n(6)-cyclohexyladenosine and enprofylline

Theophylline has an anti-inflammatory action that may account for its clinical effectiveness in the reduction of inflammatory cells in the airways. Dendritic cells (DCs) are professional antigen-presenting cells, capable of priming naïve T cells, and play key roles in the activation of immune responses in asthma.. The purpose of this study was to investigate the effects of theophylline on human monocyte differentiation into DCs and whether this involved antagonism of adenosine receptors.. Peripheral human blood monocytes were cultured in the presence of granulocyte/macrophage-colony stimulating factor and IL-4 to induce DC differentiation. The cells were incubated with theophylline, KF17837 (a selective A2a receptor antagonist) and enprofylline (A2b receptor antagonist) and co-incubated with selective adenosine A1 and A2a receptor agonists, a phosphodiesterase inhibitor (rolipram) and adenosine deaminase (ADA) to determine their effects on DC differentiation. In addition, depletion of adenosine receptors by small interfering RNA (siRNA) was also examined.. Monocytes differentiated into myeloid DCs in the culture system. The number of DCs was remarkably reduced by 60-70% when theophylline was administered at a therapeutic concentration. This effect was concentration-dependently exacerbated, was partly mediated by cellular apoptosis and was effectively reversed by the addition of the A1 agonists [2-chloro-N(6)-cyclopentyladenosin, N(6)-cyclohexyladenosine, and N-ethylcarboxamidoadenosine (NECA)] or the A2a agonist (CGS-21680, NECA). The depletion of the adenosine A1 receptor by siRNA and addition of ADA remarkably reduced DC differentiation. Meanwhile, both enprofylline and rolipram had little effect.. Our findings suggest that the adenosine A1 (and possibly coordinated with A2a) receptors contribute to DC differentiation and survival. These findings provide further evidence that theophylline has an anti-inflammatory action in bronchial asthma.

Topics: Adenosine; Adenosine A1 Receptor Agonists; Adenosine A2 Receptor Agonists; Adenosine A2 Receptor Antagonists; Adenosine Deaminase; Adenosine-5'-(N-ethylcarboxamide); Adult; Apoptosis; Caspase 3; CD11c Antigen; Cell Differentiation; Dendritic Cells; Granulocyte-Macrophage Colony-Stimulating Factor; HLA-DR Antigens; Humans; Interleukin-4; Male; Monocytes; Phenethylamines; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Receptor, Adenosine A1; Receptors, Purinergic P1; Recombinant Proteins; RNA, Small Interfering; Rolipram; Theophylline; Xanthines

The mechanism of action of aminophylline in prolonging seizures was tested in amygdala-kindled rats. Aminophylline prolonged the afterdischarge duration of kindled seizures. This seizure-prolonging action of aminophylline was strongly antagonized by the adenosine A1 agonist cyclohexyladenosine and partially antagonized by the benzodiazepine partial agonist RO 15-1788. However, the specific benzodiazepine antagonist CGS 8216 did not affect the seizure-prolonging action of aminophylline. Also, the potent anticonvulsant effect of diazepam on kindled seizures, which was completely antagonized by CGS 8216, was unaffected by aminophylline. Furthermore, a range of benzodiazepine inverse agonists, GABA antagonists, phosphodiesterase inhibitors and xanthines did not prolong afterdischarge durations. These results demonstrate that the seizure-prolonging action of aminophylline is due to block of A1 adenosine receptors since it is prevented by adenosine A1 agonists.

Topics: Adenosine; Aminophylline; Amygdala; Animals; Brain; Carbolines; Diazepam; Flumazenil; Kindling, Neurologic; Male; Picrotoxin; Pyrazoles; Pyrrolidinones; Rats; Rats, Inbred Strains; Receptors, Purinergic; Rolipram; Seizures; Theophylline; Xanthines

The antinociceptive effects of the stable adenosine analogues N6-phenylisopropyladenosine (L-PIA), N6-cyclohexyladenosine (CHA) and 5'-N-ethylcarboxamidoadenosine (NECA) were investigated in conscious rats using cutaneous thermal tests (hot plate and tail flick). Subcutaneous administration of the adenosine analogues induced a dose-dependent antinociceptive response for all agents. However, NECA was approximately 15 times more potent than PIA and CHA. Approximately the same potency order and response was seen when the adenosine analogues were administered intrathecally at the lumbar level. By this route of administration, the adenosine analogues were approximately 10-20 times more potent than after S.C. administration. Intracerebroventricular administration (lateral ventricles), however, induced a variable response, in most cases a slight hyperalgesia. The nonspecific adenosine antagonist theophylline (S.C.) rapidly reduced the antinociceptive effect induced by PIA (S.C.) but enprofylline, a bronchodilating xanthine with low ability to antagonize adenosine did not influence PIA-induced antinociception. It is concluded that stable adenosine analogues and presumably adenosine itself have potent antinociceptive effects via specific adenosine receptors in the rat. The effects seem to be mediated mainly by a spinal mechanism of action.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Analgesics; Animals; Dose-Response Relationship, Drug; Male; Phenylisopropyladenosine; Rats; Rats, Inbred Strains; Theophylline; Xanthines