[Experimental study of pharmacological hypothermia: enhanced neuroprotective effect of a novel 5-HT 1 A agonist SUN N4057 by the pharmacological hypothermia].
OBJECTIVE
5-hydroxytryptamine(5-HT) 1 A receptor agonists have a potentially marked neuroprotective reaction by both neuroprotective and hypothermic effects. We previously reported (1) the neuroprotective effect against the cerebral ischemia under normothermic condition, and (2) the hypothermic effect of the novel compound of 5-HT 1 A agonist, SUN N4057. The present investigation was designed to examine the enhancement of the neuroprotective effect by its pharmacological hypothermia.


METHODS
In 24 anesthetized cats(body weight 1.9-4.6 kg), the left middle cerebral artery(MCA) occlusion was performed via the transorbital approach. Just after MCA occlusion, SUN N4057(6 micrograms/kg/min) was infused. Physiological parameters were measured continuously, and arterial blood gas was analyzed hourly for 6 hours and maintained within the normal ranges. Animals were randomly allocated to the following three groups: (1) ischemic controls infused with sterile saline(Group A, n = 8), (2) SUN N4057 under normothermic condition(Group B, n = 8), (3) SUN N4057 (Group C, n = 8). Then, brain coronal sections of 3 mm in thickness were stained with 1% triphenyltetrazolium chloride(TTC) solution, and hemispheric infarct volumes were calculated by using a computerized image analysis system.


RESULTS
There were no significant differences in any physiological parameters among 3 groups. In Group C, brain temperature decreased significantly starting 1 hour after MCA occlusion and dropped by 2.1 +/- 0.7 degrees C 5 hours. Infarct volumes were 35.6 +/- 6.9% (Group A), 23.3 +/- 5.8% (Group B) and 12.3 +/- 11.3% (Group C), respectively. There were significant differences among three groups(p < 0.05).


CONCLUSIONS
On the basis of these data, we conclude that SUN N4057 provides more effective neuroprotection by the combination of hypothermic and neuroprotective effects. Chemical hypothermia may lead to a new therapeutic approaches for treatment of brain ischemia.
Uchiyama
Y
Y
Department of Neurosurgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan.
Okuno
S
S
Nakase
H
H
Sakaki
T
T
Inoue
T
T
Koyama
M
M
D000818:Animals; D001831:Body Temperature / Q000187:drug effects*; D001921:Brain / Q000187:drug effects; D020520:Brain Infarction / Q000517:prevention & control*; D002415:Cats; D005260:Female; D007036:Hypothermia, Induced / Q000379:methods*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D018696:Neuroprotective Agents; D017366:Serotonin Receptor Agonists