Elektrophysiologische Untersuchungen zu Einflüssen von ionotropen Glutamatantagonisten sowie 5-HT1A-Agonisten auf die Kaliumchlorid-induzierte "spreading depression" im neokortikalen Hirnschnittpräparat der adulten Ratte

Spreading Depression (SD) induced Neocortical Hyperexcitability and Pharmacology of SD in vitro Repetitive cortical spreading depression (SD) and SD-like events, associated with a massive depolarization of neuronal and glial cells, is thought to play a key role in the induction of neuronal damage in the peri-infarct zone following experimental focal cerebral ischemia. In addition, experimental and clinical data suggest that SD is the underlying mechanism of neurological disturbances during migraine auras as well. However, detailed analyses on the consequences of repetitive SDs on cortical function and involved receptors are lacking. Using an in vitro rat model of SD I investigated in this thesis the electrophysiological properties of repetitive potassium chloride (KCl)-induced SDs, their influence on synaptic neurotransmission and the effects of ionotropic glutamate antagonists and 5-HT1A agonists in neocortical slices obtained from adult rats. Whereas repetitive SDs revealed only non-significant variations in duration, amplitude and integral when elicited at intervals of 30 min, paired-pulse inhibition of extracellularly recorded field potential responses was significantly affected by repetitive SD even under normoxic conditions. Compared to the control recordings, each SD episode caused a significant decrease in the efficacy of intracortical GABAergic inhibition by approximately 10%. Since excitatory synaptic transmission was unaffected, these data indicate that repetitive SDs cause a selective suppression of GABAergic function even in the non-ischemic brain. None of the compounds tested prevented the SD-induced cortical disinhibition. However, the SDassociated negative shift in the extracellular DC potential was reduced by ketamine, a selective N-methyl-D-aspartic acid (NMDA-) receptor antagonist. Ketamine significantly (p < 0.01) reduced the amplitude of the first SD peak and blocked the second SD peak. Ketamine also decreased the SD duration at half maximal amplitude (p < 0.05). NBQX, a selective α-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist did not affect the SDaccompanied cortical depolarization, whereas selective 5-hydroxytryptamine (5-HT)1A receptor agonists 8-OH-DPAT and BAY x 3702 shortened concentration-dependently the duration of the SD up to 50 %. Nevertheless, both 5-HT1A receptor agonists caused a strong disinhibition of neuronal function with a tendency towards paired-pulse facilitation as well. Thus, repetitive SD and SD-like events may induce neuronal hyperexcitability due to a selective suppression of intrinsic inhibitory GABAergic function. Under normoxic conditions, SD-induced disinhibition may be involved in the generation and maintenance of migraine or associated neurological disturbances. Under hypoxic-ischemic conditions, neuronal hyperexcitability may contribute to the gradual expansion of the ischemic core and the metabolic deterioration of the penumbral tissue after SD episodes. This underlines the deleterious effect of SD to the outcome of focal cerebral ischemia. Although the precise mechanisms of SD generation and propagation remains far from established, the present pharmacological profile of KCl-induced SD in vitro links the induction and propagation of SD in rat neocortical slices mainly to a local increase of [K]e and a subsequent activation of NMDAreceptors. This corroborates the neuroprotective effect of a NMDAreceptor blockade observed in various in vitro and in vivo models. However, as it has been demonstrated in clinical trials, NMDAreceptor antagonists in use today cause psychomimetic and cardiovascular side effects in humans and are therefore currently of low clinical benefit. The activation of 5-HT1A receptors by selective agonists represents a new pharmacological strategy in the treatment of acute ischemic stroke, since shortened SD waves may represent a less energy-consuming process under conditions of limited energy supply and are probably associated with an efflux of excitatory neurotransmitters to a lesser extent. The potential clinical benefit of 5-HT1A receptor agonists remains to be investigated in clinical trials, since systemic administration of these compounds after the onset of acute focal cerebral ischemia might interfere with normal functions of glutamatergic neurotransmission in the intact, non-ischemic brain.