Pentylenetetrazol-kindling in mice overexpressing heat shock protein 70.
Journal - Naunyn-Schmiedeberg's archives of pharmacology (Germany )
Kindling induced by the convulsant pentylenetetrazol (PTZ) is an accepted model of primary generalized epilepsy. Because seizures represent a strong distressing stimulus, stress-induced proteins such as heat shock proteins might counteract the pathology of increased neuronal excitation. Therefore, the aim of the present study was to determine whether PTZ kindling outcome parameters are influenced by heat shock protein 70 (Hsp70) overexpression in Hsp70 transgenic mice as compared to the respective wild-type mice. Kindling was performed by nine intraperitoneal injections of PTZ (ED(16) for induction of clonic-tonic seizures, every 48 h); control animals received saline instead of PTZ. Seven days after the final injection, all mice received a PTZ challenge dose. Outcome parameters included evaluation of seizure stages and overall survival rates. In addition, histopathological findings such as cell number in hippocampal subfields CA1 and CA3 were determined. The onset of the highest convulsion stage was delayed in Hsp70 transgenic mice as compared to wild-type mice, and overall survival during kindling was improved in Hsp70 transgenic mice as compared to wild-type mice. In addition, a challenge dose after termination of kindling produced less severe seizures in Hsp70 transgenic mice than in wild-type mice. PTZ kindling did not result in significant subsequent neuronal cell loss in CA1 or CA3 neither in wild-type mice nor in the Hsp70 transgenic mice. The results of the present experiments clearly demonstrate that overexpression of Hsp70 exerts protective effects regarding seizure severity and overall survival during PTZ kindling. In addition, the decreased seizure severity in Hsp70 transgenic mice after a challenge dose suggests an interference of Hsp70 with the developmental component of kindling.
|ISSN : ||0028-1298|
|Mesh Heading : ||Animals Convulsants Disease Models, Animal Dose-Response Relationship, Drug HSP70 Heat-Shock Proteins Hippocampus Injections, Intraperitoneal Kindling, Neurologic Male Mice Mice, Inbred C57BL Mice, Inbred CBA Mice, Transgenic Pentylenetetrazole Seizures administration & dosage toxicity genetics drug effects metabolism physiology administration & dosage chemically induced physiopathology|
|Mesh Heading Relevant : ||physiology drug effects toxicity|
Differential effects of mu-opioid receptor agonists in a hippocampal hypoxia/hypoglycemia model.
Journal - Brain research (Netherlands )
BACKGROUND: In rat hippocampal slices, a short hypoxia/hypoglycemia causes immediate loss of evoked potentials (population spike amplitude) in the CA1 region and the extent of electrophysiological restoration during reperfusion can serve as a parameter for cell function. Previous experiments using this model revealed that exposure to morphine aggravates the neurotoxic effects of a subsequent hypoxia/hypoglycemia in a concentration-dependent manner. Therefore, the aim of the present study was to evaluate the effects of additional mu-opioid receptor (MOPr) agonists on the electrophysiological restoration after hypoxia/hypoglycemia. METHODS: Rat hippocampal slices were exposed to either morphine (10 microM), pethidine (10 microM), fentanyl (100 nM/1 microM) or to the synthetic peptide [d-Ala2, N-Me-Phe4, Glycinol5]-enkephalin (DAMGO, 10 microM) for 60 min; thereafter, slices underwent a brief hypoxic/hypoglycemic episode followed by reperfusion (drug-free) for 2.5 h. Electrophysiological recording consisted of determination of population spike amplitude in CA1 in response to constant stimulation of Schäffer's collaterals. RESULTS: Exposure to morphine prior to hypoxia/hypoglycemia resulted in a significantly impaired electrophysiological recovery during reperfusion when compared to controls. Following exposure to pethidine, the electrophysiological recovery was slightly reduced, whereas fentanyl or DAMGO did not affect restoration of population spike amplitude during reperfusion. CONCLUSIONS: The results of the present study demonstrate that different MOPr agonists differentially influence the electrophysiological recovery of hippocampal slices following a brief hypoxia/hypoglycemia. It is speculated that known receptor-internalizing opioids such as fentanyl or DAMGO may have less neurotoxic effect in hypoxia/hypoglycemia than the non-internalizing drug morphine.
|ISSN : ||0006-8993|
|Mesh Heading : ||Analgesics, Opioid Animals Data Interpretation, Statistical Electrophysiology Enkephalin, Ala(2)-MePhe(4)-Gly(5)- Evoked Potentials Fentanyl Hippocampus Hypoglycemia Hypoxia, Brain Male Meperidine Rats Rats, Wistar Receptors, Opioid, mu Reperfusion Injury pharmacology pharmacology drug effects physiology pharmacology drug effects pharmacology physiopathology|
|Mesh Heading Relevant : ||physiopathology physiopathology physiopathology agonists|