The temporal constraints of protection of neuronal damage by post-ischemic hypothermia was investigated in the gerbil model of global ischemia. Three experimental paradigms were used: 1) Hypothermia was initiated prior to ischemia followed by warming to normothermia immediately post ischemia; 2) Hypothermia of different durations was initiated immediately after reflow and 3) Six hours of hypothermia was initiated at various times following reperfusion. Hypothermia during 5 minutes of ischemia followed by warming to normal body temperature immediately post ischemia resulted in near complete protection of the hippocampus from CA1 cell loss. Hypothermic durations of 1/2, 1, 2, 4, and 6 hours beginning immediately following reperfusion resulted in progressively increased protection from ischemic damage (6 +/- 6%, 21 +/- 10%, 34 +/- 15%, 75 +/- 16% and 77 +/- 12%, respectively). Six hours of hypothermia delayed for 1 hour after reperfusion resulted in 49 +/- 9% protection. No reduction of ischemic damage was observed if 6 hours of hypothermia was delayed for 3 hour after reflow. These data suggest that: 1) Hypothermia during ischemia protects the brain from damage; 2) Hypothermia initiated immediately following reperfusion must have a duration of 2 hours or more to be effective and 3) Six hours of hypothermia is effective if initiated within 1 hour of reperfusion.

Lamotrigine had neuroprotective effects in a gerbil model of global cerebral ischemia. Lamotrigine protected gerbils against behavioral deficits resulting from 15 minutes of carotid occlusion and also prevented histological damage resulting from 5 and 15 minutes of global cerebral ischemia.

Kraemer, and R.M. Ferris: Overview of the CNS pharmacology of BW 137OU87: a chemically novel, reversible, selective MAO-A inhibitor with potential to be a new antidepressant drug. Drug Dev. Res. 25:181-190, 1992. BW 13701187 is a potent, reversible, selective inhibitor of rat and human brain MAO-A with a competitive mechanism of action. The E D , , of BW 13701187 for inhibition of MAO-A in rat brain is 8 mg/kg after oral administration, and the duration of action exceeds 7 hr. The ED, , dose for inhibition of MAO-A (20 mg/kg) elevates NE, DA, and 5-HT levels in brains of rats without significantly potentiating the blood pressure effects of a 15 rng/kg oral dose of tyramine. This dose of tyramine, extrapolated to man, exceeds the amount that could be consumed at one time from dietary sources. No inhibition of MAO-B has been observed with BW 13701187 either in vitro or ex vivo. BW 13701187 was effective in the 5-hydroxytryptophan potentiation test over the dose range that produced MAO-A inhibition in brain in both rats and mice, and it reduced swim stress induced immobility in the Porsolt test. The compound has positive effects on abnormal social behavior produced by early social deprivation in the rhesus monkey. BW 13701187 had no adverse cardiovascular effects in dogs or rats. It also had no significant pharmacological effects on various isolated tissue preparations and did not cause changes in the neuronal transport or the receptor systems which mediate the antidepressant effects or side effects of the tricyclic antidepressants. An acute oral dose 100 times that which produced an 80% inhibition of brain MAO-A exhibited no signs of toxicity. BW 137OU87 appears to be a safe reversible MAO-A inhibitor with potential for treating depression, anxiety conditions, panic, phobias, obsessive compulsive behaviors, and borderline personality disorders.

Carroll, M., and 0. Beek: Blood pressure effects of monoamine oxidase inhibitors in response to orally administered tyramine in the rat. Drug Dev. Res. 2321 5-21 8, 1992.The reversible monoamine oxidase-A inhibitors BW 1370U87, BW 61 6U76, brofaromine, and moclobemide, and the irreversible nonselective monoamine oxidase inhibitor phenelzine were compared for potentiation of the pressor response to oral tyramine. Conscious rats were pretreated with doses of the monoamine oxidase inhibitors sufficient to produce 80% inhibition of brain monoamine oxidase, and then were challenged with orally administered tyramine. Blood pressure was monitored prior to and after tyramine, and peak pressor responses were compared. At a dose of 15 mg/kg tyramine, the pressor response of BW 1370U87 was statistically similar to the vehicle control response. BW 6161176, brofaromine, and moclobemide elicited mild tyramine pressor effects, whereas phenelzine resulted in a marked elevation of blood pressure. Higher doses of tyramine elicited blood pressure elevations from all of the monoamine oxidase inhibitors.

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