Comparison of ketamine stereoisomers on tissue metabolic activity in an invitro model of global cerebral ischaemia

Ketamine (2-o-chlorophenenyl-2-methylaminocyclohexanone hydrochloride) is a dissociative general anaesthetic with neuroprotective properties. Since ke tamine is optically active, we compared the neuroprotective efficacy of the (+)- or (-)-enantiomers in global cerebral ischaemia. Rat corticostriatal slices superfused with, or incubated in, artificial CSF at 34 degreesC were subjected to a brief ischaemic insult. Dopamine efflux was measured using fast cyclic voltammetry. Tissue metabolism was determined with 2,3,5-triphe nyltetrazolium chloride staining, a marker of mitochondrial enzyme activity . In control slices, ischaemia caused rapid striatal dopamine release (to 1 22 muM over 18 s) after an initial delay of 149s. Racemic ketamine (100 mu mol/l) significantly delayed (by 24%, P < 0.05), slowed (by 63%, P < 0.01) and reduced (by 27%, P < 0.05) ischaemia-induced dopamine release. Ischaemi a (10 min) also caused significant decreases in striatal (25%, P < 0.01) an d cortical (31%, P < 0.001) metabolic activity, manifested as a drop in mea n TTC staining intensity. Racemic ketamine and its (+)- and (-)-enantiomers teach 100 <mu>M) attenuated the loss of metabolic activity in the striatum . However, in the cortex, only (+)-ketamine (100 muM) was significantly neu roprotective. We conclude that neuroprotection by ketamine in cerebral isch aemia is both region- and isomer-dependent. (C) 2001 Elsevier Science Ltd. All rights reserved.