Comparison of ketamine stereoisomers on tissue metabolic activity in an in vitro model of global cerebral ischaemia.
Ketamine (2-o-chlorophenenyl-2-methylaminocyclohexanone hydrochloride) is a dissociative general anaesthetic with neuroprotective properties. Since ketamine 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 degrees C were subjected to a brief ischaemic insult. Dopamine efflux was measured using fast cyclic voltammetry. Tissue metabolism was determined with 2,3,5-triphenyltetrazolium chloride staining, a marker of mitochondrial enzyme activity. In control slices, ischaemia caused rapid striatal dopamine release (to 122 microM over 18 s) after an initial delay of 149s. Racemic ketamine (100 micromol/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. Ischaemia (10 min) also caused significant decreases in striatal (25%, P<0.01) and cortical (31%, P<0.001) metabolic activity, manifested as a drop in mean TTC staining intensity. Racemic ketamine and its (+)- and (-)-enantiomers (each 100 microM) attenuated the loss of metabolic activity in the striatum. However, in the cortex, only (+)-ketamine (100 microM) was significantly neuroprotective. We conclude that neuroprotection by ketamine in cerebral ischaemia is both region- and isomer-dependent.
Mathews
K S
KS
Neurotransmission Laboratory, Academic Department of Anaesthesia and Intensive Care, St Bartholomew's and the Royal London School of Medicine and Dentistry, Royal London Hospital, Whitechapel, London E1 1BB, UK.
Toner
C C
CC
McLaughlin
D P
DP
Stamford
J A
JA
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007649:Ketamine / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
D007649:Ketamine