative stress supports an antiapoptotic application of flupirtine [17].
• 4. The selective alpha2-adrenoceptor antagonist SKF-86466 (10 microM), the selective 5-HT1A antagonist NAN 190 as well as the selective GABA(B) antagonist 2-hydroxysaclofen (10 microM) failed to block the flupirtine effect on the inward rectifier [11].

Gene context of Flupirtine

• Furthermore, addition of 10 or 100 microM: flupirtine before incubation with TNF-alpha led to an approximately threefold increase of Bcl-2 expression [22].
• Our data demonstrate that flupirtine up-regulates the expression of Bcl-2 protein in OLN cells; this Bcl-2 induction is associated with a reduced rate of TNF-alpha-induced cell death [22].
• In contrast, the oncogene proteins for TIAR and ICH-1t, were lower in flupirtine-treated cells than in control cells [16].
• By contrast, retigabine and flupirtine (each at 10 microM) were less effective in counteracting NMDA- or OGD-induced toxicity in the CA1 region [21].
• Based on these in vitro data and on the favorable pharmacokinetic profile of the drug, we strongly suggest that flupirtine may prove useful for treatment of patients with prion disease [5].

Analytical, diagnostic and therapeutic context of Flupirtine

• The results indicate that flupirtine produces analgesia by spinal inhibition of nociceptive impulse transmission from afferent nerve fibres to neurones sending their axons to the brain and, in addition, by supraspinal inhibition of nociceptive impulse transmission to the thalamus [23].
• Microinjection of flupirtine (1.7 micrograms/rat) made in the PAG did not reduce, but increased the spontaneous and C fibre-evoked activity in ascending axons [24].
• Flupirtine administered 20 min before ischaemia reduced the depression of the b-wave during occlusion and accelerated recovery during reperfusion [25].
• Quantitation of flupirtine and its active acetylated metabolite by reversed-phase high-performance liquid chromatography using fluorometric detection [26].
• Pentazocine and flupirtine effects on spontaneous and evoked EEG activity [27].

References