Status Epilepticus — the Role of Cholinergic Mechanisms

Proceedings of the 9th International Multidisciplinary Conference «Stress and Behavior» Saint-Petersburg, Russia, 16–19 May 2005.Epilepsy is the result of highly complex structural, biochemical, electrophysiological changes these occur at various level not only within the brain but also in the entire body. Status epilepticus (SE) is the most dangerous increasing of pathological activity of brain leading to loss of the consciousness and failure of all regulations of vital functions on the border of survival. After investigation by W.A. Turski (1983) and E.A. Cavalherio (1991, 1995) this model of SE is reminiscent of that human temporal lobe epilepsies which often begins thith prolonged SE in infancy and develops with recurrent seizures in later life. Li-pilcarpine model is a model of partial limbic seizures that progress to secondary generalized SE. The epileptogenic effect of cholinergic agents depend on the fascilitation of burst discharges in hippocampal pyramidal neurons by means a block of the K+ transmembrane current. Super-activation of neurons of hippocamp during pilocarpine-induced SE leads to cell death. Seizures-related excitoxicity involves glutamate receptors and Ca2+ influx. (Avanzini, Fariello, 1997). The EEG is helpful in further dividing SE into those that are generalized from onset, or have a partial onset. The investigation of thresholds and time of SE duration in Li-pilocarpine model has to deal not only with blockade of muscarinic (M1-M5) cholinergic receptors but also with the general problem of GABAA receptors desensitization. The aims of our study were: 1) to compare the special feature of LiCl-pilocarpine SE in the Wistar rats and Guinea pigs; 2) to evaluate the correlation between neocortex EEG patterns of brain and behavioral manifestation of fits (videorecord); 3) the investigation of condition of developing chronical epilepsy. The lithium-pilcarpine model was studied in vivo in guinea pig and rat (adult and pups). The animals were operated (deep farmotal narcosis) and chronicle silver electrodes implanted in cortex and hippocamp using the atlases of rat brain (Fifkova, Marshall, 1962) and Guinea pig brain (Rapisarda, Bacchelli, 1977). Protocol in rats (P.Mares, H.Kubova, 1964): 1 day before rat were injected an aqueous solution of LiCl (3mmol/kg i.p. Acros’) and 24 h later pilocarpine HCl (40 mg/kg i.p. Acros) made in saline, experimental SE was stopped by paraldehyde (0.6 mg/kg). Protocol in Guinea pigs (M.de Curtis): 1 day before Guinea pigs were injected an aqueous solution of LiCl (127 mg/kg, i.p.) and 24 h later scopolamine 1 mg/kg, pilocarpine HCl (55 or 100 mg/kg i.p.) made in saline, experimental SE was stopped by diazepam (10 mg/kg). PTZ (Sigma) injected i.p. by a modified method (25 mg/kg x 3) or bolus injection of 100 mg/kg. Control registration of basic EEG was performed during interictal periods for evaluation of chronic epileptogenesis. Motor seizures evaluated with presently accepted scale of motor convulsions in rats. The guinea pigs as shown are more sensitive to epileptogenes. The survival of animals after SE was the main problem of developing of chronicle epilepsy. Immediately blocking of SE by diazepam is required after clonic-tonic stage. These animals could be save during long tiome after several SE and for the further analysis of brain damage by MRI. In rats the character of epileptics seizures in developing brain and adult brain of rats were investigated. The lines of modulation and inhibition epileptics statues by sacricine and intranasal application of neuropeptide thyroliberin in ultra-low doses are demonstrated. The short-term changes (signal regulated kinase signaling cascade, Kv4.2potassium channels) and the long-term changes (loss of selective type of interneurons, excitatory circuits by mossy fiber sprouting) that promotion the epileptic state and recurrent seizures in limbic structure are connected with cholinergic mechanisms. The study was supported by Cariplo Foundation, Landau Network — Centro Volta, Italy