Pharmacology and Therapeutics - Research Publications

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2006 - 2009 20
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Type: Journal Article × Start date: 2006 × End date: 2009 ×

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    Purinergic receptors are part of a signalling system for proliferation and differentiation in distinct cell lineages in human anagen hair follicles
    Greig, AVH ; Linge, C ; Burnstock, G (SPRINGER, 2008-12)
    We investigated the expression of P2X(5), P2X(7), P2Y(1) and P2Y(2) receptor subtypes in adult human anagen hair follicles and in relation to markers of proliferation [proliferating cell nuclear antigen (PCNA) and Ki-67], keratinocyte differentiation (involucrin) and apoptosis (anticaspase-3). Using immunohistochemistry, we showed that P2X(5), P2Y(1) and P2Y(2) receptors were expressed in spatially distinct zones of the anagen hair follicle: P2Y(1) receptors in the outer root sheath and bulb, P2X(5) receptors in the inner and outer root sheaths and medulla and P2Y(2) receptors in living cells at the edge of the cortex/medulla. P2X(7) receptors were not expressed. Colocalisation experiments suggested different functional roles for these receptors: P2Y(1) receptors were associated with bulb and outer root sheath keratinocyte proliferation, P2X(5) receptors were associated with differentiation of cells of the medulla and inner root sheaths and P2Y(2) receptors were associated with early differentiated cells in the cortex/medulla that contribute to the formation of the hair shaft. The therapeutic potential of purinergic agonists and antagonists for controlling hair growth is discussed.
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    ATP signalling in epilepsy
    Kumaria, A ; Tolias, CM ; Burnstock, G (SPRINGER, 2008-12)
    This paper focuses on a role for ATP neurotransmission and gliotransmission in the pathophysiology of epileptic seizures. ATP along with gap junctions propagates the glial calcium wave, which is an extraneuronal signalling pathway in the central nervous system. Recently astrocyte intercellular calcium waves have been shown to underlie seizures, and conventional antiepileptic drugs have been shown to attenuate these calcium waves. Blocking ATP-mediated gliotransmission, therefore, represents a potential target for antiepileptic drugs. Furthermore, while knowledge of an antiepileptic role for adenosine is not new, a recent study showed that adenosine accumulates from the hydrolysis of accumulated ATP released by astrocytes and is believed to inhibit distant synapses by acting on adenosine receptors. Such a mechanism is consistent with a surround-inhibitory mechanism whose failure would predispose to seizures. Other potential roles for ATP signalling in the initiation and spread of epileptiform discharges may involve synaptic plasticity and coordination of synaptic networks. We conclude by making speculations about future developments.
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    ATP release from the human ureter on distension and P2X3 receptor expression on suburothelial sensory nerves
    Calvert, RC ; Thompson, CS ; Burnstock, G (SPRINGER, 2008-12)
    It is not clear how the increase in intraluminal pressure behind an obstructing ureteric calculus causes an increase in action potential frequency in ureteric sensory nerves so the pain messages are transmitted to the brain. It has been proposed that ureteric distension causes urothelial release of ATP, which activates purinoceptors on suburothelial nociceptive sensory nerves. The purpose of this study was to determine whether distension of the human ureter results in the release of ATP and whether the nociceptive P2 receptor, P2X(3), is expressed on suburothelial sensory nerves in the human ureter. Human ureter segments were perfused with Krebs solution and intermittently distended to a range of pressures. Samples of perfusate were collected throughout and the ATP concentration ([ATP]) was determined using a luciferin-luciferase assay. Sections of ureter were stained using antibodies against P2X(3) and capsaicin receptors (TRPV1). [ATP] rose to more than 10 times baseline levels after distension beyond a threshold of 25-30 cmH(2)O. Immunofluorescence studies on consecutive frozen sections showed that suburothelial nerves stained positively for P2X(3) and capsaicin receptors, with no staining in controls. These findings are consistent with the hypothesis that purinergic signalling is involved in human ureteric mechanosensory transduction, leading to nociception.
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    Erratum to: P2X(5) and P2X (7) receptors in human warts and CIN 612 organotypic raft cultures of human papillomavirus infected keratinocytes.
    Greig, AVH ; Cuthill, S ; Linge, C ; Clayton, E ; Burnstock, G (Springer Science and Business Media LLC, 2006-11)
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    P2X(5) and P2X(7) receptors in human warts and CIN-612 organotypic raft cultures of human papillomavirus infected keratinocytes.
    Greig, AVH ; Cuthill, S ; Linge, C ; Clayton, E ; Burnstock, G (Springer Science and Business Media LLC, 2006-09)
    Purinergic receptors, which bind adenosine 5'-triphosphate (ATP), are expressed on human cutaneous keratinocytes and in squamous cell carcinomas. Studies on normal human epidermis and primary keratinocyte cultures have suggested that P2X(5) receptors are likely to be involved in keratinocyte differentiation and P2X(7) receptors are likely to be part of the machinery of end stage terminal differentiation/apoptosis of keratinocytes. P2X(7) receptor agonists can significantly reduce primary keratinocyte cell numbers in culture. Human papillomaviruses are increasingly recognised as important human carcinogens in the development of non-melanoma skin cancers. In our study, immunohistochemical analysis for P2X(5) and P2X(7) receptors was performed on paraffin sections of normal human skin, warts, raft cultures of normal human keratinocytes and raft cultures of CIN 612 cells, a model of keratinocytes infected with human papillomavirus type 31. In warts there was up-regulation of the expression of P2X(5) receptors. A similar pattern was seen in the CIN 612 raft cultures. Both P2X(5) and P2X(7) receptors were found in the nuclei of koilocytes, abnormal keratinocytes characteristic of human papillomavirus infection. P2X(5) and P2X(7) receptors may provide a new focus for therapeutic research into treatments for warts because these receptors can induce cell differentiation and cell death.
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    P2 receptors in cardiovascular regulation and disease
    Erlinge, D ; Burnstock, G (SPRINGER, 2008-03)
    The role of ATP as an extracellular signalling molecule is now well established and evidence is accumulating that ATP and other nucleotides (ADP, UTP and UDP) play important roles in cardiovascular physiology and pathophysiology, acting via P2X (ion channel) and P2Y (G protein-coupled) receptors. In this article we consider the dual role of ATP in regulation of vascular tone, released as a cotransmitter from sympathetic nerves or released in the vascular lumen in response to changes in blood flow and hypoxia. Further, purinergic long-term trophic and inflammatory signalling is described in cell proliferation, differentiation, migration and death in angiogenesis, vascular remodelling, restenosis and atherosclerosis. The effects on haemostasis and cardiac regulation is reviewed. The involvement of ATP in vascular diseases such as thrombosis, hypertension and diabetes will also be discussed, as well as various heart conditions. The purinergic system may be of similar importance as the sympathetic and renin-angiotensin-aldosterone systems in cardiovascular regulation and pathophysiology. The extracellular nucleotides and their cardiovascular P2 receptors are now entering the phase of clinical development.
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    Increased 5-HT(3)-mediated signalling in pelvic afferent neurons from mice deficient in P2X(2) and/or P2X (3) receptor subunits.
    Ma, B ; Wynn, G ; Dunn, PM ; Burnstock, G (Springer Science and Business Media LLC, 2006-09)
    Extracellular ATP and 5-hydroxytryptamine (5-HT) are both involved in visceral sensory pathways by interacting with P2X and 5-HT(3) receptors, respectively. We have investigated the changes in P2X and 5-HT(3)-mediated signalling in pelvic afferent neurons in mice deficient in P2X(2) and/or P2X(3) subunits by whole-cell recording of L(6)-S(2) dorsal root ganglion (DRG) neurons and by multi-unit recording of pelvic afferents of the colorectum. In wildtype DRG neurons, ATP evoked transient, sustained or mixed (biphasic) inward currents. Transient currents were absent in P2X(3) (-/-) neurons, whereas sustained currents were absent in P2X(2) (-/-) DRG neurons. Neither transient nor sustained currents were observed following application of ATP or alpha,beta-methylene ATP (alpha,beta-meATP) in P2X(2)/P2X(3) (Dbl-/-) DRG neurons. 5-HT was found to induce a fast inward current in 63% of DRG neurons from wildtype mice, which was blocked by tropisetron, a 5-HT(3) receptor antagonist. The percentage of DRG neurons responding to 5-HT was significantly increased in P2X (2) (-/-), P2X(3) (-/-) and P2X(2)/P2X(3) (Dbl-/-) mice, and the amplitude of 5-HT response was significantly increased in P2X(2)/P2X(3) (Dbl-/-) mice. The pelvic afferent response to colorectal distension was attenuated in P2X(2)/P2X(3) (Dbl-/-) mice, but the response to serosal application of 5-HT was enhanced. Furthermore, tropisetron resulted in a greater reduction in pelvic afferent responses to colorectal distension in the P2X(2)/P2X(3) (Dbl-/-) preparations. These data suggest that P2X receptors containing the P2X(2) and/or P2X(3) subunits mediate purinergic activation of colorectal afferents and that 5-HT signalling in pelvic afferent neurons is up-regulated in mice lacking P2X(2) or P2X(3) receptor genes. This effect is more pronounced when both subunits are absent.
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    Adenosine 5'-triphosphate and its relationship with other mediators that activate pelvic nerve afferent neurons in the rat colorectum.
    Wynn, G ; Burnstock, G (Springer Science and Business Media LLC, 2006-09)
    Evidence of a role for purinergic signalling in visceral afferents involving P2X(2), P2X(3) and P2Y(1) receptors exists, which appears to be important during inflammation. This study aimed to evaluate the degree of interaction between adenosine 5'-triphosphate (ATP) and other mediators that activate sensory nerves in the colorectum. Recordings from pelvic nerve afferents were made during application of agents to the in-vitro colorectal preparation. Analysis allowed calculation of single unit activity. When applied individually, bradykinin (78%) and 5-hydoxytryptamine (77%) activated the greatest number of neurons, followed by substance P, protons, ATP and capsaicin. Prostaglandin E(2) stimulated the least number (54%) and had a longer latency. Seventy-seven percent of all units studied either responded to both ATP and capsaicin or to neither, giving the greatest degree of activity correlation. Five percent of units were activated by all seven agents and no units were activated by a single agent alone. 5-hydroxytryptamine, capsaicin and protons, when co-applied with ATP, increased pelvic nerve activity to a greater degree than the sum of the individual responses. It is concluded that ATP activates pelvic nerve afferents and acts synergistically with protons, capsaicin and 5-hydroxytryptamine. The pattern of neuronal activation suggests that visceral afferents are polymodal but the receptor expression on their terminals is variable.
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    Metals and Alzheimer's disease
    Adlard, PA ; Bush, AI (IOS PRESS, 2006-11)
    There is increasing evidence to support a role for both the amyloid beta-protein precursor (AbetaPP) and its proteolytic fragment, amyloid beta (Abeta), in metal ion homeostasis. Furthermore, metal ions such as zinc and copper can interact with both AbetaPP and Abeta to potentiate Alzheimer's disease by participating in the aggregation of these normal cellular proteins and in the generation of reactive oxygen species. In addition, metal ions may interact on several other AD-related pathways, including those involved in neurofibrillary tangle formation, secretase cleavage of AbetaPP and proteolytic degradation of Abeta. As such, a dysregulation of metal ion homeostasis, as occurs with both aging and in AD, may foster an environment that can both precipitate and accelerate degenerative conditions such as AD. This offers a broad biochemical front for novel therapeutic interventions.