28 results found
Chan TG, Ruehl CL, Morse SV, et al., 2021, Modulation of amyloid-beta aggregation by metal complexes with a dual binding mode and their delivery across the blood-brain barrier using focused ultrasound, Chemical Science, Vol: 12, Pages: 9485-9493, ISSN: 2041-6520
One of the key hallmarks of Alzheimer's disease is the aggregation of the amyloid-β peptide to form fibrils. Consequently, there has been great interest in studying molecules that can disrupt amyloid-β aggregation. While a handful of molecules have been shown to inhibit amyloid-β aggregation in vitro, there remains a lack of in vivo data reported due to their inability to cross the blood–brain barrier. Here, we investigate a series of new metal complexes for their ability to inhibit amyloid-β aggregation in vitro. We demonstrate that octahedral cobalt complexes with polyaromatic ligands have high inhibitory activity thanks to their dual binding mode involving π–π stacking and metal coordination to amyloid-β (confirmed via a range of spectroscopic and biophysical techniques). In addition to their high activity, these complexes are not cytotoxic to human neuroblastoma cells. Finally, we report for the first time that these metal complexes can be safely delivered across the blood–brain barrier to specific locations in the brains of mice using focused ultrasound.
Ries M, Watts H, Mota B, et al., 2021, Annexin-A1 restores cerebrovascular integrity concomitant with reduced amyloid-β and tau pathology, Brain: a journal of neurology, Vol: 144, Pages: 1526-1541, ISSN: 0006-8950
Alzheimer’s disease (AD), characterized by brain deposits of amyloid-β(Aβ) plaques and neurofibrillary tangles, is also linked to neurovascular dysfunction and blood-brain barrier (BBB) breakdown, affecting the passage of substances into and out of the brain. We hypothesized that treatment of neurovascular alterations could be beneficial in AD. Annexin A1 (ANXA1) is a mediator of glucocorticoids anti-inflammatory action that can suppress microglial activation and reduce BBB leakage. We have reported recently that treatment with recombinant human ANXA1 (hrANXA1) 2reduced Aβ levels by increased degradation in neuroblastoma cells and phagocytosis by microglia. Here, we show the beneficial effects of hrANXA1 in vivo by restoring efficient BBB function and decreasing Aβ and tau pathology in 5xFAD mice and Tau-P301L mice. We demonstrate that young 5xFAD mice already suffer cerebrovascular damage, while acute pre-administration of hrANXA1 rescued the vascular defects. Interestingly, the ameliorated BBB permeability in young 5xFAD mice by hrANXA1 correlated with reduced brain A load, due to increased clearance and degradation of Aβ by the insulin degrading enzyme (IDE). The systemic anti-inflammatory properties of hrANXA1 were also observed in 5XFAD mice, increasing IL-10 and reducing TNF-α expression. Additionally, the prolonged treatment with hrANXA1 reduced the memory deficits and increased synaptic density in young 5xFAD mice. Similarly, in Tau-P301L mice, acute hrANXA1 administration restored vascular architecture integrity, affecting the distribution of tight junctions, and reduced tau phosphorylation. The combined data support the hypothesis that the BBB breakdown early in AD can be restored by hrANXA1 as a potential therapeutic approach.
Saczewski J, Hudson A, Scheinin M, et al., 2016, Transfer of SAR information from hypotensive indazole to indole derivatives acting at alpha-adrenergic receptors: In vitro and in vivo studies, European Journal of Medicinal Chemistry, Vol: 115, Pages: 406-415, ISSN: 0223-5234
In a search for novel antihypertensive drugs we applied scaffold hopping from the previously described α1-adrenergic receptor antagonists, 1-[(imidazolin-2-yl)methyl]indazoles. The aim was to investigate whether the α-adrenergic properties of the indazole core were transferable to the indole core. The newly obtained 1-[(imidazolin-2-yl)methyl]indole analogues were screened in vitro for their binding affinities for α1-and α2-adrenoceptors, which allowed the identification of the target-based SAR transfer (T_SAR transfer) as well as structure-based SAR transfer (S_SAR transfer) events. However, when screened in vivo with use of anaesthetized male Wistar rats, the new indole ligands showed a different hemodynamic profile than expected. Instead of the immediate hypotensive effect characteristic of peripheral vasodilatator α1 blockers, a biphasic effect was observed, reminiscent of clonidine-like centrally acting antihypertensive agents. This was supported by subsequent in vitro functional studies in [35S]GTPγS binding assay, where the indole analogues displayed partial agonist properties at α2-adrenergic receptors. Since no correlation was found between the in vitro binding to α-adrenoceptors and the in vivo hemodynamic effects of the two series of indazole and indole bioisosteric compounds, in a search for new imidazoline-containing adrenergic drugs, the structure-based SAR transfer information obtained from in vitro binding studies should be treated with caution.
Zhao H, Huang H, Ologunde R, et al., 2015, Xenon Treatment Protects against Remote Lung Injury after Kidney Transplantation in Rats, ANESTHESIOLOGY, Vol: 122, Pages: 1312-1326, ISSN: 0003-3022
Andreou AP, Efthymiou M, Yu Y, et al., 2015, Protective Effects of Non-Anticoagulant Activated Protein C Variant (D36A/L38D/A39V) in a Murine Model of Ischaemic Stroke, PLOS One, Vol: 10, ISSN: 1932-6203
Ischaemic stroke is caused by occlusive thrombi in the cerebral vasculature. Although tissue-plasminogenactivator (tPA) can be administered as thrombolytic therapy, it has majorlimitations, which include disruption of the blood-brain barrier and an increased risk ofbleeding. Treatments that prevent or limit such deleterious effects could be of major clinicalimportance. Activated protein C (APC) is a natural anticoagulant that regulates thrombingeneration, but also confers endothelial cytoprotective effects and improved endothelialbarrier function mediated through its cell signalling properties. In murine models of stroke,although APC can limit the deleterious effects of tPA due to its cell signalling function, its anticoagulantactions can further elevate the risk of bleeding. Thus, APC variants such asAPC(5A), APC(Ca-ins) and APC(36-39) with reduced anticoagulant, but normal signallingfunction may have therapeutic benefit. Human and murine protein C (5A), (Ca-ins) and (36-39) variants were expressed and characterised. All protein C variants were secreted normally,but 5-20% of the protein C (Ca-ins) variants were secreted as disulphide-linked dimers.Thrombin generation assays suggested reductions in anticoagulant function of 50- to57-fold for APC(36-39), 22- to 27-fold for APC(Ca-ins) and 14- to 17-fold for APC(5A). Interestingly,whereas human wt APC, APC(36-39) and APC(Ca-ins) were inhibited similarly byprotein C inhibitor (t½ - 33 to 39 mins), APC(5A) was inactivated ~9-fold faster (t½ - 4 mins).Using the murine middle cerebral artery occlusion ischaemia/repurfusion injury model, incombination with tPA, APC(36-39), which cannot be enhanced by its cofactor protein S, significantlyimproved neurological scores, reduced cerebral infarct area by ~50% and reducedoedema ratio. APC(36-39) also significantly reduced bleeding in the brain induced by administrationof tPA, whereas wt APC did not. If our data can be extrapolated to clinical settings,then APC(36-39
Huang H, Benzonana LL, Zhao H, et al., 2014, Prostate cancer cell malignancy via modulation of HIF-1 alpha pathway with isoflurane and propofol alone and in combination, British Journal of Cancer, Vol: 111, Pages: 1338-1349, ISSN: 1532-1827
Background: Surgery is considered to be the first line treatment for solid tumours. Recently, retrospective studies reported thatgeneral anaesthesia was associated with worse long-term cancer-free survival when compared with regional anaesthesia. This hasimportant clinical implications; however, the mechanisms underlying those observations remain unclear. We aim to investigate theeffect of anaesthetics isoflurane and propofol on prostate cancer malignancy.Methods: Prostate cancer (PC3) cell line was exposed to commonly used anaesthetic isoflurane and propofol. Malignant potentialwas assessed through evaluation of expression level of hypoxia-inducible factor-1a (HIF-1a) and its downstream effectors, cellproliferation and migration as well as development of chemoresistance.Results: We demonstrated that isoflurane, at a clinically relevant concentration induced upregulation of HIF-1a and itsdownstream effectors in PC3 cell line. Consequently, cancer cell characteristics associated with malignancy were enhanced, withan increase of proliferation and migration, as well as development of chemoresistance. Inhibition of HIF-1a neosynthesis throughupper pathway blocking by a PI-3K-Akt inhibitor or HIF-1a siRNA abolished isoflurane-induced effects. In contrast, the intravenousanaesthetic propofol inhibited HIF-1a activation induced by hypoxia or CoCl2. Propofol also prevented isoflurane-induced HIF-1aactivation, and partially reduced cancer cell malignant activities.Conclusions: Our findings suggest that modulation of HIF-1a activity by anaesthetics may affect cancer recurrence followingsurgery. If our data were to be extrapolated to the clinical setting, isoflurane but not propofol should be avoided for use in cancersurgery. Further work involving in vivo models and clinical trials is urgently needed to determine the optimal anaesthetic regimenfor cancer patients.
Benzonana L, Watts HR, Ma D, 2014, Hypoxia-inducible Factors Are Already "Active" in the Von Hippel-Lindau-deficient Renal Cell Carcinoma-4 Cells Reply, ANESTHESIOLOGY, Vol: 120, Pages: 1524-1524, ISSN: 0003-3022
Vizcaychipi MP, Watts HR, O'Dea KP, et al., 2014, The Therapeutic Potential of Atorvastatin in a Mouse Model of Postoperative Cognitive Decline, ANNALS OF SURGERY, Vol: 259, Pages: 1235-1244, ISSN: 0003-4932
Kapila AK, Watts HR, Wang T, et al., 2014, The Impact of Surgery and Anesthesia on Post-Operative Cognitive Decline and Alzheimer's Disease Development: Biomarkers and Preventive Strategies, JOURNAL OF ALZHEIMERS DISEASE, Vol: 41, Pages: 1-13, ISSN: 1387-2877
Benzonana LL, Perry NJS, Watts HR, et al., 2013, Isoflurane, a Commonly Used Volatile Anesthetic, Enhances Renal Cancer Growth and Malignant Potential via the Hypoxia-inducible Factor Cellular Signaling Pathway In Vitro, ANESTHESIOLOGY, Vol: 119, Pages: 593-605, ISSN: 0003-3022
Benzonana LL, Perry NJ, Watts HR, et al., 2013, Isoflurane, a commonly used volatile anesthetic, enhances renal cancer growth and malignant potential via the hypoxia-inducible factor cellular signaling pathway in vitro., Anesthesiology, Vol: 119, Pages: 593-605
Growing evidence indicates that perioperative factors, including choice of anesthetic, affect cancer recurrence after surgery although little is known about the effect of anesthetics on cancer cells themselves. Certain anesthetics are known to affect hypoxia cell signaling mechanisms in healthy cells by up-regulating hypoxia-inducible factors (HIFs). HIFs are also heavily implicated in tumorigenesis and high levels correlate with poor prognosis.
Zhao H, Watts HR, Chong M, et al., 2013, Xenon Treatment Protects Against Cold Ischemia Associated Delayed Graft Function and Prolongs Graft Survival in Rats, AMERICAN JOURNAL OF TRANSPLANTATION, Vol: 13, Pages: 2006-2018, ISSN: 1600-6135
Crawley JTB, Efthymiou M, Yu Y, et al., 2013, Protective effects of non-anticoagulant activated protein C variant (D36A/L38D/A39V) in a murine model of ischaemic stroke, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 11, Pages: 64-64, ISSN: 1538-7933
Lloyd DG, Adeyi O, Watts HR, et al., 2013, Xenon or nitrous oxide reduce but isoflurane enhances amyloid beta-induced neuronal death in vitro, Meeting of the Anaesthetic-Research-Society, Publisher: ELSEVIER SCI LTD, Pages: 881-881, ISSN: 0007-0912
Saczewski J, Hudson A, Laird S, et al., 2012, N-(Imidazolidin-2-ylidene)-1-arylmethanamine Oxides: Synthesis, Structure and Pharmacological Evaluation, ARCHIV DER PHARMAZIE, Vol: 345, Pages: 33-42, ISSN: 0365-6233
Benzonana LL, Watts H, Ma D, 2012, Effects of Isoflurane on cytoskeletal re-arrangement of renal cell carcinoma cells, INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, Vol: 30, Pages: S28-S28, ISSN: 1107-3756
Benzonana LL, Perry NJ, Watts HR, et al., 2011, Isoflurane increases the metastatic potential of renal cell carcinoma cells via the hypoxia inducible factor pathway-an in vitro study, CANCER RESEARCH, Vol: 71, ISSN: 0008-5472
Benzonana LL, Perry NJ, Watts HR, et al., 2011, Isoflurane increases the metastatic potential of renal cell carcinoma cells via the hypoxia inducible factor pathway- an in vitro study, CANCER RESEARCH, Vol: 71, ISSN: 0008-5472
Benzonana LL, Huang H, Perry NJ, et al., 2011, Isoflurane friend or foe? An in vitro study to investigate the effects of isoflurane on metastatic potential of renal and prostate cancer, INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, Vol: 28, Pages: S41-S41, ISSN: 1107-3756
Gu J, Sun P, Zhao H, et al., 2011, Dexmedetomidine provides renoprotection against ischemia-reperfusion injury in mice, CRITICAL CARE, Vol: 15, ISSN: 1466-609X
Saczewski J, Hudson A, Scheinin M, et al., 2011, Synthesis and Biological Activities of 2-[(Heteroaryl)methyl]imidazolines, Bioorganic & Medicinal Chemistry, Pages: ---, ISSN: 0968-0896
Saczewski J, Hudson A, Laird S, et al., 2011, N-(Imidazolidin-2-ylidene)-1-arylmethanamine Oxides: Synthesis, Structure and Pharmacological Evaluation., Arch Pharm (Weinheim)
Watts HR, Anderson PJ, Ma D, et al., 2010, Differential effects of amyloid-beta peptide aggregation status on in vivo retinal neurotoxicity., Eye and Brain., Vol: 2, Pages: 121-137
Aruoma OI, Jen SSM, Watts HR, et al., 2009, Acute and chronic effects of intravitreally injected beta-amyloid on the neurotransmitter system in the retina, TOXICOLOGY, Vol: 256, Pages: 92-100, ISSN: 0300-483X
Anderson PJB, Watts HR, Jen S, et al., 2009, Differential effects of interleukin-1beta and S100B on amyloid precursor protein in rat retinal neurons., Clin Ophthalmol, Vol: 3, Pages: 235-242, ISSN: 1177-5467
PURPOSE: Interleukin-1beta (IL-1beta) and S100B calcium binding protein B (S100B) have been implicated in the pathogenesis of Alzheimer's disease. Both are present in and around senile plaques and have been shown to increase levels of amyloid precursor protein (APP) mRNA in vitro. However, it is not known how either of these substances affects APP in vivo. METHODS: We have studied the effects of IL-1beta and S100B on the expression and processing of APP using a retinal-vitreal model. We have also investigated the effect of amyloid beta peptide (Abeta) on APP in the same system and the regulation of S100B production by Abeta and IL-1beta from retinal glial cells. RESULTS: Retinal ganglion cells constitutively express APP. However, after intravitreal injection of IL-1beta or Abeta there was a marked reduction in APP levels as detected by Western blotting and IL-1beta produced a decrease in APP immunoreactivity (IR). Nissl staining showed that the integrity of the injected retinas was unchanged after injection. Two days after S100B injection, there was a small reduction in APP-IR but this was accompanied by the appearance of some intensely stained large ganglion cells and there was some up-regulation in APP holoprotein levels on Western blot. Seven days post-S100B injection, these large, highly stained cells had increased in number throughout the retina. Injection of Abeta and IL-1beta also caused an increase in S100B production within the retinal Müller glial cells. CONCLUSION: These results support the hypothesis that S100B (a glial-derived neurotrophic factor) and IL-1beta (a pro-inflammatory cytokine) can modulate the expression and processing of APP in vivo and so may contribute to the progression of Alzheimer's disease.
Watts HR, Vince V, Walsh DT, et al., 2007, Alterations in presenilin 1 processing by amyloid-beta peptide in the rat retina, EXPERIMENTAL BRAIN RESEARCH, Vol: 181, Pages: 69-77, ISSN: 0014-4819
Strong AJ, Anderson PJ, Watts HR, et al., 2007, Peri-infarct depolarizations lead to loss of perfusion in ischaemic gyrencephalic cerebral cortex., Brain, Vol: 130, Pages: 995-1008
In the light of accumulating evidence for the occurrence of spontaneous cortical spreading depression and peri-infarct depolarizations in the human brain injured by trauma or aneurysmal subarachnoid haemorrhage, we used DC electrode recording and laser speckle imaging to study the relationship between depolarization events and perfusion in the ischaemic, gyrencephalic brain. In 14 adult male cats anaesthetized with chloralose, one cerebral hemisphere was exposed and the middle cerebral artery occluded. Surface cortical perfusion in core and penumbral territories was imaged semiquantitatively at intervals of 13 s for 4 h. Cortical surface DC potential was recorded. Time interval between changes in DC potential and in perfusion was examined, and this comparison was repeated using microelectrodes for DC potential in five similar experiments in a second laboratory. Mean pre-occlusion perfusion was 11707 +/- 4581 units (equivalent to CBF (cerebral blood flow) approximately 40.5 +/- SD 14.4 ml/100 g/min), and fell on occlusion to 5318 +/- 2916 (CBF approximately 17.1 +/- 8.3), 5291 +/- 3407 (CBF approximately 17.0 +/- 10.1), and 6711 +/- 3271 (CBF approximately 22.2 +/- 9.6), quickly recovering to 8704 +/- 4581 (CBF approximately 29.5 +/- 14.4), 9741 +/- 4499 (CBF approximately 33.3 +/- 14.1) and 10 314 +/- 3762 (CBF approximately 35.4 +/- 11.4) on the core, intermediate and outer penumbral gyri, respectively. Mean perfusion later fell secondarily on core and intermediate gyri but, overall, was preserved on the outer (upper level of perfusion) gyrus during the period of observation. Pattern and severity of transient changes in perfusion associated with depolarization events varied with gyral location; falls in perfusion were sometimes profound and irreversible, and followed rather than preceded depolarization. In this model of occlusive stroke, reductions in perfusion linked to peri-infarct depolarization events contribute to secondary deterioration in penumbral areas. Th
Hodges H, Watts H, Reuter I, 2003, Stem cells: prospects for functional repair of brain damage., Transplant Proc., Vol: 35, Pages: 1250-1255
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