Article
Mechanisms of effect of mild hypothermia-induced neuroprotection on Matrix-Metalloproteinase (MMP) activity after experimental subarachnoid hemorrhage (SAH): The differential roles of MMP-2 and MMP-9
Beeinflussung der Matrix-Metalloproteinase-Aktivität im Rahmen einer Hypothermie-induzierten Neuroprotektion nach experimenteller Subarachnoidalblutung: Unterschiedliche Bedeutungen von MMP-2 und MMP-9
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Published: | May 30, 2008 |
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Objective: Mild hypothermia (33°C) improves functional recovery following experimental SAH without affecting regional cerebral blood flow (rCBF), intracranial pressure (ICP), or brain edema formation. The current study investigated MMP-2 and MMP-9 activation, a process potentially involved in the development of vasospasm and blood-brain barrier opening, as a potential molecular target of hypothermia treatment after SAH.
Methods: Rats were subjected to SAH by endovascular puncture and assigned to a control group and two groups with induction of two hours hypothermia 60 and 180 minutes after SAH (n=10 per group). Bilateral rCBF, ICP, blood pressure (MABP), and cerebral perfusion pressure (CPP) were continuously monitored for 6 hours. MMP-2 & -9 activities were quantified 7 days thereafter in cortical and subcortical brain regions using gelatine zymography.
Results: Animals were allocated to 3 groups depending on the extent of SAH: °I = immediately lethal (death during monitoring period; 14%), °II = protracted lethal (death within 24 hours; 23%), °III = nonlethal (animals surviving 24 hours; 63%). In SAH °I and °II rCBF remained below 20% of baseline whereas in °III rCBF recovered to 60% baseline. In SAH °II and °III CPP remained in the range of 40-60 mmHg (°I: <30mmHg). rCBF and CPP did not correlate indicating early vasoconstriction depending on the grade of SAH. As reported previously, hypothermia did not influence post-hemorrhagic rCBF and ICP. MMP-2 but not MMP-9 expression was reduced in subcortical regions in both hypothermia groups.
Conclusions: Early rCBF reduction most likely caused by acute vasospasm seems to play a pivotal role for early survival of animals following SAH. In animals surviving SAH, MMP-9 is not reduced by hypothermia thereby explaining the missing effect on brain edema formation. Accordingly, hypothermia-induced neuroprotection may be mediated by a reduction of MMP-2 activity.