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Summary: It has been shown in vitro that dihydrolipoate (DL-6,8-dithioloctanoic acid) has antioxidant activity against microsomal lipid peroxidation. We tested dihy drolipoate for its neuroprotective activity using models of hypoxic and excitotoxic neuronal damage in vitro and rodent models of cerebral ischemia in vivo. In vitro, neu ronal damage was induced in primary neuronal cultures derived form 7-day-old chick embryo telencephalon by adding either 1 mM cyanide or I mM glutamate to the cultures. Cyanide-exposed and dihydrolipoate-treated (10-9_10-7 M) cultures showed an increased protein and ATP content compared with controls. The glutamate exposed cultures treated with dihydrolipoate (10 -7_10 -5 M) showed a decreased number of damaged neurons. In vivo, dihydrolipoate treatment (50 and 100 mg/kg) reThere is evidence that in the course of cerebral ischemia, reactive oxygen species accumulate within the brain tissue (Flamm et aI., 1978; Rehn crona et aI., 1982; Yoshida et aI., 1982; Kirsch et aI., 1987; Bromont et aI., 1989; Oliver et aI. , 1990). Lipid peroxidation as well as oxidation of proteins and nucleic acids are supposed to contribute to the neuronal injury after cerebral ischemia (Hall and Braughler, 1989; Siesjo et aI., 1989). The rise of reactive oxygen species within the cerebral tissue may be prevented by agents that have antioxidant activity. Indeed, various antioxidants have been shown to reduce neuronal injury after cerebral isch emia (Yamamoto et aI., 1983; Berry et aI., 1987; Abe et aI., 1988; Patt et aI., 1988 78 duced brain infarction after permanent middle cerebral artery occlusion in mice and rats. Dihydrolipoate treat ment (50 and 100 mg/kg) could not ameliorate neuronal damage in the rat hippocampus or cortex caused by 10 min of forebrain ischemia. A comparable neuroprotection was obtained by using dimethylthiourea, both in vitro (10-7 and 10-6 M) and at a dose of 750 mg/kg in the focal ischemia models. Lipoate, the oxidized form of dihydro lipoate, failed to reduce neuronal injury in any model tested. We conclude that dihydrolipoate, similarly to di methylthiourea, is able to protect neurons against isch emic damage by diminishing the accumulation of reactive oxygen species within the cerebral tissue.

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The purpose of the present study was to investigate the neuroprotective action of nimodipine. Furthermore, the influence of nimodipine on postischemic local CBF (LCBF) was examined. Forebrain ischemia of the rat was performed for 10 min by bilateral carotid clamping, administration of trimethaphan, and blood withdrawal to obtain an MABP of 40 mm Hg. LCBF was measured after 10 min of postischemic recirculation by injecting [14C]iodoantipyrine in saline solution. Nimodipine (0.1, 0.3, and 1.0 mg/kg) was suspended in miglyol oil and applied orally 60 min prior to ischemia. Histological evaluation was performed 7 days after ischemia. Hippocampal neuronal damage was determined as the percentage of necrotic neurons. After preischemic application of nimodipine, neuronal damage was significantly reduced in the hippocampal CA1 subfield. Postischemic LCBF was not affected by treatment with nimodipine. These findings show that nimodipine is able to protect neurons against ischemic damage. The neuroprotective effect of nimodipine was not mediated by a postischemic cerebral vasodilation, but by a direct action on the neurons.