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International Journal of Molecular... Jun 2024NMDA receptor antagonists have potential for therapeutics in neurological and psychiatric diseases, including neurodegenerative diseases, epilepsy, traumatic brain... (Review)
Review
NMDA receptor antagonists have potential for therapeutics in neurological and psychiatric diseases, including neurodegenerative diseases, epilepsy, traumatic brain injury, substance abuse disorder (SUD), and major depressive disorder (MDD). ()-ketamine was the first of a novel class of antidepressants, rapid-acting antidepressants, to be approved for medical use. The stereoisomer, ()-ketamine (arketamine), is currently under development for treatment-resistant depression (TRD). The compound has demonstrated efficacy in multiple animal models. Two clinical studies disclosed efficacy in TRD and bipolar depression. A study by the drug sponsor recently failed to reach a priori clinical endpoints but post hoc analysis revealed efficacy. The clinical value of ()-ketamine is supported by experimental data in humans and rodents, showing that it is less sedating, does not produce marked psychotomimetic or dissociative effects, has less abuse potential than ()-ketamine, and produces efficacy in animal models of a range of neurological and psychiatric disorders. The mechanisms of action of the antidepressant effects of ()-ketamine are hypothesized to be due to NMDA receptor antagonism and/or non-NMDA receptor mechanisms. We suggest that further clinical experimentation with ()-ketamine will create novel and improved medicines for some of the neurological and psychiatric disorders that are underserved by current medications.
Topics: Ketamine; Humans; Animals; Antidepressive Agents; Nervous System Diseases; Receptors, N-Methyl-D-Aspartate; Mental Disorders; Stereoisomerism
PubMed: 38928508
DOI: 10.3390/ijms25126804 -
International Journal of Molecular... Jun 2024The objective of this study was to assess the impact of acute and chronic treatment with oxcarbazepine on its anticonvulsant activity, neurological adverse effects, and...
The objective of this study was to assess the impact of acute and chronic treatment with oxcarbazepine on its anticonvulsant activity, neurological adverse effects, and protective index in mice. Oxcarbazepine was administered in four protocols: once or twice daily for one week (7 × 1 or 7 × 2) and once or twice daily for two weeks (14 × 1 or 14 × 2). A single dose of the drug was employed as a control. The anticonvulsant effect was evaluated in the maximal electroshock test in mice. Motor and long-term memory impairment were assessed using the chimney test and the passive avoidance task, respectively. The concentrations of oxcarbazepine in the brain and plasma were determined via high-performance liquid chromatography. Two weeks of oxcarbazepine treatment resulted in a significant reduction in the anticonvulsant (in the 14 × 1; 14 × 2 protocols) and neurotoxic (in the 14 × 2 schedule) effects of this drug. In contrast, the protective index for oxcarbazepine in the 14 × 2 protocol was found to be lower than that calculated for the control. No significant deficits in memory or motor coordination were observed following repeated administration of oxcarbazepine. The plasma and brain concentrations of this anticonvulsant were found to be significantly higher in the one-week protocols. Chronic treatment with oxcarbazepine may result in the development of tolerance to its anticonvulsant and neurotoxic effects, which appears to be dependent on pharmacodynamic mechanisms.
Topics: Animals; Oxcarbazepine; Mice; Anticonvulsants; Electroshock; Male; Disease Models, Animal; Seizures; Brain; Memory, Long-Term; Carbamazepine; Avoidance Learning
PubMed: 38928457
DOI: 10.3390/ijms25126751 -
International Journal of Molecular... Jun 2024Cannabidiol (CBD), a phytocannabinoid, appeared to satisfy several criteria for a safe approach to preventing drug-taking behavior, including opioids. However, most...
Cannabidiol (CBD), a phytocannabinoid, appeared to satisfy several criteria for a safe approach to preventing drug-taking behavior, including opioids. However, most successful preclinical and clinical results come from studies in adult males. We examined whether systemic injections of CBD (10 mg/kg, i.p.) during extinction of oxycodone (OXY, 3 mg/kg, i.p.) induced conditioned place preference (CPP) could attenuate the reinstatement of CPP brought about by OXY (1.5 mg/kg, i.p.) priming in adolescent rats of both sexes, and whether this effect is sex dependent. Accordingly, a priming dose of OXY produced reinstatement of the previously extinguished CPP in males and females. In both sexes, this effect was linked to locomotor sensitization that was blunted by CBD pretreatments. However, CBD was able to prevent the reinstatement of OXY-induced CPP only in adolescent males and this outcome was associated with an increased cannabinoid 1 receptor (CB1R) and a decreased mu opioid receptor (MOR) expression in the prefrontal cortex (PFC). The reinstatement of CCP in females was associated with a decreased MOR expression, but no changes were detected in CB1R in the hippocampus (HIP). Moreover, CBD administration during extinction significantly potentialized the reduced MOR expression in the PFC of males and showed a tendency to potentiate the reduced MOR in the HIP of females. Additionally, CBD reversed OXY-induced deficits of recognition memory only in males. These results suggest that CBD could reduce reinstatement to OXY seeking after a period of abstinence in adolescent male but not female rats. However, more investigation is required.
Topics: Animals; Cannabidiol; Male; Female; Oxycodone; Rats; Receptor, Cannabinoid, CB1; Receptors, Opioid, mu; Prefrontal Cortex; Analgesics, Opioid; Conditioning, Psychological
PubMed: 38928357
DOI: 10.3390/ijms25126651 -
International Journal of Molecular... Jun 2024Tanshinone IIA (T2A) is a bioactive compound that provides promise in the treatment of glioblastoma multiforme (GBM), with a range of molecular mechanisms including the...
Tanshinone IIA (T2A) is a bioactive compound that provides promise in the treatment of glioblastoma multiforme (GBM), with a range of molecular mechanisms including the inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) and the induction of autophagy. Recently, T2A has been demonstrated to function through sestrin 2 (SESN) to inhibit mTORC1 activity, but its possible impact on autophagy through this pathway has not been investigated. Here, the model system and GBM cell lines were employed to investigate the cellular role of T2A in regulating SESN to inhibit mTORC1 and activate autophagy through a GATOR2 component MIOS. In , T2A treatment induced autophagy and inhibited mTORC1 activity, with both effects lost upon the ablation of SESN (sesn) or MIOS (mios). We further investigated the targeting of MIOS to reproduce this effect of T2A, where computational analysis identified 25 novel compounds predicted to strongly bind the human MIOS protein, with one compound (MIOS inhibitor 3; Mi3) reducing cell proliferation in two GBM cells. Furthermore, Mi3 specificity was demonstrated through the loss of potency in the mios cells regarding cell proliferation and the induction of autophagy. In GBM cells, Mi3 treatment also reduced mTORC1 activity and induced autophagy. Thus, a potential T2A mimetic showing the inhibition of mTORC1 and induction of autophagy in GBM cells was identified.
Topics: Glioblastoma; Abietanes; Humans; Mechanistic Target of Rapamycin Complex 1; Autophagy; Cell Line, Tumor; Dictyostelium; Cell Proliferation; Nuclear Proteins; Sestrins
PubMed: 38928292
DOI: 10.3390/ijms25126586 -
International Journal of Molecular... Jun 2024Curcumin, a polyphenol derived from , used as a dietary spice, has garnered attention for its therapeutic potential, including antioxidant, anti-inflammatory, and...
Curcumin, a polyphenol derived from , used as a dietary spice, has garnered attention for its therapeutic potential, including antioxidant, anti-inflammatory, and antimicrobial properties. Despite its known benefits, the precise mechanisms underlying curcumin's effects on consumers remain unclear. To address this gap, we employed the genetic model and leveraged two omics tools-transcriptomics and metabolomics. Our investigation revealed alterations in 1043 genes and 73 metabolites upon supplementing curcumin into the diet. Notably, we observed genetic modulation in pathways related to antioxidants, carbohydrates, and lipids, as well as genes associated with gustatory perception and reproductive processes. Metabolites implicated in carbohydrate metabolism, amino acid biosynthesis, and biomarkers linked to the prevention of neurodegenerative diseases such as schizophrenia, Alzheimer's, and aging were also identified. The study highlighted a strong correlation between the curcumin diet, antioxidant mechanisms, and amino acid metabolism. Conversely, a lower correlation was observed between carbohydrate metabolism and cholesterol biosynthesis. This research highlights the impact of curcumin on the diet, influencing perception, fertility, and molecular wellness. Furthermore, it directs future studies toward a more focused exploration of the specific effects of curcumin consumption.
Topics: Animals; Drosophila melanogaster; Curcumin; Metabolome; Transcriptome; Antioxidants; Diet; Metabolomics
PubMed: 38928266
DOI: 10.3390/ijms25126559 -
International Journal of Molecular... Jun 2024Aging (senescence) is an unavoidable biological process that results in visible manifestations in all cutaneous tissues, including scalp skin and hair follicles....
Aging (senescence) is an unavoidable biological process that results in visible manifestations in all cutaneous tissues, including scalp skin and hair follicles. Previously, we evaluated the molecular function of adenosine in promoting alopecia treatment in vitro. To elucidate the differences in the molecular mechanisms between minoxidil (MNX) and adenosine, gene expression changes in dermal papilla cells were examined. The androgen receptor (AR) pathway was identified as a candidate target of adenosine for hair growth, and the anti-androgenic activity of adenosine was examined in vitro. In addition, ex vivo examination of human hair follicle organ cultures revealed that adenosine potently elongated the anagen stage. According to the severity of alopecia, the ratio of the two peaks (terminal hair area/vellus hair area) decreased continuously. We further investigated the adenosine hair growth promoting effect in vivo to examine the hair thickness growth effects of topical 5% MNX and the adenosine complex (0.75% adenosine, 1% penthenol, and 2% niacinamide; APN) in vivo. After 4 months of administration, both the MNX and APN group showed significant increases in hair density (MNX + 5.01% ( < 0.01), APN + 6.20% ( < 0.001)) and thickness (MNX + 5.14% ( < 0.001), APN + 10.32% ( < 0.001)). The inhibition of AR signaling via adenosine could have contributed to hair thickness growth. We suggest that the anti-androgenic effect of adenosine, along with the evaluation of hair thickness distribution, could help us to understand hair physiology and to investigate new approaches for drug development.
Topics: Alopecia; Humans; Male; Receptors, Androgen; Adenosine; Hair Follicle; Signal Transduction; Minoxidil; Female; Animals; Hair
PubMed: 38928239
DOI: 10.3390/ijms25126534 -
International Journal of Molecular... Jun 2024It has been reported that Mizoribine is an immunosuppressant used to suppress rejection in renal transplantation, nephrotic syndrome, lupus nephritis, and rheumatoid...
It has been reported that Mizoribine is an immunosuppressant used to suppress rejection in renal transplantation, nephrotic syndrome, lupus nephritis, and rheumatoid arthritis. The molecular chaperone HSP60 alone induces inflammatory cytokine IL-6 and the co-chaperone HSP10 alone inhibits IL-6 induction. HSP60 and HSP10 form a complex in the presence of ATP. We analyzed the effects of Mizoribine, which is structurally similar to ATP, on the structure and physiological functions of HSP60-HSP10 using Native/PAGE and transmission electron microscopy. At low concentrations of Mizoribine, no complex formation of HSP60-HSP10 was observed, nor was the expression of IL-6 affected. On the other hand, high concentrations of Mizoribine promoted HSP60-HSP10 complex formation and consequently suppressed IL-6 expression. Here, we propose a novel mechanism of immunosuppressive action of Mizoribine.
Topics: Ribonucleosides; Interleukin-6; Chaperonin 60; Humans; Immunosuppressive Agents; Animals; Mice
PubMed: 38928158
DOI: 10.3390/ijms25126452 -
International Journal of Molecular... Jun 2024Pain management in neonates continues to be a challenge. Diverse therapies are available that cause loss of pain sensitivity. However, because of side effects, the...
Pain management in neonates continues to be a challenge. Diverse therapies are available that cause loss of pain sensitivity. However, because of side effects, the search for better options remains open. Dexmedetomidine is a promising drug; it has shown high efficacy with a good safety profile in sedation and analgesia in the immature nervous system. Though dexmedetomidine is already in use for pain control in neonates (including premature neonates) and infants as an adjunct to other anesthetics, the question remains whether it affects the neuronal activity patterning that is critical for development of the immature nervous system. In this study, using the neonatal rat as a model, the pharmacodynamic effects of dexmedetomidine on the nervous and cardiorespiratory systems were studied. Our results showed that dexmedetomidine has pronounced analgesic effects in the neonatal rat pups, and also weakly modified both the immature network patterns of cortical and hippocampal activity and the physiology of sleep cycles. Though the respiration and heart rates were slightly reduced after dexmedetomidine administration, it might be considered as the preferential independent short-term therapy for pain management in the immature and developing brain.
Topics: Dexmedetomidine; Animals; Rats; Animals, Newborn; Analgesics, Non-Narcotic; Analgesia; Pain Management; Male; Rats, Sprague-Dawley; Pain; Heart Rate; Female; Nervous System
PubMed: 38928091
DOI: 10.3390/ijms25126385 -
Biomedicines Jun 2024Cannabinoids are reported to have neuroprotective properties and play a role in neurogenesis and neuroplasticity in in vitro and in vivo models. Cannabinol (CBN) is a...
Cannabinoids are reported to have neuroprotective properties and play a role in neurogenesis and neuroplasticity in in vitro and in vivo models. Cannabinol (CBN) is a minor cannabinoid produced by the degradation of Δ-tetrahydrocannabinol in L. and exhibits anti-oxidant, analgesic, anti-bacterial, and anti-inflammatory effects. In this study, we explored the biological effects of 20 µM CBN (6.20 µg/mL) on differentiated NSC-34 cells by MTT assay and next-generation sequencing analysis on the transcriptome. KEGG and Gene Ontology enrichment analyses have been performed to evaluate potential CBN-associated processes. Our results highlighted the absence of any cytotoxic effect of CBN. The comparative transcriptomic analysis pointed out the downregulation of , and genes, which are known to suppress the cell cycle. , , , , , , , , , , , , , , , and genes, renowned for their role as cell cycle progression activators, were instead upregulated. Our work suggests that CBN regulates the expression of many genes related to the cell cycle, which are required for axonal maturation, migration, and synaptic plasticity, while not affecting the expression of genes involved in cell death or tumorigenesis.
PubMed: 38927547
DOI: 10.3390/biomedicines12061340 -
Biomolecules Jun 2024In recent years, there has been growing interest in the development of metal-free, environmentally friendly, and cost-effective biopolymer-based piezoelectric strain...
In recent years, there has been growing interest in the development of metal-free, environmentally friendly, and cost-effective biopolymer-based piezoelectric strain sensors (bio-PSSs) for flexible applications. In this study, we have developed a bio-PSS based on pure deoxyribonucleic acid (DNA) and curcumin materials in a thin-film form and studied its strain-induced current-voltage characteristics based on piezoelectric phenomena. The bio-PSS exhibited flexibility under varying compressive and tensile loads. Notably, the sensor achieved a strain gauge factor of 407 at an applied compressive strain of -0.027%, which is 8.67 times greater than that of traditional metal strain gauges. Furthermore, the flexible bio-PSS demonstrated a rapid response under a compressive strain of -0.08%. Our findings suggest that the proposed flexible bio-PSS holds significant promise as a motion sensor, addressing the demand for environmentally safe, wearable, and flexible strain sensor applications.
Topics: Curcumin; DNA; Graphite; Biopolymers; Biosensing Techniques
PubMed: 38927101
DOI: 10.3390/biom14060698