[Vitamine-like substances L-carnitine and acetyl-L-carnitine: from biochemical studies to medicine].

Recently reported data clarify our understanding of the molecular aspects of carnitine in medicine. Carnitine is a compound necessary for the transport of acyl-CoA across the inner mitochondrial membrane for their beta-oxidation. Only L-isomer of carnitine is biologically active. The D-isomer may actually compete with L-carnitine for absorption and transport, increasing the risk of carnitine deficiency. By interaction with CoA, carnitine is involved in the intermediary metabolism by modulating free CoA pools in the cell. Detoxification properties and anabolic, antiapoptotic and neuroprotective roles of carnitine is presented. Carnitine deficiency occurs as a primary genetic defect of carnitine transport and secondary to a variety of genetic and acquired disorders. The pathophysiological states associated with carnitine deficiency have been summarized. L-Carnitine is effective for the treatment of primary and secondary carnitine deficiencies. Acetyl-L-carnitine improves cognition in the brain, significantly reversed age-associated decline in mitochondrial membrane potential and improved ambulatory activity. The therapeutic effects of carnitine and acetylcarnitine are discussed.

[Comparative study of permeability of derivatives of gamma-aminobutyric and gamma-hydroxybutyric acids through hemato-encephalic barrier]. / Sravnitel'noe izuchenie pronitsaemosti cherez gematoéntsefalicheskii bar'ier preparatov proizvodnykh g-aminomaslianoi i g-oksimaslianoi kislot.

The authors studied the permeability of the blood-brain barrier (CEB) to two nootropics: calcium ketogomopantothenate (KRA-Ca), a GABA derivative, and and calcium salt of oxybutyrate (OB-Ca), a derivative of GOBA. It was established that both preparations penetrate the CEB easily and are found in the brain at different intervals after their administration. However, essential differences in the distribution constant of these drugs were disclosed: KPA-Ca permeated the CEB more intensively and was accumulated in larger amounts in the late-term intervals.

[Analogs of 3'-dephospho-CoASH with a phosphodiester bond as substrates of the S-acetylation reaction, catalyzed by acetyl-CoA-synthetase fom rabbit myocardium]. / Analogi 3'-defosfo-CoASH s fosfodiéfirnoi sviaz'iu kak substraty reaktsii S-atsetilirovaniia, kataliziruemoi atsetil-CoA-sintetazoi miokarda krolika.

A number of earlier unknown 3'-dephospho-CoASH analogues with the pyrophosphate fragment replaced by an ester or phosphodiester bond were synthesized and tested in S-acetylation reaction, catalyzed by acetyl-CoA synthetase (EC 6.2.1.1) from rabbit myocardium. 3'-Dephospho-CoASH analogues with a phosphodiester bond, e.g. (Ia), had a lower affinity and diminished kinetic parameters than 3'-dephospho-CoASH (Km = 1 and 0.2 mM, respectively). The adenine substitution in (Ia) by guanine or hypoxanthine (but not cytosine) residue resulted in a loss of substrate properties. 3'-Dephospho-CoASH with an ester bond were not capable of accepting acetate under conditions used and only slightly inhibited the enzymic activity.

Interaction of acetyl-CoA fragments with rat liver acetyl-CoA carboxylase.

The interaction of acetyl-CoA fragments with rat liver acetyl-CoA carboxylase has been studied. Dephosphorylated acetyl-CoA did not actually differ from acetyl-CoA in its substrate properties. Non-nucleotide analogues of the substrate, S-acetylpantatheine and it's 4'-phosphate, also possess substrate properties (Vmax = 1.5% and 15% of the maximal rate value of acetyl-CoA carboxylation, respectively). The nucleotide fragment in the acetyl-CoA molecule produces a marked effect on the thermodynamics of the substrate-enzyme interaction, and is apparently involved in activation and appropriate orientation of the acetyl group in the active site. The better substrate properties of S-acetylpantetheine 4'-phosphate and the inhibitory properties of pantetheine 4'-phosphate, compared to the unphosphorylated analogues, evidence an important role of the 5'-beta-phosphate of 3'-phosphorylated ADP residue in acetyl-CoA binding to the enzyme.

[Substrate specificity of acetyl-CoA-carboxylase from the rat liver]. / Izuchenie substratnoi spetsifichnosti atsetil-CoA-karboksilazy pecheni krysy.

The interaction between acetyl-CoA fragments and rat liver acetyl-CoA carboxylase was studied. It was found that the 3'-phosphate group did not interfere with the enzyme interaction since the substrate properties of acetyl-dephospho-CoA and acetyl-CoA are nearly identical. The non-nucleotide substrate analogs S-acetyl-pantethin and its 4'-phosphate) also displayed substrate properties (V = 1.5% and 15% of the V for acetyl-CoA carboxylation respectively). The nucleotide fragment of the acetyl-CoA molecule produced an appreciable effect on the thermodynamics of this substrate interaction with the enzyme. Its physiological role consists in all probability, in the activation and propes orientation of the acetyl group in the enzyme active center. The far more pronounced substrate properties of S-acetyl pantethin 4'-phosphate and the inhibitory properties of pantethin 4'-phosphate (compared to non-phosphorylated analogs) suggest the essential role of the beta-phosphate residue of ADP in the acetyl-CoA binding to the enzyme. The data obtained suggest also that the hydrophobic region responsible for the acyl radical binding, has a site which specifically recognizes the beta-mercaptoethyl residue of the CoA pantethin fragment. The pivotal role in the acetyl-CoA carboxylase interaction with the substrate is ascribed to the productive binding of the acetyl radical; the contribution of individual fragment of the CoA molecule is variable.

[Changes in the brain GABA system after repeated injections of pyridoxal-5'-phosphate and its Schiff base with GABA]. / Izmeneniia v sisteme GAMK golovnogo mozga pri mnogokratnom in''etsirovanii piridoksal'-5'-fosfata i ego shiffova osnovaniia s GAMK.

A state of the gamma-aminobutyric acid (GABA) system (glutamate, glutamate decarboxylase, GABA, GABA-alpha-ketoglutarate aminotransferase) and the coupled reactions (alpha-ketoglutarate dehydrogenase complex, aspartate- and alanine aminotransferases) was studied in three brain structures (cerebellum, brain cortex and truncus cerebri) after multiple administration of pyridoxal-5'-phosphate (PALP) and its Shiff base with GABA (5 injections at doses 10.0 and 15.0 mg/kg of body mass, respectively). Non-coenzymatic effects of PALP were found to prevail within 1 hr after its last administration: inhibition of PALP-dependent aminotransferases and activation of the alpha-keto-glutarate oxidative decarboxylation were observed. The opposite effects were detected after addition of PALP to brain homogenates in vitro. Administration of the PALP-GABA complex exhibited qualitatively similar to those of PALP effects on the reactions studied in brain. The data obtained suggest that parenteral administration of the coenzyme preparation caused a number of metabolic effects, which are sometimes far from unambigously predicted theoretical considerations. The similarity of PALP and PALP-GABA effects appears to demonstrate ready biotransformation of the Shiff base with liberation of PALP and GABA.

[Antihypoxic properties of GABA-containing vitamin derivatives]. / Antigipoksicheskie svoistva GAMK-soderzhashchikh proizvodnykh vitaminov.

The antihypoxic properties of GABA-containing vitamin derivatives (pyridoxalphosphate-GABA, picamilone, pantogam, sodium homopantothenate) as compared with GABA were studied. All agents were found to increase mouse life expectancy under hypoxia in contrast to GABA.

[The effect of calcium pantothenate and homopantothenate on [14C]-GABA absorption by slices of rat cerebral cortex]. / Vliianie pantotenata i gomopantotenata kal'tsiia na pogloshchenie [14C]-GAMK srezami kory golovnogo mozga krys.

Calcium D-pantothenate (Ca D-P) and calcium D-homopantothenate (Ca D-HP) (pantogam) exhibiting antagonism in a number tests of pharmacological screening were shown to inhibit the absorption of [14C]-GABA (0.2 microM) by the rat brain cortex slices (3 mm) incubated in calcium-free medium. The effect of Ca D-HP manifests at its low concentrations (10(-6) M) and that of Ca D-P at high concentrations (10(-6) M). The data obtained are discussed in relation to the possible influence of the anion and cation components of the studied compounds.

[Effect of repeated injections of GABA on the GABA shunt and various associated reactions in the rat brain]. / Vliianie mnogokratnykh in''ektsii GAMK na GAMK-shunt i nekotorye sviazannye s nim reaktsii v golovnom mozge krys.

Effect of repeated administrations of gamma-amino butyric acid (GABA) at doses corresponding to those which are used in clinical medicine, on the state of GABA-shunt and intensity of alpha-ketoglutarate dehydrogenase and aminotransferase reactions as well as on the level of GABA and glutamate was studied in cerebellum, cortex and trunkus cerebri of rat brain. Administration of GABA (5 injections at a dose of 5 mg/kg) caused distinct alterations in central nervous system, which involved activation of GABA-transaminase, utilizing GABA, and inactivation of glutamate decarboxylase, producing the amine, as well as a decrease of GABA and glutamate levels and an increase in alpha-ketoglutarate utilization and activation of aminotransferase reactions. These alterations were especially distinct in cerebellum, where initial high intensity of GABA shunt functioning and minimal level of GABA were observed. The alterations observed suggest the existence of pronounced stimulating effect of GABA, even at low doses, on reactions of energy metabolism in brain.

[Alteration of the acute toxicity and various pharmacologic effects of streptomycin sulfate by calcium 4'-phosphopantothenate]. / Izmenenie ostroi toksichnosti i nekotorykh farmakologicheskikh éffektov streptomitsina sul'fata 4'-fosfopantotenatom kal'tsiia.

The effect of calcium 4'-phosphopantothenate (CPP) on acute toxicity of streptomycin and the decrease by the antibiotic of the muscle working capacity, "holes" reflex, body temperature and oxygen intake was studied on 258 albino mice weighing 22-26 g. Medical calcium pantothenate (CPA) was used for control purposes. CPP is an antagonist of streptomycin sulfate. In a dose of 1/10 or 1/5 of the LD50 injected intraperitoneally CPP lowered acute toxicity of streptomycin and prevented its effect in a dose of 0.11--1.1 g/kg injected subcutaneously on the muscle working capacity, "holes" reflex and body temperature. The spectrum index of the CPP antitoxic effect was equal to 22.5. By its acute toxicity CPP (LD50 1.18 +/- 0.07 g/kg) did not differ from CPA (LD50 1.25 +/- 0.08 g/kg). The efficacy of CPP, by its antitoxic spectrum, was 1.8 times higher than that of CPA. CPA lowered the streptomycin effect on the "holes" reflex and body temperature, while CPP prevented it. Both the drugs did not influence the decrease in the oxygen consumption induced by streptomycin.

[Adaptive changes in brain metabolism during chronic alcoholic intoxication]. / Adaptatsionnye izmeneniia obmena veshchestv v golovnom mozgu pri khronicheskoi alkogolnoi intoksikatsii.

Chronically alcoholized intoxication (1.5--2 months) induces adaptation of cerebral neurones to changing equilibrium states of biochemical processes by altering the activity of enzymes of GABA metabolism, reduction of alanine and aspartate transaminase activity and increase of LDH and succinate dehydrogenase activity. In the cerebellum and cerebral hemispheres during alcohol abstinacy the activity of GABA-T, succinate dehydrogenase and aspartate transaminase was reduced while that of LDH and alanine transaminase was increased. The administration of fusarinic acid (100 mg/kg i. p.) to control animals induced a sharp increase of GAD activity in both structures of the brain. The stimulatory effects of fusarinic acid were not observed when it was administered to animals receiving alcohol chronically. Motor activity or rats was markedly reduced during chronical alcoholism and the first days of alcohol abstinacy (24--48 h), as well as following injection fusarinic acid and homopantothenic acid. The increase of locomotion and the vertical component of motor activity was observed only following one week or one month after alcohol abstinacy.

[Intake dynamics of GABA and its pantoate derivative in mice brain areas]. / Dinamika nadkhodzhennia gamk ta ii spoluki z pantoatom viddili golovnogo mozku mishei.

After subcutaneous administration in equimolar, close to therapeutic, doses accumulation of 1-14C-PANTOGAB exceeds accumulation of 1-14C-GABA in the brain areas only at early stages of observations: 7.5 and 15 min. In blood at all the time except for 4 h, the amount of 1-14C-PANTOGAB exceeds essentially the content of 1-14C-GABA. Maximum of 14C-PANTOGAB accumulation in the brain is observed 30 min later and that of 14C-GABA by 60 min. Difference in distribution of both preparations between the brain areas are inconsiderable. In the period of maximum accumulation there is a tendency to a more intensive 1-14C-PANTOGAB incorporation into the cerebellum, and 1-14C-GABA into truncus cerebri. The dynamics of accumulation in the brain and removing of the studied compounds from blood evidences for better absorption from the place of administration and for a weaker biotransformation of PANTOGAB as compared to GABA.