Tianeptine: An atypical antidepressant with multimodal pharmacology

Background: Tianeptine is an atypical antidepressant marketed as Stablon since the late 1980’s. While chemically very similar to tricyclic antidepressants, tianeptine was thought to have the apparently paradoxical mechanism of action of enhancing serotonin reuptake. However, recent data highlight a multimodal pharmacology for tianeptine including actions at glutamatergic synapses (inhibiting NMDA receptors and an indirect effect on AM-PA receptors) coupled with agonist effects at mu opioid receptors (-receptors). Objective: We have reviewed clinical and preclinical data for tianeptine to provide a compre-hensive study of its pharmacology. Results: Clinical trials show that tianeptine is at least as efficacious as first-line antidepres-sant treatments, with improved tolerability as it is significantly less prone to disrupting the patient's normal functionality. Tianeptine appears more efficacious in males than females, although these gender-specific differences may be accounted for by pharmacokinetics. Pre-clinical data suggest that the ability to stabilise glutamatergic neurotransmission may underlie tianeptine’s ability to improve cognitive function and anxiety-related symptoms. Alternative-ly, μ-receptor activation of the mTOR signalling pathway could lead tianeptine to be a fast-acting antidepressant. Agonist actions at μ-receptors could also explain the potential abuse li-ability and dependence issues seen with high dose tianeptine. Conclusion: Tianeptine itself is off patent, but it still holds much promise as an experimental tool yielding valuable insights into the molecular mechanisms underlying depression

Combined administration of buprenorphine and naltrexone produces antidepressant-like effects in mice

Opiates have been used historically for the treatment of depression. Renewed interest in the use of opiates as antidepressants has focussed on the development of kappa opioid receptor (κ-receptor) antagonists. Buprenorphine acts as a partial μ-opioid receptor agonist and a κ-receptor antagonist. By combining buprenorphine with the opioid antagonist naltrexone, the activation of μ-opioid receptors would be reduced and the κ-antagonist properties enhanced. We have established that a combination dose of buprenorphine (1mg/kg) with naltrexone (1mg/kg) functions as a short-acting κ-antagonist in the mouse tail withdrawal test. Furthermore, this dose combination is neither rewarding nor aversive in the conditioned place preference paradigm and is without significant locomotor effects. We have shown for the first time that systemic co-administration of buprenorphine (1mg/kg) with naltrexone (1mg/kg) in CD-1 mice produced significant antidepressant-like responses in behaviours in both the forced swim test and novelty induced hypophagia task. Behaviours in the elevated plus maze and light dark box were not significantly altered by treatment with buprenorphine alone, or in combination with naltrexone. We propose that the combination of buprenorphine with naltrexone represents a novel, and potentially a readily translatable approach, to the treatment of depression

Antidepressant-like effects of BU10119, a novel buprenorphine analogue with mixed κ/μ receptor antagonist properties, in mice

Background and Purpose: The κ receptor antagonists have potential for treating neuropsychiatric disorders. We have investigated the in vivo pharmacology of a novel buprenorphine analogue, BU10119, for the first time. Experimental Approach: To determine the opioid pharmacology of BU10119 (0.3–3 mg·kg −1, i.p.) in vivo, the warm-water tail-withdrawal assay was applied in adult male CD1 mice. A range of behavioural paradigms was used to investigate the locomotor effects, rewarding properties and antidepressant or anxiolytic potential of BU10119. Additional groups of mice were exposed to a single (1 × 2 h) or repeated restraint stress (3× daily 2 h) to determine the ability of BU10119 to block stress-induced analgesia. Key Results: BU10119 alone was without any antinociceptive activity. BU10119 (1 mg·kg −1) was able to block U50,488, buprenorphine and morphine-induced antinociception. The κ antagonist effects of BU10119 in the tail-withdrawal assay reversed between 24 and 48 h. BU10119 was without significant locomotor or rewarding effects. BU10119 (1 mg·kg −1) significantly reduced the latency to feed in the novelty-induced hypophagia task and reduced immobility time in the forced swim test, compared to saline-treated animals. There were no significant effects of BU10119 in either the elevated plus maze or the light–dark box. Both acute and repeated restraint stress-induced analgesia were blocked by pretreatment with BU10119 (1 mg·kg −1). Parallel stress-induced increases in plasma corticosterone were not affected. Conclusions and Implications: BU10119 is a mixed κ/μ receptor antagonist with relatively short-duration κ antagonist activity. Based on these preclinical data, BU10119 has therapeutic potential for the treatment of depression and other stress-induced conditions. Linked Articles: This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc. </p

Tianeptine: An atypical antidepressant with multimodal pharmacology

Background: Tianeptine is an atypical antidepressant marketed as Stablon since the late 1980’s. While chemically very similar to tricyclic antidepressants, tianeptine was thought to have the apparently paradoxical mechanism of action of enhancing serotonin reuptake. However, recent data highlight a multimodal pharmacology for tianeptine including actions at glutamatergic synapses (inhibiting NMDA receptors and an indirect effect on AM-PA receptors) coupled with agonist effects at mu opioid receptors (-receptors). Objective: We have reviewed clinical and preclinical data for tianeptine to provide a compre-hensive study of its pharmacology. Results: Clinical trials show that tianeptine is at least as efficacious as first-line antidepres-sant treatments, with improved tolerability as it is significantly less prone to disrupting the patient's normal functionality. Tianeptine appears more efficacious in males than females, although these gender-specific differences may be accounted for by pharmacokinetics. Pre-clinical data suggest that the ability to stabilise glutamatergic neurotransmission may underlie tianeptine’s ability to improve cognitive function and anxiety-related symptoms. Alternative-ly, μ-receptor activation of the mTOR signalling pathway could lead tianeptine to be a fast-acting antidepressant. Agonist actions at μ-receptors could also explain the potential abuse li-ability and dependence issues seen with high dose tianeptine. Conclusion: Tianeptine itself is off patent, but it still holds much promise as an experimental tool yielding valuable insights into the molecular mechanisms underlying depression

Antidepressant-like effects of BU10119, a novel buprenorphine analogue with mixed κ/μ receptor antagonist properties, in mice

Background and Purpose: The κ receptor antagonists have potential for treating neuropsychiatric disorders. We have investigated the in vivo pharmacology of a novel buprenorphine analogue, BU10119, for the first time. Experimental Approach: To determine the opioid pharmacology of BU10119 (0.3–3 mg·kg −1, i.p.) in vivo, the warm-water tail-withdrawal assay was applied in adult male CD1 mice. A range of behavioural paradigms was used to investigate the locomotor effects, rewarding properties and antidepressant or anxiolytic potential of BU10119. Additional groups of mice were exposed to a single (1 × 2 h) or repeated restraint stress (3× daily 2 h) to determine the ability of BU10119 to block stress-induced analgesia. Key Results: BU10119 alone was without any antinociceptive activity. BU10119 (1 mg·kg −1) was able to block U50,488, buprenorphine and morphine-induced antinociception. The κ antagonist effects of BU10119 in the tail-withdrawal assay reversed between 24 and 48 h. BU10119 was without significant locomotor or rewarding effects. BU10119 (1 mg·kg −1) significantly reduced the latency to feed in the novelty-induced hypophagia task and reduced immobility time in the forced swim test, compared to saline-treated animals. There were no significant effects of BU10119 in either the elevated plus maze or the light–dark box. Both acute and repeated restraint stress-induced analgesia were blocked by pretreatment with BU10119 (1 mg·kg −1). Parallel stress-induced increases in plasma corticosterone were not affected. Conclusions and Implications: BU10119 is a mixed κ/μ receptor antagonist with relatively short-duration κ antagonist activity. Based on these preclinical data, BU10119 has therapeutic potential for the treatment of depression and other stress-induced conditions. Linked Articles: This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc. </p

Butea monosperma seed extract mediated biosynthesis of ZnO NPs and their antibacterial, antibiofilm and anti-quorum sensing potentialities

Nanoparticles (NPs) prepared through safer, eco-friendly and natural-based products can be used various applications including antimicrobial and biomedical applications. Quorum sensing (QS) is a complex system for intercellular communication that regulates the expression of many virulence determinants, in the opportunistic Pseudomonas aeruginosa. Thus, the disruption of QS-mediated communication system could be an alternative strategy to combat infection caused by drug resistant P. aeruginosa. In this study, zinc oxide nanoparticles (ZnO NPs) were synthesized by using seed extract of Butea monosperma and further characterized by XRD, SEM and TEM. The biosynthesized ZnO NPs were then subjected to the investigation of their antibacterial, antibiofilm activities as well as the anti-quorum sensing potentialities for biomedical applications. The minimum inhibitory concentration (MIC) value against P. aeruginosa was found 1600 mg/ml, and it was found that ZnO NPs effectively reduced virulence factors Viz. swarming and swimming of P. aeruginosa by 62.8 and 45%, respectively. Exopolysaccharides production was also affected by ZnO NPs which indicate the disruption of biofilm formation. Further, the in silico docking analysis displayed that ZnO NPs efficiently interacted within QS (Las/Rhl) mechanism of P. aeruginosa by binding to the catalytic cleft of LasI synthase (Gly-116-ZnO = 2.8 angstrom), RhlI synthase (Gly-180-ZnO = 3.7 angstrom) and transcription receptor protein LasR receptor (Asn-141-ZnO = 2.9 angstrom), RhlR receptor (Tyr-72 -ZnO = 2.6 angstrom). Thus, it was concluded that the effective interaction of ZnO NPs with Las and Rhl system led to the inactivation of autoinducers such as N-acyl homoserine lactones (AHL) molecules which finally led to the inactivation of QS and down regulation of virulence determinants. Consequently, the present in vitro and in silico results obtained suggest that the synthesized ZnO NPs can be efficiently used as potent antimicrobial agents to prevent the colonization, biofilm formation as well as anti-QS-mediated determinants caused by pathogenic drug resistant bacteria. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of King Saud University