Bis maltolato oxovanadium (BMOV) and ischemia/reperfusion-induced acute kidney injury in rats
© Almac et al.; licensee Springer. 2014
Received: 30 July 2013
Accepted: 11 November 2013
Published: 27 February 2014
The aim of the present study was to test the potential protective effects of the organic vanadium salt bis (maltolato) oxovanadium (BMOV; 15 mg/kg) in the context of renal ischemia/reperfusion (30 min of ischemia) and its effects on renal oxygenation and renal function in the acute phase of reperfusion (up to 90 min post-ischemia).
Ischemia was established in anesthetized and mechanically ventilated male Wistar rats by renal artery clamping. Renal microvascular and venous oxygenation were measured using phosphorimetry. Creatinine clearance rate, sodium reabsorption, and renal oxygen handling efficiency were considered markers for renal function.
The main findings were that BMOV did not affect the systemic and renal hemodynamic and oxygenation variables and partially protected renal sodium reabsorption.
Pretreatment with the organic vanadium compound BMOV did not protect the kidney from I/R injury.
Acute kidney injury (AKI) is a frequent and costly clinical complication in critically ill patients. Using the RIFLE criteria in 20,126 hospitalized patients, Uchino et al. has found that 20% of the patients had some degrees of acute renal impairment and 3.7% of these patients had AKI . Ischemia/reperfusion (I/R) injury occurring during surgery and shock is one of the major causes of this condition in native and transplanted kidneys [1–5]. The pathogenesis and pathophysiology of I/R-induced AKI is highly complex [4, 5]. In addition to hypoxic hit consequent to ischemia, the reperfusion phase has been associated with additional renal injury. I/R-induced activation of inflammatory pathways has been shown to worsen AKI [6–9]. Furthermore, increased production of radical oxygen species (ROS) and reactive nitrogen species (RNS) [10–13] and a regional imbalance between vasoactive mediators are believed to be of great importance in the development of AKI by leading impaired microcirculatory perfusion and to cellular damage, apoptosis, and irreversible organ failure [4, 5].
In this respect, vanadium compounds are promising in the prevention and treatment of ischemic AKI. Vanadium is an essential trace element in humans and plays various roles through different pathways in metabolism [14, 15]. Recent findings suggest that vanadium may play a pivotal role in the regulation of physiological cell growth, survival, and metabolism. Most biologically active forms of vanadium are the inorganic vanadate salt vanadyl sulfate (VOSO4) and the organic vanadium salt bis oxovanadium (BMOV). Especially, the organic BMOV can be used in vitro and in vivo for its beneficial regulatory metabolic roles without major side effects. BMOV and other vanadium compounds have demonstrated protective against ischemic cascades, apoptosis, and vascular endothelial dysfunction while supporting tissue repair in the heart and the brain [14–16].
In the present study, we therefore aimed to investigate the potential protective effects of BMOV in the acute phase of renal I/R and AKI. To this end, rats received 0 or 15 mg/kg BMOV intravenously 30 min before renal artery clamping, and we measured renal oxygenation and renal function up to 90 min of reperfusion.
All experiments in this study were approved by the Institutional Animal Experimentation Committee of the Academic Medical Center of the University of Amsterdam. Care and handling of the animals were in accordance with the EU Directive 2010/63/EU for animal experiments and guidelines for Institutional and Animal Care and Use Committees. The study has been carried out in accordance with the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals. Experiments were performed on 18 Wistar male rats (Harlan, the Netherlands) with mean ± SD body weight of 320 ± 30 g.
The rats were anesthetized with an intraperitoneal injection of a mixture of 100 mg/kg ketamine (Nimatek®, Eurovet, Bladel, the Netherlands), 0.5 mg/kg medetomidine (Domitor, Pfizer, New York, NY, USA), and 0.05 mg/kg atropine sulfate (Centrafarm, Etten-Leur, the Netherlands). After tracheotomy, the animals were mechanically ventilated with a FiO2 of 0.4. Body temperature was maintained at 37°C ± 0.5°C during the entire experiment by external warming. The ventilator settings were adjusted to maintain end-tidal PCO2 between 30 and 35 mmHg and arterial PCO2 between 35 and 40 mmHg.
Vessels were cannulated with polyethylene catheters (outer diameter = 0.9 mm; Braun, Melsungen, Germany) for drug and fluid administration and hemodynamic monitoring. A catheter in the right carotid artery was connected to a pressure transducer to monitor mean arterial blood pressure (MAP) and heart rate. The right femoral artery was cannulated for blood sampling. The right femoral vein was cannulated for continuous infusion of Ringer’s lactate (15 mL/kg/h; Baxter, Utrecht, the Netherlands) and ketamine (50 mg/kg/h; Nimatek®, Eurovet, Bladel, the Netherlands).
The left kidney was exposed, decapsulated, and immobilized in a Lucite kidney cup (K. Effenberger, Pfaffingen, Germany) via a 4-cm incision in the left flank. Renal vessels were carefully separated under preservation of nerves and adrenal gland. A perivascular ultrasonic transit time flow probe was placed around the left renal artery (type 0.7 RB; Transonic Systems Inc., Ithaca, NY, USA) and connected to a flow meter (T206, Transonic Systems Inc.) to continuously measure renal blood flow (RBF). An estimation of the renal vascular resistance (RVR) was made as RVR [dynes/sec/cm5] = MAP/RBF. The left ureter was isolated, ligated, and cannulated with a polyethylene catheter for urine collection.
After the surgical protocol (approximately 60 min), one optical fiber was placed 1 mm above the decapsulated kidney and another optical fiber 1 mm above the renal vein to measure oxygenation in the renal microvasculature and renal vein, respectively, using phosphorimetry. A small piece of aluminum foil was placed on the dorsal site of the renal vein to prevent the contribution of underlying tissue to the phosphorescence signal in the venous oxygenation measurement. Oxyphor G2 (a two-layer glutamate dendrimer of tetra-(4-carboxy-phenyl) benzoporphyrin, Oxygen Enterprises Ltd., Philadelphia, PA, USA) was subsequently infused (6 mg/kg IV over 5 min) followed by a 30-min stabilization period. A short description of phosphorimetry is given below, and a more detailed description of the technology has been provided elsewhere [17–20].
After baseline measurements were performed 30 min after Oxyphor G2 infusion, the rats were randomly assigned to one of the following groups: sham-operated time control (n = 6), I/R control (n = 6), and I/R with 15 mg/kg BMOV (n = 6). Considering this is the first study in which BMOV is being utilized in a model of renal I/R injury, we decided to use the recommended dosage (15 mg/kg) by CFM Pharma (Almere, the Netherlands). BMOV solutions were prepared in 2-mL isotonic saline, and infusion was initiated 30 min prior to renal ischemia at an infusion rate of 2 mL/h. Control rats received the same volume of isotonic saline without BMOV. Renal ischemia was created by 30-min clamping of the renal artery, and following the release of the clamp, measurements were continued up to 90 min of reperfusion. The experiments were terminated by infusion of 1 mL of 3 M potassium chloride (KCl).
Arterial blood samples (0.5 mL) were taken from the femoral artery at baseline and 15 and 90 min after reperfusion. The blood samples were replaced by the same volume of Voluven® (Fresenius Kabi Ltd., Runcom, UK). Samples were analyzed for blood gas values (ABL505 blood gas analyzer, Radiometer, Copenhagen, Denmark), hemoglobin concentration, and hemoglobin oxygen saturation (OSM3, Radiometer). Additionally, plasma creatinine concentrations were determined in all samples.
Renal microvascular and venous oxygenation
Microvascular oxygen tension in the renal cortex (CμPO2), outer medulla (MμPO2), and renal venous oxygen tension (PrvO2) were measured by oxygen-dependent quenching of phosphorescence lifetimes of the systemically infused albumin-targeted (and therefore circulation-confined) phosphorescent dye Oxyphor G2. Oxyphor G2 (a two-layer glutamate dendrimer of tetra-(4-carboxy-phenyl) benzoporphyrin) has two excitation peaks (λexcitation1 = 440 nm, λexcitation2 = 632 nm) and one emission peak (λemission = 800 nm). These optical properties allow (near) simultaneous lifetime measurements in microcirculation of the kidney cortex and the outer medulla due to different optical penetration depths of the excitation light. For the measurement of renal venous PO2 (PrvO2), a mono-wavelength phosphorimeter was used. Oxygen measurements based on phosphorescence lifetime techniques rely on the principle that phosphorescence can be quenched by energy transfer to oxygen resulting in the shortening of the phosphorescence lifetime. A linear relationship between reciprocal phosphorescence lifetime and oxygen tension (given by the Stern-Volmer relation) allows quantitative measurement of PO2[17–20].
Renal oxygen delivery and consumption
Arterial oxygen content (AOC) was calculated by (1.31 × hemoglobin × SaO2) + (0.003 × PaO2), where SaO2 is arterial oxygen saturation and PaO2 is arterial partial pressure of oxygen. Renal venous oxygen content (RVOC) was calculated as (1.31 × hemoglobin × SrvO2) + (0.003 × PrvO2), where SrvO2 is venous oxygen saturation and PrvO2 is renal vein partial pressure of oxygen (measured using phosphorimetry). Renal oxygen delivery per gram of renal tissue was calculated as DO2 (mL/min/g) = RBF × AOC. Renal oxygen consumption per gram of renal tissue was calculated as VO2 (mL/min/g) = RBF × (AOC − RVOC). The renal oxygen extraction ratio was calculated as O2 ER (%) = VO2/DO2 × 100.
For the analysis of urine volume, creatinine concentration, and sodium (Na+) concentration at the end of the protocol, urine samples from the left ureter were collected for 10 min. Creatinine clearance rate (CLcrea) per gram of renal tissue was calculated with the standard formula: CLcrea (mL/min/g) = (U × V)/P, where U is the urine creatinine concentration, V is the urine volume per unit time, and P is the plasma creatinine concentration. Renal oxygen consumption efficiency for sodium transport (VO2/TNa+) was assessed as the ratio of the renal VO2 over the total amount of sodium reabsorbed (TNa+, [mmol/min]). TNa+ was calculated according to the following: ((CLcrea × PNa+) − (UNa+ × V)), where PNa+ is the plasma concentration of sodium.
Statistical analysis was performed using GraphPad Prism version 5.0 for Windows (GraphPad Software, San Diego, CA, USA). Data are presented as mean ± SD unless otherwise stated. Statistical significance of differences between groups was tested using one-way ANOVA with Bonferroni post hoc tests. P values <0.05 were considered significant.
Systemic and renal hemodynamic variables at BL, R15, and R90
BL (t = 0 min)
R15 (t = 45 min)
R90 (t = 120 min)
104 ± 4
101 ± 4
99 ± 4
108 ± 11
104 ± 7
90 ± 18
I/R + BMOV
108 ± 13
102 ± 24
92 ± 12
4.7 ± 0.5
4.6 ± 0.6
4.6 ± 0.5
4.6 ± 1.0
2.8 ± 0.5*
3.3 ± 0.1*
I/R + BMOV
4.2 ± 1.1
2.7 ± 0.4*
3.4 ± 0.3*
1,777 ± 172
1,793 ± 244
1,735 ± 153
2,004 ± 672
3,097 ± 451*
2,216 ± 502*
I/R + BMOV
2,190 ± 723
3,217 ± 1,251*
2,178 ± 240*
DO2 [mL O2/min/g]
1.21 ± 0.14
1.13 ± 0.14
1.18 ± 0.11
1.10 ± 0.24
0.65 ± 0.13*
0.72 ± 0.03*
I/R + BMOV
1.05 ± 0.32
0.64 ± 0.14*
0.77 ± 0.10*
VO2 [mL O2/min/g]
0.14 ± 0.07
0.13 ± 0.04
0.15 ± 0.02
0.13 ± 0.10
0.10 ± 0.02*
0.09 ± 0.01*
I/R + BMOV
0.13 ± 0.07
0.11 ± 0.05
0.10 ± 0.04*
65 ± 7
62 ± 7
60 ± 6
63 ± 6
59 ± 9
54 ± 5
I/R + BMOV
66 ± 2
61 ± 9
64 ± 6**
52 ± 6
51 ± 9
49 ± 7
54 ± 5
50 ± 5
49 ± 2
I/R + BMOV
50 ± 5
50 ± 4
48 ± 3
Systemic and renal hemodynamic and oxygenation variables
Renal I/R did not significantly affect MAP, but decreased RBF and increased RVR, which was associated with decreases in both renal DO2 and VO2. BMOV did not affect any of these macrocirculatory hemodynamic and oxygenation variables. CμpO2 and MμpO2 were similar before and after reperfusion. At the end of the protocol, CμpO2 was significantly higher in the BMOV treated group compared to the I/R control group.
Renal function parameters
At the end of the protocol, renal DO2 and VO2 were decreased proportionally. Renal TNa+ was significantly reduced in the I/R control group, but in the group receiving BMOV, this decrease was not statistically significant. Renal creatinine clearance rate decreased after I/R, both with and without BMOV administration; however, it did not reach a level of significance in both groups. Similarly renal oxygen handling efficacy (VO2/TNa+) were maintained after I/R in both groups.
The aim of the present study was to test the potential protective effects of BMOV (15 mg/kg) in the acute phase of renal I/R and its effects on renal oxygenation and renal function up to 90 min post-ischemia. The main findings were that (1) BMOV did not significantly affect the systemic or the renal hemodynamic and oxygenation variables and (2) BMOV partially protected TNa+ after I/R. Furthermore, we found that microcirculatory oxygenation in the renal cortex and medulla tended to decrease after I/R. In contrast to the non-treated animals, cortical microcirculatory oxygenation was preserved in the BMOV-treated animals, but no significant differences were seen in the renal medulla.
To our knowledge, this is the first study investigating the effects of organic vanadium compound BMOV in the context of renal I/R injury. Inorganic vanadium compounds are documented to be nephrotoxic, particularly if used chronically , but organic vanadium compounds, such as BMOV, are known to have less side effects. In experimental studies, both pre- and post-ischemic administrations of vanadium compounds have been shown to be cytoprotective. We believe that preventive strategies are essential in order to minimize I/R injury. Therefore, we administered BMOV 30 min before the onset of ischemia. The optimal dosage of BMOV in order to prevent renal I/R injury is unknown, but administration of 15 mg/kg is recommended by the manufacturer, which is also comparable to the doses used in earlier studies .
Earlier studies investigating the beneficial effects of vanadium compounds after I/R injury in vivo have mainly been focused on the brain and on the heart. However, the type of vanadium, the type of administration, and the timing of administration varied significantly between studies. In the context of brain I/R, Kawano et al. showed in adult Mongolian gerbils that were subjected to 5-min forebrain ischemia that intraventricular injection of orthovanadate 30 min before ischemia blocked delayed neuronal death . Hasegawa et al. demonstrated the neuroprotective effects of post-ischemic intraperitoneal administration of sodium orthovanadate in rats with transient middle cerebral artery occlusion 1 and 28 days after ischemia . In a subsequent study, the authors determined the therapeutic time window (0, 45, and 90 min post-middle cerebral artery occlusion) and the neuroprotective dose (2 mL/kg and 12.5, 25, 37.5, and 50 mM) of sodium orthovanadate in rats . Later, Shioda et al. found in a mouse model of transient middle cerebral artery occlusion that pre- and post-treatments with bis(1-oxy-2-pyridinethiolato)oxovanadium(IV) significantly reduced infarct volume in a dose-dependent manner and thereby provided neuroprotection in brain I/R injury . The same group also showed that i.p. administration of bis(1-oxy-2-pyridinethiolato)oxovanadium(IV) markedly enhanced brain ischemia-induced neurogenesis in the subgranular zone of the mouse hippocampus . Additionally, they found that amelioration of cognitive dysfunction following brain ischemia was positively correlated with vanadium-induced neurogenesis. Li et al. found that bisperoxovanadium attenuated cellular apoptosis in developing rat brain rescued neurons from hypoxia-ischemia brain damage . Liu et al., furthermore, showed that 4 weeks of administration of sodium orthovanadate in drinking water significantly improved the outcome in rats with streptozotocin-induced diabetes after cerebral ischemia and reperfusion in terms of neurobehavioral function . In the context of myocardial I/R, Geraldes et al. showed in isolated perfused rat hearts that the presence of vanadate during ischemia resulted in attenuation of acidosis and reduced lactate accumulation . In anesthetized rats, Liem et al. showed that intravenous infusion of BMOV in doses of 3.3, 7.5, and 15 mg/kg i.v. decreased myocardial infarct size dose-dependently when administered before occlusion . Administration of the low dose during ischemia just before reperfusion was ineffective, but administration of the higher doses was equally cardioprotective as compared with administration before occlusion. Bhuiyan et al. showed that post-ischemic treatment with bis(1-oxy-2-pyridinethiolato)oxovanadium(IV) significantly reduced infarct size and improved cardiac function in a dose-dependent manner . That same group also showed that post-treatment with vanadyl sulfate significantly reduced the infarct size and significantly decreased the elevated left ventricular end-diastolic pressure, improved left ventricular developed pressure, and left ventricular contractility in a dose-dependent manner. Keyes et al. showed that the intravenous administration of bisperoxovanadium significantly reduced myocardial infarct size and improved cardiac function .
As demonstrated by many of the studies referenced above, vanadium compounds activate protein kinase B (Akt) signaling through inhibition of protein tyrosine phosphatases. Akt is an important signaling molecule that modulates many cellular processes such as cell growth, survival, and metabolism. Hence, by activating Akt signaling, vanadium compounds elicit cytoprotection in brain and myocardial I/R injuries. This would make vanadium also a potential candidate for reducing I/R injury in the kidney.
It must be acknowledged that our study has some limitations. Investigation of the dose-dependent response to BMOV, a longer follow-up after I/R, the acting mechanisms of BMOV, and histological evaluation of the effects of I/R and BMOV are the important limitations of our study. Since the potential benefits of BMOV in the context of I/R were never studied before, we chose to perform a relatively simple, short-term study in which we mainly focused on the effects of BMOV on renal oxygenation and function. However, longer studies are required in which different doses of BMOV are given and more detailed analysis of the involved pathways is done, together with histological evaluation. Furthermore, we used creatinine clearance rate and sodium reabsorption as measures of renal function, but we admit that these methods can lead to imprecision due to back leak phenomena and slight tubular creatinine secretion.
In conclusion, pretreatment with the organic vanadium compound BMOV did not significantly affect the systemic or the renal hemodynamic and oxygenation variables and only partially protected renal sodium reabsorption after I/R. However, longer studies are required in which different doses of BMOV are given and more detailed analysis of the involved pathways is done, together with histological evaluation to fully understand the potential protective role of BMOV in the context of renal I/R.
- Uchino S, Bellomo R, Goldsmith D, Bates S, Ronco C: An assessment of the RIFLE criteria for acute renal failure in hospitalized patients. Crit Care Med 2006, 34: 1913–1917. 10.1097/01.CCM.0000224227.70642.4FView ArticleGoogle Scholar
- Zanardo G, Michielon P, Paccagnella A, Rosi P, Caló M, Salandin V, Da Ros A, Michieletto F, Simini G: Acute renal failure in the patient undergoing cardiac operation: prevalence, mortality rate, and main risk factors. J Thorac Cardiovasc Surg 1994, 107: 1489–1495.Google Scholar
- Schwilk B, Wiedeck H, Stein B, Reinelt H, Treiber H, Bothner U: Epidemiology of acute renal failure and outcome of haemodiafiltration in intensive care. Intensive Care Med 1997, 23: 1204–1211. 10.1007/s001340050487View ArticleGoogle Scholar
- Bonventre JV, Weinberg JM: Recent advances in the pathophysiology of ischemic acute renal failure. J Am Soc Nephrol 2003, 14: 2199–2210. 10.1097/01.ASN.0000079785.13922.F6View ArticleGoogle Scholar
- Weight SC, Bell PR, Nicholson ML: Renal ischaemia-reperfusion injury. Br J Surg 1996, 83: 162–170. 10.1002/bjs.1800830206View ArticleGoogle Scholar
- Li L, Okusa MD: Blocking the immune response in ischemic acute kidney injury: the role of adenosine 2A agonists. Nat Clin Pract Nephrol 2006, 2: 432–444.View ArticleGoogle Scholar
- Okusa MD: The inflammatory cascade in acute ischemic renal failure. Nephron 2002, 90: 133–138. 10.1159/000049032View ArticleGoogle Scholar
- Linas SL, Whittenburg D, Parsons PE, Repine JE: Ischemia increases neutrophil retention and worsens acute renal failure: role of oxygen metabolites and ICAM-1. Kidney Int 1995, 48: 1548–1591.View ArticleGoogle Scholar
- Ueda N, Walker P, Shah SV: Oxidant stress in acute renal failure. In Acute renal failure: new concepts and therapeutic strategies. Edited by: Goligorsky MS, Stein JH. Churchill Livingstone, New York; 1995.Google Scholar
- Noiri E, Peresleni T, Miller F, Goligorsky MS: In vivo targeting of inducible NO synthase with oligodeoxynucleotides protects rat kidney against ischemia. J Clin Investig 1996, 97: 2377–2383. 10.1172/JCI118681View ArticleGoogle Scholar
- Vinas JL, Sola A, Hotter G: Mitochondrial NOS upregulation during renal I/R causes apoptosis in a peroxynitrite-dependent manner. Kidney Int 2006, 69: 1403–1409.View ArticleGoogle Scholar
- Walker LM, Walker PD, Imam SZ, Ali SF, Mayeux PR: Evidence for peroxynitrite formation in renal ischemia-reperfusion injury: studies with the inducible nitric-oxide synthase inhibitor L-N6-(1-iminoethyl)-lysine. J Pharmacol Exp Ther 2000, 295: 417–422.Google Scholar
- Legrand M, Mik EG, Johannes T, Payen D, Ince C: Renal hypoxia and dysoxia after reperfusion of the ischemic kidney. Mol Med 2008, 14: 502–516.View ArticleGoogle Scholar
- Bhuiyan MS, Shioda N, Fukunaga K: Targeting protein kinase B/Akt signalling with vanadium compounds for cardioprotection. Expert Opin Ther Targets 2008, 12: 1217–1227. 10.1517/14728188.8.131.527View ArticleGoogle Scholar
- Bhuiyan MS, Fukunaga K: Cardioprotection by vanadium compounds targeting Akt-mediated signaling. J Pharmacol Sci 2009, 110: 1–13. 10.1254/jphs.09R01CRView ArticleGoogle Scholar
- Bhuiyan MS, Takada Y, Shioda N, Moriguchi S, Kasahara J, Fukunaga K: Cardioprotective effect of vanadyl sulfate on ischemia/reperfusion-induced injury in rat heart in vivo is mediated by activation of protein kinase B and induction of FLICE-inhibitory protein. Cardiovasc Ther 2008, 26: 10–23.View ArticleGoogle Scholar
- Johannes T, Mik EG, Ince C: Dual-wavelength phosphorimetry for determination of cortical and subcortical microvascular oxygenation in rat kidney. J Appl Physiol 2006, 100: 1301–1310.View ArticleGoogle Scholar
- Mik EG, Johannes T, Ince C: Monitoring of renal venous PO2 and kidney oxygen consumption in rats by a near-infrared phosphorescence lifetime technique. Am J Physiol Renal Physiol 2008, 294: F676-F681. 10.1152/ajprenal.00569.2007View ArticleGoogle Scholar
- Vinogradov SA, Fernandez-Seara MA, Dupan BW, Wilson DF: A method for measuring oxygen distributions in tissue using frequency domain phosphorometry. Comp Biochem Physiol A Mol Integr Physiol 2002, 132: 147–152. 10.1016/S1095-6433(01)00541-4View ArticleGoogle Scholar
- Dunphy I, Vinogradov SA, Wilson DF: Oxyphor R2 and G2: phosphors for measuring oxygen by oxygen-dependent quenching of phosphorescence. Anal Biochem 2002, 310: 191–198. 10.1016/S0003-2697(02)00384-6View ArticleGoogle Scholar
- de la Torre A, Granero S, Mayayo E, Corbella J, Domingo JL: Effect of age on vanadium nephrotoxicity in rats. Toxicol Lett 1999, 105(1):75–82. 10.1016/S0378-4274(98)00385-3View ArticleGoogle Scholar
- Liem DA, Gho CC, Gho BC, Kazim S, Manintveld OC, Verdouw PD, Duncker DJ: The tyrosine phosphatase inhibitor bis(maltolato)oxovanadium attenuates myocardial reperfusion injury by opening ATP-sensitive potassium channels. J Pharmacol Exp Ther 2004, 309: 1256–1262. 10.1124/jpet.103.062547View ArticleGoogle Scholar
- Kawano T, Fukunaga K, Takeuchi Y, Morioka M, Yano S, Hamada J, Ushio Y, Miyamoto E: Neuroprotective effect of sodium orthovanadate on delayed neuronal death after transient forebrain ischemia in gerbil hippocampus. J Cereb Blood Flow Metab 2001, 21: 1268–1280.View ArticleGoogle Scholar
- Hasegawa Y, Morioka M, Hasegawa S, Matsumoto J, Kawano T, Kai Y, Yano S, Fukunaga K, Kuratsu J: Therapeutic time window and dose dependence of neuroprotective effects of sodium orthovanadate following transient middle cerebral artery occlusion in rats. J Pharmacol Exp Ther 2006, 317: 875–881. 10.1124/jpet.105.096677View ArticleGoogle Scholar
- Shioda N, Ishigami T, Han F, Moriguchi S, Shibuya M, Iwabuchi Y, Fukunaga K: Activation of phosphatidylinositol 3-kinase/protein kinase B pathway by a vanadyl compound mediates its neuroprotective effect in mouse brain ischemia. Neuroscience 2007, 148: 221–229. 10.1016/j.neuroscience.2007.05.040View ArticleGoogle Scholar
- Shioda N, Han F, Morioka M, Fukunaga K: Bis(1-oxy-2-pyridinethiolato)oxovanadium(IV) enhances neurogenesis via phosphatidylinositol 3-kinase/Akt and extracellular signal regulated kinase activation in the hippocampal subgranular zone after mouse focal cerebral ischemia. Neuroscience 2008, 155: 876–887. 10.1016/j.neuroscience.2008.05.056View ArticleGoogle Scholar
- Li D, Qu Y, Mao M, Zhang X, Li J, Ferriero D, Mu D: Involvement of the PTEN-AKT-FOXO3a pathway in neuronal apoptosis in developing rat brain after hypoxia-ischemia. J Cereb Blood Flow Metab 2009, 29: 1903–1913. 10.1038/jcbfm.2009.102View ArticleGoogle Scholar
- Liu Z, Li P, Zhao D, Tang H, Guo J: Protection by vanadium, a contemporary treatment approach to both diabetes and focal cerebral ischemia in rats. Biol Trace Elem Res 2012, 145: 66–70. 10.1007/s12011-011-9168-9View ArticleGoogle Scholar
- Geraldes CF, Castro MM, Sherry AD, Ramasamy R: Influence of vanadate on glycolysis, intracellular sodium, and pH in perfused rat hearts. Mol Cell Biochem 1997, 170: 53–63. 10.1023/A:1006899932108View ArticleGoogle Scholar
- Keyes KT, Xu J, Long B, Zhang C, Hu Z, Ye Y: Pharmacological inhibition of PTEN limits myocardial infarct size and improves left ventricular function postinfarction. Am J Physiol Heart Circ Physiol 2010, 298: H1198-H1208. 10.1152/ajpheart.00915.2009View ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.