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Toshiki Aoki, Katsunobu Takenaka, Satoshi Suzuki, Neal F. Kassell, Oren Sagher and Kevin S. Lee

✓ The importance of factors within hemolysate in modulating oxyhemoglobin (oxyHb)-induced contraction was examined in an in vitro model of rabbit basilar arteries. When the basilar arteries were exposed to purified oxyHb alone, the contractile response observed was significantly weaker than that seen in arteries exposed to hemolysate containing an equal concentration of oxyHb. In order to delineate the nature of the factors within hemolysate that facilitate contraction, hemolysate was fractionated, and various components were tested individually for their ability to elicit this effect. A low-molecular-weight fraction of hemolysate, ranging from 0.5 to 2.0 kD, elicited only a mild contraction. However, when this fraction was combined with purified oxyHb, the contractile response was comparable in magnitude to that of unfractionated hemolysate. These studies confirm that purified oxyHb is capable of inducing contraction in vitro. The data also demonstrate that oxyHb elicits a significantly weaker contraction than does hemolysate. In addition, the results suggest that low-molecular-weight components in hemolysate (in the 0.5- to 2.0-kD range), while incapable of inducing a potent contraction alone, may act in concert with oxyHb to elicit the vasoconstriction seen following subarachnoid hemorrhage.

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Yongcheng Jin, Oren Sagher, Quoc-Anh Thai, Neal F. Kassell and Kevin S. Lee

✓ Papaverine (PPV) is a nonspecific vasodilator with widespread clinical uses in the treatment of arterial spasm. It has also been utilized in an attempt to reverse cerebral vasospasm. Recent angiographic results have demonstrated significant reversal of vasospasm in large vessels after selective intra-arterial application of PPV; however, these impressive results lacked good clinical correlation. In this study, phorbol dibutyrate was used to stimulate protein kinase C in an in vitro model of cerebral microvessels. Papaverine was found to elicit a dose-dependent exacerbation of phorbol dibutyrate-induced microvascular constriction in this model system. Because protein kinase C is thought to play a key role in the development of cerebral vasospasm, PPV-induced vasoconstriction represents a potentially important deleterious effect that may not be apparent on angiography. Such a constrictor response may compromise the beneficial vasodilatory effect seen with intra-arterial injection of PPV.

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EDITOR'S PERSPECTIVE ON ARTICLE 1

Mechanisms of edema formation after intracerebral hemorrhage: effects of thrombin on cerebral blood flow, blood-brain barrier permeability, and cell survival in a rat model

Kevin R. Lee, Nobuyuki Kawai, Seoung Kim, Oren Sagher and Julian T. Hoff

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Kevin R. Lee, Nobuyuki Kawai, Seoung Kim, Oren Sagher and Julian T. Hoff

Recently, the authors showed that thrombin contributes to the formation of brain edema following intracerebral hemorrhage. The current study examines whether the action of thrombin is due to an effect on cerebral blood flow (CBF), vasoreactivity, blood-brain barrier (BBB) function, or cell viability. In vivo solutions of thrombin were infused stereotactically into the right basal ganglia of rats. The animals were sacrificed 24 hours later; CBF and BBB permeability were measured. The actions of thrombin on vasoreactivity were examined in vitro by superfusing thrombin on cortical brain slices while monitoring microvessel diameter with videomicroscopy. In separate experiments C6 glioma cells were exposed to various concentrations of thrombin and lactate dehydrogenase release, a marker of cell death, was measured. The results indicate that thrombin induces BBB disruption as well as death of parenchymal cells, whereas CBF and vasoreactivity are not altered. The authors conclude that cell toxicity and BBB disruption by thrombin are triggering mechanisms for the edema formation that follows intracerebral hemorrhage.

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Kevin R. Lee, Nobuyuki Kawai, Seoung Kim, Oren Sagher and Julian T. Hoff

✓ Recently, the authors showed that thrombin contributes to the formation of brain edema following intracerebral hemorrhage. The current study examines whether the action of thrombin is due to an effect on cerebral blood flow (CBF), vasoreactivity, blood-brain barrier (BBB) function, or cell viability. In vivo solutions of thrombin were infused stereotactically into the right basal ganglia of rats. The animals were sacrificed 24 hours later; CBF and BBB permeability were measured. The actions of thrombin on vasoreactivity were examined in vitro by superfusing thrombin on cortical brain slices while monitoring microvessel diameter with videomicroscopy. In separate experiments C6 glioma cells were exposed to various concentrations of thrombin, and lactate dehydrogenase release, a marker of cell death, was measured. The results indicate that thrombin induces BBB disruption as well as death of parenchymal cells, whereas CBF and vasoreactivity are not altered. The authors conclude that cell toxicity and BBB disruption by thrombin are triggering mechanisms for the edema formation that follows intracerebral hemorrhage.

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Oren Sagher, Dah-Luen Huang and R. Clinton Webb

✓ Induction of hypothermia is used routinely in neurosurgical and cardiovascular operations to protect the brain from ischemic insult. However, despite a plethora of experimental evidence supporting the use of hypothermia to protect the brain from ischemia, clinical experience using deliberate hypothermia in humans has not shown a convincing benefit. The authors tested the hypothesis that hypothermia and rewarming alter tone in human cerebral vessels and may interfere with cerebral perfusion in the setting of deliberate hypothermia. They examined human cerebral arteries during hypothermia (32°C and 17°C) and during rewarming to delineate the direct effects of cooling and rewarming on cerebrovascular tone. Artery segments obtained from autopsy material and from specimens excised at elective temporal lobectomies were tested in tissue baths using isometric tension measurements. Temperature-induced changes in vascular tone were measured and quantified with respect to contractile responses to serotonin (5-HT; 10−6 M). Cooling induced mild relaxation in cerebral vessels (−38 ± 12% 5-HT response in 50 vessels from autopsy specimens, −69 ± 10% 5-HT response in 51 vessels from lobectomy specimens). On rewarming, vessels contracted significantly beyond their baseline tone (108 ± 18% 5-HT response in 50 vessels from autopsy specimens, 42 ± 12% 5-HT response in 51 vessels from lobectomy specimens). Rewarming-induced hypercontractility was inhibited by the tyrosine kinase inhibitor genistein (−5 ± 7% vs. 70 ± 23% 5-HT response, genistein vs. control, 14 segments, p < 0.05) and enhanced by the tyrosine phosphatase inhibitor sodium orthovanadate (339 ± 54% vs. 104 ± 20% 5-HT response, sodium orthovanadate vs. control, five segments, p < 0.05), indicating a possible role for tyrosine kinase activation in the rewarming-induced contraction.

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Miroslav P. Bobek and Oren Sagher

✓ The authors present the case of a 47-year-old man who, after undergoing microvascular decompression for trigeminal neuralgia, experienced symptomatic pain relief but developed prolonged aseptic meningitis. This case is unusual in that the patient remained dependent on steroid medications for nearly 5 months following the initial surgery and the aseptic meningitis did not resolve until after surgical removal of the Teflon used to pad the trigeminal nerve. The pathophysiological characteristics of the body's reaction to implanted Teflon are discussed along with the rationale for removing this substance in cases of prolonged intractable aseptic meningitis.

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Oren Sagher and Dah-Luen Huang

Object. Spinal cord stimulation (SCS) is frequently used for the treatment of chronic pain. Although the mechanisms by which SCS alleviates pain are unclear, they are believed to involve changes within the dorsal horn of the spinal cord. Spinal cord stimulation has also been found to cause significant vasodilation in the peripheral vasculature. The mechanisms underlying this effect are thought to involve sympathetic blockade. A rostral vasodilatory effect has also been described, but changes in cerebral blood flow (CBF) have been poorly delineated. Using laser Doppler flowmetry (LDF), the authors examined the effects of cervical SCS on CBF in rats.

Methods. Cervical SCS was found to result in a significant increase in cortical LDF values (83 ± 11% [mean ± standard error of the mean]). The increase in cortical LDF values was not accompanied by a significant increase in systemic blood pressure. Stimulation of the upper cervical spinal cord was more effective in inducing LDF changes than was that of the lower cervical cord. Changes in SDS-induced LDF values were significantly attenuated after spinal cord transection at the cervicomedullary junction and by the administration of the sympathetic blocker hexamethonium.

Conclusions. These results indicate that cervical SCS may induce cerebral vasodilation and that this effect may involve indirect effects on vasomotor centers in the brainstem as well as an alteration in sympathetic tone.

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Oren Sagher, Dah-Luen Huang and Richard F. Keep

Object. The authors previously showed that spinal cord stimulation (SCS) increases cerebral blood flow in rats, indicating that this technique may be useful in the treatment of focal cerebral ischemia. In the present study, the neuroprotective potential of SCS in the setting of middle cerebral artery occlusion (MCAO) was investigated.

Methods. The authors induced permanent, focal cerebral ischemia by using either suture-induced occlusion or direct division of the MCA in Sprague—Dawley rats. Electrical stimulation of the cervical spinal cord was performed during cerebral ischemia. Cerebral blood flow was assessed using both laser Doppler flowmetry (LDF) and quantitative radiotracer analysis. Stroke volumes were analyzed after 6 hours of ischemia.

Spinal cord stimulation resulted in a 52.7 ± 13.3% increase in LDF values (nine animals). Following MCAO, LDF values decreased by 64.1 ± 3.6% from baseline values (10 animals). Spinal cord stimulation subsequently increased LDF values to 30.9 ± 13.5% below original baseline values. These findings were corroborated using radiotracer studies. Spinal cord stimulation in the setting of transcranial MCAO significantly reduced stroke volumes as well (from 203 ± 33 mm3 [control] to 32 ± 8 mm3 [MCAO plus SCS], seven animals in each group, p < 0.001). Similarly, after suture-induced MCAO, SCS reduced stroke volumes (from 307 ± 29 mm3 [control] to 78 ± 22 mm3 [MCAO plus SCS], 10 animals in each group, p < 0.001).

Conclusions. A strategy of performing SCS for the prevention of critical ischemia is feasible and may have the potential for the treatment and prevention of stroke.

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Sachin Patel, Dah-Luen Huang and Oren Sagher

Object. Cervical spinal cord stimulation (SCS) has been found to augment cerebral blood flow (CBF) in a number of animal models, although the mechanisms underlying the cerebrovascular effects of SCS are poorly described. In this study, the authors examined the role of sympathetic tone in CBF alterations induced by SCS in rats.

Methods. Spinal cord stimulation was performed at three intervals while CBF was monitored with laser Doppler flowmetry (LDF). Either hexamethonium (5, 10, or 20 mg/kg), prazosin (0.25, 0.5, or 1 mg/kg), idazoxan (0.5, 1, or 2 mg/kg), propranolol (1, 2, or 4 mg/kg), or vehicle was administered intravenously before the second stimulation. Changes in LDF values due to SCS were recorded as the percentage of change from baseline values and were analyzed. In vehicle-treated animals, SCS increased LDF values by 60.5 ± 1.8% over baseline, whereas both high-dose hexamethonium and prazosin completely abolished the SCS-induced increases in LDF values. On the other hand, LDF values increased by 50.9 ± 4% and 61.4 ± 4% after SCS in the presence of idazoxan or propranolol, respectively. Administration of sympathetic nervous system blockers resulted in a variable degree of systemic hypotension as well. Nevertheless, induced hypotension without sympathetic blockade had only a minimal effect on SCS-induced augmentation of LDF values (48 ± 1.4% over baseline).

Conclusions. Sympathetic tone plays a major role in SCS-induced increases in CBF. This effect seems to be mediated primarily by α1-adrenergic receptors. Systemic hypotension alone cannot explain the effects of sympathetic blockade on the SCS response. Clinical use of SCS in the treatment of cerebral ischemia should take α1-adrenergic receptor sympathetic tone into account.