Levodopa (biological precursor of dopamine) is sometimes used instead of dopamine for synthesis of highly adhesive polycatecholamine coatings on different materials. However, in comparison of ...polydopamine, little is known about biological safety of poly(levodopa) coatings and their efficacy in binding of therapeutically active substances. Therefore, thermally polymerized curdlan hydrogel was modified via two different modes using levodopa instead of commonly used dopamine and then coupled with gentamicin – aminoglycoside antibiotic. Physicochemical properties, biological safety and antibacterial potential of the hydrogels were evaluated. Poly(levodopa) deposited on curdlan exhibited high stability in wide pH range and blood or plasma, were nontoxic in zebrafish model and favored blood clot formation. Simultaneously, one of hydrogel modification modes allowed to observe high gentamicin binding capacity, antibacterial activity, relatively high nontoxicity for fibroblasts and was unfavorable for fibroblasts adhesion. Such modified poly(levodopa)-modified curdlan showed therefore high potential as wound dressing biomaterial.
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•Curdlan hydrogel was coated with polymerized levodopa.•Poly(levodopa)-deposits are stable in organic liquids and safe for blood properties.•Hydrogels are nontoxic for primary fibroblasts cultures and inhibit their adhesion.•Nontoxicity of poly(levodopa)-modified hydrogels was confirmed in zebrafish model.•Modified hydrogels abundantly bind gentamicin and show high antibacterial properties.
Drug abuse is a worldwide problem that leads to negative physical, mental, and economic consequences. Although pharmacological strategies for drug addiction management have been widely studied, ...therapeutic options with high efficacy and a low side-effects profile are still limited. Recently, there has been a growing interest in oxytocin (OT) and vasopressin (AVP) systems as potential therapeutic targets for the treatment of drug abuse. OT and AVP are hypothalamic neuropeptides involved in numerous physiological processes. Additionally, studies show that these neurohormones are highly implicated in the modulation of a wide range of behaviors. Interestingly, ample evidence has shown that both, OT and AVP are able to decrease the consumption of different drugs of abuse, as well as to ameliorate their rewarding and reinforcing effects. Furthermore, OT and AVP have been strongly involved in prosocial effects and social reward. In particular, OT has been shown to be able to shift drug-induced reward into social-induced reward, mainly due to its interaction with the dopaminergic system. This phenomenon is also reflected in the results of clinical trials where intranasal OT shows promising efficacy in managing substance use disorder. Therefore, the aim of this review is to comprehensively characterize the involvement of OT and AVP in the rewarding and other behavioral effects of drugs of abuse in animal models, with a particular highlight on the impact of social factors on the observed effects. Understanding this relationship may contribute to higher drug development success rates, as a result of a more profound and deliberate studies design.
Sporadic Alzheimer's disease (SAD) is a slowly progressive neurodegenerative disorder. This study aimed to investigate neuroprotective potential of tadalafil (TAD) and bergapten (BG) in SAD-induced ...cognitive impairment in mice. SAD was induced by single injection of streptozotocin (STZ; 3 mg/kg, ICV). STZ resulted in AD-like pathologies including Aβ deposition, tau aggregation, impaired insulin and Wnt/β-catenin signaling, as well as autophagic dysfunction and neuroinflammation. Administration of TAD or BG at doses of 20 and 25 mg/kg, respectively, for 21 consecutive days attenuated STZ-induced hippocampal insult, preserved neuronal integrity, and improved cognitive function in the Morris water maze and object recognition tests paralleled by reduction in Aβ expression by 79 and 89% and tau hyperphosphorylation by 60 and 61%, respectively. TAD and BG also enhanced protein expression of pAkt, pGSK-3β, beclin-1 and methylated protein phosphatase 2A (PP2A) and gene expression of cyclin D1, while raised BDNF immunoreactivity. Furthermore, TAD and BG boosted hippocampal levels of cGMP, PKG, Wnt3a, and AMPK and reduced expression of β-catenin and mTOR by 74% and 51%, respectively. TAD and BG also halted neuroinflammation by reducing IL-23 and IL-27 levels, as well as protein expression of NF-κB by 62% & 61%, respectively. In conclusion, this study offers novel insights on the neuroprotective effects of TAD or BG in the management of SAD as evidenced by improved cognitive function and histological architecture. This could be attributed to modulation of the crosstalk among PI3K/Akt/GSK-3β, PP2A, mTOR/autophagy, cGMP/PKG, and Wnt/β-catenin signaling cascades and mitigation of neuroinflammation.
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•TAD and BG reduced STZ-induced hippocampal insult and improved cognitive function.•TAD and BG ameliorated the crosstalk between cGMP/PKG and Wnt/β-catenin cassettes.•TAD and BG halted neuroinflammation.•TAD and BG reduced Aβ deposition and Tau hyperphosphorylation.
Intracellular signalling pathways have been extensively studied as therapeutic targets for the treatment of mental diseases. Our attention has been caught by two kinases potentially involved in ...anxiety, ERK1/2 and CaMKII. The study aimed to examine changes in the activation of ERK1/2 and CaMKII concerning anxiolytic-like behaviours in mice.
To evaluate anxiety-related response in mice, we used the open field test and the elevated plus maze test. Behavioural studies were complemented with the immunoblotting analysis to identify proteins of interest in the cortex, hippocampus, and striatum. We analysed the phosphorylation status of ERK1/2 and CaMKII in mice treated with a well-known anxiolytic drug – diazepam. Next, the blockade of ERK1/2 pathway by SL-327, a selective MEK1/2 inhibitor, was checked for anxiolytic action. Finally, the co-administration of subeffective doses of diazepam and SL-327 was investigated for a potential synergistic anxiolytic effect.
Anxiolytic effects of acute diazepam are accompanied by decreased p-ERK1/2 and upregulation of p-CaMKII. Subchronic treatment with SL-327 leads to the manifestation of anxiolytic-like behaviours and changes in the phosphorylation status of both kinases in a diazepam-like manner. Co-administration of subeffective doses of SL-327 and diazepam induces anxiolysis, which is CaMKII-independent and correlates to selectively decreased phosphoactive ERK1/2 in the hippocampus.
The MEK-ERK pathway is significantly involved in anxiolytic action of diazepam and its prolonged inhibition produces anxiolytic-like phenotype in mice. ERK inhibition could be used to manage anxiety symptoms in a benzodiazepine-sparing regimen for treatment of anxiety.
Subchronic SL-327 and acute diazepam induce anxiolytic-like behaviours in mice in the elevated plus maze and the open field test. Anxiolytic-like behaviours were accompanied by decreased levels of pERK1/2 in the prefrontal cortex, hippocampus and striatum. Co-administration of subeffective SL-327 and diazepam expresses their synergistic effect on anxiety-related behaviours presumably in a hippocampus-dependent manner. The graphical abstract was created with BioRender.com. Display omitted
•SL-327- and diazepam-induced anxiolytic-like behaviours correlate with ↓ p-ERK1/2 and ↑ p-CaMKII.•SL-327 and diazepam have a synergistic effect on anxiety, correlated with hippocampal ↓ p-ERK1/2.•Targeting the MEK-ERK pathway may be beneficial in the treatment of anxiety disorders.•MEK inhibitors could play the role of adjuvants in diazepam-sparing therapy of anxiety.
Illustrating the role of inhibiting TLR4/MyD88/NF-κB/NLRP3 and driving microglia polarization towards M2 in the neuroprotective and memory-improving effects of scoparone in OVX/D-Gal rats. Scoparone ...reduces OVX/D-Gal-induced Aβ aggregation and tau hyperphosphorylation. It exerts its anti-inflammatory and neuroprotective effects via inhibiting TLR4/MyD88/TRAF-6/TAK-1 pathway and consequently inhibits the downstream effectors, NF-κB and JNK. Moreover, inhibition of NF-κB by scoparone abrogates the NLRP3 inflammasome activation and in turn mitigates caspase-1 production and IL-1β/18 secretion. Further, scoparone-induced inhibition of NLRP3 suppresses the neurotoxic M1 while enhances the neuroprotective M2 activated microglia markers. These effects contribute to scoparone’s ability to reduce neuro-inflammation, neuronal degeneration, Aβ aggregation, and tau hyperphosphorylation. D-Gal D-galactose, OVX ovariectomy, Aβ amyloid-β, TLR4 toll-like receptor 4, MyD88 myeloid differentiation factor 88, TRAF-6 tumor necrosis factor (TNF) receptor-associated factor-6, TAK-1 transforming growth factor-β (TGF-β)-activated kinase-1, NF-κB nuclear factor-κB, JNK c-Jun N-terminal Kinase, NLRP3 nucleotide-binding oligomerization domain (NOD)-like receptor protein 3, IL-18 interleukin-18, IL-1β interleukin-1β, CD cluster of differentiation.
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•Scoparone mitigated OVX/D-Gal-induced neuroinflammation and Alzheimer’s hallmarks.•Scoparone improved rats’ memory functions and the hippocampal photomicrographs.•Modulation of TLR4 axis by scoparone is a core signaling in mediating its effects.•NLRP3 inhibition and M2 microglial shifting underlie scoparone’s neuroprotection.•Scoparone is a prosperous candidate for Alzheimer’s disease management.
Neuroinflammation mediated by microglia activation is a critical contributor to Alzheimer's disease (AD) pathogenesis. Dysregulated microglia polarization in terms of M1 overactivation with M2 inhibition is involved in AD pathological damage. Scoparone (SCO), a coumarin derivative, displays several beneficial pharmacological effects including anti-inflammatory and anti-apoptotic properties, however, its neurological effect in AD is still elusive. This study investigated the neuroprotective potential of SCO in AD animal model focusing on determining its effect on M1/M2 microglia polarization and exploring the plausible mechanism involved via investigating its modulatory role on TLR4/MyD88/NF-κB and NLRP3 inflammasome. Sixty female Wistar rats were randomly allocated into four groups. Two groups were sham-operated and treated or untreated with SCO, and the other two groups were subjected to bilateral ovariectomy (OVX) and received D-galactose (D-Gal; 150 mg/kg/day, i.p) alone or with SCO (12.5 mg/kg/day, i.p) for 6 weeks. SCO improved memory functions of OVX/D-Gal rats in the Morris water maze and novel object recognition tests. It also reduced the hippocampal burden of amyloid-β42 and p-Tau, additionally, the hippocampal histopathological architecture was prominently preserved. SCO inhibited the gene expression of TLR4, MyD88, TRAF-6, and TAK-1, additionally, p-JNK and NF-κBp65 levels were significantly curbed. This was associated with repression of NLRP3 inflammasome along with M1-to-M2 microglia polarization shifting as exemplified by mitigating pro-inflammatory M1 marker (CD86) and elevating M2 neuroprotective marker (CD163). Therefore, SCO could promote microglia transition towards M2 through switching off TLR4/MyD88/TRAF-6/TAK-1/NF-κB axis and inhibiting NLRP3 pathway, with consequent mitigation of neuroinflammation and neurodegeneration in OVX/D-Gal AD model.
•Xanthotoxin modifies anxiety-related behavior in two animal models: zebrafish and mice.•Xanthotoxin exerted reversed U-shape effect on anxiety behaviors in both models.•The predictive power of ...zebrafish for behavioral research of natural compounds was proven.
The ever-present trend for introducing new drugs of natural origin with anxiolytic properties meets healthcare needs of the population, whose almost 34 % struggles with anxiety-related disorders. At the same time, animal assays that could serve as fast and reliable models of anxiety-like behaviors are of great interest to scientists. Thus, the aim of the present study was to evaluate the utility of the zebrafish model for assessing the influence of natural compounds on anxiety in comparison with the well-known mouse model. Secondly, this study is also the first attempt to investigate the influence of a naturally occurring metabolite, i.e. xanthotoxin, on anxiety-related behaviors. The anxiety level in zebrafish was assessed by measuring thigmotaxis, a specific animal behavior to move closer to the boundaries of an open area and to avoid its center. In mice, the elevated plus maze test was chosen to study anxiety-related behaviors. Our results show that xanthotoxin exerted reversed U-shape effect on anxiety behaviors in both models. The similar pattern of xanthotoxin-induced anxiety-related behaviors in both animal models not only confirms the pharmacological properties of xanthotoxin but also proves the predictive power of the zebrafish model for behavioral research of natural compounds.
According to the Chief Sanitary Inspectorate, 75% of the compounds identified as new psychoactive substances in Poland are represented by synthetic cathinones. The aim of the presented paper is to ...describe the pharmacological profile of synthetic cathinones, including the structure-activity relationship and its impact on their biological effects. This article also includes a review of the literature on fatal and non-fatal intoxication cases associated with the administration of well-described synthetic cathinones, as well as their new derivatives. This review also characterises the influence of the amendment to the Act of August 2018 concerning the prevention of drug abuse on the process of banning new drugs and the current legal situation related to the abuse of new psychoactive substances.
Rationale
Mephedrone is a frequently overused drug of abuse that belongs to the group of novel psychoactive substances. Although its mechanism of action, as well as toxic and psychoactive effects, ...has been widely studied, the role of different factors that could contribute to the increased vulnerability to mephedrone abuse is still poorly understood.
Objectives
The aim of the presented study was to assess the impact of several factors (sex differences, social-conditioning, and chronic mild unpredictable stress — CMUS) on the liability to mephedrone-induced reward in Wistar rats.
Methods
The rewarding effects of mephedrone in male and female rats were assessed using the conditioned place preference (CPP) procedure. Furthermore, the impact of social factor and stress was evaluated in male rats using social-CPP and CMUS-dependent CPP, respectively.
Results
Mephedrone induced classic-CPP in female (10 mg/kg), as well as in male (10 and 20 mg/kg) rats. However, the impact of mephedrone treatment during social-CPP was highly dose-dependent as the rewarding effects of low dose of mephedrone (5 mg/kg; non-active in classic-CPP) were potentiated when administered during social-conditioning. Interestingly, social-conditioning with a higher dose of 20 mg/kg (that induced classic-CPP) was able to reverse these effects. Finally, CMUS potentiated rewarding effects of a low dose of mephedrone (5 mg/kg) and increased the level of corticosterone in rats’ prefrontal cortex and hippocampus.
Conclusions
Altogether, the presented results give new insight into possible factors underlying the vulnerability to mephedrone abuse and can serve as a basis for further studies assessing mechanisms underlying observed effects.
Nicotine, the primary psychoactive component of tobacco, is the most widely used drug of abuse. Although the substance is well-known, there is still a lack of information concerning its long-term ...neurological and physiological effects and its mechanisms of action. In order to search for new, effective drugs in the therapy of nicotinism, as well as to design new drugs that exert positive nicotine-like effects, further experiments are needed, ideally also using new behavioural models and paradigms. A wide range of complex behaviours – including aggression, anxiety, long- and short-term memory, object discrimination and colour preference – have recently been comprehensively classified and characterized in the zebrafish model. Zebrafish offer an attractive experimental platform, based on a microscale in vivo bioassays, which can be used to investigate psychoactive drugs, their effects on the central nervous system and potential treatments of drug addictions. In this review, we present recent data revealing the potential of the zebrafish model to evaluate the effects and molecular mechanisms of nicotine by taking into consideration its impact on anxiety, learning and memory, addiction and social behaviours.
•Zebrafish models represent a robust bioassay platform which can be applied to investigate nicotine activity.•Zebrafish can be used to evaluate anxiety-, memory-, addiction- and social-related effects of nicotine.•Zebrafish models fill the gap between in vitro and rodent studies in the field of psychoactive substances
Background
The aim of this study is to preliminary evaluate the antiparkinsonian activity of furanocoumarin—xanthotoxin, in two behavioral animal models, zebrafish larvae treated with ...6-hydroxydopamine and mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in order to compare both models.
Methods
Xanthotoxin was isolated from
Pastinaca sativa
L. (
Apiaceae
) fruits. Then, the compound was administered by immersion to zebrafish 5 days after fertilization (dpf) larvae or intraperitoneally to male Swiss mice, as a potential therapeutic agent against locomotor impairments.
Results
Acute xanthotoxin administration at the concentration of 7.5 µM reversed locomotor activity impairments in 5-dpf zebrafish larvae. In mice model, acute xanthotoxin administration alleviated movement impairments at the concentration of 25 mg/kg.
Conclusions
The similar activity of the same substance in two different animal models indicates their compatibility and proves the potential of in vivo bioassays based on zebrafish models. Results of our study indicate that xanthotoxin may be considered as a potential lead compound in the discovery of antiparkinsonian drugs.
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