Background/Objectives: Inflammation and oxidative stress are key factors contributing to the initiation and progression of liver fibrosis in chronic obstructive cholestasis. Pantothenic acid (PA) and some of its derivatives have been reported to exhibit moderate anti-inflammatory, antioxidant, and regenerative effects. This study aimed to evaluate the redox-modulating effects of PA derivatives—panthenol (PL), pantethine (PT), and hopantenic acid (HPA) in a rat model of chronic obstructive cholestasis induced by common bile duct ligation (BDL). Methods: Macroscopic, histological, and ultrastructural alterations in the liver were assessed, along with molecular markers of oxidative stress, inflammation, and parameters of the glutathione (GSH) system. Results: BDL-induced liver injury was associated with enhanced lipid peroxidation, mitochondrial structural alterations, depletion of GSH, increased levels of protein S-glutathionylation (PSSG), and elevated thiobarbituric acid-reactive substances in mitochondria. Treatment with PL and, to a lesser extent, PT was associated with attenuation of hepatocellular ultrastructural damage, reduced bile duct hyperplasia, decreased inflammatory and necrotic changes, and moderate improvement in fibrosis-related parameters. In contrast, HPA (a PA antagonist) did not demonstrate hepatoprotective effects and it was associated with more pronounced liver injury. Conclusions: Chronic BDL is accompanied by suppression of glutathione redox capacity and enhanced oxidative stress. PL and PT, but not HPA, were associated with reduced levels of protein S-glutathionylation and partial restoration of redox balance. The protective effects of PL and PT may contribute to their antifibrotic activity, potentially through direct antioxidant capacity or redox-modulating mechanisms associated with the GSH system.

We explored the possibility of antioxidant and antifibrotic effects of panthenol (PL) associated with modulation of coenzyme A (CoA) biosynthesis in the liver in a rat model of chronic obstructive cholestasis induced by bile duct ligation (BDL). We found that PL increased alcohol dehydrogenase (ADH) activity in the liver of BDL rats. PL and its analog pantethine increased pantothenate kinase (PANK) activity, restored hepatic CoA levels reduced by BDL, lowered protein-bound CoA, and normalized impaired mitochondrial functions associated with induced oxidative stress after BDL. These effects were accompanied by decreased collagen deposition and improved morphological features of hepatocytes. In contrast, PANK inhibitor, hopantenic acid (HPA), reduced hepatic CoA levels, aggravated hepatocellular damage, and promoted fibrosis. In the human hepatic stellate cell line LX-2, PL exhibited no cytotoxicity over a wide concentration range, increased intracellular CoA levels, decreased reactive oxygen species (ROS) production, and attenuated collagen accumulation associated with oxidative stress in vitro. Importantly, inhibition of ADH by 4-methylpyrazole completely abolished the protective effects of panthenol, indicating that its activity depends on metabolic pathways involving CoA. Notably, PL did not directly reduce H2O2 or superoxide anion radical production in cell-free systems but significantly suppressed lipid peroxidation in liposomes and red blood cells in vitro. Ultimately, these findings indicate that the antioxidant and antifibrotic effects of PL are associated with modulation of CoA metabolism and enhanced resistance of biological membranes to oxidative damage.

Unraveling the complex roles of oxidation products – including reactive oxygen species, reactive nitrogen species, reactive sulfur species (RSS), metalloproteins, and iron–sulfur (Fe–S) clusters – which are integrated through the reactive species interactome (RSI), remains a key challenge in neurochemistry and neuropharmacology. These reactive species strongly influence energy metabolism and redox homeostasis in the brain, particularly during neurodegeneration. This review highlights the impact of nitrosative/oxidative stress, focusing on early events in neurodegeneration: Reduced tricarboxylic acid (TCA) cycle activity, a shift toward succinate utilization, glutamate accumulation, and redox imbalance. The resulting peroxynitrite anion impairs the mitochondrial respiratory chain complex I and the antiradical defense system. A fall in glutathione (GSH) levels and redox potential promotes an imbalance in redox couples, iron-driven Fenton reactions, and impaired Fe–S cluster biogenesis, thereby uncoupling oxidative phosphorylation and initiating redox-driven neurodegeneration. The intramitochondrial localization of the electron transport chain, Fe–S cluster biogenesis, TCA cycle enzymes, and heme biosynthesis raises questions about their regulation by nutritional and aging factors, the dichotomy of iron utilization in Fe–S clusters and heme, the role of succinyl-coenzyme A (CoA) in heme biosynthesis and succinate-driven phosphorylation, and the relationship between CoA metabolism and intraneuronal iron delivery. Addressing these issues offers the potential to stabilize energy metabolism and modulate RSI generation, where providing mitochondria with a continuous supply of reduced components and maintaining a negative redox potential support the neuroprotective actions of selected metabolic therapy agents. These include CoA biosynthesis pre-cursors with antioxidant and anti-inflammatory properties and the ability to enhance GSH biosynthesis. Progress toward effective neuroprotection in both neuropathology and aging may require an integrated strategy to modulate RSI and RSSs effects, prevent metalloproteome imbalance, and preserve the energy-producing capacity of neural structures.

Alzheimer's-like disease was simulated in female adult Wistar CRL(WI) WUBR rats by 6-week intragastric administration of aluminum chloride at a dose of 200 mg/kg body mass. In the presence of the developed oxidative stress (OS), we found a decrease in the activities of the tricarboxylic acid cycle (TCA cycle) enzymes and an increase in the activities of the pentose phosphate pathway (PPP) dehydrogenases, as well as a reduction of SH-and SS-groups in proteins along with an increased SH/SS ratio and glutathionylation with simultaneous decreases of glutathione (GSH) and the GSH/GSSG ratio and its redox potential. The glutathione system enzymes were changed multidirectionally, with glutathione reductase remaining stable. Decreased activities of GSH biosynthesis enzymes and cysteine content were noticed. The intragastric administration of the CoA biosynthesis modulators D-panthenol (PL), D-pantethine, or D-homopantothenate (HPA) at a dose of 200 mg/kg from the fifth week of the experiment caused either reduction or leveling of OS manifestations in blood plasma, an increase in acetyl cholinesterase, normalization of the activities of TCA cycle and PPP enzymes and the P-SH level (not the SH/SS ratio), and a significant reduction of S-glutathionylation, as well as increases in the GSH level, the GSH/GSSG ratio and the redox potential in the hemispheres. The effect of CoA system modulators was manifested in activation of glutathione transferase, a decrease of glutathione peroxidase and less evident activation of GSH biosynthesis enzymes (that is, PL) although they contributed to the elevation of the cysteine content due to reduced protein S-cysteinylation. The levels and the ratio of CoA/acetyl-CoA (except for PL) were not changed by toxicosis and the OS modulators. The feasibility of nonconenzyme effects was confirmed by the administration of HPA. The phenomenon of redox activity of the CoA biosynthesis modulators with clearly directional effects on the glutathione system and the TCA cycle and PPP enzymes during alleviation of OS and aluminum neurotoxicosis is discussed.

The processes of biotransformation of pantothenic acid (Pan) in the biosynthesis and hydrolysis of CoA, key role of pantothenate kinase (PANK) and CoA synthetase (CoASY) in the formation of the priority mitochondrial pool of CoA, with a high metabolic turnover of the coenzyme and limited transport of Pan across the blood-brain barrier are considered. The system of acetyl-CoA, a secondary messenger, which is the main substrate of acetylation processes including formation of N-acetyl aspartate and acetylcholine, post-translational modification of histones, predetermines protection of the neurons against degenerative signals and cholinergic neurotransmission. Biochemical mechanisms of neurodegenerative syndromes in the cases of PANK and CoASY defects, and the possibility of correcting of CoA biosynthesis in the models with knockouts of these enzymes have been described. The data of a post-mortem study of the brains from the patients with Huntington’s and Alzheimer’s diseases are presented, proving Pan deficiency in the CNS, which is especially pronounced in the pathognomonic neurostructures. In the frontal cortex of the patients with Parkinson’s disease, combined immunofluorescence of anti-CoA- and anti-tau protein was detected, reflecting CoAlation during dimerization of the tau protein and its redox sensitivity. Redox activity and antioxidant properties of the precursors of CoA biosynthesis were confirmed in vitro with synaptosomal membranes and mitochondria during modeling of aluminum neurotoxicity accompanied by the decrease in the level of CoA in CNS. The ability of CoA biosynthesis precursors to stabilize glutathione pool in neurostructures, in particular, in the hippocampus, is considered as a pathogenetic protection mechanism during exposure to neurotoxins, development of neuroinflammation and neurodegeneration, and justifies the combined use of Pan derivatives (for example, D-panthenol) and glutathione precursors (N-acetylcysteine). Taking into account the discovery of new functions of CoA (redox-dependent processes of CoAlation of proteins, possible association of oxidative stress and deficiency of Pan (CoA) in neurodegenerative pathology), it seems promising to study bioavailability and biotransformation of Pan derivatives, in particular of D-panthenol, 4′-phospho-pantetheine, its acylated derivatives, and compositions with redox pharmacological compounds, are promising for their potential use as etiopathogenetic agents.

Alzheimer’s-like disease was simulated in female adult Wistar CRL(WI) WUBR rats by 6-week intragastric administration of aluminium chloride at a dose of 200 mg/kg body mass. In the presence of developed oxidative stress (OS), we found a decrease in the activities of tricarboxylic acid cycle (TCA cycle) enzymes and an increase in the activities of pentose phosphate pathway (PPP) dehydrogenases as well as a reduction of SH-and SS-groups in proteins (P) along with the increased SH/SS ratio and glutathionylation with simultaneous decreases of glutathione (GSH) and the GSH/GSSG ratio and its redox potential in the brain hemispheres. The glutathione system enzymes were changed multidirectionally, with glutathione reductase remaining stable. Decreased activities of GSH biosynthesis enzymes and cysteine content were noticed. The intragastric administration of the CoA biosynthesis modulators D-panthenol (PL), D-pantethine or D-homopantothenate (HPA) at a dose of 200 mg/kg since the 5th week of the experiment caused either reduction or leveling of OS manifestations in blood plasma, an increase in acetyl cholinesterase, normalization of the activities of TCA cycle and PPP enzymes, P-SH level (not the SH/SS ratio) and a considerable reduction of S-glutathionylation as well as increases in GSH level, the GSH/GSSG ratio and redox potential in the hemispheres. The effect of CoA system modulators was manifested in activation of glutathione transferase, a decrease of glutathione peroxidase and less evident activation of GSH biosynthesis enzymes (PL) although they contributed to the elevation of cysteine content due to the reduced protein S-cysteinylation. The levels and the ratio of CoA/acetyl-CoA (except for PL) were not changed by toxicosis and the OS modulators. The feasibility of non-conenzyme effects was confirmed by the administration of HPA. The phenomenon of redox activity of the CoA biosynthesis modulators with clearly directional effects on the glutathione system and the TCA cycle and PPP enzymes during alleviation of OS and aluminium neurotoxicosis is discussed.

An Alzheimer-like pathological process was induced in mature female Wistar CRL: (WI) WUBR rats using aluminum chloride (200 mg/kg, intragastrically, 6 weeks) in order to model redox imbalance and oxidative stress (OS) in the hippocampus and study the possibilities of their correction 2 weekly administration of coenzyme A biosynthesis modulators (panthenol – PL, pantethine – PT, homopantothenate – HP) at a dose of 200 mg/kg intragastrically for 2 weeks). Against the background of activation of peroxidation processes and a decrease in acetylcholinesterase activity, a decrease in the reduction potential of glutathione and the level of the acid-soluble fraction of CoA was observed with a simultaneous increase in the activity of glutathione-metabolizing enzymes (GR, GPx, GST), the process of S-glutathionylation of proteins and the level of protein thiols. The consumption of the precursors of CoA biosynthesis in full (PL, PT) or in part (HP) had an antioxidant effect, restored the activity of AChE, the level and reduction potential of glutathione and glutathione-metabolizing enzymes, the process of S-glutathionylation, and stimulated the activity of enzymes generating NADPH+. Taking into account the low modulating effect of coenzyme precursors on the level of CoA in the hippocampus and their high redox pharmacological activity, their non-coenzymatic effect on redox mechanisms leading to an increase in the bioavailability of reducing equivalents and energy status is assumed.

We investigated the nephroprotective effect of D-panthenol in rhabdomyolysis-induced acute kidney injury (AKI). Adult male Wistar rats were injected with 50% glycerol solution to induce rhabdomyolysis. Animals with rhabdomyolysis were injected with D-panthenol (200 mg/kg) for 7 days. On day 8, we examined AKI markers, renal histology, antioxidant capacity, and protein glutathionylation in kidneys to uncover mechanisms of D-panthenol effects. Rhabdomyolysis kidneys were shown to have pathomorphological alterations (mononuclear infiltration, dilatation of tubules, and hyaline casts in Henle’s loops and collecting ducts). Activities of skeletal muscle damage markers (creatine kinase and lactate dehydrogenase) increased, myoglobinuria was observed, and creatinine, BUN, and pantetheinase activity in serum and urine rose. Signs of oxidative stress in the kidney tissue of rhabdomyolysis rats, increased levels of lipid peroxidation products, and activities of antioxidant enzymes (SOD, catalase, and glutathione peroxidase) were all alleviated by administration of D-panthenol. Its application improved kidney morphology and decreased AKI markers. Mechanisms of D-panthenol’s beneficial effects were associated with an increase in total coenzyme A levels, activity of Krebs cycle enzymes, and attenuation of protein glutathionylation. D-Panthenol protects kidneys from rhabdomyolysis-induced AKI through antioxidant effects, normalization of mitochondrial metabolism, and modulation of glutathione-dependent signaling.

The changes in the parameters of oxidative stress, energy metabolism, and redox potential of the glutathione system in the rat brain following cerebral ischemia were studied. To correct metabolic disorders, the pantothenic acid derivatives were used in combination with precursors of glutathione biosynthesis and selenium substances.Cerebral ischemia was modeled by ligating the both common carotid arteries in rats for 2 h. Drugs were administered i.p. in the following doses: panthenol – 400 mg/kg, N-acetylcysteine – 150, nanoselen – 1 mg/kg, three times: 1 h before ligation of the carotid arteries, at the time of ligation and 1 hour after ligation. We showed that the development of oxidative stress caused by ischemia is accompanied by the changes in the parameters of energy metabolism and the pentose phosphate pathway in the cerebral hemispheres. Simultaneously, there are a decrease in the GSH level, an increase in the GSSG content, a decrease in the GSH/GSSG ratio, and the activation of enzymes of redox transformations of glutathione.The redox potential of the glutathione system decreases and shifts towards oxidation, while the level of S-glutathionylated proteins increases. Thus, the value of the GSH/GSSG ratio and the protein glutathionylation intensity are the sensitive indicators of the redox potential in the brain tissue and can be used as markers of the extent of changes in the redox balance. The panthenol injection to animals leads to a decrease in the content of free radical oxidation products, violations of oxidative phosphorylation and restoration of thiol-disulfide balance in the brain. When panthenol is administered together with N-acetylcysteine and nanoselen, the corrective effect of panthenol is enhanced.

Abstract—We studied changes in the indices of free-radical oxidation and thiol-disulfide status in the brain structures in the experimental model of Parkinson’s disease (PD) induced by administration of rotenone to rats. Pantothenic acid derivatives, such as panthenol (PL), pantethine (PT), and homopantothenic acid (HPA) were used as neuromodulators. It was found that redox imbalance in the brain induced by rotenone is accompanied by the activation of free-radical processes, pronounced inhibition of antioxidant defense, a considerable decrease in the glutathione system reduction potential, and increased protein glutathionylation. The strongest changes were in the basal ganglia of the brain. PL and PT but not HPA, decrease the changes in the free-radical oxidation and thiol-disulfide balance in the brain structures. During experimental neurotoxicosis, the mechanisms of neuroprotective action of PL and PT, which are linked with the changes in the biosynthesis of CoA, are, obviously, related to their ability to increase the reduction potential of the glutathione system, thus mitigating the effects of oxidative stress.

Using an experimental model of aluminum neurotoxicosis, it was established that under conditions of chronic administration of aluminum chloride to rats, oxidative stress develops and inhibits the redox potential of the glutathione system in the mitochondrial and postmitochondrial fractions of the cerebral hemispheres. It was shown that the ingestion of N-acetylcysteine, as well as its combined use with coenzyme A biosynthesis precursors (D-panthenol or D-pantetin) against the background of aluminum neurotoxicosis, leads to a marked decrease in the production of reactive oxygen species by mitochondria, a decrease in the production of thiobarbituric acid reactive substances, and normalization of GSH content and its biosynthesis in brain tissue. The results indicate a high efficiency of the biosynthesis precursor of glutathione N-acetylcysteine in the prevention of oxidative stress in the chronic model of aluminum neurotoxicosis, which may be the rationale for its use as a modulator of mitochondrial redox status in the development of neurodegenerative pathology.

We studied changes in S-glutathionylated proteins (PSSG) content in rat brain structures in different experimental models of neurodegenerative pathology, as well as the possibility of correcting these changes with pantothenic acid derivatives. We have shown that the content of PSSG significantly increases in brain structures in all the models of neurotoxicosis that we studied, and this increase is observed to the greatest extent precisely in those structures where a particular neurotoxin has the most pronounced effect. Thus, the content of PSSG is a sensitive marker of post-translational protein modification. Precursors of CoA reduce S-glutathionylation of proteins, since HPA, which is not a precursor of CoA, does not have a protective effect in relation to PSSG.

SOME PROBLEMS OF MEASUREMENT OF THIOLS AND DISULFIDES N CLINICAL MATERIAL REVIEW

Free-radical-mediated processes are involved in a variety of physiological events, while oxidative stress and related redox deregulation are implicated in various pathological events. Tripeptide glutathione plays an important role in the antioxidant defense of the brain, particularly in the maintenance of the optimal redox state in neurons and glial cells. We studied the combined effects of pantothenic acid derivatives, pantothenol and calcium pantothenate, and memantine, which is a glutamate receptor antagonist that is widely used for the treatment of dementia, on amnesia induced by scopolamine in rats. Scopolamine induced amnesia in rats; however, unexpectedly, this effect was even more expressed in the memantine-pretreated animals. Memory impairments were less manifested in the rats that were pretreated with memantine in combination with panthenol or calcium pantothenate. The detrimental scopolamine effect on memory was accompanied by significant depletions of glutathione and coenzyme A in the brain. While memantine recovered the glutathione status to some extent, it nevertheless further aggravated the scopolamine influence on coenzyme A levels. An alleviation of scopolamine-induced memory impairments that was observed after combined pretreatment with memantine and panthenol or calcium pantothenate was accompanied by a normalization of coenzyme A levels, while the effects on glutathione redox did not correlate with the behavioral data.

Изучали влияние дипептида “глицил-пролин” (3 мг/кг) на изменения содержания нейроактивных аминокислот (аспартата, глицина, аланина, таурина, ГАМК, глутамата), активности ферментов ГАМК-шунта (ГАМК-трансаминазы, дегидрогеназы янтарного полуальдегида, глутаматдекарбоксилазы) и метаболизма глутамата (глутаматдегидрогеназы, аланин- и аспартат- трансаминаз) в больших полушариях мозга крыс после 6 ч ишемии мозга при трех способах введения препарата: внутрибрюшинном, субконьюктивальном и интраназальном. Установлено, что гли-про проявляет наиболее выраженное корригирующее действие в отношении ишемических нарушений при интраназальном способе введения.

We studied the effects of the glycyl-proline dipeptide (Gly-Pro) at a dose of 3 mg/kg on the contents of neuroactive amino acids, including aspartate, glycine, alanine, taurine, GABA, and glutamate, the activity of the enzymes of the GABA shunt, such as GABA-transaminase, succinic semialdehyde dehydrogenase, and glutamate decarboxylase, and enzymes of glutamate metabolism, such as glutamate dehydrogenase and alanine and aspartate transaminases in the neocortex of rats subjected to 6-h brain ischemia. We used three means of dipeptide administration, including intraperitoneal, subconjunctival, and intranasal. We found that the protective anti-ischemic effect of Gly-Pro was mostly expressed after intranasal administration.