ISSN:
1471-4159
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
Abstract: Excitotoxicity and defects in neuronal energy metabolism have both been implicated in the pathogenesis of neurode-generative disease. These two mechanisms may be linked through the NMDA receptor, activation of which is dependent on neuronal membrane potential. Because the ability to maintain membrane potential is dependent on neuronal energy metabolism, bioenergetic defects may affect NMDA receptor-mediated excitotoxicity. We now report that reversible inhibition of succinate dehydrogenase (SDH), an enzyme central to both the tricarboxylic acid cycle and the electron transport chain, produces an “excitotoxic” lesion in rat striatum that can be blocked by the NMDA antagonist MK-801. Male Sprague-Dawley rats received intrastriatal stereotaxic injections of the SDH inhibitor malonic acid (1 or 2 μmol) in combination with intraperitoneal injections of vehicle or MK-801 (5 mg/kg) 30 min before and 210 min after malonic acid. Animals were killed 72 h after surgery, and brains were processed for histology, cytochrome oxidase activity, and [3H]MK-801 and [3H]AMPA autoradiography. The higher dose of malonic acid (2 μmol) produced large lesions that were markedly attenuated by treatment with MK-801 (28.1 ± 3.6 vs. 4.7 ± 2.6 mm3; p 〈 0.001). [3H]MK-801 and [3H]AMPA binding were reduced in the lesions by 60 and 63%, respectively. One micromole of malonic acid produced smaller lesions that were almost completely blocked by MK-801 treatment (9.6 ± 1.3 vs. 0.06 ± 0.04 mm3; p 〈 0.0001). The toxic effects of malonic acid were due specifically to inhibition of SDH inasmuch as co injection of a threefold excess of sgccinate with the malonic acid blocked the striatal lesions (p 〈 0.002). We conclude that inhibition of SDH can lead to NMDA receptor-mediated excitotoxic neuronal death. These results have implications for the pathogenesis of and therapy for neurodegenerative diseases.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1111/j.1471-4159.1993.tb03634.x
