Neuroprotective Effects of MK-801 in Different Rat Stroke Models for Permanent Middle Cerebral Artery Occlusion

Abstract

Background and Purpose-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.

Complications and Pitfalls in Rat Stroke Models for Middle Cerebral Artery Occlusion

“…1,4,5,12 This complication was confirmed by MRI ( Figure 4) and postmortem examination in 1 out of 11 animals in group I (9%) and in 1 out of 14 rats in group II (7%). SAH can lead to serious side effects such as vasospasm and intracerebral hemorrhage, and thus can confound the results of experimental stroke studies.…”

“…This causes hypothalamic infarction with associated pathologic hyperthermia that confounds neuroprotective drug evaluation. [3][4][5] The recently introduced macrosphere model has been developed to overcome this side effect by the intra-arterial embolization of 6 TiO 2 spheres that selectively block blood flow to the MCA main stem without obstructing the HA. This model avoids hypothalamic infarction and pathological hyperthermia but does not allow for reperfusion.…”

“…This model avoids hypothalamic infarction and pathological hyperthermia but does not allow for reperfusion. 4,5,6 The present study was designed to evaluate validity, complications, and side effects of 3 different MCAO models (permanent MCAO using the suture and the macrosphere models and transient occlusion with the suture technique). MRI and MRA have been applied to identify model failures.…”

Combination Therapy of Rosiglitazone, a Peroxisome Proliferator‐Activated Receptor‐γ Ligand, and NMDA Receptor Antagonist (MK‐801) on Experimental Embolic Stroke in Rats

“…In agreement with our results, Suzuki et al [6] reported that intravenous administration of MK-801 at the dose of 0.1 mg/kg immediately after middle cerebral artery occlusion showed neuroprotective effects without side effects. Moreover, Gerriets et al [5] also found that MK-801 was neuroprotective after macrosphere model of ischaemic brain injury in rats. Behavioural tests showed that MK-801 could improve both neurological deficits scores (motor function) and sedation assessment scores (level of arousal).…”

“…Under pathological conditions, overactivation of these receptors cause an excessive amount of Ca 2+ influx into the nerve cells, which then triggers a variety of processes that can lead to necrosis or apoptosis [4]. In line with this, it has been shown that NMDA receptor antagonists reduce damage in animal models of stroke [5,6].…”