We compared the neurotoxic profile of racemic
bupivacaine and
levobupivacaine in: (i) a mouse model of
N-methyl-D-aspartate (
NMDA)-induced
seizures and (ii) in an in vitro model of excitotoxic cell death. When used at high doses (36 mg/kg) both
bupivacaine and
levobupivacaine reduced the latency to
NMDA-induced
seizures and increased seizure severity. However,
levobupivacaine-treated animals underwent less severe
seizures as compared with
bupivacaine-treated animals. Lower doses of
levobupivacaine and
bupivacaine had opposite effects on
NMDA-induced
seizures. At doses of 5 mg/kg,
levobupivacaine increased the latency to
partial seizures and prevented the occurrence of
generalized seizures, whereas
bupivacaine decreased the latency to
partial seizures and did not influence the development of
generalized seizures. In in vitro experiments, we exposed primary cultures of mouse cortical cells, containing both neurons and astrocytes, to 100 microM
NMDA for 10 min for the induction of excitotoxic neuronal death. This treatment killed 70-80% of the neuronal population, as assessed 24 h after the excitotoxic pulse. In this particular model, both
levobupivacaine and
bupivacaine were neuroprotective against
NMDA toxicity. However, neuroprotection by
levobupivacaine was seen at lower concentrations (with respect to
bupivacaine) and was maintained at concentrations of 3 mM, which are much higher than the plasma security threshold for the drug in vivo. In contrast, no protection against
NMDA toxicity was detected when 3 mM concentrations of
bupivacaine were applied to the cultures. Our data show a better neurotoxic profile of
levobupivacaine as compared to racemic
bupivacaine, and are indicative of a safer profile of
levobupivacaine in clinical practice.