Development of the New Group of Indole-Derived Neuroprotective Drugs Affecting Oxidative Stress

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 stress-related 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, etc. 2. Based on stobadine, (--)-cis-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole, a well-known 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 N-2 position. A total of >70 derivatives were prepared. 3. In a mice model of head trauma, some of the new stobadine derivatives administered i.v. 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 assessment. 4. 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 0.03-10.0x10(-6) mol l(-1). Both the neuroprotective and antioxidant effect of the compound closely resembled those of stobadine, melatonin, 21-aminosteroids, alpha-phenyl-tert-butylnitrone and others, all well-established antioxidants, except the range of effective concentrations was by 1-2 orders lower in SMe1EC2. 5. 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. 6. Acute toxicity of some of the new pyridoindoles was diminished compared to stobadine. That might be due to the virtually full elimination of stobadine's undesired alpha (1)-adrenolytic activity attained by appropriate modifications of its molecule. 7. The new pyridoindoles extend the range of available neuroprotectants interfering with oxidative stress in neuronal tissue.

Antioxidant action of the hexahydropyridoindole SMe1EC2 in the cellular system of isolated red blood cellsin vitro

“…1) has been subject of extensive preclinical studies. It revealed significant neuroprotection in the murine model of acute head trauma 6,8 and in vitro rat hippocampal slices exposed to transient hypoxia/reoxygenation. [9][10][11] Under conditions of experimental diabetes of rats, SMe1EC2 attenuated endothelial injury and restored the reduced endothelium-mediated relaxation in diabetic animals.…”

Synthesis of New 2-Substituted Phenyl-1H-Indoles via Fischer Indole Reaction

“…Indole derivatives are used as neuroprotective agent affecting oxidative stress 4 , neurotransmitter serotonin 5 (5-HT 5-hydroxytriptamine) involved in various physiological functions such as appetite, sleep, body temperature, indolodioxane is found to be active hypertensive agent 6 , INF55 is an inhibitor of NorA efflux pump in the human pathogenic bacterium staphylococcus aureus 7 . Different indole derivatives like tryptans are used as antimigrain and anti-inflammatory [8][9] , anticonvulsant 10 , antimicrobial 11 , antimalarial 12 and anticancer 13 .…”

Substituted derivatives of indole acetic acid as aldose reductase inhibitors with antioxidant activity: structure-activity relationship

“…Other authors recorded the ALR2 inhibition activity of acidic derivatives of structurally related indoles (Da Settimo et al 2003;Nicolaou and Demopoulos 2003;Sun et al 2003;Suzen and Buyukbingol 2003;Suzen et al 2007). The antioxidant activity of indole-based compounds has recently been thoroughly reviewed (Suzen 2006(Suzen , 2007Stolc et al 2006;Suzen et al 2006;Reiter et al 2008;Augustyniak et al 2010;Juranek et al 2010;Shirinzadeh et al 2010).…”