Development of the New Group of IndoleDerived Neu

Authors: S Štolc V Šnirc M Májeková Z Gáspárová A Gajdošíková S Štvrtina

Publish Date: 2006/05/17

Volume: 26, Issue: 7-8, Pages: 1493-1502

PDF Link

Abstract

1 The role of oxidative stress and accordingly uncontrolled reactive oxygen species generation/action have been widely documented in a number of different neuronal pathologies However the concept of pharmacological interventions in prevention and therapy of oxidative stressrelated diseases has not found adequate application in clinical practice This may be due to the insufficient efficacy of drugs available their unsuitable pharmacokinetics side effects toxicity etc2 Based on stobadine −cis28dimethyl2344a59bhexahydro1Hpyrido43bindole a wellknown antioxidant free radical scavenger and neuroprotectant it was attempted to develop new stobadine derivatives with improved pharmacodynamic and toxicity profiles on applying molecular design synthesis and adequate tests Stobadine molecule was modified mostly by electron donating substitution on the benzene ring and by alkoxycarbonyl substitution at N2 position A total of 70 derivatives were prepared3 In a mice model of head trauma some of the new stobadine derivatives administered iv immediately after the trauma significantly improved sensomotoric outcome in the animals assessed 1 h later Accordingly decrease in brain edema was proved histologically as well as by brain wet weight assessment4 Putative neuroprotective action of the compounds was confirmed on rat hippocampal slices exposed to reversible 6 min hypoxia/low glucose by analysis of synaptic transmission in CA1 region neurons Irreversible impairment of neurotransmission resulting from the hypoxia was significantly reduced by the presence of SMe1EC2 one of the new compounds in concentration range 003−100×10−6 mol l−1 Both the neuroprotective and antioxidant effect of the compound closely resembled those of stobadine melatonin 21aminosteroids alphaphenyltertbutylnitrone and others all wellestablished antioxidants except the range of effective concentrations was by 1–2 orders lower in SMe1EC25 A remarkable antioxidant efficacy was observed in the new compounds in rat brain homogenates exposed to iron/ascorbate system by protection of lipids and creatine kinase against the oxidative impairment A link between the neuroprotective and antioxidant/ scavenger properties in the compounds can be assumed

Keywords: