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NEUROPHARMACOLOGY
Department of Neurosurgery, Kumamoto University School of Medicine, Kumamoto, Japan (Y.H., M.M., S.H., J.M., T.K., Y.K., S.Y., J.K.); and Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Tohoku, Japan (K.F.)
Received October 7, 2005; accepted February 2, 2006.
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Abstract |
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). After arterial occlusion, necrotic cell death is predominant in the ischemic core (Garcia et al., 1995). In contrast, apoptotic cell death accounts for delayed neuronal death in the penumbra (Charriaut-Marlangue et al., 1996), where antiapoptotic agents rescue cells from neuronal death. Although restoration of the cerebral blood flow immediately after ischemia reduces the infarct size in the ischemic penumbra, reperfusion-induced injuries have been observed (Marchal et al., 1999). Despite efforts to develop novel drugs to rescue neurons from delayed neuronal death in the penumbral region (Zivin, 1997), few currently available drugs are effective in stroke patients.
The transition metal vanadium (atomic weight, 50.9415) is widely distributed in the environment; it exhibits various biological and physiological effects in the human body (Elberg et al., 1994; Brichard and Henquin, 1995). Vanadium compounds mimic many of the physiological actions of insulin; they lead to an increase in hexose uptake, glycogen synthesis, glycolysis, and fatty acid synthesis in insulin-responsive tissues (Shechter, 1990). Vanadate inhibits protein tyrosine phosphatases by acting as a transition state of a phosphate analog and by forming a reversible bond through cysteine residues (Morinville et al., 1998). Moreover, it indirectly activates nonreceptor protein tyrosine kinase in cell-free systems (Elberg et al., 1994). Thus, vanadate increases tyrosine phosphorylation via the inhibition of nonselective protein tyrosine phosphatases and activation of tyrosine kinases.
Akt (protein kinase B) and extracellular signal-regulated kinase (ERK) are kinases known to inhibit apoptosis. A number of studies have indicated that activated Akt and ERK promote neuroprotection during cerebral ischemia (Li et al., 2003; Kilic et al., 2005). We documented that sodium orthovanadate (Na3VO4; SOV) activates Akt through phosphoinositide 3-kinase and ERK, thereby eliciting neuroprotection against hippocampal delayed neuronal death in gerbils. There was a correlation between the activity of Akt and ERK, and the neuroprotective efficacy of SOV and the administration of both SOV and the kinase inhibitors decreased the protective effects (Kawano et al., 2001). We also demonstrated that SOV treatment ameliorates ischemic neuronal injury following transient middle cerebral artery occlusion (MCAO) in rats via both Akt and ERK activation, that it results in a lower blood glucose level, and that it elicits gradual regional cerebral blood flow (rCBF) recovery (Hasegawa et al., 2003).
In addition to evoking therapeutic efficacy, vanadium compounds have also been shown to produce a variety of side effects, including hematologic and biochemical alterations, renal toxicity, immunotoxicity, and mutagenicity (Jandhyala and Hom, 1983; Zaporowska and Wasilewski, 1992; Sakurai, 1994; Domingo et al., 1995). Thus, safety and therapeutic time window should be determined in experimental animals.
In this study, we evaluated the potential clinical usefulness of SOV. We determined the effective dose and therapeutic time window to elicit the neuroprotective effect of SOV in rats. We also measured physiological parameters, blood glucose levels, and rCBF.
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Materials and Methods |
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rCBF Measurements. Changes in rCBF were recorded on the dura of the left parietal cortex using a laser Doppler flowmeter (ALF21; Advance, Tokyo, Japan) attached to a hollow plastic tube. The rats were placed in a stereotaxic frame and craniectomy (2 mm lateral and 1 mm caudal to the bregma) was performed carefully using a drill. After the tube was fixed to the bone with resin, the flow-meter probe was inserted. Changes in rCBF were expressed as a percentage of the pretreatment basal level.
Induction of Focal Ischemia. The rats were removed from the stereotaxic apparatus, and reversible focal ischemia was induced by occluding the middle cerebral artery using the intraluminal technique (Hasegawa et al., 2003). In brief, under an operating microscope, the left common carotid artery was exposed through a midline incision in the neck. Approximately 20 mm of 3-0 nylon suture coated with poly-L-lysine were introduced into the left internal through the common carotid artery. The animals were allowed to recover from anesthesia as soon as occlusion of middle cerebral artery. In this study, most of the animals recovered from anesthesia within 15 min. Ninety minutes later, they were again briefly anesthetized for removal of the nylon suture to allow reperfusion. Neurologic examinations were performed 10 min before reperfusion using a modification of the neurologic score of Bederson et al. (1986). Accordingly, grade 0 was recorded in the absence of observable deficits, grade 1 in the presence of forelimb flexion, grades 2 and 3 when there was decreased resistance to lateral pushing in the absence or presence of circling, respectively, and grade 4 was assigned to comatose animals. Rats with grades 0 and 4 were excluded from further experiments.
Measurement of the Volume of Ischemic Brain Injury. The animals were decapitated 24 h post-MCAO. Their brains were quickly removed, placed in cold saline solution for 10 min, and then cut into 2-mm-thick coronal slices using a rodent brain matrix. Six selected sections (±5, ±3, and ±1 mm from the bregma) were stained for 30 min in a 2% solution of 2,3,5-triphenyltetrazolium chloride (TTC) at 37°C. The area of ischemic brain injury was measured using the NIH Image Software. Infarct areas were corrected to compensate for edema formation by subtracting the area of the intact ipsilateral hemisphere from the area of the intact contralateral hemisphere. Then, the total infarct areas on each slice were added together and multiplied by slice thickness to obtain the infarct volume.
Determination of the Therapeutic Time Window. At 0, 45, or 90 min post-MCAO, groups of eight rats each were i.p. injected with 2 ml/kg saline or 50 mM SOV. The infarct volume was determined 24 h post-MCAO by TTC staining.
Dose Dependence and Effect of Repeat Administrations of Low-Dose SOV. Groups of eight rats with transient MCAO received 2 ml/kg saline or 12.5 (4.6 mg/kg), 25 (9.2 mg/kg), or 37.5 (13.8 mg/kg) mM SOV i.p. at 0 min post-MCAO. The data of infarct volume of 50 mM (18.4 mg/kg) SOV-administrated group obtained from the study of therapeutic time window were used as the data of 50 mM SOV. Another group was injected with 2 ml/kg 12.5 mM SOV at 0 and again at 45 min post-MCAO. The infarct volume was determined 24 h post-MCAO by TTC staining.
Effect of Blood Glucose Level during MCAO on Infarct Size. SOV leads to a decrease in blood glucose. Therefore, to examine the effect of decreased blood glucose on the results obtained in ischemic SOV-treated rats, we performed a set of experiments shown in Fig. 3. We injected three groups of eight rats each with saline (2 ml/kg, controls) or 2 ml/kg 12.5 mM SOV without (group B) or with (group C) the additional administration of 10% glucose and measured their blood glucose levels every 15 min during a 90-min period. Identical experiments were performed on three groups of rats subjected to 90-min MCAO, and the infarct volume in these animals was determined at 24 h post-MCAO.
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). At 45 and 90 min post-MCAO or at pre-MCAO time points, four rats in each group were decapitated their brains were removed, and the indicated regions were dissected out in cold saline under a microscope. Each sample was kept at -80°C until use. Frozen tissues were homogenized and sonicated with a Biorupture instrument (UCD-200TM; Cosmo Bio, Tokyo, Japan) at 0°C in 0.2 ml of homogenization buffer containing 50 mM Tris-HCl, pH 7.5, 0.5% Triton X-100, 4 mM EGTA, 10 mM EDTA, 0.5 M NaCl, 1 mM Na3VO4, 30 mM sodium pyrophosphate, 50 mM NaF, 50 µg/ml leupeptin, 25 µg/ml pepstatin A, 50 µg/ml trypsin inhibitor, and 1 mM dithiothreitol. Insoluble materials were removed by 15-min centrifugation at 15,000g. The protein content in each supernatant fraction was determined using Bradford's solution. Individual samples were applied to a 10% acrylamide denaturing gel and subjected to SDS-polyacrylamide gel electrophoresis, and then the proteins were transferred for 1 h at 70 V to an Immobilon polyvinylidene difluoride membrane (Millipore Corp., Bedford, MA). Blotting membranes were incubated for 1 h with 5% nonfat milk in phosphate-buffered saline containing 0.1% Tween 20 (PBST) at room temperature and then incubated overnight at 4°C with a 1:200 dilution of anti-phospho-Akt (Ser473) antibody (Cell Signaling Technology, Beverly, MA) or a 1:500 dilution of anti-mitogen-activated protein kinase-activated (diphosphorylated) ERK-1 and 2 antibody (Sigma-Aldrich, St. Louis MO) in nonfat milk in PBST. After several washes with PBST, the membranes were incubated for 1 h with horseradish peroxidase-conjugated anti-rabbit antibody (Vector Laboratories, Burlingame, CA) diluted 1:5000 and processed with enhanced chemiluminescence Western blotting detection reagents (Amersham Pharmacia Biotech, Arlington Heights, IL). The images were scanned and analyzed semiquantitatively using the NIH Image Software. Changes in the phosphorylation of Akt-Ser-473 and ERK were expressed as a percentage of the preischemia level. Statistical Analysis. All values are expressed as the mean ± S.D. Blood gases, blood glucose levels, and rCBF were analyzed by one-way ANOVA, and infarct volume in measurement of therapeutic time window and dose dependence and phosphorylation of Akt (Ser473) and ERK were analyzed by nonrepeated one-way ANOVA; for statistical comparison of groups at each time point, we used the unpaired Student's t test. Differences of p < 0.05 were considered statistically significant.
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Results |
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), at 50 mM, SOV delivered at 0 min post-MCAO resulted in a remarkable decrease in the infarct volume (42 ± 34 mm3,34 ± 28%). SOV was neuroprotective even when delivered as late as 90 min post-MCAO (83 ± 25 mm3, 69 ± 21%). Delivery at 0 min produced protective effects similar to those observed in rats injected at 45 min post-MCAO (47 ± 34 mm3, 35 ± 29%).
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Physiological Parameters. Blood gas analysis (Table 1) showed that the controls manifested mild alkalosis at 90 min post-MCAO. In rats treated with 50 mM SOV, we observed mild CO2 elevation leading to mild acidosis at 90 min post-MCAO. The injection of SOV at 45 or 90 min post-MCAO produced a dose-dependent increase in PO2. There were no statistically significant changes in hematocrit (data not shown).
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In the controls, the blood glucose level pre- and at 45 and 90 min post-MCAO was not significantly different (Table 2). However, in all SOV-treated rats, it was significantly lower at 45 min post-MCAO, and the decrease was SOV dose-dependent. At 90 min post-MCAO, it recovered to the pre-MCAO level in rats injected with 12.5 or 25 mM SOV. Blood glucose in rats treated with 37.5 mM or 50 mM SOV and in those injected twice with 12.5 mM SOV was significantly lower than in the controls.
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As shown in Table 2, at 45 min post-MCAO, the groups did not differ significantly with respect to rCBF. At 90 min, only rats treated with 50 mM SOV had significantly lower rCBF than the controls. The saline- and SOV-treated rats did not differ significantly in their neurological scores and blood pressure readings (data not shown).
Effect of Maintained Blood Glucose Level on Infarct Volume. Because the SOV-induced decrease in blood glucose may affect its neuroprotection (Hasegawa et al., 2003), we compared the infarct volume in SOV-treated rats that did, or did not, receive an injection of glucose. In addition, we measured blood glucose in non-MCAO rats that did or did not receive SOV (Fig. 3, A and B). Glucose-untreated rats injected at 0 and 45 min post-MCAO with 12.5 mM SOV (group B in Fig. 3A) showed a gradual decrease in the blood glucose level. On the other hand, there was no significant difference in blood glucose between the controls (group A) and rats treated with both SOV (12.5 mM, 0 and 45 min post-MCAO) and glucose (10%, 30 and 75 min post-MCAO) (group C).
The administration of glucose to SOV-treated ischemic rats did not significantly affect the infarct volume. However, the administration of SOV with or without additional glucose did result in a significant reduction in the infarct volume compared with the controls (Fig. 3C).
Western Blot Analysis of Akt and ERK-2 Phosphorylation after Transient MCAO. We already reported that SOV was neuroprotective only in the penumbra area of the ipsilateral cortex and that the activation of Akt and ERK was correlated with its neuroprotective effect (Hasegawa et al., 2003). Here, we studied the time course of Akt and ERK activities (phosphorylation) in rats treated with SOV immediately after MCAO. Figure 4A shows the changes in Akt-Ser-473 phosphorylation in the penumbra area. In rats treated with saline only (control) and those injected with 12.5 mM SOV at 0 min post-MCAO, Akt-Ser-473 phosphorylation was significantly decreased at 45 (40 ± 18% versus 55 ± 19%) and 90 (54 ± 22% versus 58 ± 24%) min post-MCAO. On the other hand, in rats treated with 50 mM SOV at 0 min post-MCAO, it was not significantly different from the pre-MCAO level at 45 and 90 min post-MCAO (81 ± 11% and 130 ± 23%, respectively). Interestingly, rats treated with repeated injection of 12.5 mM SOV at 0 and again at 45 min post-MCAO maintained Akt phosphorylation at 90 min that was similar to the pre-MCAO level (108 ± 14%).
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In gerbils, the phosphorylation of ERK-1 (44 kDa) and ERK-2 (42 kDa) was decreased following ischemia induction (Kawano et al., 2001). Therefore, we also assessed ERK-2 phosphorylation in our rats. As shown in Fig. 4B, in the controls and in rats treated with a single injection of 12.5 mM SOV at 0 min post-MCAO, there was a significant decrease in ERK-2 phosphorylation at 45 (35 ± 23% versus 46 ± 32%) and 90 (43 ± 10% versus 56 ± 18%) min post-MCAO. On the other hand, in rats treated with 50 mM SOV, ERK-2 phosphorylation was maintained to the pre-MCAO level by 45 and 90 min post-MCAO (101 ± 46% and 118 ± 34%, respectively). The changes in ERK-2 and Akt phosphorylation were similar. However, a second injection of 12.5 mM SOV at 45 min post-MCAO failed to restore ERK-2 phosphorylation by 90 min post-MCAO (77 ± 9%).
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Discussion |
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). Their mitogenic effects may be due to their inhibition of tyrosine phosphatases and their potentiation of the autophosphorylation of tyrosine kinases of growth hormone receptors on the cell membrane (Tracey and Gresser, 1986). Orthovanadate reportedly induced cell death and exhibited antineoplastic properties (Cruz et al., 1995). Vanadium compounds may exert inhibiting effects on ion transport-coupled ATPase (Cantley et al., 1978) or induce p53 activation mainly through H2O2 generation (Huang et al., 2000), which results in cell death. The morphological changes and cytotoxic effects seen in cells may depend on the SOV concentration and the length of exposure (Cruz et al., 1995; Figiel and Kaczmarek, 1997). Because the period of administration is short, the mitogenic effect(s) of these agents do not need to be considered in stroke patients. Our previous histological study disclosed no evidence of neurotoxicity in the contralateral hemisphere of ischemic rats treated with 50 mM orthovanadate 28 days earlier (Hasegawa et al., 2003). Furthermore, our present results indicate that the SOV dose could be reduced without compromising its neuroprotective effects.
We previously reported that the antiapoptotic effects of Akt and ERK resulted in neuroprotection against hippocampal delayed neuronal death in gerbils (Kawano et al., 2001). We also documented that SOV ameliorated ischemic neuronal cell injury and that its effect was associated with the combined activation of Akt and ERK, a decrease in blood glucose levels, and the gentle recovery of rCBF (Hasegawa et al., 2003). In the current study, we focused on determining which factor(s) was the most important for SOV-induced neuroprotection.
We found that rats treated at 0 min post-MCAO with 50 mM SOV manifested significantly lower rCBF at 90 min post-MCAO than the controls. The gentle recovery of rCBF may contribute to neuroprotection by avoiding the generation of free radicals or inflammatory cytokines. However, the rCBF in rats treated with 37.5 mM SOV, which exerted the same level of neuroprotection as 50 mM, was not statistically different from the controls. Therefore, we postulate that the gradual rCBF recovery contributes only weakly to the neuroprotection induced by SOV.
Hypoglycemic ischemia leads to major metabolic derangement and an increase in brain tissue damage (Vannucci et al., 1980; Wass and Lanier, 1996). In contrast, hyperglycemia adversely affects the energy metabolism in patients with cerebral ischemia due to severe lactic acidosis and results in poor clinical outcomes (Gardiner et al., 1982; Nedergaard, 1987). Because normoglycemic cats with MCAO experienced less brain damage and lower mortality (de Courten-Myers et al., 1994), the blood glucose revel was thought to be a major factor in their prognosis.
Based on our previous observation that in rats, 50 mM SOV significantly reduced the blood glucose level, although it remained within the normal range (Hasegawa et al., 2003). We hypothesized that the lowering of blood glucose was one important effect of SOV in the prevention of ischemic neuronal injury. Therefore, in the current study, we attempted to maintain the blood glucose level by injecting SOV-treated rats with glucose. However, we observed no significant difference in the infarct volume of rats treated at 0 and 45 min post-MCAO with 12.5 mM SOV, irrespective of whether they were or were not additionally injected with 10% glucose. Based on this observation, we postulated that the SOV-induced decrease in blood glucose did not contribute strongly to its neuroprotective effect.
In growth factor-mediated signaling cascades, Akt is involved in antiapoptotic signaling downstream from phosphoinositide 3-kinase. The direct or indirect phosphorylation by active Akt of BAD, caspase-9, cyclic AMP-responsive element binding protein, nuclear factor-
B, and forkhead transcription factors results in antiapoptotic effects (Datta et al., 1997; Cardone et al., 1998; Du and Montminy, 1998; Brunet et al., 1999; Romashkova and Makarov, 1999). We speculated that SOV stimulated the Akt-related antiapoptotic transcription factor pathway and rescued penumbra regions affected by apoptotic mechanisms (Kawano et al., 2001) and that Akt activation underlies the effect of SOV observed in our study (Hasegawa et al., 2003). ERK, also known as mitogen-activated protein kinase, is normally activated in response to growth and differentiation factors; its increased phosphorylation has been reported in rodents with transient MCAO (Alessandrini et al., 1999). We have shown that SOV activates ERK, resulting in neuroprotection against forebrain ischemia in gerbils (Kawano et al., 2001). The current study revealed that in rats treated with a single injection of 12.5 mM SOV, Akt and ERK phosphorylation was not maintained at 45 min post-MCAO. Although a second injection of 12.5 mM SOV had no effect of ERK activation at 90 min post-MCAO, it did activate Akt. Therefore, we suggest that Akt activation was mainly involved in the observed SOV-induced neuroprotection. We further postulate that the recovery of Akt activity in the early stage of ischemia may further enhance the neuroprotective effects of SOV.
In conclusion, SOV belongs to a novel class of compounds available for the treatment of stroke patients. It also manifests a therapeutic time window of at least 90 min. Less than 50 mM SOV, especially twice administration of 12.5 mM or single injection of 25 mM SOV, may help to reduce the SOV dose. Vanadium compounds have been used to treat patients with diabetes mellitus without lethal side effects (Goldfine et al., 1995; Boden et al., 1996). Because the required treatment period in patients with cerebral ischemia is short and temporary (1-2 weeks), SOV may be of use in the clinical setting. Studies are ongoing in our laboratory to determine whether stroke patients can be treated safely and effectively with SOV.
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: Akt, protein kinase B; ERK, extracellular-signal regulated kinase; SOV, sodium orthovanadate; MCAO, middle cerebral artery occlusion; rCBF, regional cerebral blood flow; TTC, 2,3,5-triphenyltetrazolium chloride; PBST, phosphate-buffered saline containing 0.1% Tween 20.
Address correspondence to: Dr. Motohiro Morioka, Department of Neurosurgery, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan. E-mail: morioka{at}kaiju.medic.kumamoto-u.ac.jp
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, p < 0.05; 
