Partielle Resistenz Chorea Huntington transgener Mäuse gegen globale cerebrale Ischämie

Abstract

Excitotoxicity plays a keyrole in acute ischemic neuronal death as well as neurodegenerative diseases such as Huntington's disease (HD). Surprisingly it has been found that HD transgenic mice are resistant to intrastriatal injections of excitotoxic substances. We investigated whether HD transgenic mice are also resistant to global cerebral ischemia, installed by temporary bilateral occlusion of the common carotid arteries. Since the neurons of the hippocampus are known to show the lowest ischemic tolerances we especially investigated these neurons. We found out that HD transgenic mice are partially resistant to a global cerebral ischemia of 15 and 20 minutes duration. After 60 minutes of global cerebral ischemia, no substantial difference between transgenic mice and wildtype littermates could be seen. Neuronal tolerance can be experimentally induced by so-called "preconditioning", where a short-term ischemia triggers the overexpression of neuroprotective proteins, e.g. Heat-shock-proteins, which then induce a tolerance against a second hypoxemia. In our model, ischemic tolerance was not blocked by pre-treatment of mice with cycloheximide, an unspecific protein synthesis inhibitor. We therefore conclude that there must be a different mechanism - independent of the short term expression of endogenous neuroprotective proteins. This mechanism is so far unknown. Our results show that an increased tolerance does not only exist in the striatum of transgenic mice, but also in the hippocampus and that this tolerance also includes ischemic stimuli