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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 maximium increase of 361% ± 35% in ROS production. The lazaroid compound U-83836E (at concentrations ranging from 10-9 to 5 x 10-6 M) completely inhibited this increase, with an IC50 value of 3.02 ± 1.08 x 10-7 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 μM. 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 B(max) to 1341 ± 192 fmol mg-1. When U-83836E was coadministered with KA, the B(max) was reduced to 765 ± 122 fmol mg-1, which was not significantly different from the B(max) obtained from untreated rats (B(max): 518 ± 33 fmol mg-1). We conclude that treatment with the lazaroid U-83836E might be a suitable therapeutic strategy in neurodegenerative disorders.