Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
Add more filters










Database
Language
Publication year range
1.
Brain Res ; 1458: 67-75, 2012 Jun 06.
Article in English | MEDLINE | ID: mdl-22552114

ABSTRACT

Neuronal cholinergic transmission is a prerequisite for proper CNS function. Consequently, disturbance of this system is associated with a number of pathophysiological conditions such as Parkinson's disease, Alzheimer's disease, schizophrenia and ADHD. Consequently, drug discovery efforts have spurred considerable research endeavours into identifying specific compounds for this system. Nicotinic acetylcholine receptors (nAChR) are ligand gated ion channels involved in cholinergic transmission. nAChRs are homo- or heteromeric pentamers with α4ß2 receptors being the most abundant heteromer. The stoichiometry of α4ß2 receptors can be either (α4)(3)(ß2)(2) or (α4)(2)(ß2)(3) representing channels with low (LS) or high (HS) sensitivity, respectively, to endogenous ligands. In the present study we applied the partial nAChR α4ß2 LS and HS agonist NS3956 and the LS selective positive allosteric modulator NS9283 to investigate the role of α4ß2 in Parkinson and pain models. In 6-OHDA lesioned rats, NS3956 increased rotational behaviour when rats were co-treated with nomifensine. This effect was absent in the presence of mecamylamine. In contrast, co-treatment with NS3956 and NS9283 reduced rotational behaviour in the animals. In a rat formalin pain model NS3956 induced an analgesic response that was strongly potentiated by NS9283. Finally in vitro experiments were applied to determine dopamine release from striatal minces. NS3956 induced a concentration dependent release while NS9283 was unable to potentiate agonist induced release. Together these results emphasize involvement of α4ß2 nAChR in rotational and analgesic responses and confirm striatal α4ß2 receptors to be of the HS form.


Subject(s)
Nicotinic Agonists/pharmacology , Pain/physiopathology , Parkinsonian Disorders/physiopathology , Receptors, Nicotinic/physiology , Allosteric Regulation/drug effects , Allosteric Regulation/physiology , Animals , Azepines/pharmacology , Corpus Striatum/drug effects , Corpus Striatum/physiology , Female , Male , Oxadiazoles/pharmacology , Oxidopamine/toxicity , Pain/chemically induced , Pain Measurement/drug effects , Pain Measurement/methods , Parkinsonian Disorders/chemically induced , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Rats, Wistar , Rotation
2.
J Pharmacol Exp Ther ; 328(1): 28-39, 2009 Jan.
Article in English | MEDLINE | ID: mdl-18820135

ABSTRACT

Calcium-activated potassium channels are attractive targets for the development of therapeutics for overactive bladder. In the current study, we addressed the role of calcium-activated potassium channels of small (SK; K(Ca)2) and intermediate (IK; K(Ca)3) conductance in bladder function pharmacologically. We identified and characterized a novel positive modulator of SK/IK channels, 4,5-dichloro-1,3-diethyl-1,3-dihydro-benzoimidazol-2-one (NS4591). In whole-cell patch-clamp experiments, NS4591 doubled IK-mediated currents at a concentration of 45 +/- 6 nM(n = 16), whereas 530 +/- 100 nM (n = 7) was required for doubling of SK3-mediated currents. In acutely dissociated bladder primary afferent neurons, the presence of SK channels was verified using apamin and 1-ethyl-2-benzimidazolinone. In these neurons, NS4591 (10 microM) inhibited the number of action potentials generated by suprathreshold depolarizing pulses. NS4591 also reduced carbachol-induced twitches in rat bladder detrusor rings in an apamin-sensitive manner. In vivo, NS4591 (30 mg/kg) inhibited bladder overactivity in rats and cats induced by capsaicin and acetic acid, respectively. In conclusion, the present study supports the involvement of calcium-activated potassium channels in bladder function and identifies NS4591 as a potent modulator of IK and SK channels that is effective in animal models of bladder overactivity.


Subject(s)
Afferent Pathways/drug effects , Benzimidazoles/pharmacology , Chloride Channels/physiology , Neurons/physiology , Small-Conductance Calcium-Activated Potassium Channels/physiology , Urinary Bladder/innervation , Urinary Bladder/physiology , Action Potentials/drug effects , Action Potentials/physiology , Animals , Calcium Chloride/pharmacology , Cell Line , Cell Membrane/drug effects , Cell Membrane/physiology , Chloride Channels/drug effects , Female , Ganglia, Spinal/drug effects , Ganglia, Spinal/physiology , Humans , Kidney , Magnesium Chloride/pharmacology , Neurons/drug effects , Potassium/pharmacology , Potassium Channels/drug effects , Potassium Channels/physiology , Rats , Rats, Sprague-Dawley , Small-Conductance Calcium-Activated Potassium Channels/drug effects , Urinary Bladder/drug effects , Urination/drug effects , Urination/physiology
3.
Neuroscience ; 158(1): 344-52, 2009 Jan 12.
Article in English | MEDLINE | ID: mdl-18616988

ABSTRACT

The stimulation of extrasynaptic N-methyl-D-aspartate (NMDA) receptors triggers cell death pathways and has been suggested to play a key role in cell degeneration and neuron loss associated with glutamate-induced excitotoxicity. In contrast, synaptic NMDA receptors promote neuronal survival. One mechanism through which extrasynaptic NMDA receptors damage neurons may involve Clca1, which encodes a putative calcium-activated chloride channel. Here we show that Clca1 expression is induced in cultured rat hippocampal neurons exposed to oxygen/glucose-free media; this induction is mediated by a signaling pathway activated by extrasynaptic NMDA receptors. Clca1 mRNA levels also increased in the gerbil hippocampus following a transient forebrain ischemia caused by bilateral carotid occlusion. Microelectrode array recordings revealed that oxygen-glucose deprivation enhances hippocampal network firing rates, which induces c-fos transcription through a signaling pathway that, in contrast to Clca1, is activated by synaptic but not extrasynaptic NMDA receptors. Thus, conditions of low oxygen/glucose lead to the activation of both extrasynaptic and synaptic NMDA receptors that regulate distinct target genes. Clca1 may be part of the genomic death program triggered by extrasynaptic NMDA receptors; it could be a marker for ischemic brain damage and a possible target for therapeutic interventions.


Subject(s)
Chloride Channels/metabolism , Hippocampus/metabolism , Hypoxia-Ischemia, Brain/metabolism , Neurons/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Action Potentials/physiology , Animals , Biomarkers/metabolism , Cells, Cultured , Chloride Channels/genetics , Gene Expression Regulation/genetics , Gerbillinae , Hippocampus/physiopathology , Hypoxia-Ischemia, Brain/genetics , Hypoxia-Ischemia, Brain/physiopathology , Male , Mice , Mice, Inbred C57BL , Nerve Degeneration/genetics , Nerve Degeneration/metabolism , Nerve Degeneration/physiopathology , Nerve Net/metabolism , Nerve Net/physiopathology , Proto-Oncogene Proteins c-fos/metabolism , RNA, Messenger/metabolism , Synapses/metabolism , Synaptic Transmission/physiology
4.
Brain Res ; 1064(1-2): 161-5, 2005 Dec 07.
Article in English | MEDLINE | ID: mdl-16309632

ABSTRACT

The temporal profile of Arc gene expression after acute and chronic electroconvulsive stimulations (ECS) was studied using semi-quantitative in situ hybridisation in the rat cortex. A single ECS strongly and temporarily increased Arc mRNA levels in dentate granular cells with maximal induction seen up to 4 h after the stimulus, but returned to baseline at 24 h. A single ECS also increased expression of Arc mRNA in the CA1 and the parietal cortex, but the expression peaked within 1 h and returned to baseline levels within 2 h. Repeated or chronic ECS is a model of electroconvulsive therapy and it would be predicted that gene products involved in antidepressant effects accumulate after repeated ECS. However, repeated ECS reduced Arc gene expression in the CA1 24 h after the last stimulus. These results indicate that Arc is an immediate early gene product regulated by an acute excitatory stimulus, but not accumulated by long term repetitive ECS and therefore not a molecular biomarker for antidepressant properties. More likely, Arc is likely a molecular link to the decline in memory consolidation seen in depressive patients subjected to electroconvulsive therapy.


Subject(s)
Cerebral Cortex/metabolism , Cytoskeletal Proteins/metabolism , Electroshock , Nerve Tissue Proteins/metabolism , Parietal Lobe/metabolism , RNA, Messenger/metabolism , Animals , Cytoskeletal Proteins/genetics , Depressive Disorder/metabolism , Depressive Disorder/therapy , Disease Models, Animal , Electroconvulsive Therapy , Gene Expression Regulation/physiology , Hippocampus/metabolism , Male , Memory/physiology , Nerve Tissue Proteins/genetics , Rats , Rats, Sprague-Dawley
SELECTION OF CITATIONS
SEARCH DETAIL
...