Neuroprotection by the α2-adrenoceptor agonist, dexmedetomidine, in rat focal cerebral ischemia (original) (raw)
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Journal of Neural Transmission, 2001
Increased sympathetic tone is a consequence of cerebral ischemia. Although the role of catecholamines in ischemic damage is still unclear, in some experimental ischemia models α 2-adrenergic agonism has proved to be neuroprotective. In the present work we have compared the effects of transient and permanent middle cerebral artery occlusion (MCAO) on the infarct volume, and, also, examined whether a selective α 2-adrenergic receptor agonist, dexmedetomidine (9µg/kg or 15 µg/kg i.v.), is able to reduce ischemic damage after transient or permanent MCAO in rats. Permanent MCAO led to a significantly larger infarct volume than transient occlusion (p Ͻ 0.05). The rats receiving the higher dose of dexmedetomidine were detectected to have smaller (statistically non-significant) infarct volume in the cortex (30.9%) and in the striatum (20.3%) after transient occlusion. Additionally, dexmedetomidine caused significant variations in the physiological parameters.
Dexmedetomidine produces its neuroprotective effect via the a 2A-adrenoceptor subtype
Eur J Pharmacol, 2004
Which of the three α2-adrenoceptor subtypes of α2A, α2B, or α2C mediates the neuroprotective effect of dexmedetomidine was examined in cell culture as well as in an in vivo model of neonatal asphyxia. Dexmedetomidine dose-dependently attenuated neuronal injury (IC50=83±1 nM) in neuronal-glial co-cultures derived from wild-type mice; contrastingly, dexmedetomidine did not exert neuroprotection in injured cells from transgenic mice (D79N) expressing dysfunctional α2A-adrenoceptors. An α2A-adrenoceptor subtype-preferring antagonist 2-[(4,5-Dihydro-1H-imidazol-2-yl)methyl]-2,3-dihydro-1-methyl-1H-isoindole maleate (BRL44408) completely reversed dexmedetomidine-induced neuroprotection, while other subtype-preferring antagonists 2-[2-(4-(2-Methoxyphenyl)piperazin-1-yl)ethyl]-4,4-dimethyl-1,3-(2H,4H)-isoquinolindione dihydrochloride (ARC239) (α2B) and rauwolscine (α2C) had no significant effect on the neuroprotective effect of dexmedetomidine in neuronal-glial co-cultures. Dexmedetomidine also protected against exogenous glutamate induced cell death in pure cortical neuron cultures assessed by flow cytometry and reduced both apoptotic and necrotic types of cell death. Likewise this neuroprotective effect was antagonised by BRL44408 but not ARC239 or rauwolscine. Dexmedetomidine exhibited dose-dependent protection against brain matter loss in vivo (IC50=40.3±6.1 μg/kg) and improved the neurologic functional deficit induced by the hypoxic-ischemic insult. Protection by dexmedetomidine against hypoxic-ischemic-induced brain matter loss was reversed by the α2A-adrenoceptor subtype-preferring antagonist BRL44408; neither ARC239 nor rauwolscine reversed the neuroprotective effect of dexmedetomidine in vivo. Our data suggest that the neuroprotective effect of dexmedetomidine is mediated by activation of the α2A adrenergic receptor subtype.
Turkish Neurosurgery, 2012
AIm: To compare the effect of dexmedetomidine administered by intracisternal route with by intravenous route on brain tissue of rat after incomplete cerebral ischemia. mAterIAl and methOds: Cerebral ischemia was produced by the combination of right common carotid artery occlusion and hemorrhagic hypotension during 30 minutes. Thirty minutes before the ischemia, 0.1 ml 0.9% NaCl (Group SIC, n=6) or 9 µg/kg dexmedetomidine (Group DIC, n=6) was administered into the cisterna magna. For the intravenous groups, 9 µg/kg dexmedetomidine (Group DIV, n=6) or 0.9% NaCl (Group CONTROL, n=6) 5 ml/kg/h was given in 2 hours. After 24 hours, the lipid peroxidation levels were measured in the brain tissue and plasma. Hippocampal formations were used for histopathological examination. results: Intravenous dexmedetomidine produced a decrease in baseline mean arterial blood pressure and plasma glucose concentrations. There was a significant difference between the DIV group and DIC, SIC, CONTROL groups regarding the brain lipid peroxidation levels (p<0.001, p<0.001, p=0.001, respectively), and regarding the picnotic neuronal cell count (p<0.001, p=0.01, p=0.009, respectively). Mean plasma lipid peroxidation levels of the DIV group was different from the DIC group (p=0.003). COnClusIOn: Systemically administered dexmedetomidine had neuroprotective effect in ischemia-induced neuronal damage, but centrally administered dexmedetomidine did not.
Surgical Neurology, 2009
Background: Subarachnoid hemorrhage is a serious condition, often accompanied by cerebral vasospasm, which may lead to brain ischemia and neurologic deterioration. We evaluated if dexmedetomidine has neuroprotective effects in the hippocampus of vasospastic SAH rabbits or not. Materials and Methods: Eighteen New Zealand rabbits were taken. An experimental SAH model was formed by injecting 0.9 mL of autologous arterial blood per 1 kg of body weight to the cisterna magna of 12 rabbits. Craniotomy was performed in the control group (n = 6) except performing experimental SAH. Rabbits in the SAH-alone (n = 6) group were infused with 5 mL · kg −1 · h −1 0.9% sodium chloride, and rabbits (n = 6) in the SAH-dexmedetomidine group were infused with 5 μg · kg −1 · h −1 dexmedetomidine for 2 hours, 48 hours after SAH was established. Rabbits of all groups were sacrificed via penthotal 24 hours after dexmedetomidine administration. Brains were removed immediately, and hippocampal tissues were blocked from the right hemisphere for histopathologic study. In addition to this, hippocampal tissues of left hemispheres were dissected for biochemical analyses to evaluate MDA levels, activity of XO, and SOD. Results: The histopathologic study showed that dexmedetomidine may have a neuroprotective effect in SAH-induced hippocampal injuries. The biochemical parameters support the neuroprotective effect of dexmedetomidine (P b .05). Conclusion: Our study showed that dexmedetomidine may have a neuroprotective effect in the hippocampus of vasospastic SAH rabbits.
Experimental Brain …, 2005
The present study was undertaken to investigate the effects of the alpha2 adrenergic agonist, clonidine, on the near complete cerebral ischemia (NCFI) evoked release of glutamate and aspartate from normo- and hyperglycemic rodent brain tissue using microdialysis tissue techniques. Hemodynamic variables, blood lactate, and glucose levels were monitored throughout the 40 min NCFI occlusion period. After 48 h, rats were killed and the extent of neuronal injury was determined in the cortex, striatum, and hippocampus. Hemodynamic variables recorded during ischemia improved with clonidine treatment in both normo- and hyperglycemic groups. Glutamate and aspartate levels were greatly increased over control values during normo- and hyperglycemic NCFI treatment. Clonidine pretreatment suppressed the release of both glutamate and aspartate during NCFI in normo- and hyperglycemic rodents when compared with NCFI-treated normo- and hyperglycemic rats without the drug. Significant neuroprotection of cells in the cortex, striatum, and hippocampus was also observed in drug-treated animals 48 h postischemia. The combined effects of diminished glutamate release after NCFI and reduced neuronal injury in both normo- and hyperglycemic states suggests that clonidine treatment during NCFI is neuroprotective. The neuroprotective effect of clonidine during ischemia may be ascribed to both a sensitization of central sympathetic activity and a reduced release of glutamate thereby reducing NMDA receptor activation and neuronal damage.
Background: Dexmedetomidine is a specific agonist of the α2A-adrenoceptor with sedative, analgesic, neuro-protective, and anti-delirious effects. At clinically relevant concentrations, it stimulates both inhibitory auto-receptors and post-junctional receptors found on astrocytes, but not on neurons. The stimulated pathway releases epidermal growth factor receptor (EGFR) agonist(s) that can act on all brain cell types. Dexmedetomidine’s ability to improve treatment and prognosis in critically ill patients in the ICU is clinically relevant. Methods: Dexmedetomidine’s neuro-protectant mechanisms of action were tested during oxidative damage, using cultured astrocytes and the very vulnerable glutamatergic cerebellar granule neurons. Primary cultures of cerebellar granule neurons prepared from 7-day-old CD-1 mice were cultured for 8 days, and primary cultures of astrocytes from newborn CD-1 mice for 3 weeks until full maturation. Cell viability during extended incubation with and without H2O2 was tested by a methylthiazoletetrazolium (MTT) assay, and released heparin-binding epidermal growth factor (HB-EGF) in medium from astrocyte cultures measured by sandwich ELISA. Results: Dexmedetomidine administration directly to H2O2-exposed neurons had no cyto-protective effect. Conditioned medium from astrocytes treated for 30-120 min with 50 nM dexmedetomidine increased neuronal survival by >50%, provided astrtocytic α2-adrenoceptors were not atipamezole-inhibited. Dexmedetomidine’s protective effect was also prevented when neuronal treatment with astrocyte-conditioned medium took place in the presence of AG 1478, inhibiting neuronal EGF receptors. Conclusion: At clinically relevant concentrations dexmedetomidine is neuro-protective against oxidative damage by stimulating astrocytic α2-adrenoceptors, causing release of HB-EGF. HB-EGF in turn activates neuronal EGF receptors. At these concentrations dexmedetomidine has no direct neuronal effect.
The protective effect of aminoguanidine on cerebral ischemic damage in the rat brain
Physiological research / Academia Scientiarum Bohemoslovaca, 2004
The NADPH-diaphorase (NADPH-d) histochemical technique is commonly used to localize the nitric oxide (NO) produced by the enzyme nitric oxide synthase (NOS) in neural tissue. The expression of inducible nitric oxide synthase (iNOS) is induced in the late stage of cerebral ischemia, and NO produced by iNOS contributes to the delay in recovery from brain neuronal damage. The present study was performed to investigate whether the increase in nitric oxide production via inducible nitric oxide synthase was suppressed by the administration of aminoguanidine, a selective iNOS inhibitor, as it follows a decrease of NADPH-diaphorase activity (a marker for NOS) after four-vessel occlusion used as an ischemic model. The administration of aminoguanidine (100 mg/kg i.p., twice per day up to 3 days immediately after the ischemic insult) reduced the number of NADPH-diaphorase positive cells to control levels. Our results indicated that aminoguanidine suppressed NADPH-diaphorase activity, and also ...
The effects of dexmedetomidine dosage on cerebral vasospasm in a rat subarachnoid haemorrhage model
Journal of Clinical Neuroscience, 2010
We investigated the effect of two different doses of dexmedetomidine on vasospasm in a rat model of subarachnoid haemorrhage (SAH). SAH was induced by injecting 0.3 mL blood into the cisterna magna in all rat groups except the control (Group C). At 1 hour and 24 hours after SAH, 5 lg/kg dexmedetomidine was given to group D5, and 10 lg/kg dexmedetomidine was given to group D10. No medication was administered to the haemorrhage group (Group H). Malondialdehyde (MDA) and paraoxonase (PON) levels were measured at 48 hours after SAH. Mean wall thickness (MWT), mean luminal diameter (MLD), and proliferating cell nuclear antigen (PCNA) expression of the basilar artery were evaluated. MDA levels and MWT were lower in the dexmedetomidine groups. The lowest MDA levels and MWT were found in Group D10. The MLD was lowest in Group H. PCNA expression was observed only in Group D10. We concluded that dexmedetomidine reduces oxidative stress and vasospasm following SAH in a dose-dependent manner.
Focal cerebral ischemia (Stroke) is the cessation or severe reduction of blood flow to an area of the brain that through activation of a complex cytotoxic cascade results in neuronal cell death. The present study was designed to examine the effects of post-ischemic treatment with aminoguanidine (AG) on cortical, striatal infarct volume as well as neurological dysfunctions. Rats (n=23) were allocated to sham, saline or AG (300 mg/kg)-treated groups. Ischemia was induced by 90 minutes middle cerebral artery occlusion, followed by 24 hrs reperfusion. Saline or AG was administered intraperitoneal at one hour after induction of ischemia. At the end of 24hrs reperfusion, neurological deficit score was tested and cortical, striatal infarct volumes were determined by Triphenyltetrazolium chloride staining. Administration of AG (300 mg/kg) at one hours after ischemia resulted in a significantly lower cortical (85±25 vs. 210±13 mm 3), striatal (35±5 vs. 58±10 mm 3) infarct volumes, and neurol...