Abstract
BackgroundGlobal cerebral ischemia following cardiac arrest is associated with increased cerebral vasoconstriction and decreased cerebral blood flow, contributing to delayed neuronal cell death and neurological detriments in affected patients. We hypothesize that upregulation of contractile ETB and 5-HT1B receptors, previously demonstrated in cerebral arteries after experimental global ischemia, are a key mechanism behind insufficient perfusion of the post-ischemic brain, proposing blockade of this receptor upregulation as a novel target for prevention of cerebral hypoperfusion and delayed neuronal cell death after global cerebral ischemia. The aim was to characterize the time-course of receptor upregulation and associated neuronal damage after global ischemia and investigate whether treatment with the MEK1/2 inhibitor U0126 can prevent cerebrovascular receptor upregulation and thereby improve functional outcome after global cerebral ischemia. Incomplete global cerebral ischemia was induced in Wistar rats and the time-course of enhanced contractile responses and the effect of U0126 in cerebral arteries were studied by wire myography and the neuronal cell death by TUNEL. The expression of ETB and 5-HT1B receptors was determined by immunofluorescence.ResultsEnhanced vasoconstriction peaked in fore- and midbrain arteries 3 days after ischemia. Neuronal cell death appeared initially in the hippocampus 3 days after ischemia and gradually increased until 7 days post-ischemia. Treatment with U0126 normalised cerebrovascular ETB and 5-HT1B receptor expression and contractile function, reduced hippocampal cell death and improved survival rate compared to vehicle treated animals.ConclusionsExcessive cerebrovascular expression of contractile ETB and 5-HT1B receptors is a delayed response to global cerebral ischemia peaking 3 days after the insult, which likely contributes to the development of delayed neuronal damage. The enhanced cerebrovascular contractility can be prevented by treatment with the MEK1/2 inhibitor U0126, diminishes neuronal damage and improves survival rate, suggesting MEK1/2 inhibition as a novel strategy for early treatment of neurological consequences following global cerebral ischemia.
Highlights
The principal cause of global cerebral ischemia is cardiac arrest (CA), representing nearly 70% of all deaths of patients after out– of-hospital cardiac arrests
It is well-established that global cerebral ischemia is associated with a post-ischemic phase of reduced cerebral blood flow (CBF) termed delayed postischemic hypoperfusion (PDH), which may contribute to delayed neuronal cell death where the neurons in the CA1 region of the hippocampus are vulnerable, resulting in persistent cognitive deficits [6]
Upregulation of vasocontractile endothelin type B (ETB) and 5hydroxytryptamine type 1B (5-HT1B) receptors has previously been demonstrated in cerebral artery smooth muscles 48 hours after experimental global cerebral ischemia [7]. We suggest that this change in vasoconstrictor receptor expression pattern results in an increased contractile tone of the affected arteries and thereby decrease tissue perfusion contributing to delayed neuronal cell death.we hypothesize that upregulation of vasocontractile receptors after global cerebral ischemia could be a novel target for pharmacological prevention of post-ischemic hypoperfusion and delayed neuronal death
Summary
The principal cause of global cerebral ischemia is cardiac arrest (CA), representing nearly 70% of all deaths of patients after out– of-hospital cardiac arrests. Imbalance between local vasodilators and vasoconstrictors, cerebral edema and blood brain barrier breakdown has been reported as contributory mechanisms of dysregulated cerebral blood flow (CBF) after global cerebral ischemia in both animals and humans [3,4,5]. It is well-established that global cerebral ischemia is associated with a post-ischemic phase of reduced CBF termed delayed postischemic hypoperfusion (PDH), which may contribute to delayed neuronal cell death where the neurons in the CA1 region of the hippocampus are vulnerable, resulting in persistent cognitive deficits [6]. The expression of ETB and 5-HT1B receptors was determined by immunofluorescence
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