O. G. Tokareva

Intravenous treatment with coenzyme Q10 improves neurological outcome and reduces infarct volume after transient focal brain ischemia in rats

Abstract: Coenzyme Q10 (CoQ10) crosses the blood–brain barrier when administered intravenously and accumulates in the brain. In this study, we investigated whether CoQ10 protects against ischemia-reperfusion injury by measuring neurological function and brain infarct volumes in a rat model of transient focal cerebral ischemia. In male Wistar rats, we performed transient middle cerebral artery occlusion (tMCAO) for 60 minutes, followed by reperfusion for 24 hours or 7 days. Forty-five minutes after the onset of occlusion (or 15 minutes before reperfusion), rats received a single intravenous injection of solubilized CoQ10 (30 mg·mL−1·kg−1) or saline (2 mL/kg). Sensory and motor function scores and body weights were obtained before the rats were killed by decapitation, and brain infarct volumes were calculated using tetrazolium chloride staining. CoQ10 brain levels were measured by high-performance liquid chromatography with electrochemical detection. CoQ10 significantly improved neurological behavior and reduced weight loss up to 7 days after tMCAO (P < 0.05). Furthermore, CoQ10 reduced cerebral infarct volumes by 67% at 24 hours after tMCAO and 35% at 7 days (P < 0.05). Cerebral ischemia resulted in a significant reduction in endogenous CoQ10 in both hemispheres (P < 0.05). However, intravenous injection of solubilized CoQ10 resulted in its increase in both hemispheres at 24 hours and in the contralateral hemisphere at 7 days (P < 0.05). Our results demonstrate that CoQ10 is a robust neuroprotective agent against ischemia-reperfusion brain injury in rats, improving both functional and morphological indices of brain damage.

Cardioprotection with Intravenous Injection of Coenzyme Q10 is limited by Time of Administration after Onset of Myocardial Infarction in Rats

Objective: Coenzyme Q 10 (CoQ 10 ) levels are decreased in patients with cardiovascular diseases. The bioavailability of orally ingested CoQ 10 is limited to 2–3%, and long-term administration is required to increase the level of CoQ10 in myocardium for cardioprotection. Intravenous (IV) administration of solubilized CoQ10 immediately after coronary occlusion has been shown to increase myocardial levels rapidly and to protect against cardiac ischemia. The aim of this study was to determine the length of time following onset of myocardial infarction (MI) for which a single IV administration of CoQ 10 was cardioprotective. Methods: A single IV injection of solubilized CoQ10 (30 mg/kg, 1 ml/kg) or saline (1 ml/kg) was administered at either minute 60 or minute 180 after the onset of MI induced by coronary artery ligation in rats. Results: Twenty-one days after injection, CoQ 10 levels were still high in both the 60 and 180 minute groups. Rats treated with CoQ10 60 min after ligation had a significantly larger mass of viable left ventricle (LV) myocardium, limited LV dilatation, and improved cardiac contractile and relaxation capacity compared with controls. CoQ10 levels were significantly correlated with LV end-systolic volume (r=-0.65), end-diastolic volume (r=-0.56), ejection fraction (r-=0.67), and LV relaxation (r=-0.64) (p<0.001). IV administration of CoQ 10 180 min after occlusion prevented signs of right ventricle hypertrophy but did not limit LV damage. Conclusion: A single IV injection of solubilized CoQ 10 (30 mg/kg) at minute 60 effectively limited LV damage and deterioration of function after coronary ligation in rats; however, the same protective effects were not seen with CoQ 10 injection administered at minute 180.

Neuroprotective Effectiveness of Intravenous Ubiquinone in Rat Model of Irreversible Cerebral Ischemia

The neuroprotective effect of ubiquinone (coenzyme Q10)was demonstrated on the rats model of ischemic stroke provoked by persistent 24-h occlusion of the middle cerebral artery. Coenzyme Q10 (30 mg/kg) was injected intravenously in 60 min after artery occlusion. Ubiquinone crossed the blood-brain barrier, accumulated in the brain, and produced a neuroprotective effect: it alleviated ischemia-induced neurological deficit and reduced the size of necrotic zone by 49% in comparison with rats receiving physiological saline.

Hplc estimation of coenzyme Q(10) redox status in plasma after intravenous coenzyme Q(10) administration

The pharmacokinetics of the total pool of coenzyme Q(10) (Co(10)), its oxidized (ubiquinone) and reduced (ubiquinol, CoQ(10)H₂) forms have been investigated in rats plasma during 48 h after a single intravenous injection of a solution of solubilized CoQ(10) (10 mg/kg) to rats. Plasma levels of CoQ(10) were determined by HPLC with spectrophotometric and coulometric detection. In plasma samples taken during the first minutes after the CoQ(10) intravenous injection, the total pool of coenzyme Q(10) and proportion of CoQ(10)H₂ remained unchanged during two weeks of storage at -20°C. The kinetic curve of the total pool of coenzyme Q(10) corresponds to a one-part model (R² = 0.9932), while the corresponding curve of its oxidized form fits to the two-part model. During the first minutes after the injection a significant portion of plasma ubiquinone undergoes reduction, and after 7 h the concentration of ubiquinol predominates. The decrease in the total plasma coenzyme Q(10) content was accompanied by the gradual increase in plasma ubiquinol, which represented about 90% of total plasma CoQ(10) by the end of the first day. The results of this study demonstrate the ability of the organism to transform high concentrations of the oxidized form of CoQ(10) into the effective antioxidant (reduced) form and justify prospects of the development of parenteral dosage forms of CoQ(10) for the use in the treatment of acute pathological conditions.

Multi-Day Monitoring of Ubidecarenone Level in Rat Plasma and Tissues After a Single Intravenous Injection

The pharmacokinetics of ubidecarenone (CoQ10) in rat plasma and the kinetics of its organ levels were studied for the first time for 8-16 d after a single i.v. injection at a dose of 30 mg/kg. The pharmacokinetics followed a classical two-compartment curve. The main pharmacokinetic parameters for plasma (C0, AUC0→∞, Kα, Kel, t1/2α, t1/2el, ClT, Vd) and several organs (Cmax, Tmax, AUC0→t, ftiss) were calculated. The results proved that CoQ10 injected i.v. rapidly attained and maintained for a long time high levels in plasma, myocardium, brain, liver, and kidneys. This was potentially important for treating acute ischemic states.

Redox status and pharmacokinetics of coenzyme Q10 in rat plasma after its single intravenous administration

The pharmacokinetics of the total pool of coenzyme Q10 (CoQ10), its oxidized (ubiquinone) and reduced (ubiquinol, CoQ10H2) forms have been investigated in rats plasma during 48 h after a single intravenous injection of a solution of solubilized CoQ10 (10 mg/kg) to rats. Plasma levels of CoQ10 were determined by HPLC with spectrophotometric and coulometric detection. In plasma samples taken during the first minutes after the CoQ10 intravenous injection, the total pool of coenzyme Q10 and proportion of CoQ10H2 remained unchanged during two weeks of storage at −20°C. The kinetic curve of the total pool of coenzyme Q10 corresponds to a one-compartment model (R2 = 0.9932), while the corresponding curve of its oxidized form fits to the two-compartment model. During the first minutes after the injection a significant portion of plasma ubiquinone undergoes reduction, and after 7 h the concentration of ubiquinol predominates. The decrease in total plasma coenzyme Q10 content was accompanied by the gradual increase in plasma ubiquinol, which represented about 90% of total plasma CoQ10 by the end of the first day. The results of this study demonstrate the ability of the organism to transform high concentrations of the oxidized form of CoQ10 into the effective antioxidant (reduced) form and justify prospects of the development of parenteral dosage forms of CoQ10 for the use in the treatment of acute pathological conditions.

Estimation of the Linearity of Ubidecarenone Pharmacokinetics After Intravenous Administration

The dynamics of ubidecarenone (coenzyme Q10) levels in rat blood plasma and liver were monitored for two days after i.v. injection of solubilized ubidecarenone at doses of 10 and 30 mg/kg. The kinetic curves of the drug in plasma were exponential for both doses. The areas under the concentration—time curves differed by 8.6 times for the 10 and 30 mg/kg doses. Normalization to the dose did not superimpose them. The drug accumulated gradually in liver with the areas under the concentration—time curves differing by a factor of 4.4. These data indicated that ubidecarenone pharmacokinetics in plasma and liver were nonlinear after intravascular injection.