These data indicate that a low, clinically relevant dose of ketamine offer significant neuroprotection during prolonged exposure to NMDA but not to NOC. Combinations of reduced doses of ketamine and TPS exhibited enhanced neuroprotection against NMDA-induced neurotoxicity. Hence, combinations of these two common i.v. anaesthetics agents could be developed to protect the brain from ischaemia.

Acute brain ischemia causes neurotoxic cascades including NMDA receptors and NO. Propofol, an i.v. anesthetic, is thought to have a neuroprotective effect. We investigated the influence of propofol on NMDA/NO neurotoxicity using Shibuta's established model of primary brain cultures. Cortical neurons prepared from E16 were used after 13-14 days in culture. The neurons were exposed to various concentrations of propofol with NMDA or NO-donor. The survival rates of neurons exposed to 30 microM NMDA with or without 300 microM propofol were 12.1 +/- 2.2% and 11.9 +/- 2.2%, respectively. The survival rates exposed to 30 microM NO-donor with or without 300 microM propofol were 11.2 +/- 4.2% and 14.0 +/- 3.9%, respectively. These results suggest that neuroprotective effect of propofol is limited and propofol does not offer advantages over thiopental against NMDA/NO-induced cytotoxicity.

Many experimental and clinical studies have shown that hypothermia confers cerebroprotective benefits against ischemic insults. Because of the many conflicting reports on hypothermic neuroprotection, we undertook this cellular study to identify the optimal temperature or a range of temperatures for maximal neuroprotection at different times (6-24 hr) during ischemic insults. Cultured Wistar rat cortical neurons were exposed to oxygen deprivation at defined times and temperatures (37 degrees C normothermia, 32 degrees C mild hypothermia, 27 degrees C moderate hypothermia, 22 degrees C deep hypothermia, and 17 degrees C profound hypothermia). The survival rate of neurons was evaluated by assessing viable neurons on photomicrographs. The normothermic group demonstrated a significantly lower survival rate of cultured neurons (6 hr, 80.3% +/- 2.7%; 12 hr, 56.1% +/- 2.1%; 18 hr, 34.2% +/- 1%; 24 hr, 18.1% +/- 2.2%) compared to hypothermic groups (P < 0.001). The survival rate for the profound hypothermic group was significantly reduced (P < 0.01) compared to other hypothermic groups (at 17 degrees C: 12 hr, 85.9% +/- 2.5%, 18 hr, 74.7% +/- 3.7%, 24 hr, 58.7% +/- 2.7%). Almost equal survival rates were observed among mild, moderate, and deep hypothermic groups following <18 hr exposure to hypoxia, but the deep hypothermic group showed a significantly higher survival rate (84.1% +/- 1.6%; P < 0.001) when subjected to hypoxia for 24 hr. In conclusion, hypothermia offers marked neuroprotection against hypoxia, but attenuation of neuronal cell death was less with profound hypothermia compared to mild, moderate, and deep hypothermia. Deep hypothermia affords maximal protection of neurons compared to mild and moderate hypothermia during long-lasting hypoxia (>18 hr).

Because there are many conflicting reports on cerebroprotective effects of hypothermia and barbiturates, we examined the degree of neuroprotection at defined temperatures (normothermia, 37 degrees C; mild hypothermia, 32 degrees C; deep hypothermia, 22 degrees C; and profound hypothermia, 17 degrees C) and various concentrations (low, 4 microM; moderate, 40 microM; and high, 400 & microM) of thiopentone sodium (TPS), alone and in combination in cortical cultures exposed to prolonged hypoxia (24-48 hr). The survival rate of embryonic day (E)16 Wistar rat cortical neurons was evaluated on photomicrographs before and after experiments. During the 24-hr hypoxic period, the survival rate of neurons was maximal with combinations of mild hypothermia with 40 microM (91.6 +/- 0.7%) and 400 microM TPS (90.8 +/- 0.7%) or deep hypothermia combined with all concentrations of TPS (4 microM, 90.6 +/- 1.0%; 40 microM, 91.4 +/- 0.8%; 400 microM, 91.8 +/- 1.2%). During 48 hr hypoxia, the highest survival rate was seen with the combination of deep hypothermia and either 40 microM (90.9 +/- 0.6%) or 400 microM (91.1 +/- 1.4%) TPS. In the presence of profound hypothermia in combination with all concentrations of TPS, the survival rate was significantly reduced (P< 0.01) compared to combined application of either mild or deep hypothermia with TPS. In summary, maximal neuroprotection was attained with hypothermia and TPS in combination rather than applied individually, during prolonged hypoxic episodes (24- 48 hr). During a 24-hr hypoxic period, both mild and deep hypothermia combined with a clinically relevant concentration of TPS (40 microM) offered the highest neuroprotection. Only deep hypothermia provided maximal neuroprotection when combined with 40 microM TPS, during 48-hr hypoxia. Combination of profound hypothermia and TPS did not confer considerable neuroprotection during long lasting hypoxia.

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