ubiquinone and pantogab

Age-related changes in the acquisition and retention of memory based on the step-through active avoidance response were studied in rats and the effects of cholinergic drugs and cerebral metabolic activators on memory impairment in old rats were also tested. Six- and 12-month-old rats showed lower rates of acquisition of the active avoidance response than did 2-month-old rats. In addition, the retention of the active avoidance response in 6- and 12-month-old rats diminished rather rapidly compared with that observed in 2-month-old rats. Intraventricular injection of acetylcholine at doses of 20 and 50 ng caused a significant improvement of memory impairment in old rats. Physostigmine and arecoline also caused a significant ameliorating effect at doses of 0.02 and 0.05 mg/kg i.p. and 0.2 and 0.5 mg/kg i.p., respectively. Hopantenate calcium (100 mg/kg, p.o.), idebenone (20 and 50 mg/kg, i.p.), indeloxazine (50 mg/kg, p.o.) and DM-9384 (30 mg/kg, p.o.) also proved useful to improve memory impairment in old rats.

Topics: Acetylcholine; Aging; Animals; Benzoquinones; Brain; Central Nervous System Agents; gamma-Aminobutyric Acid; Learning; Male; Memory Disorders; Morpholines; Pantothenic Acid; Parasympathomimetics; Pyrrolidinones; Rats; Rats, Inbred Strains; Ubiquinone

The effects of idebenone and various nootropic drugs on lipid peroxidation in rat brain homogenate were examined. Idebenone inhibited lipoperoxide (LPO) production in brain homogenate in a concentration-dependent manner, with an IC50 of 38 microM. The inhibition was strongly enhanced (about 100-fold) by adding succinate, a substrate in the mitochondrial respiration. The optimal concentration of succinate was 0.5 mM. Inhibition of lipid peroxidation in brain homogenate by various nootropic drugs in the presence or absence of succinate was then examined. Drugs added to the brain homogenate at 100 microM in the absence of succinate inhibited LPO production in the order: idebenone greater than vinpocetine greater than bifemelane greater than indeloxazine greater than calcium hopantenate. However, when the drugs were added at 1 microM in the presence of succinate, only idebenone demonstrated inhibition. These results suggest that although almost all of the drugs tested inhibit lipid peroxidation in brain homogenate, only idebenone is activated by succinate, the other drugs being insensitive to this compound.

Topics: Animals; Benzhydryl Compounds; Benzoquinones; Brain; Depression, Chemical; Dose-Response Relationship, Drug; gamma-Aminobutyric Acid; In Vitro Techniques; Lipid Peroxides; Male; Morpholines; Pantothenic Acid; Quinones; Rats; Rats, Inbred Strains; Succinates; Ubiquinone; Vinca Alkaloids

The effects of idebenone (CV-2619) and its metabolites on respiratory activity and lipid peroxidation in isolated brain mitochondria from rats and dogs were studied. CV-2619 was easily reduced by canine brain mitochondria in the presence of respiratory substrates. Reduced CV-2619 (2H-CV-2619) was rapidly oxidized through the cytochrome b chain, indicating that the compound functioned simply as an electron carrier of mitochondrial respiratory system. Both nicotinamide adenine dinucleotide (NADH)- and nicotinamide adenine dinucleotide phosphate (NADPH)-dependent lipid peroxidations were examined in canine brain mitochondria in the presence of adenosine diphosphate (ADP) and Fe3+. NADH-cytochrome c reductase activity was sensitive to NADPH-dependent lipid peroxidation. CV-2619 (10(-5)M) strongly inhibited both types of the lipid peroxidation reactions and protected the resultant inactivation of the NADH-cytochrome c reductase activity. Activities of succinate oxidase in rat and canine brain mitochondria were virtually unaffected by CV-2619 and its metabolites (10(-5)-10(-6) M). On the other hand, CV-2619 markedly suppressed the state 3 respiration in glutamate oxidation in a dose dependent manner without any effect on the state 4 respiration and the ADP/O ratio in intact rat brain mitochondria. The inhibitory effect of CV-2619 was also observed in NADH-cytochrome c reductase, but not in NADH-2,6-dichlorophenolindophenol (DCIP) and NADH-ubiquinone reductases in canine brain mitochondria. These facts and results of inhibitor analysis suggest that the action site of CV-2619 is NADH-linked complex I in the mitochondrial respiratory chain and is different from that of inhibitors of oxidative phosphorylation such as rotenone, oligomycin and 2,4-dinitrophenol. Finally, the above findings suggest that CV-2619 acts as an electron carrier in respiratory chains and functions as an antioxidant against membrane damage caused by lipid peroxidation in brain mitochondria. It appears likely that the inhibition of oxygen consumption caused by CV-2619 is related to the effect on non-respiratory systems such as lipid peroxidation which also consumes oxygen.

Topics: Animals; Benzoquinones; Brain Chemistry; Dogs; Female; gamma-Aminobutyric Acid; Glutamates; Glutamic Acid; In Vitro Techniques; Lipid Peroxides; Malates; Male; Mitochondria; NADP; Oxygen Consumption; Pantothenic Acid; Pyruvates; Pyruvic Acid; Quinones; Rats; Rats, Inbred Strains; Respiration; Species Specificity; Succinates; Ubiquinone

Lipid peroxidation in rat brain mitochondria was induced by NADH in the presence of ADP and FeCl3. CV-2619 inhibited the lipid peroxidation in a concentration-dependent manner; the concentration giving 50% inhibition (IC50) was 84 microM. In addition, the inhibitory effect of CV-2619 was strongly enhanced by adding substrates of mitochondrial respiration; when succinate, glutamate, or succinate plus glutamate was added, the IC50 of CV-2619 was changed to 1.1, 10, or 0.5 microM, respectively. Metabolites of CV-2619 also inhibited the lipid peroxidation. The inhibitory effect of CV-2619 on mitochondrial lipid peroxidation disappeared when TTFA, an inhibitor of complex II in mitochondrial respiratory chain, was added. The results indicate that in mitochondria CV-2619 is changed to its reduced form which inhibits lipid peroxidation.

Topics: Animals; Antimycin A; Benzoquinones; Brain; Coenzymes; gamma-Aminobutyric Acid; Lipid Peroxides; Male; Mitochondria; NAD; Oxygen Consumption; Pantothenic Acid; Quinones; Rats; Rats, Inbred Strains; Rotenone; Thenoyltrifluoroacetone; Ubiquinone; Vitamin E

An experimental model of amnesia induced by cerebral ischemia after one-trial passive avoidance learning was established to test the effects of a novel compound, 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (idebenone, CV-2619), and some commonly used drugs in rats. One day after the vertebral artery was electrocauterized bilaterally, the common carotid artery was transiently occluded bilaterally to produce cerebral ischemia. The amnesia was estimated by the response latency for a rat to step from a light safety compartment to a dark compartment in which a foot-shock was given. The results of the retention test given 24 hr after the ischemia indicated that amnesia was successfully produced when the 200-600 sec ischemia was provided within 20 min after the avoidance learning. The effects of drugs on the amnesia induced by a 200-sec ischemia immediately after the avoidance learning were as follows: CV-2619 (10, 30 mg/kg, i.p. or p.o.) given before the retention test significantly increased the response latency, indicating a reversal effect on the amnesia. Physostigmine (0.1, 0.2 mg/kg, i.p.) and arginine-vasopressin (10 micrograms/kg, s.c.) were also effective, and calcium hopantenate (500 mg/kg, p.o.) showed a slight reversal action. Furthermore, CV-2619 (10 mg/kg, i.p.), given before or after the ischemia, significantly inhibited the appearance of amnesia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amnesia; Animals; Arginine Vasopressin; Avoidance Learning; Benzoquinones; Brain Ischemia; Conditioning, Operant; gamma-Aminobutyric Acid; Humans; Male; Pantothenic Acid; Physostigmine; Quinones; Rats; Rats, Inbred Strains; Time Factors; Ubiquinone