Neuroprotective effect of N‐acetyl‐aspartyl‐glutamate in combination with mild hypothermia in the endothelin‐1 rat model of focal cerebral ischaemia

• Published in: Journal of neurochemistry 2005-12, Vol.95 (5), p.1287-1297
• Main Authors: Van Hemelrijck, An, Hachimi‐Idrissi, Said, Sarre, Sophie, Ebinger, Guy, Michotte, Yvette
• Format: Article
• Language: English
• Subjects: Amino Acids - therapeutic use; Animals; Apoptosis; Biological and medical sciences; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - physiopathology; Brain damage; Brain Ischemia - prevention & control; caspase 3; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dipeptides - therapeutic use; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Endothelin-1 - therapeutic use; focal ischaemia; glutamate; Hypothermia; Male; Medical sciences; Medical treatment; Microdialysis - methods; Neurology; Neuroprotective Agents - therapeutic use; N‐acetyl‐aspartyl‐glutamate; Rats; Rats, Wistar; Rodents; Time Factors; Vascular diseases and vascular malformations of the nervous system; Xanthenes - therapeutic use
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2005.03450.x

Previously we showed that treatment with mild hypothermia (34°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°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.