Hemodynamic effects of clonidine outweigh potential neuroprotective effects in experimental stroke

Introduction: There are various publications reporting neuroprotective effects of alpha2-adrenoreceptor agonists, such as clonidine and dexmedetomidine, both in animal studies and in vitro. We have studied the effects of clonidine and the role of different alpha2-adrenoreceptor subtypes in an experimental stroke model using transgenic mice with deletions of alpha2-receptor subtypes.

Methods: In transgenic mice with deletions of the alpha2-adrenoreceptor subtypes alpha2B (alpha2B-ko), alpha2C (alpha2C-ko), alpha2A/C (alpha2A/C-ko) and in control animals (wt), a transient focal cerebral ischemia was induced with or without pretreatment with 0.04g/kg clonidine. For this, the right middle cerebral artery was occluded for one hour using an intraluminal monofilament. At 24 hours, the animals were scored in a neurological test (modified Bederson score). Then the infarct volume was determined as a percentage of the volume of the contralateral hemisphere in triphenyltetrazolium chloride-stained brain slices. We also studied hemodynamic parameters by invasive blood pressure and pulse measurements.

Results: There were no significant differences in infarct volumes between clonidine-pretreated animals and respective animals without pretreatment in any of the four subgroups (alpha2B-ko, alpha2C-ko, alpha2A/C-ko, wt). After pretreatment with clonidine, however, alpha2A/C-ko mice had significantly smaller infarcts (mean, 30.2%) than clonidine-pretreated alpha2B-ko mice (50.3%), alpha2C-ko mice (55.8%), and wt mice (53.7%). In the functional neurological score, no significant differences were seen. Pretreatment of wt mice with clonidine decreased blood pressure, whereas alpha2A/C-ko mice showed only an increase in the pulse rate. Moreover, the basal blood pressure values were slightly elevated in alpha2A/C-ko animals.

Conclusion: In the experimental stroke model of transient middle cerebral artery occlusion, neuroprotection mediated by clonidine could not be demonstrated. Hemodynamic effects of clonidine seem to outweigh potential neuroprotective effects.