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Your search keyword '"Jeggo, R"' showing total 3 results
Start Over Author "Jeggo, R" Topic action potentials
3 results on '"Jeggo, R"'

1. Parkinson's disease-like burst firing activity in subthalamic nucleus induced by AAV-α-synuclein is normalized by LRRK2 modulation.

Author

Andersen MA, Christensen KV, Badolo L, Smith GP, Jeggo R, Jensen PH, Andersen KJ, and Sotty F

Subjects
Action Potentials drug effects, Animals, Dependovirus genetics, Female, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 antagonists & inhibitors, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 genetics, Parkinsonian Disorders genetics, Rats, Rats, Long-Evans, Rats, Sprague-Dawley, Rats, Transgenic, Subthalamic Nucleus drug effects, alpha-Synuclein genetics, Action Potentials physiology, Dependovirus metabolism, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 deficiency, Parkinsonian Disorders metabolism, Subthalamic Nucleus metabolism, alpha-Synuclein biosynthesis
Abstract

Parkinson's disease (PD) affects motor function through degenerative processes and synaptic transmission impairments in the basal ganglia. None of the treatments available delays or stops the progression of the disease. While α-synuclein pathological accumulation represents a hallmark of the disease in its idiopathic form, leucine rich repeat kinase 2 (LRRK2) is genetically associated with familial and sporadic forms of PD. The genetic information suggests that LRRK2 kinase activity plays a role in the pathogenesis of the disease. To support a potential link between LRRK2 and α-synuclein in the pathophysiological mechanisms underlying PD, the effect of LRRK2 ablation or LRRK2 kinase pharmacological inhibition were studied in rats with adeno-associated virus-induced (AAV) α-synuclein overexpression in the nigrostriatal pathway. We first report that viral overexpression of α-synuclein induced increased burst firing in subthalamic neurons. Aberrant firing pattern of subthalamic neurons has also been reported in PD patients and neurotoxin-based animal models, and is hypothesized to play a key role in the appearance of motor dysfunction. We further report that genetic LRRK2 ablation, as well as pharmacological inhibition of LRRK2 kinase activity with PFE-360, reversed the aberrant firing pattern of subthalamic neurons induced by AAV-α-synuclein overexpression. This effect of LRRK2 modulation was not associated with any neuroprotective effect or motor improvement. Nonetheless, our findings may indicate a potential therapeutic benefit of LRRK2 kinase inhibition by normalizing the aberrant neuronal activity of subthalamic neurons induced by AAV-α-synuclein, a neurophysiological trait recapitulating observations in PD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Published
2018
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2. Characterization of a CNS penetrant, selective M1 muscarinic receptor agonist, 77-LH-28-1

Author

Langmead, C J, Austin, N E, Branch, C L, Brown, J T, Buchanan, K A, Davies, C H, Forbes, I T, Fry, V A H, Hagan, J J, Herdon, H J, Jones, G A, Jeggo, R, Kew, J N C, Mazzali, A, Melarange, R, Patel, N, Pardoe, J, Randall, A D, Roberts, C, Roopun, A, Starr, K R, Teriakidis, A, Wood, M D, Whittington, M, Wu, Z, and Watson, J

Subjects
Patch-Clamp Techniques, Time Factors, Dose-Response Relationship, Drug, Injections, Subcutaneous, Inositol Phosphates, Receptor, Muscarinic M1, Action Potentials, CHO Cells, Muscarinic Agonists, Quinolones, Transfection, Research Papers, Hippocampus, Receptors, Muscarinic, Permeability, Recombinant Proteins, Rats, Rats, Sprague-Dawley, Cricetulus, Piperidines, Cricetinae, Animals, Humans, Calcium Signaling, Injections, Intraperitoneal
Abstract

M1 muscarinic ACh receptors (mAChRs) represent an attractive drug target for the treatment of cognitive deficits associated with diseases such as Alzheimer's disease and schizophrenia. However, the discovery of subtype-selective mAChR agonists has been hampered by the high degree of conservation of the orthosteric ACh-binding site among mAChR subtypes. The advent of functional screening assays has enabled the identification of agonists such as AC-42 (4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine), which bind to an allosteric site and selectively activate the M(1) mAChR subtype. However, studies with this compound have been limited to recombinantly expressed mAChRs.In this study, we have compared the pharmacological profile of AC-42 and a close structural analogue, 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone) at human recombinant, and rat native, mAChRs by calcium mobilization, inositol phosphate accumulation and both in vitro and in vivo electrophysiology.Calcium mobilization and inositol phosphate accumulation assays revealed that both AC-42 and 77-LH-28-1 display high selectivity to activate the M1 mAChR over other mAChR subtypes. Furthermore, 77-LH-28-1, but not AC-42, acted as an agonist at rat hippocampal M1 receptors, as demonstrated by its ability to increase cell firing and initiate gamma frequency network oscillations. Finally, 77-LH-28-1 stimulated cell firing in the rat hippocampus in vivo following subcutaneous administration.These data suggest that 77-LH-28-1 is a potent, selective, bioavailable and brain-penetrant agonist at the M1 mAChR and therefore that it represents a better tool than AC-42, with which to study the pharmacology of the M1 mAChR.

Published
2008

3. Activation of 5-HT1B and 5-HT1D receptors in the rat nucleus tractus solitarius: opposing action on neurones that receive an excitatory vagal C-fibre afferent input

Author

Jeggo, R D, Wang, Y, Jordan, D, and Ramage, A G

Subjects
Male, Patch-Clamp Techniques, Time Factors, Pyridines, Action Potentials, Rats, Sprague-Dawley, Solitary Nucleus, Animals, Pyrroles, Neurons, Afferent, Neurons, Sumatriptan, Drug Synergism, Neural Inhibition, Vagus Nerve, Iontophoresis, Serotonin 5-HT1 Receptor Agonists, Research Papers, Electric Stimulation, Rats, Serotonin Receptor Agonists, Receptor, Serotonin, 5-HT1D, Benzamides, Receptor, Serotonin, 5-HT1B, Ketanserin, Serotonin Antagonists
Abstract

Central 5-HT-containing pathways are known to be important in cardiovascular regulation and a crucial area for this regulation is the nucleus tractus solitarius (NTS), which contains many of the known 5-HT receptor subtypes. In this study the role of 5-HT(1B) and 5-HT(1D) receptors, targets for the antimigraine drugs known collectively as triptans, was examined in the NTS. EXPERIMENT APPROACH: Extracellular recordings were made, in anaesthetized rats, from 109 NTS neurones that were excited by electrical stimulation of the vagus and drugs were applied ionophoretically to these neurones.The 5-HT(1B/1D) receptor agonist sumatriptan applied to 64 neurones produced a 64% reduction in the firing rate of 54 of these neurones. Ketanserin, a 5-HT(1D/2A) receptor antagonist, alone had little effect, but co-applied with sumatriptan significantly attenuated this inhibition, whilst co-application of the 5-HT(1B) receptor antagonist GR55562 resulted in potentiation of this inhibition. Sumatriptan also caused a 25% reduction in vagal afferent evoked activity as well as that caused by stimulation of cardiopulmonary afferents. In another 41 neurones the 5-HT(1B) receptor agonist CP-93 129 produced a doubling of the background firing rate in 31 of these neurones and a significant increase in both vagal afferent evoked activity and that evoked by cardiopulmonary afferent activation.Activation of 5-HT(1B) and 5-HT(1D) receptors have opposing actions on NTS neurones of excitation and inhibition, respectively. As both receptors are negatively coupled to adenylate cyclase this would indicate that they have different anatomical locations within NTS.

Published
2007

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