U-83836E prevents kainic acid-induced neuronal damage

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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 5×10–6M) completely inhibited this increase, with an IC50 value of 3.02±1.08×10–7M. 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±0.8μM. 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 neurotoxicityin vivo, the increase in the peripheral-type benzodiazepine receptor density in rat hippocampus was measured. Treatment with KA increased the Bmax to 1341±192fmol mg–1. When U-83836E was coadministered with KA, the Bmax was reduced to 765±122fmol mg–1, which was not significantly different from the Bmax obtained from untreated rats (Bmax: 518±33fmol mg–1). We conclude that treatment with the lazaroid U-83836E might be a suitable therapeutic strategy in neurodegenerative disorders.

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