Efekat ibogaina na sistem antioksidativne zaštite u perifernim tkivima i kontraktilnost terminalnog ileuma kod mužjaka pacova

Abstract

Ibogain, primenjen u jediničnoj oralnoj dozi (1-25 mg/kg telesne mase (t.m)) se koristi kao agens u sprečavanju različitih oblika zavisnosti kod ljudi. Njegovi efekti traju i do 72 h. Ex vivo rezultati pokazuju da ibogain izaziva potrošnju energije u ćelijama i njenu restituciju, što je praćeno povećanjem stvaranja reaktivnih vrsta kiseonika i aktivnosti antioksidativne odbrane. Stoga je cilj ovog rada bio da istraži efekte jedinične oralne doze ibogaina (1 ili 20 mg/kg t.m.) na antioksidativnu odbranu u različitim tkivima pacova. Posle 6 i 24 h nakon ingestije ibogaina, histološka ispitivanja su pokazala pojačanu glikogenolitičku aktivnost hepatocita, koja je bila najviša posle 24 h kod životinja koje su primile 20 mg/kg ibogaina. Nije bilo promena u aktivnosti antioksidativnih enzimani u jetri ni u eritrocitima u tim periodima što ukazuje na izostanak sistemskog efekta na nivou oksidativnog pritiska. U jetri se povećala aktivnost ksantin oksidaze kod pacova koji su primili ibogain u dozi od 20 mg/kg u poređenju sa kontrolama što ukazuje na brži obrt adenozina. Nivo TBARS u jetri je povišen kod grupe tretirane sa 1 mg/kg posle 24 h u poređenju sa kontrolama što sugeriše postojanje umerenog oksidativnog stresa. U srcu je utvrđeno da ibogain nakon 6 h smanjuje količinu proteinskih -SH grupa što ukazuje na unutar-proteinsku oksidaciju, koja zajedno sa narušenom energetskom homeostazom može dovesti do promena u srčanom radu i nastanka diskretnih oštećenja. Ibogain inhibira ex vivo kontraktilnost ileuma u nivou doza ispod mM, pri čemu je efekat kod električne stimulacije, u odnosu na toničnu, značajno veći. Rezultati pretretmana na ileumu ex vivo ukazuju da ibogain svoje dejstvo ostvaruje delimično preko KATP kanala. Ibogain izaziva u ileumu ex vivo povećanje aktivnosti superoksid dismutaze (SOD) i katalaze (KAT), ali se ti efekti gube dodavanjem glibenklamida. Ibogain menja i redoks 7 ravnotežu u testisima, a nađeno povećanje aktivnosti SOD ukazuje na delikatnost očuvanja balansa koncentracija superoksida i vodonik peroksida koja se smatra krucijalnom u procesu kapacitacije spermatozoida. Rezultati pokazuju da ibogain u primenjenim dozama utiče na redoks status posmatranih tkiva i menja aktivnost antioksidativne odbrane, ali je odgovor visoko tkivno, dozno i vremenski specifičan, bez jasne zajedničke karakteristike.

Ibogaine, administered as a single oral dose (1-25 mg/kg body weight, (b.w.)), has been used as an addiction-interrupting agent. Its effects persist for up to 72 h. Ex vivo results showed that ibogaine induced cellular energy consumption and restitution, followed by increased reactive oxygen species production and antioxidant activity. Therefore, the aim of this work was to explore the effect of a single oral dose of ibogaine (1 or 20 mg/kg b.w.) on antioxidative defenses in different rat tissues. Six and 24 h after ibogaine administration, histological examination showed glycogenolytic activity in hepatocytes, which was highest after 24 h in animals that received 20 mg/kg ibogaine. There were no changes in the activities of antioxidant enzymes in the liver and erythrocytes after ibogaine treatment, regardless of the dose. These results suggest there were no systemic ibogaine effects regarding antioxidant defense. Hepatic xanthine oxidase activity was elevated in rats that received 20 mg/kg compared to the controls, suggesting faster adenosine turnover. TBARS concentration was elevated in the group treated with 1 mg/kg after 24 h compared to the controls, suggesting mild oxidative stress. It was shown that ibogaine in heart after 6 h diminished the amount of protein -SH groups suggesting intra-protein oxidation, which along disturbed energetic homeostasis could lead to discrete cellular oxidative damages and possible heart failure. Ibogaine inhibited ex vivo ileum contractile activity with doses below mM. The effect was stronger in electrically stimulated contractions than tonic. Pretreatment with different potassium channel related agents showed that ibogaine obtained its inhibitory activity partially through KATP channels. Ibogaine induced the elevation of superoxide dismutase (SOD), catalase activity 9 ex vivo, but this effect was diminished by addition of glibenclamide. Ibogaine changed redox homeostasis in testicles as well, and elevated SOD activity suggested the importance of the preservation of delicate balance of superoxide and hydrogen peroxide concentrations that is crucial in sperm capacitation. Our results showed that ibogaine in doses applied in vivo per os influenced redox state and changed antioxidant activity, but response is highly tissue-, dose- and time- specific, without clear common characteristic.