Journal of Biomedical & Clinical Research, Jun 20, 2024
Various studies have emphasized the intricate relationship between hydrogen sulfide (H2S) and nit... more Various studies have emphasized the intricate relationship between hydrogen sulfide (H2S) and nitric oxide (NO) in regulating diverse physiological processes. In this investigation, we aimed to elucidate the effects of simultaneous inhibition of the H2S-producing enzyme cystathionine γ-lyase and the NO-producing enzyme nitric oxide synthase on food and water intake, body mass gain and body temperature in rats. Specifically, we explored the combined impact of dl-propargylglycine, an irreversible inhibitor of cystathionine γ-lyase, and Nω-Nitro-L-arginine methyl ester (l-NAME), a non-selective inhibitor of nitric oxide synthase, on these physiological parameters. Co-administration of dl-propargylglycine (50 mg/kg, i.p.) and l-NAME (50 mg/kg, i.p.) effectively suppressed food intake and body mass gain in fasted rats at 24 hours post-injection, accompanied by a notable decrease in water intake. Furthermore, this combined treatment induced a significant decline in body temperature at 90, 120, and 150 minutes post-injection compared to the control group, shedding light on the complex role of H2S and NO systems in modulating body temperature regulation. These findings enhance our understanding of the potential physiological implications of targeting the cystathionine γ-lyase/H2S and nitric oxide synthase/NO pathways.
Previous studies have explored the antinociceptive effects of riboflavin (vitamin B2) across vari... more Previous studies have explored the antinociceptive effects of riboflavin (vitamin B2) across various experimental models. However, there remains a gap in the literature regarding its potential to alleviate neuropathic pain in diabetes. This study aims to investigate the effects of riboflavin on hyperalgesia and serum glutamine-to-glutamate ratio in rats with painful diabetic neuropathy. In fasted rats, a model of painful diabetic neuropathy was induced through intraperitoneal injection of streptozotocin. In the fifth week post-injection, diabetic rats experiencing neuropathic pain were administered daily doses of riboflavin (25 or 50 mg), dissolved in their drinking water, for a duration of two weeks. Results demonstrate that riboflavin significantly reduced mechanical and cold-induced hyperalgesia in diabetic rats compared to controls. Formalin-induced hyperalgesia was alleviated by riboflavin in the second phase. Additionally, riboflavin supplementation increased the serum glutamine-to-glutamate ratio in these animals. These findings highlight the therapeutic potential of riboflavin in managing neuropathic pain associated with diabetes.
Both peripheral neuropathy and depression can be viewed as neurodegeneration's consequenc... more Both peripheral neuropathy and depression can be viewed as neurodegeneration's consequences of diabetes, at least in part coexisting with or resulting from sodium-calcium dysbalance. This study aims to assess the therapeutic potential of the orally applied reverse-mode inhibitor of the sodium-calcium exchanger (NCX) KB-R7943 in the streptozotocin (STZ) diabetes model in rats. A pilot pharmacokinetic (PK) study with high-performance liquid chromatography with high-resolution tandem mass spectrometric detection revealed higher drug exposure (AUC), lower volume of distribution (Vd) and clearance (Cl), and faster decline of the plasma concentration (ƛ) in rats with diabetes vs. controls. Brain and heart accumulation and urinary excretion of the unmetabolized KB-R7943 at least 24 h were also demonstrated in all rats. However, heart and hippocampus KB-R7943 penetration (AUCtissue/AUCplasma) was higher in controls vs. diabetic rats. The development of thermal, mechanical, and chemical-induced allodynia was assessed with the Cold plate test (CPT), Randall-Stiletto (R–S) test, and 0.5% formalin test (FT). Amitriptyline 10 mg/kg, KB-R7943 5 mg/kg, or 10 mg/kg p.o once daily was applied from the 28th to the 49th day. The body weight, coat status, CPT, R–S, and FT were evaluated on days (−5), 0, and 42. On day 41, a forced swim test and 24-h spontaneous physical activities were assessed. The chronic treatment effects were calculated as % of the maximum. A dose-depended amelioration of neuropathic and depression-like effects was demonstrated. The oral application of KB-R7943 for potentially treating neurodegenerative consequences of diabetes merits further studies. The brain, heart, and kidneys are essential contributors to the PKs of this drug, and their safety involvement needs to be further characterized.
Summary: Leptin is a 167-aminoacid polypeptide hormone which is produced by adipocytes. In the br... more Summary: Leptin is a 167-aminoacid polypeptide hormone which is produced by adipocytes. In the brain, leptin, by binding to tyrosine-kinase associated receptors, inhibits ex- pression of neuropeptide Y and agouti-related peptide. Leptin inhibits feeding, re- duces body weight and increases thermogenesis. Experimental data suggest in- volvement of GABAergic mechanisms in the regulation of feeding behavior and energy balance. The present review discusses various interactions between leptin and �� -aminobutyric acid (GABA) on the level of thermoregulation.
GABAB receptors are G-protein-coupled receptors, playing a very important role in the regulation ... more GABAB receptors are G-protein-coupled receptors, playing a very important role in the regulation of many physiological processes. The GABAB signaling pathway could modulate neurotransmission processes at the level of the preoptic area in the anterior hypothalamus, which is thought to function as the thermoregulatory center. The present study was performed to investigate the effects of GABAB agonists and antagonists on core body temperature of rats with normal weight and diet-induced obesity. The results showed that systemic administration of the GABAB antagonist CGP35348 induced significant hyper-thermia in rats with normal weight, whereas the GABAB agonist baclofen led to a decrease in body temperature. The effects of baclofen and CGP35348 on body temperature were less pronounced in rats with diet-induced obesity compared with those with normal weight. Presently it remains unclear how obesity affects the GABAB receptor function at the level of the central thermoregulatory system.
Leptin inhibits feeding, reduces body weight and increases thermogenesis. Experimental data sugge... more Leptin inhibits feeding, reduces body weight and increases thermogenesis. Experimental data suggest involvement of GABAergic mechanisms in the regulation of feeding behavior and energy balance. The present study was set to determine the effect of combinations from leptin, GABA
Leptin inhibits feeding, reduces body weight, and increases thermogenesis. Experimental data sugg... more Leptin inhibits feeding, reduces body weight, and increases thermogenesis. Experimental data suggest the involvement of GABAergic mechanisms in regulating feeding behavior and energy balance. This study aimed to determine the effects of combinations of leptin, the GABA_B agonist baclofen, and the GABA_B antagonist CGP35348 on the thermoregulation of male Wistar rats, using in vivo and in vitro experiments. For in vivo experiments, substances were administered intraperitoneally (i.p.), and body temperature was measured using thermistor probes (TX8) and monitored on a multichannel recorder (Iso-Thermex16). In vitro experiments were conducted on rat PO/AH neurons, recorded extracellularly using conventional electrophysiological equipment and brain slice preparations. Separate intraperitoneal injections of leptin and the GABA_B antagonist CGP35348 produced significant hyperthermia in rats, while the GABA_B agonist baclofen caused a decrease in core body temperature. However, the expected synergy between the hyperthermic effects of leptin and the GABA_B antagonist did not occur; instead, the combination's effect was lower than the separate administration of the GABA_B antagonist. When leptin was applied just prior to the GABA_B agonist baclofen, neither of their separate effects appeared. These in vivo effects correlated with in vitro changes in the firing rate of PO/AH neurons. The study provides new insights into the interactions between leptin and GABA in thermoregulation, advancing the understanding of the complex mechanisms involved in this process.
Comptes rendus de l’Académie bulgare des Sciences , 2017
The adipose tissue-derived hormone leptin acts via its long receptor isoform in the brain to regu... more The adipose tissue-derived hormone leptin acts via its long receptor isoform in the brain to regulate energy balance and neuroendocrine function. The goal of this study is to investigate the effects of leptin on firing rate of neurons from preoptic area of the anterior hypothalamus (PO/AH) of rats with normal weight and experimental model of obesity. Extracellular recordings were obtained from PO/AH neurons in brain slice preparations (400 µm) from Wistar rats, using conventional electrophysiological equipment. Leptin increased dosedependently the firing rate of PO/AH neurons from rats with normal weight whereas the firing rate of PO/AH neurons from rats with experimental model of obesity was not significantly altered by the action of leptin. The feeding of rodents with high-calorie diet leads to obesity, resulting in hyperleptinemia. The failure of elevated leptin levels to suppress feeding and mediate weight loss in common forms of obesity defines a state of so-called leptin resistance (attenuation of leptin signalling). This is the reason for reduced change in the firing rate upon administration of leptin on PO/AH neurons from rats with obesity. Our results provide future direction for further research on the complex interactions between thermoregulation and energy homeostasis.
Comptes rendus de l’Académie bulgare des Sciences, 2024
Diabetes mellitus is one of the most common chronic diseases in the world. Metabolomic studies ha... more Diabetes mellitus is one of the most common chronic diseases in the world. Metabolomic studies have demonstrated altered blood levels of glutamate and glutamine during type 1 diabetes and type 2 diabetes. Riboflavin is a precursor of flavin adenine dinucleotide and flavin mononucleotide, which are coenzymes necessary for the function of enzymes involved in various biochemical reactions, including those affecting amino acid metabolism. In this study, we investigated the effects of riboflavin on serum glutamate and glutamine levels in rats with streptozotocin-induced type 1 diabetes. Diabetic rats received riboflavin (25 mg, 50 mg, or 100 mg) dissolved in the drinking water daily for 2 weeks. Our results showed that riboflavin supplementation did not affect serum glutamate levels but increased serum glutamine levels in diabetic rats. We speculate that increased serum glutamine levels resulting from riboflavin supplementation may have beneficial effects during diabetes.
Both peripheral neuropathy and depression can be viewed as neurodegeneration's consequences of di... more Both peripheral neuropathy and depression can be viewed as neurodegeneration's consequences of diabetes, at least in part coexisting with or resulting from sodium-calcium dysbalance. This study aims to assess the therapeutic potential of the orally applied reverse-mode inhibitor of the sodium-calcium exchanger (NCX) KB-R7943 in the streptozotocin (STZ) diabetes model in rats. A pilot pharmacokinetic (PK) study with high-performance liquid chromatography with high-resolution tandem mass spectrometric detection revealed higher drug exposure (AUC), lower volume of distribution (Vd) and clearance (Cl), and faster decline of the plasma concentration (ƛ) in rats with diabetes vs. controls. Brain and heart accumulation and urinary excretion of the unmetabolized KB-R7943 at least 24 h were also demonstrated in all rats. However, heart and hippocampus KB-R7943 penetration (AUCtissue/AUCplasma) was higher in controls vs. diabetic rats. The development of thermal, mechanical, and chemical-induced allodynia was assessed with the Cold plate test (CPT), Randall-Stiletto (R–S) test, and 0.5% formalin test (FT). Amitriptyline 10 mg/kg, KB-R7943 5 mg/kg, or 10 mg/kg p.o once daily was applied from the 28th to the 49th day. The body weight, coat status, CPT, R–S, and FT were evaluated on days (−5), 0, and 42. On day 41, a forced swim test and 24-h spontaneous physical activities were assessed. The chronic treatment effects were calculated as % of the maximum. A dose-depended amelioration of neuropathic and depression-like effects was demonstrated. The oral application of KB-R7943 for potentially treating neurodegenerative consequences of diabetes merits further studies. The brain, heart, and kidneys are essential contributors to the PKs of this drug, and their safety involvement needs to be further characterized.
Journal of Biomedical & Clinical Research, Jun 20, 2024
Various studies have emphasized the intricate relationship between hydrogen sulfide (H2S) and nit... more Various studies have emphasized the intricate relationship between hydrogen sulfide (H2S) and nitric oxide (NO) in regulating diverse physiological processes. In this investigation, we aimed to elucidate the effects of simultaneous inhibition of the H2S-producing enzyme cystathionine γ-lyase and the NO-producing enzyme nitric oxide synthase on food and water intake, body mass gain and body temperature in rats. Specifically, we explored the combined impact of dl-propargylglycine, an irreversible inhibitor of cystathionine γ-lyase, and Nω-Nitro-L-arginine methyl ester (l-NAME), a non-selective inhibitor of nitric oxide synthase, on these physiological parameters. Co-administration of dl-propargylglycine (50 mg/kg, i.p.) and l-NAME (50 mg/kg, i.p.) effectively suppressed food intake and body mass gain in fasted rats at 24 hours post-injection, accompanied by a notable decrease in water intake. Furthermore, this combined treatment induced a significant decline in body temperature at 90, 120, and 150 minutes post-injection compared to the control group, shedding light on the complex role of H2S and NO systems in modulating body temperature regulation. These findings enhance our understanding of the potential physiological implications of targeting the cystathionine γ-lyase/H2S and nitric oxide synthase/NO pathways.
Previous studies have explored the antinociceptive effects of riboflavin (vitamin B2) across vari... more Previous studies have explored the antinociceptive effects of riboflavin (vitamin B2) across various experimental models. However, there remains a gap in the literature regarding its potential to alleviate neuropathic pain in diabetes. This study aims to investigate the effects of riboflavin on hyperalgesia and serum glutamine-to-glutamate ratio in rats with painful diabetic neuropathy. In fasted rats, a model of painful diabetic neuropathy was induced through intraperitoneal injection of streptozotocin. In the fifth week post-injection, diabetic rats experiencing neuropathic pain were administered daily doses of riboflavin (25 or 50 mg), dissolved in their drinking water, for a duration of two weeks. Results demonstrate that riboflavin significantly reduced mechanical and cold-induced hyperalgesia in diabetic rats compared to controls. Formalin-induced hyperalgesia was alleviated by riboflavin in the second phase. Additionally, riboflavin supplementation increased the serum glutamine-to-glutamate ratio in these animals. These findings highlight the therapeutic potential of riboflavin in managing neuropathic pain associated with diabetes.
Both peripheral neuropathy and depression can be viewed as neurodegeneration's consequenc... more Both peripheral neuropathy and depression can be viewed as neurodegeneration's consequences of diabetes, at least in part coexisting with or resulting from sodium-calcium dysbalance. This study aims to assess the therapeutic potential of the orally applied reverse-mode inhibitor of the sodium-calcium exchanger (NCX) KB-R7943 in the streptozotocin (STZ) diabetes model in rats. A pilot pharmacokinetic (PK) study with high-performance liquid chromatography with high-resolution tandem mass spectrometric detection revealed higher drug exposure (AUC), lower volume of distribution (Vd) and clearance (Cl), and faster decline of the plasma concentration (ƛ) in rats with diabetes vs. controls. Brain and heart accumulation and urinary excretion of the unmetabolized KB-R7943 at least 24 h were also demonstrated in all rats. However, heart and hippocampus KB-R7943 penetration (AUCtissue/AUCplasma) was higher in controls vs. diabetic rats. The development of thermal, mechanical, and chemical-induced allodynia was assessed with the Cold plate test (CPT), Randall-Stiletto (R–S) test, and 0.5% formalin test (FT). Amitriptyline 10 mg/kg, KB-R7943 5 mg/kg, or 10 mg/kg p.o once daily was applied from the 28th to the 49th day. The body weight, coat status, CPT, R–S, and FT were evaluated on days (−5), 0, and 42. On day 41, a forced swim test and 24-h spontaneous physical activities were assessed. The chronic treatment effects were calculated as % of the maximum. A dose-depended amelioration of neuropathic and depression-like effects was demonstrated. The oral application of KB-R7943 for potentially treating neurodegenerative consequences of diabetes merits further studies. The brain, heart, and kidneys are essential contributors to the PKs of this drug, and their safety involvement needs to be further characterized.
Summary: Leptin is a 167-aminoacid polypeptide hormone which is produced by adipocytes. In the br... more Summary: Leptin is a 167-aminoacid polypeptide hormone which is produced by adipocytes. In the brain, leptin, by binding to tyrosine-kinase associated receptors, inhibits ex- pression of neuropeptide Y and agouti-related peptide. Leptin inhibits feeding, re- duces body weight and increases thermogenesis. Experimental data suggest in- volvement of GABAergic mechanisms in the regulation of feeding behavior and energy balance. The present review discusses various interactions between leptin and �� -aminobutyric acid (GABA) on the level of thermoregulation.
GABAB receptors are G-protein-coupled receptors, playing a very important role in the regulation ... more GABAB receptors are G-protein-coupled receptors, playing a very important role in the regulation of many physiological processes. The GABAB signaling pathway could modulate neurotransmission processes at the level of the preoptic area in the anterior hypothalamus, which is thought to function as the thermoregulatory center. The present study was performed to investigate the effects of GABAB agonists and antagonists on core body temperature of rats with normal weight and diet-induced obesity. The results showed that systemic administration of the GABAB antagonist CGP35348 induced significant hyper-thermia in rats with normal weight, whereas the GABAB agonist baclofen led to a decrease in body temperature. The effects of baclofen and CGP35348 on body temperature were less pronounced in rats with diet-induced obesity compared with those with normal weight. Presently it remains unclear how obesity affects the GABAB receptor function at the level of the central thermoregulatory system.
Leptin inhibits feeding, reduces body weight and increases thermogenesis. Experimental data sugge... more Leptin inhibits feeding, reduces body weight and increases thermogenesis. Experimental data suggest involvement of GABAergic mechanisms in the regulation of feeding behavior and energy balance. The present study was set to determine the effect of combinations from leptin, GABA
Leptin inhibits feeding, reduces body weight, and increases thermogenesis. Experimental data sugg... more Leptin inhibits feeding, reduces body weight, and increases thermogenesis. Experimental data suggest the involvement of GABAergic mechanisms in regulating feeding behavior and energy balance. This study aimed to determine the effects of combinations of leptin, the GABA_B agonist baclofen, and the GABA_B antagonist CGP35348 on the thermoregulation of male Wistar rats, using in vivo and in vitro experiments. For in vivo experiments, substances were administered intraperitoneally (i.p.), and body temperature was measured using thermistor probes (TX8) and monitored on a multichannel recorder (Iso-Thermex16). In vitro experiments were conducted on rat PO/AH neurons, recorded extracellularly using conventional electrophysiological equipment and brain slice preparations. Separate intraperitoneal injections of leptin and the GABA_B antagonist CGP35348 produced significant hyperthermia in rats, while the GABA_B agonist baclofen caused a decrease in core body temperature. However, the expected synergy between the hyperthermic effects of leptin and the GABA_B antagonist did not occur; instead, the combination's effect was lower than the separate administration of the GABA_B antagonist. When leptin was applied just prior to the GABA_B agonist baclofen, neither of their separate effects appeared. These in vivo effects correlated with in vitro changes in the firing rate of PO/AH neurons. The study provides new insights into the interactions between leptin and GABA in thermoregulation, advancing the understanding of the complex mechanisms involved in this process.
Comptes rendus de l’Académie bulgare des Sciences , 2017
The adipose tissue-derived hormone leptin acts via its long receptor isoform in the brain to regu... more The adipose tissue-derived hormone leptin acts via its long receptor isoform in the brain to regulate energy balance and neuroendocrine function. The goal of this study is to investigate the effects of leptin on firing rate of neurons from preoptic area of the anterior hypothalamus (PO/AH) of rats with normal weight and experimental model of obesity. Extracellular recordings were obtained from PO/AH neurons in brain slice preparations (400 µm) from Wistar rats, using conventional electrophysiological equipment. Leptin increased dosedependently the firing rate of PO/AH neurons from rats with normal weight whereas the firing rate of PO/AH neurons from rats with experimental model of obesity was not significantly altered by the action of leptin. The feeding of rodents with high-calorie diet leads to obesity, resulting in hyperleptinemia. The failure of elevated leptin levels to suppress feeding and mediate weight loss in common forms of obesity defines a state of so-called leptin resistance (attenuation of leptin signalling). This is the reason for reduced change in the firing rate upon administration of leptin on PO/AH neurons from rats with obesity. Our results provide future direction for further research on the complex interactions between thermoregulation and energy homeostasis.
Comptes rendus de l’Académie bulgare des Sciences, 2024
Diabetes mellitus is one of the most common chronic diseases in the world. Metabolomic studies ha... more Diabetes mellitus is one of the most common chronic diseases in the world. Metabolomic studies have demonstrated altered blood levels of glutamate and glutamine during type 1 diabetes and type 2 diabetes. Riboflavin is a precursor of flavin adenine dinucleotide and flavin mononucleotide, which are coenzymes necessary for the function of enzymes involved in various biochemical reactions, including those affecting amino acid metabolism. In this study, we investigated the effects of riboflavin on serum glutamate and glutamine levels in rats with streptozotocin-induced type 1 diabetes. Diabetic rats received riboflavin (25 mg, 50 mg, or 100 mg) dissolved in the drinking water daily for 2 weeks. Our results showed that riboflavin supplementation did not affect serum glutamate levels but increased serum glutamine levels in diabetic rats. We speculate that increased serum glutamine levels resulting from riboflavin supplementation may have beneficial effects during diabetes.
Both peripheral neuropathy and depression can be viewed as neurodegeneration's consequences of di... more Both peripheral neuropathy and depression can be viewed as neurodegeneration's consequences of diabetes, at least in part coexisting with or resulting from sodium-calcium dysbalance. This study aims to assess the therapeutic potential of the orally applied reverse-mode inhibitor of the sodium-calcium exchanger (NCX) KB-R7943 in the streptozotocin (STZ) diabetes model in rats. A pilot pharmacokinetic (PK) study with high-performance liquid chromatography with high-resolution tandem mass spectrometric detection revealed higher drug exposure (AUC), lower volume of distribution (Vd) and clearance (Cl), and faster decline of the plasma concentration (ƛ) in rats with diabetes vs. controls. Brain and heart accumulation and urinary excretion of the unmetabolized KB-R7943 at least 24 h were also demonstrated in all rats. However, heart and hippocampus KB-R7943 penetration (AUCtissue/AUCplasma) was higher in controls vs. diabetic rats. The development of thermal, mechanical, and chemical-induced allodynia was assessed with the Cold plate test (CPT), Randall-Stiletto (R–S) test, and 0.5% formalin test (FT). Amitriptyline 10 mg/kg, KB-R7943 5 mg/kg, or 10 mg/kg p.o once daily was applied from the 28th to the 49th day. The body weight, coat status, CPT, R–S, and FT were evaluated on days (−5), 0, and 42. On day 41, a forced swim test and 24-h spontaneous physical activities were assessed. The chronic treatment effects were calculated as % of the maximum. A dose-depended amelioration of neuropathic and depression-like effects was demonstrated. The oral application of KB-R7943 for potentially treating neurodegenerative consequences of diabetes merits further studies. The brain, heart, and kidneys are essential contributors to the PKs of this drug, and their safety involvement needs to be further characterized.
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