Biomedical subjects

P Schubert

Publications and source records attributed to P Schubert.

At least 19 recordsLinked to original sources

PubMed2006

Ultrasound-assisted transthoracic biopsy: fine-needle aspiration or cutting-needle biopsy?

The present study compared the diagnostic yield of ultrasound-assisted cutting-needle biopsy (CNB) and fine-needle aspiration biopsy (FNAB) in chest lesions. A physician performed ultrasound and FNAB with a 22-G spinal needle in all patients, directly followed by a 14-G CNB in patients without contraindication. A total of 155 consecutive lesions arising from the lung (74%), pleura (12%), mediastinum (11%) or chest wall (3%) in patients with a final diagnosis of lung carcinoma (74%), other malignant tumours (12%), non-neoplastic disease (9%) or unknown (5%) were prospectively included. The overall diagnostic yield was 87%. Combined specimens were obtained in 123 lesions (79%). In these, yields of FNAB, CNB and both methods combined were 82, 76 and 89%, respectively. FNAB was significantly better than CNB in lung carcinoma (95 versus 81%) but CNB was superior in noncarcinomatous tumours and in benign lesions. On-site cytology was 90% sensitive and 100% specific for predicting a positive FNAB. One patient required drainage for pneumothorax (0.6%). Ultrasound-assisted fine-needle aspiration biopsy performed by chest physicians is an accurate and safe initial diagnostic procedure in patients with a high clinical probability of lung carcinoma. All other patients should undergo concurrent fine-needle aspiration biopsy and cutting-needle biopsy.

Adult↗

PubMed2006

Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted.

Tumours ferment glucose to lactate even in the presence of oxygen (aerobic glycolysis; Warburg effect). The pentose phosphate pathway (PPP) allows glucose conversion to ribose for nucleic acid synthesis and glucose degradation to lactate. The nonoxidative part of the PPP is controlled by transketolase enzyme reactions. We have detected upregulation of a mutated transketolase transcript (TKTL1) in human malignancies, whereas transketolase (TKT) and transketolase-like-2 (TKTL2) transcripts were not upregulated. Strong TKTL1 protein expression was correlated to invasive colon and urothelial tumours and to poor patients outcome. TKTL1 encodes a transketolase with unusual enzymatic properties, which are likely to be caused by the internal deletion of conserved residues. We propose that TKTL1 upregulation in tumours leads to enhanced, oxygen-independent glucose usage and a lactate-based matrix degradation. As inhibition of transketolase enzyme reactions suppresses tumour growth and metastasis, TKTL1 could be the relevant target for novel anti-transketolase cancer therapies. We suggest an individualised cancer therapy based on the determination of metabolic changes in tumours that might enable the targeted inhibition of invasion and metastasis.

Adenocarcinoma↗

PubMed2002

Tissue engineering of a differentiated cardiac muscle construct.

Cardiac tissue engineering is an emerging field. The suitability of engineered heart tissue (EHT) for both in vitro and in vivo applications will depend on the degree of syncytoid tissue formation and cardiac myocyte differentiation in vitro, contractile function, and electrophysiological properties. Here, we demonstrate that cardiac myocytes from neonatal rats, when mixed with collagen I and matrix factors, cast in circular molds, and subjected to phasic mechanical stretch, reconstitute ring-shaped EHTs that display important hallmarks of differentiated myocardium. Comparative histological analysis of EHTs with native heart tissue from newborn, 6-day-old, and adult rats revealed that cardiac cells in EHTs reconstitute intensively interconnected, longitudinally oriented, cardiac muscle bundles with morphological features resembling adult rather than immature native tissue. Confocal and electron microscopy demonstrated characteristic features of native differentiated myocardium; some of these features are absent in myocytes from newborn rats: (1) highly organized sarcomeres in registry; (2) adherens junctions, gap junctions, and desmosomes; (3) a well-developed T-tubular system and dyad formation with the sarcoplasmic reticulum; and (4) a basement membrane surrounding cardiac myocytes. Accordingly, EHTs displayed contractile characteristics of native myocardium with a high ratio of twitch (0.4 to 0.8 mN) to resting tension (0.1 to 0.3 mN) and a strong beta-adrenergic inotropic response. Action potential recordings demonstrated stable resting membrane potentials of -66 to -78 mV, fast upstroke kinetics, and a prominent plateau phase. The data indicate that EHTs represent highly differentiated cardiac tissue constructs, making EHTs a promising material for in vitro studies of cardiac function and tissue replacement therapy.

Action Potentials↗

PubMed2001

Identification of a stability determinant on the edge of the Tet repressor four-helix bundle dimerization motif.

Isofunctional tetracycline repressor (TetR) proteins isolated from different bacteria show a sequence identity between 38 and 88% of the residues. Their active state is a homodimer formed by a four-alpha-helix bundle as the main interaction motif. We utilize this sequence variation of isofunctional proteins to determine residues contributing to the stability of the four-helix bundle. The thermodynamic stabilities of two TetR proteins with 63% sequence identity were determined by urea-induced reversible denaturation followed by fluorescence and circular dichroism. Both methods yield identical results. The deltaG(o)U (H2O) values are 60 and 75 kJ x mol(-1). We have constructed TetR hybrid proteins derived from these wild types to identify the determinant leading to the 15 kJ x mol(-1) stability difference. Successive size reduction of the exchanged portion yielded two single residues affecting the overall protein stability. The P184Q exchange leads to a more stable protein, whereas the G181D exchange located at the solvent's exposed edge of the four-helix bundle is solely responsible for the reduced stability. Additional mutants based on crystal structures of TetR do not reveal any hint for steric interference of the Asp181 side chain with neighboring residues. Thus, this is an example for the role played by surface-exposed turn residues for the stability of four-helix bundles. We assume that the larger conformational flexibility of Gly and the reduction of the negative surface charge could favor formation of the turn on the edge of the four-helix bundle.

Amino Acid Motifs↗

PubMed2001

Glia-related pathomechanisms in Alzheimer's disease: a therapeutic target?

Reactive glial cell properties could contribute to pathomechanisms underlying Alzheimer's disease by favoring oxidative neuronal damage and beta-amyloid toxicity. A critical step is apparently reached when pathological glia activation is no longer restricted to microglia and includes astrocytes. By giving up their differentiated state, astrocytes may lose their physiological negative feed-back control on microglial NO production and even contribute to neurotoxic peroxynitrate formation. Another consequence is the impairment of the astrocyte-maintained extracellular ion homeostasis favoring excitotoxic damage. By the production of apolipoprotein-E, triggered by the microglial cytokine interleukine-1beta, reactive astrocytes could promote the transformation of beta-amyloid into the toxic form. A pharmacologically reinforced cAMP signaling in rat glial cell cultures depressed oxygen radical formation in microglia and their release of TNF-alpha and interleukine-1beta, feed-forward signals which mediate oxidative damage and secondary astrocyte activation. Cyclic AMP also favored differentiation and expression of a mature ion channel pattern in astrocytes improving their glutamate buffering. A deficient cholinergic signaling that increases the risk of pathological APP processing was compensated by an adenosine-mediated reinforcement of the second messenger calcium. A combination therapy with acetylcholine-esterase inhibitors together with adenosine raising pharmaca, therefore, may be used to treat cholinergic deficiency in Alzheimer's disease.

Alzheimer Disease↗

PubMed2001

Propentofylline, a glial modulating agent, exhibits antiallodynic properties in a rat model of neuropathic pain.

The present study was undertaken to determine whether propentofylline, a glial modulating agent, could both prevent the induction of mechanical allodynia and attenuate existing mechanical allodynia in a rodent L5 spinal nerve transection model of neuropathic pain. In a preventative paradigm, propentofylline (1 and 10 mg/kg intraperitoneally) was administered systemically daily, beginning 1 day prior to nerve transection. This regimen produced a dose-dependent decrease in mechanical allodynia (p < 0.01). In another preventative paradigm, propentofylline (0.1, 1, or 10 microg) was administered daily intrathecally via direct lumbar puncture. Intrathecal administration of propentofylline was more effective than systemic administration at dose dependently reducing mechanical allodynia (p < 0.01). The effect of systemic propentofylline on existing allodynia was examined with 0.1-, 1-, and 10-mg/kg intraperitoneal administration initiated on day 4 post L5 spinal nerve transection. Systemic propentofylline was found to be equally effective in the attenuation of existing allodynia (p < 0.01) as in the prevention of allodynia in this rodent model of neuropathic pain. Spinal cords (L4-L6 segments) were removed for immunohistochemical analysis on day 10 or 20 post-transection. Microglial and astrocytic activation was decreased by both peripheral and central administration of propentofylline in both preventative and existing allodynia paradigms. This research supports a growing body of literature highlighting the importance of glial activation in the development of persistent neuropathic pain states, and the potential to therapeutically modulate glial activation in the treatment of neuropathic pain.

Animals↗

PubMed2000

Tet repressor induction without Mg2+.

We have examined anhydrotetracycline (atc) binding to Tet repressor (TetR) in dependence of the Mg(2+) concentration. Of all tc compounds tested so far, atc has the highest affinity for TetR, with a K(A) of 9.8 x 10(11) M(-1) in the presence of Mg(2+) and 6.5 x 10(7) M(-1) without Mg(2+). Thus, it binds TetR with 500-fold higher affinity than tc under both conditions. The Mg(2+)-free binding of atc to TetR leads to induction in vitro, demonstrating that the metal is not necessary to trigger the associated conformational change. To obtain more detailed information about Mg(2+)-free induction, we constructed and prepared to homogeneity four single-alanine substitution mutants of TetR. Three of them affect residues involved in contacting Mg(2+) (TetR H100A, E147A, and T103A), and one altered residue contacts tc TetR N82A. TetR H100A and E147A are induced by atc, with and without Mg(2+), showing 110-fold and 1000-fold decreased Mg(2+)-dependent and unchanged Mg(2+)-independent atc binding, respectively. Thus, the contacts of these residues to Mg(2+) are not necessary for induction. TetR N82A is not inducible under any of the conditions employed and shows an about 4000-fold decreased atc binding constant. The Mg(2+)-dependent affinity of TetR T103A for atc is only 400-fold reduced, but no induction with atc was observed. Thus, Thr103 must be essential for the conformational change associated with induction in the absence of Mg(2+).

Alanine↗

PubMed2000

Comparison of sodium tetraethylborate and sodium tetra(n-propyl)borate as derivatization reagent for the speciation of organotin and organolead compounds in water samples.

The influence of pH on the propylation with sodium tetra(n-propyl)borate of butyl- and phenyltins as well as for trimethyl- and triethyllead was investigated. Ethylation and propylation with tetraalkylborates were compared with regard to derivatization yields and figures of merit for organotin compounds in real water samples. Similar results for limit of detection (3-12 ng/L as tin), derivatization yield (40-100%) and relative standard deviation of the method (3-10%) were achieved for derivatization with the two tetraalkylborates. Propylation is thus the preferred method for the simultaneous determination of environmentally relevant organotin and organolead compounds. The handling of the hygroscopic and air sensitive reagents NaBEt4 and NaBPr4 was simplified by dissolving them in tetrahydrofurane. The reagent solutions in tetrahydrofurane can be stored for at least one month at 4 degrees C in the dark without observing any decrease in the derivatization efficiency.

Journal Article↗

PubMed2000

Permeation of tetracyclines through membranes of liposomes and Escherichia coli.

Uptake of tetracycline (tc), 2-tetracyclinonitrile (CN-tc), and 9-(N, N-dimethylglycylamido)-6-demethyl-6-deoxytetracycline (DMG-DMDOT) by liposomes containing Tet repressor (TetR) and by Escherichia coli cells overexpressing TetR was examined. TetR specifically binds to tetracyclines, enhances their fluorescence and thereby allows selective detection of tetracyclines that have crossed the membranes. Analysis of the diffusion of tc and DMG-DMDOT into liposomes yielded permeation coefficients of (2.4 +/- 0.6) x 10-9 cm.s-1 and (3.3 +/- 0.8) x 10-9 cm.s-1, respectively. Similar coefficients were obtained for uptake of these tetracyclines by E. coli, indicating that diffusion through the cytoplasmic membrane is the rate-limiting step. The permeation coefficients translate into half-equilibration times of approximately 35 +/- 15 min and explain how efflux pumps can mediate resistance against tetracyclines. Furthermore, diffusion of CN-tc into liposomes was at least 400-fold slower than that of tc, indicating that the carboxamide group at position C2 is required for efficient permeation of tc through lipid membranes and thereby explaining the lack of antibiotic activity of CN-tc.

Biological Transport↗

PubMed2000

Trp scanning analysis of Tet repressor reveals conformational changes associated with operator and anhydrotetracycline binding.

We analysed the conformational states of free, tet operator-bound and anhydrotetracycline-bound Tet repressor employing a Trp-scanning approach. The two wild-type Trp residues in Tet repressor were replaced by Tyr or Phe and single Trp residues were introduced at each of the positions 162-173, representing part of an unstructured loop and the N-terminal six residues of alpha-helix 9. All mutants retained in vivo inducibility, but anhydrotetracycline-binding constants were decreased up to 7.5-fold when Trp was in positions 169, 170 and 173. Helical positions (168-173) differed from those in the loop (162-167) in terms of their fluorescence emission maxima, quenching rate constants with acrylamide and anisotropies in the free and tet operator-complexed proteins. Trp fluorescence emission decreased drastically upon atc binding, mainly due to energy transfer. For all proteins, either free, tet operator bound or anhydrtetracycline-bound, mean fluorescence lifetimes were determined to derive quenching rate constants. Solvent-accessible surfaces of the respective Trp side chains were calculated and compared with the quenching rate constants in the anhydrotetracycline-bound complexes. The results support a model, in which residues in the loop become more exposed, whereas residues in alpha-helix 9 become more buried upon the induction of TetR by anhydrotetracycline.

Bacterial Proteins↗

PubMed2000

Cascading glia reactions: a common pathomechanism and its differentiated control by cyclic nucleotide signaling.

A pathological glia activation, stimulated by inflammatory proteins, beta-amyloid, or brain ischemia, is discussed as a common pathogenic factor for progressive nerve cell damage in vascular and Alzheimer dementia. A critical point seems to be reached, if the cytokine-controlled microglial upregulation causes a secondary activation of astrocytes which loose the negative feedback control, are forced to give up their physiological buffering function, and may add to neuronal damage by the release of nitric oxide (NO) and by promoting toxic beta-amyloid formation. A strengthening of the cyclic adenosine-5',3'-monophosphate (cAMP) signaling exerted a differential inhibition of the stimulatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) released from cultured rat microglia, but maintained the negative feedback signal IL-6; cAMP inhibited also the release of free oxygen radicals (OR) but not of NO. Reinforcement of the NO-induced cyclic guanosine monophosphate (cGMP) increase by blockade of the phosphodiesterase (PDE) subtype-5 with propentofylline counterbalanced the toxic NO action that causes with OR neuronal damage by peroxynitrate formation. In rat cultured astrocytes, a prolonged cAMP elevation favored cell differentiation, the expression of a mature ion channel patter, and an improvement of the extracellular glutamate uptake. Cyclic AMP signaling could be strengthened by PDE blockade and by raising extracellular adenosine, which stimulates A2 receptor-mediated cAMP synthesis. Via an A1 receptor-mediated effect, elevated adenosine was found to overcome a deficient intracellular calcium mobilization resulting from an impaired muscarinic signaling at pathologically decreased acetylcholine concentrations. We suggest that pharmaca, which elevate extracellular adenosine and/or block the degradation of cyclic nucleotides, may be used to counteract glia-related neuronal damage in dementing processes.

Alzheimer Disease↗

PubMed1999

Solvent-exposed residues in the Tet repressor (TetR) four-helix bundle contribute to subunit recognition and dimer stability.

Dimerization specificity of Tet repressor (TetR) can be altered by changes in the core of the four-helix bundle that mediates protein-protein recognition. We demonstrate here that the affinity of subunit interaction depends also on the solvent-exposed residues at positions 128 and 179'-184', which interact across the dimerization surface. TetR(B) and (D), two naturally occurring sequence variants, differ at position 128 with respect to the monomer-monomer distances in the crystal structures and the charge of the amino acids, being glutamate in TetR(B) and arginine in TetR(D). In vivo analysis of chimeric TetR(B/D) variants revealed that the single E128R exchange does not alter the dimerization specificity of TetR(B) to the one of TetR(D). When combined with specificity mutations in alpha10, it is, however, able to increase dimerization efficiency of the TetR(B/D) chimera with TetR(D). A loss of contact analysis revealed a positive interaction between Arg-128 and residues located at positions 179'-184' of the second monomer. We constructed a hyperstable TetR(B) variant by replacing residues 128 and 179-184 by the respective TetR(D) sequence. These results establish that in addition to a region in the hydrophobic core residues at the solvent-exposed periphery of the dimerization surface participate in protein-protein recognition in the TetR four-helix bundle.

Amino Acid Sequence↗

PubMed1999

Long-term cephalometric changes in untreated adults compared to those treated with orthognathic surgery.

A surprisingly large amount of long-term remodeling of facial structures has been noted in the period between 1 and 5 years post-orthognathic surgery. To evaluate whether these changes are greater than in patients with similar morphology who did not have surgery, long-term changes in hard tissue landmarks were examined in 33 untreated adults and compared to long-term changes in skeletal Class II surgery patients who underwent maxillary impaction, mandibular advancement, or both. Although the changes were small in both groups, mean changes were greater in the surgical patients; the surgical patients also showed a higher percentage of significant changes. Horizontal changes were in a forward direction in the untreated group and a backward direction in the surgical groups. We conclude that normal adult growth cannot account for the long-term changes observed following jaw surgery. In some instances, postsurgical changes leading to relapse continue much longer than would have been expected.

Adolescent↗

PubMed1998

Differential regulation of microglial activation by propentofylline via cAMP signaling.

A pathological microglial activation is believed to contribute to progressive neuronal damage in neurodegenerative diseases by the release of potentially toxic agents and by triggering reactive astrocytic changes. Using cultured microglia from neonatal rat brains, we investigated the mode of propentofylline action in strengthening cAMP-dependent intracellular signaling. We compared this action with the effects of dibutyryl-cAMP, a cell-permeable cAMP analog. Propentofylline inhibited lipopolysaccharide (LPS)-induced release of both tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta in a dose-dependent manner within the therapeutic low micromolar range. However, LPS-induced release of IL-6 and NO were not affected by propentofylline. All these differential effects of propentofylline on LPS-induced microglial release were mimicked by the addition of dibutyryl-cAMP. Microglial proliferation and phorbol myristate acetate (PMA)-induced O2- release were also dose-dependently inhibited by propentofylline as well as dibutyryl-cAMP. These results suggest that propentofylline, probably via reinforcement of cAMP intracellular signaling, alters the profile of the newly adopted immune properties in a way that it inhibits potentially neurotoxic functions while maintaining beneficial functions. This differential regulation of microglial activation may explain the neuroprotective mechanism exerted by propentofylline.

Animals↗

PubMed1998

Determinants of protein-protein recognition by four helix bundles: changing the dimerization specificity of Tet repressor.

Homo- and heterodimerization is essential for the activity of many proteins, particularly transcription factors. One widely distributed structural motif for protein recognition is the four helix bundle. To understand the molecular details determining specificity of subunit recognition in a dimer formed by a four helix bundle, we investigated Tet repressor (TetR) sequence variants TetR(B) and TetR(D), which do not form heterodimers. We used molecular modeling to identify residues with the potential to determine recognition of subunits. Directed mutagenesis of these residues in TetR(B) by the TetR(D) sequence resulted in chimeric TetR(B/D) repressors with new subunit recognition specificities. The single LS192 exchange in TetR(B/D)192 in the center of the helix bundle leads to a relaxed specificity since this variant dimerizes with TetR(B) and (D). To construct a variant with a new specificity it was not sufficient to mutate the contacting residue, F197, in the other subunit. Instead, it was necessary to exchange two more residues in the vicinity of F197 and S192. The resulting TetR(B/D)188, 192,193,197 forms dimers with TetR(D) but not with TetR(B), indicating that four amino acid exchanges are sufficient to change subunit recognition. These results establish that targeted alterations in the structural complementarity of protein-protein interaction surfaces can be used to construct new recognition specificities. However, it is not sufficient to adjust the complementary residues since the surrounding amino acids contribute essentially to protein-protein recognition.

Amino Acid Sequence↗

PubMed1998

Pathological immuno-reactions of glial cells in Alzheimer's disease and possible sites of interference.

A significant role of a pathological glial cell activation in the pathogenesis of Alzheimer's disease is supported by the growing evidence that inflammatory proteins, which are produced by reactive astrocytes, promote the transformation of diffuse beta-amyloid deposits into the filamentous, neurotoxic form. A number of vicious circles, driven by the release of TNF-a and free oxygen radicals from microglial cells, may cause an upregulated microglial activation and their production of interleukin-1 which triggers, secondarily, the crucial activation of astrocytes. Reactive functional changes of glial cells seem to be controlled by an altered balance of the second messengers Ca2+ and cAMP and can be counterregulated by the endogenous cell modulator adenosine which strengthens the cAMP-dependent signalling chain. A further reinforcement of the homeostatic adenosine effects on glial cells by pharmaca, such as propentofylline, may add to neuroprotection in Alzheimer's disease.

Adenosine↗

PubMed1998

Properties of activated microglia and pharmacologic interference by propentofylline.

Ameboid microglia are activated macrophages in the developing brain. With age, these cells undergo gradual transformation into the adult form, known as ramified or resting microglia. In response to neuronal insults, microglia change their morphology and immunophenotype and proliferate to become full-blown brain macrophages. Microglia release a battery of neurotoxic substances. Responses to neuronal damage occur at various intervals after the insult, suggesting that microglia may be an attractive target for pharmacologic intervention. The cerebrospinal fluid (CSF) of Alzheimer disease (AD) patients contains antibodies that recognize activated microglia in the developing rat and in the ischemic gerbil brain. These results suggest that AD shares common mechanisms related to the activation of microglia with both these experimental models. In vitro, the xanthine derivative propentofylline (PPF) depresses the production of reactive oxygen intermediates produced by macrophages. To appreciate in vivo interactions of PPF, two models were employed: developing rats and adult gerbils exposed to ischemia. Newborn rats were administered PPF (10 mg/kg) for 7 days. Gerbils were exposed to 5 min of transient forebrain ischemia and received PPF (10 mg/kg) 24 h later until the day before sacrifice. Animals were sacrificed at 7 or 14 days after reperfusion. Brains were processed for immunocytochemistry. Reactive microglia were visualized with monoclonal antibodies OX18 and OX42 or AD-CSF microglia antibodies. In the case of ischemia, an antibody against the amyloid precursor protein (APP) (residues 676-695) was included. Newborn rats receiving PPF for 7 days displayed a dramatic reduction in the number of activated microglia compared with untreated littermates. Ischemic control in gerbils showed complete nerve death, accumulations of APP, and enhanced microglial reactivity. In gerbils receiving PPF, APP accumulation was absent or very slight, and activated microglia were downregulated. The ability of PPF to interfere with activated microglia suggests that this agent may be useful for slowing progressive nerve cell death associated with AD, which is considered to be largely influenced by pathologic glial reactions.

Adult↗

PubMed1998

Interfering with the pathologic activation of microglial cells and astrocytes in dementia.

Cascading glial cell activation is believed to play an essential pathogenic role in the development of dementia. Reactive microglia may contribute to neuronal damage by the generation of free oxygen radicals and nitric oxide (NO), which forms the particularly aggressive peroxynitrites, and by the release of potentially neurotoxic cytokines such as tumor necrosis factor-alpha (TNF-alpha). The pathologically stimulated release of interleukin-1beta (IL-1beta) from microglial cells triggers secondary activation of astrocytes, which are forced to proliferate and to give up their differentiated state. As a consequence, physiologically required astrocyte functions may be impaired, such as uptake of glutamate and K+ from the extracellular space and release of neurotrophic factors. At the same time, production of inflammatory proteins which, for example, promote the formation of toxic beta-amyloids, is reported to be stimulated in reactive astrocytes. Because the complex molecular signaling that controls glial cell activation is only beginning to be elaborated, we attempted to elucidate the role that has been adopted during evolution by the endogenous cell modulator adenosine. This nucleoside exerts a homeostatic effect on reactive glial cell functions by a sophisticated control of the second messenger interplay, counteracting a pathologically induced dysbalance of the Ca2+- and cAMP-dependent signaling. A strengthening of the cAMP-dependent signaling chains was found to counteract the proliferation rate, the formation of free oxygen radicals, and the stimulated release of TNF-alpha and IL-1beta in cultivated microglia. It also helped proliferative astrocytes to regain their differentiated state and a mature ion channel pattern. The cAMP-linked homeostatic adenosine effects could be reinforced or mimicked by propentofylline, a pharmacon that raises the effective extracellular concentration of adenosine by inhibiting its cellular reuptake and increases the cellular cyclic nucleotide content by selective phosphodiesterase inhibition. We conclude that a pharmacologically reinforced homeostatic control of the pathologically altered Ca2+/cAMP crosstalk may prevent glia-related neuronal damage, providing a potential option for the treatment of dementia.

Adenosine Triphosphatases↗