U-83836E prevents kainic acid-induced neuronal damage

Abstract

The effect of kainic acid (KA) on mitochondrial membrane potential (MMP) and reactive-oxygen species (ROS) production was studied in dissociated cerebellar granule cells from rat pups. KA induced a maximum increase of 361%+/-35% in ROS production. The lazaroid compound U-83836E (at concentrations ranging from 10(-9) to 5x10(-6) M) completely inhibited this increase, with an IC50 value of 3.02+/-1.08x10(-7) M. KA also decreased the mitochondrial membrane potential (MMP), with a maximum decrease of about 30%. Absence of Na+ in the incubation medium did not significantly alter the effect of KA on MMP. As expected, the AMPA/kainate receptor antagonist NBQX inhibited the effects of KA on MMP with an IC50 value of 1.1+/-0.8 microM. However, the lazaroid U-83836E, indomethacin, nor-dihydroguaiaretic acid and L-nitroarginine all failed to inhibit the KA-induced decrease in the MMP. Finally, to assess the neuroprotective effect of U-83836E on KA-induced neurotoxicity in vivo, the increase in the peripheral-type benzodiazepine receptor density in rat hippocampus was measured. Treatment with KA increased the Bmax to 1341+/-192 fmol mg(-1). When U-83836E was coadministered with KA, the Bmax was reduced to 765+/-122 fmol mg(-1), which was not significantly different from the Bmax obtained from untreated rats (Bmax: 518+/-33 fmol mg(-1)). We conclude that treatment with the lazaroid U-83836E might be a suitable therapeutic strategy in neurodegenerative disorders.

Role of polyamine metabolism in kainic acid excitotoxicity in organotypic hippocampal slice cultures

“…However, results from the present study indicate that there may be different downstream events of p53-dependent pathways responsible for KA neurotoxicity in different populations. In CA3, the involvement of mitochondrial dysfunction and caspase activation in p53-dependent pathway appears to be critical for KA-induced neuronal death (Liu et al 2001), a result in agreement with several reports (Gillardon et al 1997;Camins et al 1998;Prehn 1998). In CA1, however, the relationship between p53 expression and polyamines needs to be further explored.…”

“…2001), a result in agreement with several reports (Gillardon et al . 1997; Camins et al . 1998; Prehn 1998).…”

Orphenadrine prevents 3‐nitropropionic acid‐induced neurotoxicity in vitro and in vivo

“…As in the brain PBRs are concentrated in the microglia, their increase is widely being used as an indirect marker of neuronal damage ( Benavides et al ., 1990 ; Stephenson et al ., 1995 ). For example, density of PBR increases in brain regions injured by excitotoxicity ( Shoemaker et al ., 1982 ; Camins et al ., 1998 ) or focal ischemia ( Benavides et al ., 1990 ). In our experiments, 3‐NPA administration to rats increased both B max and K d for [ 3 H]‐PK 11195 binding.…”

Effect of γ-glutamylcysteine ethylester on the levels of c-fos mRNA expression, glutathione and reactive oxygen species formation in kainic acid excitotoxicity

“…Synaptosomes were pre‐incubated for 3 h at room temperature with KA or KA and GCEE in concentrations of 0.5 m m and 1 m m according to the procedure previously described by Camins et al . with minor modifications [30] . Synaptosomes were incubated with 10 m m DCF‐DA for 30 min at room temperature, then were spun at 3000 g for 5 min at 4°C and resuspended in phosphate‐buffered saline (PBS).…”