Pharmacology and Therapeutics - Research Publications
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ItemProtein kinase D and Gβγ mediate sustained nociceptive signaling by biased agonists of protease-activated receptor-2(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2019-07-05)Proteases sustain hyperexcitability and pain by cleaving protease-activated receptor-2 (PAR2) on nociceptors through distinct mechanisms. Whereas trypsin induces PAR2 coupling to Gαq, Gαs, and β-arrestins, cathepsin-S (CS) and neutrophil elastase (NE) cleave PAR2 at distinct sites and activate it by biased mechanisms that induce coupling to Gαs, but not to Gαq or β-arrestins. Because proteases activate PAR2 by irreversible cleavage, and activated PAR2 is degraded in lysosomes, sustained extracellular protease-mediated signaling requires mobilization of intact PAR2 from the Golgi apparatus or de novo synthesis of new receptors by incompletely understood mechanisms. We found here that trypsin, CS, and NE stimulate PAR2-dependent activation of protein kinase D (PKD) in the Golgi of HEK293 cells, in which PKD regulates protein trafficking. The proteases stimulated translocation of the PKD activator Gβγ to the Golgi, coinciding with PAR2 mobilization from the Golgi. Proteases also induced translocation of a photoconverted PAR2-Kaede fusion protein from the Golgi to the plasma membrane of KNRK cells. After incubation of HEK293 cells and dorsal root ganglia neurons with CS, NE, or trypsin, PAR2 responsiveness initially declined, consistent with PAR2 cleavage and desensitization, and then gradually recovered. Inhibitors of PKD, Gβγ, and protein translation inhibited recovery of PAR2 responsiveness. PKD and Gβγ inhibitors also attenuated protease-evoked mechanical allodynia in mice. We conclude that proteases that activate PAR2 by canonical and biased mechanisms stimulate PKD in the Golgi; PAR2 mobilization and de novo synthesis repopulate the cell surface with intact receptors and sustain nociceptive signaling by extracellular proteases.
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ItemEditorial: Neuronal Co-transmission(FRONTIERS MEDIA SA, 2019-03-26)
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ItemThe role of the blood-brain barrier in hypertension(WILEY, 2018-03-01)What is the topic of this review? This review highlights the importance of the blood-brain barrier in the context of diseases involving autonomic dysfunction, such as hypertension and heart failure. What advances does it highlight? It highlights the potential role of pro-inflammatory cytokines, leucocytes and angiotensin II in disrupting the blood-brain barrier in cardiovascular diseases. Advances are highlighted in our understanding of neurovascular unit cells, astrocytes and microglia, with a specific emphasis on their pathogenic roles within the brain. The blood-brain barrier (BBB) is a crucial barrier that provides both metabolic and physical protection to an immune-privileged CNS. The BBB has been shown to be disrupted in hypertension. This review addresses the importance of the BBB in maintaining homeostasis in the context of diseases related to autonomic dysfunction, such as hypertension. We highlight the potentially important roles of the immune system and neurovascular unit in the maintenance of the BBB, whereby dysregulation may lead to autonomic dysfunction in diseases such as heart failure and hypertension. Circulating leucocytes and factors such as angiotensin II and pro-inflammatory cytokines are thought ultimately to downregulate endothelial tight junction proteins that are a crucial component of the BBB. The specific mechanisms underlying BBB disruption and their role in contributing to autonomic dysfunction are not yet fully understood but are a growing area of interest. A greater understanding of these systems and advances in our knowledge of the molecular mechanisms causing BBB disruption will allow for the development of future therapeutic interventions in the treatment of autonomic imbalance associated with diseases such as heart failure and hypertension.
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ItemType-I interferons in Parkinson's disease: innate inflammatory response drives fate of neurons in model of degenerative brain disorder: An editorial comment on 'Type-I interferons mediate the neuroinflammatory response and neurotoxicity induced by rotenone'(WILEY, 2017-04)Read the commented article 'Type-I interferons mediate the neuroinflammatory response and neurotoxicity induced by rotenone' on page 75.
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ItemType-I interferons mediate the neuroinflammatory response and neurotoxicity induced by rotenone(WILEY, 2017-04)Evidence from post-mortem human brains, animal studies and cell culture models has implicated neuroinflammation in the aetiology of chronic neuropathologies including Alzheimer's and Parkinson's diseases. Although the neuroinflammatory response is considered detrimental in contributing to these pathologies, the underlying mechanisms are still not well understood. The type-I interferons (IFNs) have been well characterised in the periphery and are known to initiate/modulate the immune response. Recently, they have been implicated in ageing and we have also demonstrated increased type-I IFN expression in post-mortem human Alzheimer's and Parkinson's disease brains. We hypothesise that the type-I IFNs are key drivers of the damaging, self-perpetuating pro-inflammatory response that contributes to these chronic neuropathologies. In support of this, we have recently confirmed in models of Alzheimer's and Parkinson's disease that mice lacking the type-I IFN receptor (IFNAR1), display an attenuated neuroinflammatory response with subsequent neuroprotection. To further investigate type-I IFN-mediated neuroinflammation and the specific CNS cell types involved, this study treated primary cultured wild-type and IFNAR1-/- neurons or mixed glia with the mitochondrial complex I inhibitor, rotenone. Wild-type neurons and glia treated with 3 nM and 25 nM rotenone, respectively, exhibited a pro-inflammatory response, including increased type-I IFN expression that was attenuated in cells lacking IFNAR1. Reduced type-I IFN signalling in IFNAR1-/- neurons also conferred protection against caspase-3-mediated rotenone-induced cell death. Further, this reduced pro-inflammatory response in the IFNAR1-/- glia subsequently diminished their neurotoxic effects to wild-type neurons. In support of this, we confirmed that therapeutically targeting the type-I IFN glial response to rotenone through a specific IFNAR1 blocking monoclonal antibody was neuroprotective. Our data has confirmed that both neurons and glia contribute to the pro-inflammatory response induced by rotenone with attenuation of this response beneficial in reducing neuronal cell death. Read the Editorial Comment for this article on page 9.
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ItemType-1 Interferons Contribute to the Neuroinflammatory Response and Disease Progression of the MPTP Mouse Model of Parkinson's Disease(WILEY, 2016-09)Type-1 interferons (IFNs) are pleiotropic cytokines with a critical role in the initiation and regulation of the pro-inflammatory response. However, the contribution of the type-1 IFNs to CNS disorders, specifically chronic neuropathologies such as Parkinson's disease is still unknown. Here, we report increased type-1 IFN signaling in both post mortem human Parkinson's disease samples and in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) mouse model. In response to MPTP, mice lacking the type-1 IFN receptor (IFNAR1(-/-) ) displayed decreased type-1 IFN signaling, an attenuated pro-inflammatory response and reduced loss of dopaminergic neurons. The neuroprotective potential of targeting the type-1 IFN pathway was confirmed by reduced neuroinflammation and DA cell death in mice treated with a blocking monoclonal IFNAR1 (MAR-1) antibody. The MPTP/MAR-1 treated mice also displayed increased striatal dopamine levels and improved behavioural outcomes compared to their MPTP/IgG controls. These data, implicate for the first time, a deleterious role for the type-1 IFNs as key modulators of the early neuroinflammatory response and therefore the neuronal cell death in Parkinson's disease. GLIA 2016;64:1590-1604.
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ItemReview article: Role of magnesium sulphate in the management of Irukandji syndrome: A systematic review(WILEY, 2017-02)Signs of Irukandji syndrome (IS) suggest an underlying catecholamine storm with research demonstrating that Carukia barnesi venom causes a significant rise in adrenaline/noradrenaline serum levels. A systematic review was undertaken to ascertain the current evidence in treating IS with magnesium salts. A literature search was conducted using Scopus, Medline and ScienceDirect. Further articles were discarded via title description and/or abstract details. The remaining were read in full, and those identified as not having sufficient information regarding magnesium and patient outcomes were removed. Nine articles were identified. One article was a randomised controlled trial, which concluded that there appears to be no beneficial difference between those patients who received the magnesium sulphate (MgSO4 ) and those who received the placebo and recommended against the use of MgSO4 in IS. Of the remaining eight, one reported the failure of MgSO4 and the remaining seven were case series reporting varying success in its use. This systematic review found insufficient evidence to support any clear recommendation regarding the use of magnesium, but nor was there clear evidence to recommend against its use in IS. Two case series describe significant reduction in key symptoms and hypertension but are a non-randomised albeit prospective series with the limitations accompanying this. The reporting of recrudescence of symptoms with reduction of dose does suggest a dose-response relationship. The evidence for the use of MgSO4 is at best anecdotal, and further research is required to either confirm its benefit or confirm the randomised controlled trial.
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ItemUnlocking the Potential of Purinergic Signaling in Transplantation(WILEY, 2016-10)Purinergic signaling has been recognized as playing an important role in inflammation, angiogenesis, malignancy, diabetes and neural transmission. Activation of signaling pathways downstream from purinergic receptors may also be implicated in transplantation and related vascular injury. Following transplantation, the proinflammatory "danger signal" adenosine triphosphate (ATP) is released from damaged cells and promotes proliferation and activation of a variety of immune cells. Targeting purinergic signaling pathways may promote immunosuppression and ameliorate inflammation. Under pathophysiological conditions, nucleotide-scavenging ectonucleotidases CD39 and CD73 hydrolyze ATP, ultimately, to the anti-inflammatory mediator adenosine. Adenosine suppresses proinflammatory cytokine production and is associated with improved graft survival and decreased severity of graft-versus-host disease. Furthermore, purinergic signaling is involved both directly and indirectly in the mechanism of action of several existing immunosuppressive drugs, such as calcineurin inhibitors and mammalian target of rapamycin inhibitors. Targeting of purinergic receptor pathways, particularly in the setting of combination therapies, could become a valuable immunosuppressive strategy in transplantation. This review focuses on the role of the purinergic signaling pathway in transplantation and immunosuppression and explores possible future applications in clinical practice.