Neuroprotective effects of MK-801 in different rat stroke models for permanent middle cerebral artery occlusion: adverse effects of hypothalamic damage and strategies for its avoidance.
OBJECTIVE
Permanent middle cerebral artery occlusion (MCAO) with the use of the suture technique causes hypothalamic damage with subsequent hyperthermia, which can confound neuroprotective drug studies. In the present study the neuroprotective effects of dizocilpine (MK-801) were compared in different permanent MCAO models with and without hypothalamic damage and hyperthermia.


METHODS
Sixty Sprague-Dawley rats were treated with MK-801 or placebo, beginning 15 minutes before MCAO, and assigned to the following groups: suture MCAO (group I), macrosphere MCAO without hypothalamic damage (group II), or macrosphere MCAO with intentionally induced hypothalamic infarction (group III). Body temperature was measured at 3, 6, and 24 hours. Lesion size was determined after 24 hours (2,3,5-triphenyltetrazolium chloride staining).


RESULTS
Hypothalamic damage was present in animals in group I and was intentionally induced in group III with the use of a modified macrosphere MCAO technique. Body temperature was significantly increased 3, 6, and 24 hours after MCAO in these 2 groups of animals. Hypothalamic damage and subsequent hyperthermia could be avoided effectively by limiting the number of macrospheres (group II). MK-801 provided a highly significant neuroprotective effect in group II but not in groups I and III.


CONCLUSIONS
Hypothalamic damage with subsequent hyperthermia masked the neuroprotective effect of MK-801. This side effect can be avoided by using the macrosphere MCAO technique with a limited number of spheres. This model therefore may be more appropriate to study the effects of neuroprotective drugs in permanent focal cerebral ischemia than the suture method.
Gerriets
T
T
Department of Radiology, Experimental Neurology Research Group, Kerckhoff Klinik Bad, Nauheim, Germany. Tibo.Gerriets@neuro.med.uni-giessen.de
Stolz
E
E
Walberer
M
M
Kaps
M
M
Bachmann
G
G
Fisher
M
M
D000818:Animals; D001831:Body Temperature; D004195:Disease Models, Animal; D018450:Disease Progression; D016291:Dizocilpine Maleate / Q000627:therapeutic use*; D005334:Fever / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D007031:Hypothalamus / Q000473:pathology / Q000503:physiopathology*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D008026:Ligation; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D014025:Titanium; D016896:Treatment Outcome
D018696:Neuroprotective Agents; C009495:titanium dioxide; D016291:Dizocilpine Maleate; D014025:Titanium