Neuroprotective effect of N-acetyl-aspartyl-glutamate in combination with mild hypothermia in the endothelin-1 rat model of focal cerebral ischaemia.
Previously we showed that treatment with mild hypothermia (34 degrees C for 2 h) after a focal cerebral infarct was neuroprotective by reducing apoptosis in the penumbra (cortex), but not in the core (striatum) of the infarct. In this study we examined whether administration of N-acetyl-aspartyl-glutamate (NAAG) in combination with mild hypothermia could improve striatal neuroprotection in the endothelin-1 rat model. NAAG (10 mg/kg i.p.) was injected under normothermic (37 degrees C) or mild hypothermic conditions, either 40 min before or 20 min after the insult. NAAG reduced caspase 3 immunoreactivity in the striatum, irrespective of the time of administration and brain temperature. This neuroprotective effect could be explained, at least partially, by decreased nitric oxide synthase activity in the striatum and was blocked by the group II metabotropic glutamate receptor antagonist, LY341495. Hypothermia applied together with NAAG reduced both cortical and striatal caspase 3 immunoreactivity, as well as the overall ischaemic damage in these areas. However, no pronounced improvement was seen in total damaged brain volume. Extracellular glutamate levels did not correlate with the observed protection, whatever treatment protocol was applied. We conclude that treatment with NAAG causes the same degree of neuroprotection as treatment with hypothermia. Combination of the two treatments, although reducing apoptosis, does not considerably improve ischaemic damage.
Van Hemelrijck
An
A
Department of Pharmaceutical Chemistry and Drug Analysis, Research Group Experimental Pharmacology, and Cerebral Resuscitation Research Group, Vrije Universiteit Brussel, Brussels, Belgium.
Hachimi-Idrissi
Said
S
Sarre
Sophie
S
Ebinger
Guy
G
Michotte
Yvette
Y
D000596:Amino Acids / Q000627:therapeutic use; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology; D002545:Brain Ischemia / Q000517:prevention & control*; D004151:Dipeptides / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D019332:Endothelin-1 / Q000627:therapeutic use*; D007035:Hypothermia; D008297:Male; D017551:Microdialysis / Q000379:methods; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014966:Xanthenes / Q000627:therapeutic use
D000596:Amino Acids; D004151:Dipeptides; D019332:Endothelin-1; C114624:LY 341495; D018696:Neuroprotective Agents; D014966:Xanthenes; C027172:isospaglumic acid