Toshal Patel - Academia.edu (original) (raw)
Papers by Toshal Patel
Journal of Cardiovascular Pharmacology, 1995
ACS Medicinal Chemistry Letters, Mar 2, 2023
Alzheimers & Dementia, Jul 1, 2012
However, APP transgenic mice over express APP and even though FADmutations ensures high productio... more However, APP transgenic mice over express APP and even though FADmutations ensures high production of As species the by-products sAPP and intracellular domain of APP (AICD) are also generated, both of which have physiological functions. This leads to uncertainties as to whether the various observed phenotypes are caused by increased As or by the overproduction of sAPP, AICD or APP. To address these issues, we generated a novel type of AD mouse model by applying a gene knock-in strategy.Methods:We constructed a targeting vector of the mouse APP gene that included the humanized As sequence harboring the Swedish mutation (KM670/671NL) and the Iberian mutation (I716F). The knock-in micewere investigated by biochemical, pathological and behavioral studies.Results: The mutations in the generated mice (APP-NL/F-KI), gave rise to increased As 42 and decreased As 40 levels even in heterozygous mice (wt/NL-F) and already at the age of 2 month, so that As 42/A b 40 ratios were >15 fold increased in the brain compared to wild type mice. In addition, A b 42/A b 40 ratios of the homozygous (NL-F/NL-F) were>50 fold increased vs. wild type. So far, depositions of As 1-42, in partially thioflavin-S positive plaques, were visible from 6 month age of NL-F/NL-F mice. 5 months old homozygous mice also showed behavioral abnormality. In 12month old NL-F/NL-Fmice brain, accumulation of N3pE-As species and Asx43 species could be detected. In addition, tau phosphorylation was also accelerated in 12 month old NL-F/ NL-F mice. Conclusions: We are currently assessing this mouse model at older ages with respect to different paradigms. Such mice, after crossbreeding with other type of mouse models for AD, would be powerful mouse models in AD research.
DefinitionThe 5 region of the mRNA that is not translated into protein. It extends from the trans... more DefinitionThe 5 region of the mRNA that is not translated into protein. It extends from the transcription start site to the translation ATG start site, and contains regulatory sequences that control mRNA stability and translation efficiency.
s: McAuley MA, Patel TR, Galbraith S, McCulloch J (1994) Endothelin and its pathophysiological ro... more s: McAuley MA, Patel TR, Galbraith S, McCulloch J (1994) Endothelin and its pathophysiological role in the cerebral circulation in P h a r m a c o lo g y o f C e r e b r a l I s c h a e m ia eds. Krieglstein, J. and OberpichlerSchwenk, H. Wissenschaftliche Verlagsgesellschaft, Stuttgart p p 511-524 Patel TR, McAuley MA, McCulloch J (1994) The actions of bosentan , an endothelin receptor antagonist, on cerebral arterioles in situ B r . J . P h a rm a c o l. 112: 486P Patel TR, Galbraith S, McAuley MA, McCulloch J (1995) Cerebrovascular significance o f endothelin receptor antagonism in focal ischaemia J . C e r e b . B lo o d F lo w M e ta b . 1 5 [S u p p l 1 ] : S 140 Patel TR, McCulloch J (1995) The role of endothelins in post ischaemic hypoperfusion following transient global ischaemia J . C e r e b . B lo o d F lo w M e ta b . 1 5 [S u p p l I ] : S191 Patel TR, McAuley MA, Doherty AM, McCulloch J (1995) Pharmacological characterisation of peptide and non peptide endothelin rece...
CNS Drugs, 1996
SummaryThe actions of the endothelins (endothelin-I. endothelin-2 and endothelin-3) are mediated ... more SummaryThe actions of the endothelins (endothelin-I. endothelin-2 and endothelin-3) are mediated via endothelin-A (EA) and endothelin-B (ETB) receptors. the former generally mediating vasoconstriction and the latter vasodilation.Peptide antagonists selective for either receptor sUbtype [e.g. BQ 123 (ETA) and BQ 788 (ETB)] and combined ETA/ETB receptor antagonists (e.g. PD 145065 and TAK 044) have been developed. More recently. small molecule non-peptide antagonists have also been synthesised. ETA receptor-selective agents include PD 155080 and BMS 182874. while Ro 46-2005 and bosentan are combined ETA/ETB receptor antagonists.The role of the endothelin family of vasoconstrictor peptides in the pathophysiology of cerebrovascular disease has been speculated upon. Increases in plasma and CSF levels of endothelin-I in delayed vasospasm following subarachnoid haemorrhage and acute ischaemic stroke have implicated the endothelins in these cerebrovascular diseases. The development of non-p...
Pharmaceutical Research
Purpose TAK-831 is a highly selective and potent inhibitor of D-amino acid oxidase (DAAO) current... more Purpose TAK-831 is a highly selective and potent inhibitor of D-amino acid oxidase (DAAO) currently under clinical development for schizophrenia. In this study, a mechanistic multilayer quantitative model that parsimoniously connects pharmacokinetics (PK), target occupancy (TO) and D-serine concentrations as a pharmacodynamic (PD) readout was established in mice. Methods PK, TO and PD time-profiles were obtained in mice and analyzed by mechanistic binding kinetics model connected with an indirect response model in a step wise fashion. Brain distribution was investigated to elucidate a possible mechanism driving the hysteresis between PK and TO. Results The observed nonlinear PK/TO/PD relationship was well captured by mechanistic modeling framework within a wide dose range of TAK-831 in mice. Remarkably different brain distribution was observed between target and reference regions, suggesting that the target-mediated slow binding kinetics rather than slow penetration through the bloo...
Neurochemical research, Jan 5, 2017
Irregular N-methyl-D-aspartate receptor (NMDAR) function is one of the main hypotheses employed t... more Irregular N-methyl-D-aspartate receptor (NMDAR) function is one of the main hypotheses employed to facilitate understanding of the underlying disease state of schizophrenia. Although direct agonism of the NMDAR has not yielded promising therapeutics, advances have been made by modulating the NMDAR co-agonist site which is activated by glycine and D-serine. One approach to activate the co-agonist site is to increase synaptic D-serine levels through inhibition of D-amino acid oxidase (DAO), the major catabolic clearance pathway for this and other D-amino acids. A number of DAO inhibitors have been developed but most have not entered clinical trials. One exception to this is sodium benzoate which has demonstrated efficacy in small trials of schizophrenia and Alzheimer's disease. Herein we provide data on the effect of sodium benzoate and an optimised Takeda compound, PGM030756 on ex vivo DAO enzyme occupancy and cerebellar D-serine levels in mice. Both compounds achieve high levels...
Journal of Neurotrauma, Nov 1, 1999
Although both intracerebral and subdural hematomas induce brain edema, previous studies have indi... more Although both intracerebral and subdural hematomas induce brain edema, previous studies have indicated that they may have different cerebrovascular effects. Our own investigations have demonstrated that while subdural hematomas (SDH) are associated with ischemia this is not the case following intracerebral hematomas (ICH). Previous studies have demonstrated a decrease in energy-dependent transport of glutamine across the blood-brain barrier (BBB) following focal cerebral ischemia. The present study investigates this further by examining the effects of SDH, ICH, and intracerebral thrombin injections, an agent involved in ICH-induced injury, on blood to brain glutamine transport. The injection of 200 microL of blood into the subdural space induced a marked reduction in glutamine transport (Ki, influx rate constant) into the cerebral cortex at 4 and 24 h following SDH (sham, 105+/-4% of contralateral cortex; SDH 4 h, 63+/-5%, p<0.01; SDH 24 h, 47+/-12%, p<0.05). There were no significant changes in glutamine Ki in subcortical areas following SDH. Following ICH (200-microL clot); however, there were only modest decreases in glutamine Ki in subcortical areas (sham, 98+/-2% of right cortex; ICH 4 h, 91+/-5%, p<0.01; ICH 24 h, 91+/-2%, p<0.05). Intracerebral injection of thrombin (5U) had minimal effect on glutamine Ki, in subcortical areas, at 4 h and induced a modest decrease in transport at 24 h (sham, 98+/-2% of right cortex; thrombin 4 h, 98+/-2%; thrombin 24 h, 86+/-2%, p<0.05). The present studies demonstrate marked differences in the effects of ICH and SDH on BBB function.
Journal of Cardiovascular Pharmacology, 1995
The role of endogenous endothelins (ETs) in mediating postischemic hypoperfusion after transient ... more The role of endogenous endothelins (ETs) in mediating postischemic hypoperfusion after transient global ischemia was investigated in halothane-anesthetized rats. Pretreatment with the broad spectrum ETA and ETB antagonist bosentan (17 mumol/kg) had minimal effect on postischemic hypoperfusion, as measured by hydrogen clearance, in the caudate nucleus and the parietal cortex during 3 h after bilateral common carotid artery occlusion with concomitant hemorrhagic hypotension (transient global ischemia). In cerebral blood flow (CBF) measured by [14C]iodoantipyrine autoradiography at 90 min after carotid occlusion with concomitant hemorrhagic hypotension, bosentan treatment failed to alter CBF in any of the cerebral cortical regions examined. No changes in CBF, as measured by hydrogen clearance, were observed after transient bilateral common carotid artery occlusion. [14C]Iodoantipyrine autoradiography at 90 min post occlusion failed to demonstrate any increases in cerebral blood flow after transient bilateral common carotid artery occlusion in any of the 35 brain regions examined in anesthetized rats.
Objectives Donepezil is an acetylcholinesterase inhibitor commonly used in the treatment of Alzhe... more Objectives Donepezil is an acetylcholinesterase inhibitor commonly used in the treatment of Alzheimer’s disease to help alleviate the decline in cognition seen in this disease. Its mechanism of action is to prevent the breakdown of acetylcholine by the enzyme acetyl cholinesterase in the synaptic cleft and therefore enhancing the strength of signal transmission between neurons. As far as we know characterisation of the effect of donepezil alone on brain activity and metabolism has not been attempted so the aim of this study was to determine what effect donepezil, at a range of doses, had on both brain activity and brain glucose metabolism. This was done using a technique that ran both methods simultaneously to allow reduction of animals used as well as improving intersubject variability between the methods and allowing the results to easily be compared and translatable, with the hope that this simultaneous combination could be used as an in vivo assay for other potential cognition e...
Neurochemical Monitoring in the Intensive Care Unit, 1995
Progress in Medicinal Chemistry, 2014
This chapter reviews the current status of γ-secretase modulators, highlighting key compounds by ... more This chapter reviews the current status of γ-secretase modulators, highlighting key compounds by each company involved in the area. The review focuses on the three main chemotypes: acids, imidazoles and related derivatives and natural products. A section on chemical biology and ligand-binding site elucidation studies is also included. The primary source of information is drawn from peer reviewed literature as this permits analysis of PK-PD relationships and subsequent comment. Discussion of the patent literature is included for completeness. From this analysis, the key issues and challenges in the area are highlighted. The review concludes with a summary of the clinical development status and comment on future prospects of the field.
Encyclopedia of Neuroscience, 2009
Neuroscience Letters, 2006
c-Jun N-terminal kinases (JNKs) are implicated in cell death in neurodegenerative disorders. Ther... more c-Jun N-terminal kinases (JNKs) are implicated in cell death in neurodegenerative disorders. Therefore, JNK inhibitors could act as neuroprotective agents. To evaluate potential candidates, reproducible and quantitative CNS in vivo models are required. To that end, a pentylenetetrazoleinduced seizure model was explored. c-Jun phosphorylation was detected in hippocampal extracts by blotting c-Jun immunoprecipitates with phosphorylation-specific antibodies. Pentylenetetrazole administration induced rapid and reproducible increases in c-Jun phosphorylation. However, special attention had to be paid to the composition of the extraction buffer to ensure stabilization of protein phosphorylation, as demonstrated using internal standards of phosphorylated recombinant c-Jun. As JNK and its upstream activator MKK4 are activated by phosphorylation, these events were also evaluated. In principle, kinase inhibitors could act at the level of JNK or upstream kinases to inhibit c-Jun phosphorylation. MKK4 phosphorylation was dramatically increased in response to pentylenetetrazole but, again, only when appropriate phosphatase inhibitors were in the extraction buffer. In contrast, JNK was found to be constitutively phosphorylated and unaltered upon pentylenetetrazole treatment. The JNK inhibitor SP600125 was shown to inhibit c-Jun phosphorylation without affecting MKK4 phosphorylation. Our procedures enable analysis of JNK pathway signalling in a CNS model and, also, should be applicable to that of other protein phosphorylation events in vivo.
Neuroscience Letters, 2008
Journal of Neurotrauma, 1999
Although both intracerebral and subdural hematomas induce brain edema, previous studies have indi... more Although both intracerebral and subdural hematomas induce brain edema, previous studies have indicated that they may have different cerebrovascular effects. Our own investigations have demonstrated that while subdural hematomas (SDH) are associated with ischemia this is not the case following intracerebral hematomas (ICH). Previous studies have demonstrated a decrease in energy-dependent transport of glutamine across the blood-brain barrier (BBB) following focal cerebral ischemia. The present study investigates this further by examining the effects of SDH, ICH, and intracerebral thrombin injections, an agent involved in ICH-induced injury, on blood to brain glutamine transport. The injection of 200 microL of blood into the subdural space induced a marked reduction in glutamine transport (Ki, influx rate constant) into the cerebral cortex at 4 and 24 h following SDH (sham, 105+/-4% of contralateral cortex; SDH 4 h, 63+/-5%, p<0.01; SDH 24 h, 47+/-12%, p<0.05). There were no significant changes in glutamine Ki in subcortical areas following SDH. Following ICH (200-microL clot); however, there were only modest decreases in glutamine Ki in subcortical areas (sham, 98+/-2% of right cortex; ICH 4 h, 91+/-5%, p<0.01; ICH 24 h, 91+/-2%, p<0.05). Intracerebral injection of thrombin (5U) had minimal effect on glutamine Ki, in subcortical areas, at 4 h and induced a modest decrease in transport at 24 h (sham, 98+/-2% of right cortex; thrombin 4 h, 98+/-2%; thrombin 24 h, 86+/-2%, p<0.05). The present studies demonstrate marked differences in the effects of ICH and SDH on BBB function.
Journal of Cerebral Blood Flow & Metabolism, 1996
The actions of Bosentan and PD155080, non peptide endothelin receptor antagonists, were examined ... more The actions of Bosentan and PD155080, non peptide endothelin receptor antagonists, were examined in feline pial arterioles in situ following middle cerebral artery (MCA) occlusion to gain insight into the cerebro vascular influence of endogenous endothelins in focal ce rebral ischaemia. Immediately following permanent MCA occlusion, all pial arterioles overlying the suprasylvian and ectosylvian gyri displayed marked dilatations, which were maintained in a population of vessels but differen tiated into sustained constrictions in others. Perivascular subarachnoid microinjections of Bosentan (30 J..L M), PDl55080 (30 J..L M), and artificial CSF (pH 7. 2) were per formed between 30 and 210 min following MCA occlu sion. The perivascular microapplication of Bosentan (30 J..L M) and PD155080 (30 J..L M) around pial vessels overlying the suprasylvian and ectosylvian gyri, which are within the territory of the occluded MCA, elicited an increase in the calibre of postocclusion dilated and constricted pial arterioles. The perivascular microapplication of PD155080 (30 J..L M) around postocclusion constricted ar terioles overlying the ectosylvian and suprasylvian gyri elicited an increase in the calibre of arterioles (69 ± 49% from preinjection baseline; n = 8). The perivascular mi croapplication of Bosentan (30 J..L M) around postocclusion constricted arterioles overlying the ectosylvian and su prasylvian gyri also elicited an increase in the calibre of arterioles (68 ± 60% from preinjection baseline; n = 13).
Journal of Cerebral Blood Flow & Metabolism, 1996
These investigations characterised the cerebrovascular effects of an endothelin ETA-receptor anta... more These investigations characterised the cerebrovascular effects of an endothelin ETA-receptor antagonist PD156707 in normal and ischaemic cat brain. A dose of PD156707 that inhibited the effects of exogenous endothelin-1 was established in nonischaemic cerebral resistance arterioles. Perivascular microapplication of the endothelin–receptor antagonist PD156707 (0.03–3 μ M) had a minimal effect on nonischaemic pial resistance arterioles. The perivascular coapplication of PD156707 and ET-1 (10 n M) effected a dose-dependent attenuation of the ET-1 vasoconstrictive response (IC50 = 0.1 μ M). Intravenous administration of PD156707 (3 μmol/kg bolus + 5 μmol/kg/h infusion) attenuated the vasoconstriction elicited by perivascular ET-1 (10 n M) in normal pial arterioles (ET-1 vasoconstriction: −37 ± 13% from preinjection baseline; after intravenous PD156707: 6 ± 10% from preinjection baseline). In the focal ischaemia studies, cerebral perfusion was measured in the suprasylvian and ectosylvian...
Journal of Cerebral Blood Flow & Metabolism, 1996
The role of endogenous endothelins in medi ating postischaemic hypoperfusion after transient glob... more The role of endogenous endothelins in medi ating postischaemic hypoperfusion after transient global ischaemia was investigated in halothane-anaesthetised rats. Pretreatment with the broad-spectrum (ETA and ETB) endothelin antagonist, Bosentan (l7lLmollkg) had minimal effect on postischaemic hypoperfusion, mea sured by hydrogen clearance, in the caudate nucleus and the parietal cortex in the 3 h after bilateral common ca rotid artery occlusion with concomitant haemorrhagic hy potension (transient global ischaemia). In a separate se ries of rats with CBF measured by [14Cjiodoantipyrine autoradiography at 90 min after carotid occlusion with concomitant haemorrhagic hypotension, Bosentan treat ment failed to significantly alter CBF in any of the 35 brain regions examined. No significant alterations in
Journal of Cardiovascular Pharmacology, 1995
ACS Medicinal Chemistry Letters, Mar 2, 2023
Alzheimers & Dementia, Jul 1, 2012
However, APP transgenic mice over express APP and even though FADmutations ensures high productio... more However, APP transgenic mice over express APP and even though FADmutations ensures high production of As species the by-products sAPP and intracellular domain of APP (AICD) are also generated, both of which have physiological functions. This leads to uncertainties as to whether the various observed phenotypes are caused by increased As or by the overproduction of sAPP, AICD or APP. To address these issues, we generated a novel type of AD mouse model by applying a gene knock-in strategy.Methods:We constructed a targeting vector of the mouse APP gene that included the humanized As sequence harboring the Swedish mutation (KM670/671NL) and the Iberian mutation (I716F). The knock-in micewere investigated by biochemical, pathological and behavioral studies.Results: The mutations in the generated mice (APP-NL/F-KI), gave rise to increased As 42 and decreased As 40 levels even in heterozygous mice (wt/NL-F) and already at the age of 2 month, so that As 42/A b 40 ratios were >15 fold increased in the brain compared to wild type mice. In addition, A b 42/A b 40 ratios of the homozygous (NL-F/NL-F) were>50 fold increased vs. wild type. So far, depositions of As 1-42, in partially thioflavin-S positive plaques, were visible from 6 month age of NL-F/NL-F mice. 5 months old homozygous mice also showed behavioral abnormality. In 12month old NL-F/NL-Fmice brain, accumulation of N3pE-As species and Asx43 species could be detected. In addition, tau phosphorylation was also accelerated in 12 month old NL-F/ NL-F mice. Conclusions: We are currently assessing this mouse model at older ages with respect to different paradigms. Such mice, after crossbreeding with other type of mouse models for AD, would be powerful mouse models in AD research.
DefinitionThe 5 region of the mRNA that is not translated into protein. It extends from the trans... more DefinitionThe 5 region of the mRNA that is not translated into protein. It extends from the transcription start site to the translation ATG start site, and contains regulatory sequences that control mRNA stability and translation efficiency.
s: McAuley MA, Patel TR, Galbraith S, McCulloch J (1994) Endothelin and its pathophysiological ro... more s: McAuley MA, Patel TR, Galbraith S, McCulloch J (1994) Endothelin and its pathophysiological role in the cerebral circulation in P h a r m a c o lo g y o f C e r e b r a l I s c h a e m ia eds. Krieglstein, J. and OberpichlerSchwenk, H. Wissenschaftliche Verlagsgesellschaft, Stuttgart p p 511-524 Patel TR, McAuley MA, McCulloch J (1994) The actions of bosentan , an endothelin receptor antagonist, on cerebral arterioles in situ B r . J . P h a rm a c o l. 112: 486P Patel TR, Galbraith S, McAuley MA, McCulloch J (1995) Cerebrovascular significance o f endothelin receptor antagonism in focal ischaemia J . C e r e b . B lo o d F lo w M e ta b . 1 5 [S u p p l 1 ] : S 140 Patel TR, McCulloch J (1995) The role of endothelins in post ischaemic hypoperfusion following transient global ischaemia J . C e r e b . B lo o d F lo w M e ta b . 1 5 [S u p p l I ] : S191 Patel TR, McAuley MA, Doherty AM, McCulloch J (1995) Pharmacological characterisation of peptide and non peptide endothelin rece...
CNS Drugs, 1996
SummaryThe actions of the endothelins (endothelin-I. endothelin-2 and endothelin-3) are mediated ... more SummaryThe actions of the endothelins (endothelin-I. endothelin-2 and endothelin-3) are mediated via endothelin-A (EA) and endothelin-B (ETB) receptors. the former generally mediating vasoconstriction and the latter vasodilation.Peptide antagonists selective for either receptor sUbtype [e.g. BQ 123 (ETA) and BQ 788 (ETB)] and combined ETA/ETB receptor antagonists (e.g. PD 145065 and TAK 044) have been developed. More recently. small molecule non-peptide antagonists have also been synthesised. ETA receptor-selective agents include PD 155080 and BMS 182874. while Ro 46-2005 and bosentan are combined ETA/ETB receptor antagonists.The role of the endothelin family of vasoconstrictor peptides in the pathophysiology of cerebrovascular disease has been speculated upon. Increases in plasma and CSF levels of endothelin-I in delayed vasospasm following subarachnoid haemorrhage and acute ischaemic stroke have implicated the endothelins in these cerebrovascular diseases. The development of non-p...
Pharmaceutical Research
Purpose TAK-831 is a highly selective and potent inhibitor of D-amino acid oxidase (DAAO) current... more Purpose TAK-831 is a highly selective and potent inhibitor of D-amino acid oxidase (DAAO) currently under clinical development for schizophrenia. In this study, a mechanistic multilayer quantitative model that parsimoniously connects pharmacokinetics (PK), target occupancy (TO) and D-serine concentrations as a pharmacodynamic (PD) readout was established in mice. Methods PK, TO and PD time-profiles were obtained in mice and analyzed by mechanistic binding kinetics model connected with an indirect response model in a step wise fashion. Brain distribution was investigated to elucidate a possible mechanism driving the hysteresis between PK and TO. Results The observed nonlinear PK/TO/PD relationship was well captured by mechanistic modeling framework within a wide dose range of TAK-831 in mice. Remarkably different brain distribution was observed between target and reference regions, suggesting that the target-mediated slow binding kinetics rather than slow penetration through the bloo...
Neurochemical research, Jan 5, 2017
Irregular N-methyl-D-aspartate receptor (NMDAR) function is one of the main hypotheses employed t... more Irregular N-methyl-D-aspartate receptor (NMDAR) function is one of the main hypotheses employed to facilitate understanding of the underlying disease state of schizophrenia. Although direct agonism of the NMDAR has not yielded promising therapeutics, advances have been made by modulating the NMDAR co-agonist site which is activated by glycine and D-serine. One approach to activate the co-agonist site is to increase synaptic D-serine levels through inhibition of D-amino acid oxidase (DAO), the major catabolic clearance pathway for this and other D-amino acids. A number of DAO inhibitors have been developed but most have not entered clinical trials. One exception to this is sodium benzoate which has demonstrated efficacy in small trials of schizophrenia and Alzheimer's disease. Herein we provide data on the effect of sodium benzoate and an optimised Takeda compound, PGM030756 on ex vivo DAO enzyme occupancy and cerebellar D-serine levels in mice. Both compounds achieve high levels...
Journal of Neurotrauma, Nov 1, 1999
Although both intracerebral and subdural hematomas induce brain edema, previous studies have indi... more Although both intracerebral and subdural hematomas induce brain edema, previous studies have indicated that they may have different cerebrovascular effects. Our own investigations have demonstrated that while subdural hematomas (SDH) are associated with ischemia this is not the case following intracerebral hematomas (ICH). Previous studies have demonstrated a decrease in energy-dependent transport of glutamine across the blood-brain barrier (BBB) following focal cerebral ischemia. The present study investigates this further by examining the effects of SDH, ICH, and intracerebral thrombin injections, an agent involved in ICH-induced injury, on blood to brain glutamine transport. The injection of 200 microL of blood into the subdural space induced a marked reduction in glutamine transport (Ki, influx rate constant) into the cerebral cortex at 4 and 24 h following SDH (sham, 105+/-4% of contralateral cortex; SDH 4 h, 63+/-5%, p<0.01; SDH 24 h, 47+/-12%, p<0.05). There were no significant changes in glutamine Ki in subcortical areas following SDH. Following ICH (200-microL clot); however, there were only modest decreases in glutamine Ki in subcortical areas (sham, 98+/-2% of right cortex; ICH 4 h, 91+/-5%, p<0.01; ICH 24 h, 91+/-2%, p<0.05). Intracerebral injection of thrombin (5U) had minimal effect on glutamine Ki, in subcortical areas, at 4 h and induced a modest decrease in transport at 24 h (sham, 98+/-2% of right cortex; thrombin 4 h, 98+/-2%; thrombin 24 h, 86+/-2%, p<0.05). The present studies demonstrate marked differences in the effects of ICH and SDH on BBB function.
Journal of Cardiovascular Pharmacology, 1995
The role of endogenous endothelins (ETs) in mediating postischemic hypoperfusion after transient ... more The role of endogenous endothelins (ETs) in mediating postischemic hypoperfusion after transient global ischemia was investigated in halothane-anesthetized rats. Pretreatment with the broad spectrum ETA and ETB antagonist bosentan (17 mumol/kg) had minimal effect on postischemic hypoperfusion, as measured by hydrogen clearance, in the caudate nucleus and the parietal cortex during 3 h after bilateral common carotid artery occlusion with concomitant hemorrhagic hypotension (transient global ischemia). In cerebral blood flow (CBF) measured by [14C]iodoantipyrine autoradiography at 90 min after carotid occlusion with concomitant hemorrhagic hypotension, bosentan treatment failed to alter CBF in any of the cerebral cortical regions examined. No changes in CBF, as measured by hydrogen clearance, were observed after transient bilateral common carotid artery occlusion. [14C]Iodoantipyrine autoradiography at 90 min post occlusion failed to demonstrate any increases in cerebral blood flow after transient bilateral common carotid artery occlusion in any of the 35 brain regions examined in anesthetized rats.
Objectives Donepezil is an acetylcholinesterase inhibitor commonly used in the treatment of Alzhe... more Objectives Donepezil is an acetylcholinesterase inhibitor commonly used in the treatment of Alzheimer’s disease to help alleviate the decline in cognition seen in this disease. Its mechanism of action is to prevent the breakdown of acetylcholine by the enzyme acetyl cholinesterase in the synaptic cleft and therefore enhancing the strength of signal transmission between neurons. As far as we know characterisation of the effect of donepezil alone on brain activity and metabolism has not been attempted so the aim of this study was to determine what effect donepezil, at a range of doses, had on both brain activity and brain glucose metabolism. This was done using a technique that ran both methods simultaneously to allow reduction of animals used as well as improving intersubject variability between the methods and allowing the results to easily be compared and translatable, with the hope that this simultaneous combination could be used as an in vivo assay for other potential cognition e...
Neurochemical Monitoring in the Intensive Care Unit, 1995
Progress in Medicinal Chemistry, 2014
This chapter reviews the current status of γ-secretase modulators, highlighting key compounds by ... more This chapter reviews the current status of γ-secretase modulators, highlighting key compounds by each company involved in the area. The review focuses on the three main chemotypes: acids, imidazoles and related derivatives and natural products. A section on chemical biology and ligand-binding site elucidation studies is also included. The primary source of information is drawn from peer reviewed literature as this permits analysis of PK-PD relationships and subsequent comment. Discussion of the patent literature is included for completeness. From this analysis, the key issues and challenges in the area are highlighted. The review concludes with a summary of the clinical development status and comment on future prospects of the field.
Encyclopedia of Neuroscience, 2009
Neuroscience Letters, 2006
c-Jun N-terminal kinases (JNKs) are implicated in cell death in neurodegenerative disorders. Ther... more c-Jun N-terminal kinases (JNKs) are implicated in cell death in neurodegenerative disorders. Therefore, JNK inhibitors could act as neuroprotective agents. To evaluate potential candidates, reproducible and quantitative CNS in vivo models are required. To that end, a pentylenetetrazoleinduced seizure model was explored. c-Jun phosphorylation was detected in hippocampal extracts by blotting c-Jun immunoprecipitates with phosphorylation-specific antibodies. Pentylenetetrazole administration induced rapid and reproducible increases in c-Jun phosphorylation. However, special attention had to be paid to the composition of the extraction buffer to ensure stabilization of protein phosphorylation, as demonstrated using internal standards of phosphorylated recombinant c-Jun. As JNK and its upstream activator MKK4 are activated by phosphorylation, these events were also evaluated. In principle, kinase inhibitors could act at the level of JNK or upstream kinases to inhibit c-Jun phosphorylation. MKK4 phosphorylation was dramatically increased in response to pentylenetetrazole but, again, only when appropriate phosphatase inhibitors were in the extraction buffer. In contrast, JNK was found to be constitutively phosphorylated and unaltered upon pentylenetetrazole treatment. The JNK inhibitor SP600125 was shown to inhibit c-Jun phosphorylation without affecting MKK4 phosphorylation. Our procedures enable analysis of JNK pathway signalling in a CNS model and, also, should be applicable to that of other protein phosphorylation events in vivo.
Neuroscience Letters, 2008
Journal of Neurotrauma, 1999
Although both intracerebral and subdural hematomas induce brain edema, previous studies have indi... more Although both intracerebral and subdural hematomas induce brain edema, previous studies have indicated that they may have different cerebrovascular effects. Our own investigations have demonstrated that while subdural hematomas (SDH) are associated with ischemia this is not the case following intracerebral hematomas (ICH). Previous studies have demonstrated a decrease in energy-dependent transport of glutamine across the blood-brain barrier (BBB) following focal cerebral ischemia. The present study investigates this further by examining the effects of SDH, ICH, and intracerebral thrombin injections, an agent involved in ICH-induced injury, on blood to brain glutamine transport. The injection of 200 microL of blood into the subdural space induced a marked reduction in glutamine transport (Ki, influx rate constant) into the cerebral cortex at 4 and 24 h following SDH (sham, 105+/-4% of contralateral cortex; SDH 4 h, 63+/-5%, p<0.01; SDH 24 h, 47+/-12%, p<0.05). There were no significant changes in glutamine Ki in subcortical areas following SDH. Following ICH (200-microL clot); however, there were only modest decreases in glutamine Ki in subcortical areas (sham, 98+/-2% of right cortex; ICH 4 h, 91+/-5%, p<0.01; ICH 24 h, 91+/-2%, p<0.05). Intracerebral injection of thrombin (5U) had minimal effect on glutamine Ki, in subcortical areas, at 4 h and induced a modest decrease in transport at 24 h (sham, 98+/-2% of right cortex; thrombin 4 h, 98+/-2%; thrombin 24 h, 86+/-2%, p<0.05). The present studies demonstrate marked differences in the effects of ICH and SDH on BBB function.
Journal of Cerebral Blood Flow & Metabolism, 1996
The actions of Bosentan and PD155080, non peptide endothelin receptor antagonists, were examined ... more The actions of Bosentan and PD155080, non peptide endothelin receptor antagonists, were examined in feline pial arterioles in situ following middle cerebral artery (MCA) occlusion to gain insight into the cerebro vascular influence of endogenous endothelins in focal ce rebral ischaemia. Immediately following permanent MCA occlusion, all pial arterioles overlying the suprasylvian and ectosylvian gyri displayed marked dilatations, which were maintained in a population of vessels but differen tiated into sustained constrictions in others. Perivascular subarachnoid microinjections of Bosentan (30 J..L M), PDl55080 (30 J..L M), and artificial CSF (pH 7. 2) were per formed between 30 and 210 min following MCA occlu sion. The perivascular microapplication of Bosentan (30 J..L M) and PD155080 (30 J..L M) around pial vessels overlying the suprasylvian and ectosylvian gyri, which are within the territory of the occluded MCA, elicited an increase in the calibre of postocclusion dilated and constricted pial arterioles. The perivascular microapplication of PD155080 (30 J..L M) around postocclusion constricted ar terioles overlying the ectosylvian and suprasylvian gyri elicited an increase in the calibre of arterioles (69 ± 49% from preinjection baseline; n = 8). The perivascular mi croapplication of Bosentan (30 J..L M) around postocclusion constricted arterioles overlying the ectosylvian and su prasylvian gyri also elicited an increase in the calibre of arterioles (68 ± 60% from preinjection baseline; n = 13).
Journal of Cerebral Blood Flow & Metabolism, 1996
These investigations characterised the cerebrovascular effects of an endothelin ETA-receptor anta... more These investigations characterised the cerebrovascular effects of an endothelin ETA-receptor antagonist PD156707 in normal and ischaemic cat brain. A dose of PD156707 that inhibited the effects of exogenous endothelin-1 was established in nonischaemic cerebral resistance arterioles. Perivascular microapplication of the endothelin–receptor antagonist PD156707 (0.03–3 μ M) had a minimal effect on nonischaemic pial resistance arterioles. The perivascular coapplication of PD156707 and ET-1 (10 n M) effected a dose-dependent attenuation of the ET-1 vasoconstrictive response (IC50 = 0.1 μ M). Intravenous administration of PD156707 (3 μmol/kg bolus + 5 μmol/kg/h infusion) attenuated the vasoconstriction elicited by perivascular ET-1 (10 n M) in normal pial arterioles (ET-1 vasoconstriction: −37 ± 13% from preinjection baseline; after intravenous PD156707: 6 ± 10% from preinjection baseline). In the focal ischaemia studies, cerebral perfusion was measured in the suprasylvian and ectosylvian...
Journal of Cerebral Blood Flow & Metabolism, 1996
The role of endogenous endothelins in medi ating postischaemic hypoperfusion after transient glob... more The role of endogenous endothelins in medi ating postischaemic hypoperfusion after transient global ischaemia was investigated in halothane-anaesthetised rats. Pretreatment with the broad-spectrum (ETA and ETB) endothelin antagonist, Bosentan (l7lLmollkg) had minimal effect on postischaemic hypoperfusion, mea sured by hydrogen clearance, in the caudate nucleus and the parietal cortex in the 3 h after bilateral common ca rotid artery occlusion with concomitant haemorrhagic hy potension (transient global ischaemia). In a separate se ries of rats with CBF measured by [14Cjiodoantipyrine autoradiography at 90 min after carotid occlusion with concomitant haemorrhagic hypotension, Bosentan treat ment failed to significantly alter CBF in any of the 35 brain regions examined. No significant alterations in