inositol-1-4-5-trisphosphate and Seizures

Acetylcholine (ACh) is a powerful excitatory neurotransmitter in the brain. Stimulation of brain cholinergic muscarinic receptors (mAChR) cause persistent tonic-clonic convulsions. mAChRs are coupled to G-protein which mediates the receptor stimulation to phospholipidase C (PLC). PLC hydrolyses phosphatidylinositol-4,5-bisphosphate (PI), a membrane phospholipid, into two second messengers, inositol-1,4,5-trisphosphate (Ins(1,4,5)P3), and diacylglycerol (DAG). Both messengers cause neuronal stimulation and when in excess, may contribute to neuronal injury. Indirect cholinergic agonists organophosphates (OPs) such as soman, paraoxon, and malaoxon, and direct cholinergic agonists, such as pilocarpine, are powerful convulsants. They stimulate brain mAChR-coupled to PI signalling as indicated by decreased brain inositol and increased brain inositol monophosphates, metabolites in PI turnover, and indirectly reflect the activity of the brain PI system. In rats, during cholinergic convulsions, brain inositol decreases, and inositol monophosphates increase prior to and during convulsions. Persistent convulsions cause neuronal injury especially in the hippocampus and cortex, and associated increase in brain Ca2+. The mechanisms of convulsions and associated neuronal have remained open, but both in vitro and in vivo data provide evidence that facilitated PI signalling and increases in free intracellular Ca2+ may have an important role in these events. Age and female sex amplify the effects of cholinergic brain stimulation and convulsions.

Topics: Animals; Brain Diseases; Calcium; Diglycerides; Female; GTP-Binding Proteins; Humans; Inositol 1,4,5-Trisphosphate; Lithium; Male; Receptors, Cholinergic; Second Messenger Systems; Seizures; Sex Factors

To elucidate the role of the large conductance calcium-activated potassium channel (BK(Ca) channel) in the production of bursting activity, which is characteristic of convulsions, effects of iberiotoxin (IbTX), a selective blocker of the BK(Ca) channel, on bursting activity, induced by various procedures were examined using primary cultured neurons from the cerebral cortex of mice. IbTX completely inhibited bursting activity induced by pentylenetetrazol (PTZ), caffeine, 1,4,5-inositol triphosphate (IP3) and direct forced increase of intracellular calcium. Inherent spontaneous bursting activity in the cerebral cortical neurons of the El mouse, which shows a high susceptibility to convulsions was also completely inhibited by IbTX. Apamin, a specific blocker of the small conductance calcium-activated potassium channel (SK(Ca) channel) showed no inhibition of bursting activity. These findings suggest that the BK(Ca) channel is essential for the production of bursting activity, and also suggest the possibility of clinical use of blocking agents of the BK(Ca) channel against intractable epilepsy.

Topics: Action Potentials; Animals; Apamin; Caffeine; Calcium; Cells, Cultured; Cerebral Cortex; Epilepsy; Inositol 1,4,5-Trisphosphate; Ion Transport; Large-Conductance Calcium-Activated Potassium Channels; Mice; Mice, Neurologic Mutants; Patch-Clamp Techniques; Pentylenetetrazole; Peptides; Potassium Channels; Potassium Channels, Calcium-Activated; Seizures

Previous investigations have indicated that soman-induced convulsions involve the inositol lipid signalling system. We previously reported that 10 min after the onset of seizures, inositol 1,4,5-triphosphate (IP3) build-up was coupled to activation of non-muscarinic receptor subtypes. In the present study, we demonstrate that (1) in addition to muscarinic receptors, histamine H1 subtypes and glutamate metabotropic receptors contribute to the first IP3 increase (first 10 min of seizures) and (2) the histamine H1 subtype and glutamate metabotropic receptors are also involved in the second step of inositol phosphate response (after 10 min of seizures). alpha 1-adrenoceptor and 5-HT2 receptors, known to be coupled to phosphoinositide turnover, did not participate in soman-induced IP3 response. Neurochemical interactions between cholinergic, histamine H1 and glutamate metabotropic systems, responsible of the phosphoinositide hydrolysis under soman are envisaged.

Topics: Animals; Chlorpheniramine; Dimethyl Sulfoxide; Electroencephalography; Inositol 1,4,5-Trisphosphate; Ketanserin; Male; Prazosin; Rats; Rats, Wistar; Receptors, Muscarinic; Seizures; Signal Transduction; Soman

The mechanism of action of lithium, the primary treatment for bipolar affective disorder, is unknown but may involve inhibition of second messenger production in the brain. Therefore, the concentrations of three second messengers, inositol 1,4,5 trisphosphate (Ins 1,4,5P3), cyclic adenosine monophosphate (AMP), and cyclic guanosine monophosphate (GMP), were measured in rat cerebral cortex and hippocampus after acute or chronic lithium administration, as well as after treatment with the cholinergic agonist pilocarpine alone or in combination with lithium at a dose that induces seizures only in lithium pretreated rats. Neither acute nor chronic lithium treatment altered the hippocampal or cortical concentration of Ins 1,4,5P3, cyclic AMP, or cyclic GMP. Pilocarpine administered alone increased Ins 1,4,5P3 in both regions, did not alter cyclic AMP, and slightly increased cyclic GMP in the cortex. Coadministration of lithium plus pilocarpine caused large increases in the concentrations of all three second messengers and the production of each of them was uniquely attenuated: lithium reduced pilocarpine-induced increases of Ins 1,4,5P3 in the cortex at 60 min; chronic lithium administration reduced stimulated cyclic AMP production in the hippocampus; and chronic lithium treatment impaired stimulated cyclic GMP production in both regions. In summary, chronic lithium treatment appeared only to reduce Ins 1,4,5P3 and cyclic AMP concentrations after a long period of stimulation whereas cyclic GMP production was reduced by chronic lithium administration after both short and long periods of stimulation. Thus cyclic GMP was most sensitive to lithium and lithium attenuation of second messenger formation may be most important in excessively activated pathways.

Topics: Animals; Brain Mapping; Cerebral Cortex; Chlorides; Cyclic AMP; Cyclic GMP; Dose-Response Relationship, Drug; Hippocampus; Inositol 1,4,5-Trisphosphate; Lithium; Lithium Chloride; Male; Pilocarpine; Radioligand Assay; Rats; Rats, Inbred Strains; Seizures