Neuroprotection of HydroxynicotinylAmide 18 against Lipid Peroxidationand,Memory Impairment

Abstract

Hydroxynicotinyl amide 18, a novel radical-scavenging agent, was developed for neuroprotection. 18 showed substantial ex vivo inhibitory action against lipid peroxidation in mice brain regardless of low in vitro inhibition. These indicated that 18 effectively reached the brain, the target site. Electron paramagnetic resonance (EPR) verified the scavenging ability of 18 by showing suppression of the HO? and O2?? radicals resulting in the decrease of signal areas of PBN/OH and DMPO/OOH, respectively. Neuropharmacology of 18 was investigated in mice in comparison with chroman amide 12P, a potent neuroprotective-radical scavenger. 18 at 100 mg/kg, i.p. was the promising compound as it showed significant suppression (18.16%) on the hypermotility induced by methamphetamine (MAP), but did not reduce locomotor activity in normal condition as 12P did. The suppression demonstrated the enhancement of brain delivery and the antagonism against aberrant dopamine release. In water maze test, 18 (100 mg/kg, i.p.) as well as 12P (200 mg/kg) and tacrine (3 mg/kg), significantly reduced the learning and memory impairment induced by scopolamine (0.5 mg/kg), 18 was more potent than 12P. These results support the enhanced brain delivery of 18 as well as provide additional evidence for the role of radical scavenger in the modulation of brain neurotransmitters in the aberrant condition.