Nicergoline enhances glutamate re-uptake and protects against brain damage in rat global brain ischemia.
Whereas a 2-3 degrees C decrease in intraischemic brain temperature can be neuroprotective, mild brain hyperthermia significantly worsens outcome. Our previous study suggested that an ischemic injury mechanism which is sensitive to temperature may not actually increase the extracellular glutamate concentration ([Glu](e)) during the intraischemic period, but rather impairs the Glu re-uptake system, which has been suggested to be involved in the reversed uptake of Glu. We speculated that enhancing Glu re-uptake, pharmacologically or hypothermically, may shorten exposure to high [Glu](e) in the postischemic period and thereby decrease its deleterious excitotoxic effect on neuronal cells. In the present study, rats treated with nicergoline (32 mg/kg, i.p.), an ergot alkaloid derivative, showed minimal inhibition of the [Glu](e) elevation which characteristically occurs during the 10-min intraischemic period, while Glu re-uptake was dramatically improved in the postischemic period, when severe transient global ischemia was caused by mild hyperthermia. Moreover, the nicergoline (32 mg/kg, i.p.) treated rats showed reduced cell death morphologically and clearly had a far lower mortality. The present study suggests that the development of therapeutic strategies aimed at inhibition or prevention of the reversed uptake of glutamate release during ischemia, i.e., activation of the glutamate uptake mechanism, is a promising approach to reduce neural damage occurring in response to brain ischemia.
Asai
S
S
Department of Pharmacology, Nihon University School of Medicine, 30 Oyaguchi-Kami Machi, Itabashi-ku, Japan. satoshi@med.nihon-u.ac.jp
Zhao
H
H
Yamashita
A
A
Jike
T
T
Kunimatsu
T
T
Nagata
T
T
Kohno
T
T
Ishikawa
K
K
D000317:Adrenergic alpha-Antagonists / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000502:physiology; D002545:Brain Ischemia / Q000188:drug therapy*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000648:ultrastructure; D018698:Glutamic Acid / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009530:Nicergoline / Q000627:therapeutic use*; D051381:Rats; D011921:Rats, Inbred WKY
D000317:Adrenergic alpha-Antagonists; D018698:Glutamic Acid; D009530:Nicergoline