1,721,097 research outputs found
Processing of adenosine receptor agonists in rat and human whole blood
No full textA stability study of adenosine receptor agonists in rat and human whole blood was performed. The compounds were incubated at 37 degrees in fresh blood, and aliquots of the incubation mixture were hemolyzed at regular time intervals and analyzed with HPLC. N6-cyclopentyladenosine (CPA) and N6-cyclobutyladenosine (CBA) were degraded, whereas N6-cyclohexyladenosine, N6-cycloheptyladenosine and N6-sulfophenyladenosine were not. 2-Chloroadenosine had a half-life very similar to that of CPA. However, the 2'-, 3'-, and 5'-deoxyribose derivatives of CPA remained intact. The nucleoside transport inhibitor nitrobenzylthioinosine attenuated CBA and CPA metabolism in rat blood as did the inhibitor of adenosine deaminase erythro-9-(2-hydroxy-3-nonyl)adenine, albeit at relatively high concentrations. Complete blockade of CBA and CPA degradation was achieved by a preincubation of rat and human blood with the adenosine kinase (AK) inhibitor 5'-amino-5'-deoxyadenosine. We conclude that the two adenosine analogues are metabolized by AK both in rat and in human whole blood
Dopamine-Responsive Isoforms of Adenylyl Cyclase as Coincidence Detectors in Development and Function of Dopaminergic Neurons
No full textAccumulating evidence on molecular mechanisms leading to the differentiation of neurons with retained dopaminergic fate and function suggests the induction of such differentiation as a potential form of treatment of many neurodegenerative disorders, such as Parkinson's disease (PD) and schizophrenia. Signals conveyed by the effector enzyme adenylyl cyclase (AC) appear to be important for survival or mature functioning of neurons. Indeed, although drugs interfering with this pathway have been traditionally considered to target membrane receptors coupled to G-proteins, the ACs can be thought as new interesting “druggable” target, being known to work as signaling catalysts. We discuss herein the advance of isoform-selective stimulator and/or inhibitor compounds for AC that could lead to cell-specific pharmacotherapeutics for treating dopamine (DA)-mediated disorders, including neuropsychiatric, neurodegenerative and neuroapoptotic diseases. In this context, the calcium- and DA-sensitive isoforms of AC are considered as potential key cues for dopaminergic neuronal patterning and maintenance. In particular, cell lines differentiating dopaminergic properties and expressing selective DA- and calcium-sensitive isoforms of AC are taken into account for new therapeutic and experimental tools in inducing regenerative processes or to evaluate how cAMP signals discriminate among sympatho-adrenal heterogenic lineages of neurons
Adenylyl cyclases as innovative therapeutic goals.
No full textPharmacological modulation of intracellular cyclic AMP (cAMP) signalling could provide new therapeutic and experimental tools. Although drugs interfering with this pathway have traditionally targeted membrane receptors, the effector enzyme adenylyl cyclase (AC), which functions as a signalling catalyst, also presents an interesting target. Thus, development of isoform
selective stimulator and/or inhibitor compounds for AC could lead to organ-specific pharmacotherapeutics for treating heart failure, cancer, and neurodegenerative diseases. In this review, the potential of AC as the object of drug therapy is discussed
High glucose-induced barrier impairment of human retinal pigment epithelium is ameliorated by treatment with Goji berry extracts through modulation of cAMP levels.
No full textHuman retinal pigment epithelium cells were used to investigate the mechanisms underlying blood-retinal barrier disruption under conditions of chronic hyperglycemia. The treatment with 25 mM glucose caused a rapid drop in the transepithelial electrical resistance (TEER), which was reversed by the addition of either a methanolic extract from Goji (Lycium barbarum L.) berries or its main component, taurine. Intracellular cAMP levels increased concurrently with the high glucose-induced TEER decrease, and were correlated to an increased activity of the cytosolic isoform of the enzyme adenylyl cyclase. The treatment with plant extract or taurine restored control levels. Data are discussed in view of a possible prevention approach for diabetic retinopathy
Can pharmaceutical co-crystals provide an opportunity to modify the biological properties of drugs?
No full textPoorly soluble and/or permeable molecules jeopardize the discovery and development of innovative medicines. Pharmaceutical co-crystals, formed by an active pharmaceutical substance (API) and a co-crystal former, can show enhanced dissolution and permeation values compared with those of the parent crystalline pure phases. It is currently assumed that co-crystallization with pharmaceutical excipients does not affect the pharmacological activity of an API or, indeed, might even improve physical properties such as solubility and permeability. However, as we highlight here, the biological behavior of co-crystals can differ drastically with respect to that of their parent physical mixtures
Quercetin and quercetin-3-O-glucoside interact with different components of the cAMP signaling cascade in human retinal pigment epithelial cells
No full textAims The ability of the plant flavonol quercetin and its conjugated form quercetin-3-glucoside, compared to that of the anthocyanin cyanidin-3-glucoside, to interfere with 3′,5′-cyclic adenosine monophosphate (cAMP) efflux was investigated in cultured human retinal pigment epithelial (HRPE) cells. Main methods HRPE cells were stimulated for a time course with 1 μM adrenaline, in the presence and absence of increasing concentrations of anthocyanins or flavonols, then intracellular and extracellular cAMP levels obtained from whole cells and cAMP synthetized by the activity of adenylate cyclase in cell membrane fractions were determined by radiochemical assay. Key findings The treatment with either compound caused a significant lowering in extracellular cAMP concentrations deriving from a time course cell stimulation with 1 μM epinephrine. As to quercetin, the effect was shown to rely on the inhibition of cAMP efflux transporters. In the case of the glycoside, it was found to depend on the contrary on a reduction in the extent of epinephrine stimulation. Consistently, quercetin-3-glucoside inhibited the epinephrine-stimulated activity of adenylyl cyclase in membrane preparations, while quercetin was ineffective. The anthocyanin cyanidin-3-glucoside exerted similar effects as quercetin-3-glucoside. Significance Results strengthen the diverse effect of the glucosides versus the corresponding aglycones. Since differently from flavonols, anthocyanins are present in human plasma in their glycosylated form, the aglycone or glycoside forms of these plant secondary metabolites might therefore be utilized as synergistic regulators of cAMP homeostasis for therapeutical purposes
Retinal pigment epithelial cells as a therapeutic tool and target against retinopathies
No full textRetinal pigment epithelium (RPE) is a cell monolayer essential for photoreceptor function and forming the blood–retinal barrier. RPE and retinal neurons share the same origin and a polarized cytoarchitecture. Several factors determine the phagocytosis and permeability of RPE, influencing photoreceptor renewal and drug delivery, efficacy and toxicity. Adult human RPE expresses neuronal markers in vitro, indicating a potential transdifferentiation. Degeneration of the RPE leads to death of photoreceptors and retinal neurons, resulting in the vision loss of retinopathy. Here, we suggest tools for cell engineering to discover new ways for activating the endogenous regeneration of barrier functions and/or of the retinal precursors in RPE cells
Odorants could elicit repair processes in melanized neuronal and skin cells
No full textThe expression of ectopic olfactory receptors (ORs) in melanized cells, such as the human brain nigrostriatal dopaminergic neurons and skin melanocytes, is here pointed out. ORs are recognized to regulate skin melanogenesis, whereas OR expression in the dopaminergic neurons, characterized by accumulation of pigment neuromelanin, is downregulated in Parkinson's disease. Furthermore, the correlation between the pigmentation process and the dopamine pathway through α-synuclein expression is also highlighted. Purposely, these ORs are suggested as therapeutic target for neurodegenerative diseases related to the pigmentation disorders. Based on this evidence, a possible way of turning odorants into drugs, acting on three specific olfactory receptors, OR51E2, OR2AT4 and VN1R1, is thus introduced. Various odorous molecules are shown to interact with these ORs and their therapeutic potential against melanogenic and neurodegenerative dysfunctions, including melanoma and Parkinson's disease, is suggested. Finally, a direct functional link between olfactory and endocrine systems in human brain through VN1R1 is proposed, helping to counteract female susceptibility to Parkinson's disease in quiescent life
Prodrugs and Endogenous Transporters: Are They Suitable Tools for Drug Targeting into the Central Nervous System?
No full textHydrophilic drugs, or neuroactive agents characterized by high molecular weight, do not have the physico-chemical properties required for passive diffusion across the blood brain barrier (BBB). The prodrug approach by lipidization of hydrophilic drugs generally allows to sensibly increase their permeability across BBB, even if this phenomenon is often not associated to an effective entry into the brain of the lipidized drugs. It has been understood that active efflux transporters (AET) can have a very important role in extruding from the brain not only prodrugs obtained by lipidization processes, but also lipophilic drugs. On the other hand, it has been also demonstrated carrier mediated transporters (CMT), able to transport essential nutrients and hormones from the bloodstream to the CNS, can be employed for the brain targeting of appropriated designed prodrugs. This approach consists on the chemical modification of a drug into a “pseudonutrient” or, differently, on drug conjugation to essential nutrients transported by CMT systems. This review focuses the molecular aspects that regulate the activity of the CMT and AET systems for the transport of their substrates, taking into account the in vitro and in vivo studies related to these transporters and, thus, the prodrug approaches useful to target the neuroactive agents in the central nervous systems are described. Among these, the molecular Trojan horses systems are briefly illustrated as carriers for the transport in the brain of large molecular weight neuroactive agents
Nose-to-Brain Delivery of Antiviral Drugs: A Way to Overcome Their Active Efflux?
No full textAlthough several viruses can easily infect the central nervous system (CNS), antiviral drugs often show dramatic difficulties in penetrating the brain from the bloodstream since they are substrates of active efflux transporters (AETs). These transporters, located in the physiological barriers between blood and the CNS and in macrophage membranes, are able to recognize their substrates and actively efflux them into the bloodstream. The active transporters currently known to efflux antiviral drugs are P-glycoprotein (ABCB1 or P-gp or MDR1), multidrug resistance-associated proteins (ABCC1 or MRP1, ABCC4 or MRP4, ABCC5 or MRP5), and breast cancer resistance protein (ABCG2 or BCRP). Inhibitors of AETs may be considered, but their co-administration causes serious unwanted effects. Nasal administration of antiviral drugs is therefore proposed in order to overcome the aforementioned problems, but innovative devices, formulations (thermoreversible gels, polymeric micro- and nano-particles, solid lipid microparticles, nanoemulsions), absorption enhancers (chitosan, papaverine), and mucoadhesive agents (chitosan, polyvinilpyrrolidone) are required in order to selectively target the antiviral drugs and, possibly, the AET inhibitors in the CNS. Moreover, several prodrugs of antiretroviral agents can inhibit or elude the AET systems, appearing as interesting substrates for innovative nasal formulations able to target anti-Human Immunodeficiency Virus (HIV) agents into macrophages of the CNS, which are one of the most important HIV Sanctuaries of the body
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