Cytotoxicity, cytoprotection and neurotoxicity of novel deprenyl-related propargylamines, stable nitroxide free radicals, in vitro and in vivo.
Since novel synthesized deprenyl-related derivatives of nitroxides, named "JSAKs", have been shown to possess antioxidative properties, their cytotoxicity on neuronal-like PC-12 cells line was examined. The antiproliferative effect of two selected JSAKs was examined and expressed as IC10, IC50 and IC90, and compared with those of the parent nitroxide (Nx-640), model nitroxide TEMPO and deprenyl. There were substantial differences in the dose-dependence of all the observed antiproliferative and cytotoxic effects. Compared to anticancer drugs and apoptosis inducers with topoisomerase inhibitor properties (etoposide and camptothecin), novel compounds displayed cytotoxicity at considerably higher concentrations. The dose-dependent anti-apoptotic potency of JSAKs and Nx-640 was also investigated and compared to TEMPO and deprenyl effects. The observed structure-dependent correlation was very encouraging and prompted us to screen and to compare the in vivo time-dependent effects of JSAKs, Nx-640 and deprenyl administration on the rat intact nigrostriatal neurocytes. TH-immunochemistry was applied as the test method and marker for the changes in the state of the rat catecholaminergic system, also giving evidence that low-toxic and cell-permeable JSAKs can cross the blood-brain barrier, which is the mandatory prerequisite for the therapeutic application of antioxidants and drugs to the brain. Taken together, it can be concluded with great certainty that novel deprenyl-related JSAKs might be especially good candidates for further anticancer investigations in vitro and in vivo and future pharmacological applications.
Namiecinski
Michal
M
Department of Molecular Biophysics, University of Lodz, Poland.
Pulaski
Lukasz
L
Kochman
Agata
A
Skolimowski
Janusz
J
Bartosz
Grzegorz
G
Metodiewa
Diana
D
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000633:toxicity*; D009589:Nitrogen Oxides / Q000633:toxicity*; D016716:PC12 Cells / Q000187:drug effects / Q000473:pathology; D010293:Pargyline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity*; D011437:Propylamines / Q000737:chemistry / Q000633:toxicity*; D051381:Rats; D011915:Rats, Inbred BUF; D013329:Structure-Activity Relationship
D000975:Antioxidants; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; D011437:Propylamines; C009054:propargylamine; D010293:Pargyline; C039900:nitroxyl; D004298:Dopamine