Exercise-induced improvements in myocardial antioxidant capacity: the antioxidant players and cardioprotection.

Endurance exercise training is known to promote beneficial adaptations to numerous tissues including the heart. Indeed, endurance exercise training results in a cardioprotective phenotype that resists injury during an ischemia-reperfusion (IR) insult. Because IR-induced cardiac injury is due, in part, to increased production of radicals and other reactive oxygen species, many studies have explored the impact of exercise training on myocardial antioxidant capacity. Unfortunately, the literature describing the effects of exercise on the cardiac antioxidant capacity is widely inconsistent. Nonetheless, a growing body of evidence indicates that regular bouts of endurance exercise promote an increase in the expression of both superoxide dismutase 1 and 2 in cardiac mitochondria. Moreover, emerging evidence suggests that exercise also increases accessory antioxidant enzymes in the heart. Importantly, robust evidence indicates that as few as five consecutive days of endurance exercise training results in a cardiac phenotype that resists IR-induced arrhythmias, myocardial stunning, and infarction. Further, mechanistic studies indicate that exercise-induced increases in mitochondrial superoxide dismutase 2 play a key role in this adaptation. Future studies are required to provide a complete picture regarding the cellular adaptations that are responsible for exercise-induced cardioprotection.

Physical inactivity is a major contributor to ovariectomy-induced sarcopenia.

Since the mechanism(s) underlying menopause-related sarcopenia remain unknown we aimed to investigate the role of physical inactivity in its etiology. Ovariectomized and sham-operated rats were allocated into 2 experimental groups: (1) sedentary-standard housing; and (2) exercise-housed with running wheel. After a 9-month experimental period, soleus muscle structure and biochemical properties were analyzed. No differences existed in muscle fibre size or ultrastructure between sedentary sham and ovariectomized animals housed in standard conditions. In the exercise groups, average daily running distance was 10-fold less in ovariectomized compared to sham-animals. Further, in exercised animals, soleus fibre size was smaller in ovariectomized compared to sham-animals. Nonetheless, compared to both sedentary groups, muscle fibre size was larger in the exercised ovariectomized animals. Our results indicate that ovariectomy-induced sarcopenia is not due to the loss of ovarian hormones per se, but is largely due to physical inactivity.

Testosterone administration induces protection against global myocardial ischemia.

We tested the hypothesis that chronic testosterone treatment would promote a cardioprotective phenotype against ischemia/reperfusion (I/R) injury. For this study, 3-month-old F344 male rats underwent sham-surgery, orchiectomy (ORX), or ORX plus 21 days testosterone treatment (1.0 mg testosterone/day). At sacrifice, cardiac performance was assessed in a working heart model of I/R (25 min of global ischemia and 45 min of reperfusion). ORX reduced serum testosterone by approximately 98% and testosterone administration elevated serum testosterone to a concentration of 4.6-fold over that of Sham-operated controls (p<0.05). ORX did not significantly impair recovery of cardiac performance following I/R, but did increase cardiac release of lactate dehydrogenase (LDH) during pre- and post-ischemia (p<0.05). Testosterone administration prevented the ORX-induced increase in LDH during both pre- and post-ischemia and increased post-ischemic recovery of aortic flow, cardiac output, cardiac work, left ventricular developed pressure, and contractility (p<0.05) during reperfusion. Testosterone administration also increased left ventricular expression of catalase, but did not affect the expression of manganese superoxide dismutase, glutathione peroxidase, or sarcolemmal K (ATP) channel protein Kir6.2. Neither circulating nor cardiac concentrations of estradiol were altered by either treatment. We conclude that administration of high-dose testosterone confers cardioprotection through yet to be identified androgen-dependent mechanism(s).

p38 MAPK links oxidative stress to autophagy-related gene expression in cachectic muscle wasting.

Oxidative stress is a primary trigger of cachectic muscle wasting, but the signaling pathway(s) that links it to the muscle wasting processes remains to be defined. Here, we report that activation of p38 mitogen-activated protein kinase (MAPK) (phosphorylation) and increased oxidative stress (trans-4-hydroxy-2-nonenal protein modification) in skeletal muscle occur as early as 8 h after lipopolysaccharide (1 mg/kg) and 24 h after dexamethasone (25 mg/kg) injection (intraperitoneal) in mice, concurrent with upregulation of autophagy-related genes, Atg6, Atg7, and Atg12. Treating cultured C2C12 myotubes with oxidant hydrogen peroxide (4 h) resulted in increased p38 phosphorylation and reduced FoxO3 phosphorylation along with induced Atg7 mRNA expression without activation of NF-kappaB or FoxO3a transcriptional activities. Furthermore, inhibition of p38alpha/beta by SB202190 blocked hydrogen peroxide-induced atrophy with diminished upregulation of Atg7 and atrogenes [muscle atrophy F-box protein (MAFbx/Atrogin-1), muscle ring finger protein 1 (MuRF-1), and Nedd4]. These findings provide direct evidence for p38alpha/beta MAPK in mediating oxidative stress-induced autophagy-related genes, suggesting that p38alpha/beta MAPK regulates both the ubiquitin-proteasome and the autophagy-lysosome systems in muscle wasting.

Calpain-1 is required for hydrogen peroxide-induced myotube atrophy.

Recent reports suggest numerous roles for cysteine proteases in the progression of skeletal muscle atrophy due to disuse or disease. Nonetheless, a specific requirement for these proteases in the progression of skeletal muscle atrophy has not been demonstrated. Therefore, this investigation determined whether calpains or caspase-3 is required for oxidant-induced C2C12 myotube atrophy. We demonstrate that exposure to hydrogen peroxide (25 microM H2O2) induces myotube oxidative damage and atrophy, with no evidence of cell death. Twenty-four hours of exposure to H2O2 significantly reduced both myotube diameter and the abundance of numerous proteins, including myosin (-81%), alpha-actinin (-40%), desmin (-79%), talin (-37%), and troponin I (-80%). Myotube atrophy was also characterized by increased cleavage of the cysteine protease substrate alphaII-spectrin following 4 h and 24 h of H2O2 treatment. This degradation was blocked by administration of the protease inhibitor leupeptin (10 microM). Using small interfering RNA transfection of mature myotubes against the specific proteases calpain-1, calpain-2, and caspase-3, we demonstrated that calpain-1 is required for H2O2-induced myotube atrophy. Collectively, our data provide the first evidence for an absolute requirement for calpain-1 in the development of skeletal muscle myotube atrophy in response to oxidant-induced cellular stress.

Redox regulation of diaphragm proteolysis during mechanical ventilation.

Prevention of oxidative stress via antioxidants attenuates diaphragm myofiber atrophy associated with mechanical ventilation (MV). However, the specific redox-sensitive mechanisms responsible for this remain unknown. We tested the hypothesis that regulation of skeletal muscle proteolytic activity is a critical site of redox action during MV. Sprague-Dawley rats were assigned to five experimental groups: 1) control, 2) 6 h of MV, 3) 6 h of MV with infusion of the antioxidant Trolox, 4) 18 h of MV, and 5) 18 h of MV with Trolox. Trolox did not attenuate MV-induced increases in diaphragmatic levels of ubiquitin-protein conjugation, polyubiquitin mRNA, and gene expression of proteasomal subunits (20S proteasome alpha-subunit 7, 14-kDa E2, and proteasome-activating complex PA28). However, Trolox reduced both chymotrypsin-like and peptidylglutamyl peptide hydrolyzing (PGPH)-like 20S proteasome activities in the diaphragm after 18 h of MV. In addition, Trolox rescued diaphragm myofilament protein concentration (mug/mg muscle) and the percentage of easily releasable myofilament protein independent of alterations in ribosomal capacity for protein synthesis. In summary, these data are consistent with the notion that the protective effect of antioxidants on the diaphragm during MV is due, at least in part, to decreasing myofilament protein substrate availability to the proteasome.

Antioxidant administration attenuates mechanical ventilation-induced rat diaphragm muscle atrophy independent of protein kinase B (PKB Akt) signalling.

Oxidative stress promotes controlled mechanical ventilation (MV)-induced diaphragmatic atrophy. Nonetheless, the signalling pathways responsible for oxidative stress-induced muscle atrophy remain unknown. We tested the hypothesis that oxidative stress down-regulates insulin-like growth factor-1-phosphotidylinositol 3-kinase-protein kinase B serine threonine kinase (IGF-1-PI3K-Akt) signalling and activates the forkhead box O (FoxO) class of transcription factors in diaphragm fibres during MV-induced diaphragm inactivity. Sprague-Dawley rats were randomly assigned to one of five experimental groups: (1) control (Con), (2) 6 h of MV, (3) 6 h of MV with infusion of the antioxidant Trolox, (4) 18 h of MV, (5) 18 h of MV with Trolox. Following 6 h and 18 h of MV, diaphragmatic Akt activation decreased in parallel with increased nuclear localization and transcriptional activation of FoxO1 and decreased nuclear localization of FoxO3 and FoxO4, culminating in increased expression of the muscle-specific ubiquitin ligases, muscle atrophy factor (MAFbx) and muscle ring finger-1 (MuRF-1). Interestingly, following 18 h of MV, antioxidant administration was associated with attenuation of MV-induced atrophy in type I, type IIa and type IIb/IIx myofibres. Collectively, these data reveal that the antioxidant Trolox attenuates MV-induced diaphragmatic atrophy independent of alterations in Akt regulation of FoxO transcription factors and expression of MAFbx or MuRF-1. Further, these results also indicate that differential regulation of diaphragmatic IGF-1-PI3K-Akt signalling exists during the early and late stages of MV.

Mechanical ventilation promotes redox status alterations in the diaphragm.

Oxidative stress is an important mediator of diaphragm muscle atrophy and contractile dysfunction during prolonged periods of controlled mechanical ventilation (MV). To date, specific details related to the impact of MV on diaphragmatic redox status remain unknown. To fill this void, we tested the hypothesis that MV-induced diaphragmatic oxidative stress is the consequence of both an elevation in intracellular oxidant production in conjunction with a decrease in the antioxidant buffering capacity. Adult rats were assigned to one of two experimental groups: 1) control or 2) 12 h of MV. Compared with controls, diaphragms from MV animals demonstrated increased oxidant production, diminished total antioxidant capacity, and decreased glutathione levels. Heme oxygenase-1 (HO-1) mRNA and protein levels increased (23.0- and 5.1-fold, respectively) following MV. Thioredoxin reductase-1 and manganese superoxide dismutase mRNA levels were also increased in the diaphragm following MV (2.4- and 1.6-fold, respectively), although no change was detected in the levels of either protein. Furthermore, copper-zinc superoxide dismutase and glutathione peroxidase mRNA were not altered following MV, although protein content decreased -1.3- and -1.7-fold, respectively. We conclude that MV promotes increased oxidant production and impairment of key antioxidant defenses in the diaphragm; collectively, these changes contribute to the MV-induced oxidative stress in this key inspiratory muscle.

Exercise and myocardial tolerance to ischaemia-reperfusion.

UNLABELLED: It is well established that both short-term (1-5 days) and long-term (weeks to months) high intensity exercise (i.e. 70-75%VO2max) provides cardioprotection against ischaemia-reperfusion injury. However, it is unclear if moderate intensity exercise will also provide cardioprotection. AIM: Therefore, these experiments compared the protective effects of moderate vs. high intensity exercise in providing defense against ischaemia-reperfusion injury. METHODS: Male Sprague-Dawley rats were randomly assigned to one of three-experimental groups: (1) sedentary (control); (2) moderate intensity treadmill exercise (60 min day(-1) at approximately 55%VO2max); or (3) high intensity treadmill exercise (60 min day(-1) at approximately 75%VO2max). Hearts were exposed to 20 min of global ischaemia followed by 30 min reperfusion in an isolated working heart preparation. RESULTS: Compared with sedentary rats, both moderate and high intensity exercised rats maintained a higher (P < 0.05) percentage of pre-ischaemia cardiac output and cardiac work (cardiac output x systolic blood pressure) during reperfusion. No differences in the percent recovery of cardiac output and heart work existed (P > 0.05) between the two exercise groups. CONCLUSIONS: These data reveal that both moderate and high intensity exercise training provide equivalent protection against ischaemia-reperfusion injury.

Short-term exercise improves myocardial tolerance to in vivo ischemia-reperfusion in the rat.

These experiments examined the independent effects of short-term exercise and heat stress on myocardial responses during in vivo ischemia-reperfusion (I/R). Female Sprague-Dawley rats (4 mo old) were randomly assigned to one of four experimental groups: 1) control, 2) 3 consecutive days of treadmill exercise [60 min/day at 60-70% maximal O2 uptake (VO2 max)], 3) 5 consecutive days of treadmill exercise (60 min/day at 60-70% VO2 max), and 4) whole body heat stress (15 min at 42 degrees C). Twenty-four hours after heat stress or exercise, animals were anesthetized and mechanically ventilated, and the chest was opened by thoracotomy. Coronary occlusion was maintained for 30-min followed by a 30-min period of reperfusion. Compared with control, both heat-stressed animals and exercised animals (3 and 5 days) maintained higher (P < 0.05) left ventricular developed pressure (LVDP), maximum rate of left ventricular pressure development (+dP/dt), and maximum rate of left ventricular pressure decline (-dP/dt) at all measurement periods during both ischemia and reperfusion. No differences existed between heat-stressed and exercise groups in LVDP, +dP/dt, and -dP/dt at any time during ischemia or reperfusion. Both heat stress and exercise resulted in an increase (P < 0.05) in the relative levels of left ventricular heat shock protein 72 (HSP72). Furthermore, exercise (3 and 5 days) increased (P < 0.05) myocardial glutathione levels and manganese superoxide dismutase activity. These data indicate that 3-5 consecutive days of exercise improves myocardial contractile performance during in vivo I/R and that this exercise-induced myocardial protection is associated with an increase in both myocardial HSP72 and cardiac antioxidant defenses.

Short-term exercise training can improve myocardial tolerance to I/R without elevation in heat shock proteins.

We examined the effects of 3 days of exercise in a cold environment on the expression of left ventricular (LV) heat shock proteins (HSPs) and contractile performance during in vivo ischemia-reperfusion (I/R). Sprague-Dawley rats were divided into the following three groups (n = 12/group): 1) control, 2) exercise (60 min/day) at 4 degrees C (E-Cold), and 3) exercise (60 min/day) at 25 degrees C (E-Warm). Left anterior descending coronary occlusion was maintained for 20 min, followed by 30 min of reperfusion. Compared with the control group, both the E-Cold and E-Warm groups maintained higher (P < 0.05) LV developed pressure, first derivative of pressure development over time (+dP/dt), and pressure relaxation over time (-dP/dt) throughout I/R. Relative levels of HSP90, HSP72, and HSP40 were higher (P < 0.05) in E-Warm animals compared with both control and E-Cold. HSP10, HSP60, and HSP73 did not differ between groups. Exercise increased manganese superoxide dismutase (MnSOD) activity in both E-Warm and E-Cold hearts (P < 0.05). Protection against I/R-induced lipid peroxidation in the LV paralleled the increase in MnSOD activity whereas lower levels of lipid peroxidation were observed in both E-Warm and E-Cold groups compared with control. We conclude that exercise-induced myocardial protection against a moderate duration I/R insult is not dependent on increases in myocardial HSPs. We postulate that exercise-associated cardioprotection may depend, in part, on increases in myocardial antioxidant defenses.

Mechanism for obesity-induced increase in myocardial lipid peroxidation.

OBJECTIVE: To determine the mechanisms underlying the obesity-induced increase in myocardial lipid peroxidation in the fa/fa rat. We hypothesized that elevated heart work (ie rate-pressure product), an increased rate of superoxide (O2*-)) production, total myocardial lipid content, and/or insufficient antioxidant defenses are potential contributors to myocardial lipid peroxidation in obesity. DESIGN: Comparative, experimental study of myocardial tissue in 16-week-old lean control (Fa/?, normal diet), obese high-fat fed (Fa/?, 45% dietary fat), and obese fatty (fa/fa, normal diet) Zucker rats. MEASUREMENTS: Myocardial work (heart rate x systolic blood pressure), myocardial lipid content, oxidative and antioxidant enzyme activities (citrate synthase (CS), catalase (CAT), glutathione peroxidase (GPX), superoxide dismutase (SOD)), the rate of papillary muscle superoxide radical production in vitro, thiol content, basal and post-oxidative challenge myocardial lipid peroxidation levels using thiobarbituric reactive acid substances (TBARS) and lipid hydroperoxides (PEROX) as indices of lipid peroxidation. RESULTS: Compared to lean controls, the high-fat fed and fatty animals had similar elevations (P<0.05) in myocardial TBARS and PEROX (23%, 25% and 29% 45%, respectively; P<0.05), and elevated susceptibilities to oxidative stress in vitro following exposure to oxidizing agents (P<0.05). Resting heart work was slightly higher (P<0.05) in both the high-fat fed and fatty animals compared to controls. Myocardial lipid content, SOD activities and non-protein thiol (glutathione) levels were elevated (P<0.05) in high-fat fed and fatty animals compared to controls. The rate of superoxide formation by isolated papillary muscles in vitro did not differ among groups (P<0.05). Regression analysis revealed that the myocardial lipid content contributed most to myocardial lipid peroxidation (R2=0.76, P<0.05). CONCLUSIONS: Myocardial oxidative injury is closely associated with myocardial lipid content, but is not closely correlated with heart work, insufficient antioxidant defenses or a greater rate of superoxide production.

Exercise training increases heat shock protein in skeletal muscles of old rats.

PURPOSE: The effects of chronic exercise training on the expression of heat shock protein (HSP) in skeletal muscle of senescent animals are unknown. Therefore, the purpose of this study was to investigate the effects of chronic exercise training on skeletal muscle HSP expression in both young and old rats. METHODS: Young adult (3 months) and old (23 months) female Fisher 344 rats were assigned to either a sedentary control or an endurance exercise trained group (N = 6 per group). Exercised animals ran (60 min.d-1, 5 d.wk-1) on a treadmill at approximately 77% VO2peak for 10 wk. After completion of the training program, the soleus (SOL), plantaris (PL), and the red (RG) and white portions (WG) of the gastrocnemius muscles were excised, and citrate synthase (CS) activity and the relative levels of HSP72 were determined. RESULTS: Training resulted in increases (P < 0.05) in VO2peak in both young (67.6 +/- 3.1 vs 86.9 +/- 1.6 mL.kg-1.min-1) and old animals (54.5 +/- 1.8 vs 68.2 +/- 2.2 mL.kg-1.min-1). Training increased CS activity and the relative levels of HSP72 (P < 0.05) in all four skeletal muscles in both young and old animals. Specifically, compared with age-matched sedentary controls, exercise training resulted in increased (P < 0.05) levels of HSP72 in skeletal muscles of both young (SOL + 22%, PL +94%, RG + 44%, WG + 243%) and old animals (SOL +15%, PL +73%, RG +38%, WG +150%). CONCLUSIONS: These findings reveal that the exercise-induced accumulation of HSP72 in skeletal muscle differs between fast and slow muscles. Further, these data indicate that the exercise-induced accumulation of HSP72 in highly oxidative skeletal muscles (SOL and RG) is similar between young and old animals. In contrast, aging is associated with a blunted expression of HSP72 in fast skeletal muscles (PL and WG) in response to chronic exercise.

Effects of vitamin E and alpha-lipoic acid on skeletal muscle contractile properties.

Initial experiments were conducted using an in situ rat tibialis anterior (TA) muscle preparation to assess the influence of dietary antioxidants on muscle contractile properties. Adult Sprague-Dawley rats were divided into two dietary groups: 1) control diet (Con) and 2) supplemented with vitamin E (VE) and alpha-lipoic acid (alpha-LA) (Antiox). Antiox rats were fed the Con rats' diet (AIN-93M) with an additional 10,000 IU VE/kg diet and 1.65 g/kg alpha-LA. After an 8-wk feeding period, no differences existed (P > 0.05) between the two dietary groups in maximum specific tension before or after a fatigue protocol or in force production during the fatigue protocol. However, in unfatigued muscle, maximal twitch tension and tetanic force production at stimulation frequencies < or = 40 Hz were less (P < 0.05) in Antiox animals compared with Con. To investigate which antioxidant was responsible for the depressed force production, a second experiment was conducted using an in vitro rat diaphragm preparation. Varying concentrations of VE and dihydrolipoic acid, the reduced form of alpha-LA, were added either individually or in combination to baths containing diaphragm muscle strips. The results from these experiments indicate that high levels of VE depress skeletal muscle force production at low stimulation frequencies.

Gene expression of catecholamine biosynthetic enzymes following exercise: modulation by age.

Both age and exercise training are associated with tissue specific alterations in the catecholaminergic system. We examined the effect of short-term exercise training on tyrosine hydroxylase and dopamine beta-hydroxylase gene expression in adrenals and specific brain regions with aging. In addition, we examined activator protein-1 and cyclic AMP response element transcription factor binding activity in the adrenal medulla. Male, six- and 24-month-old F-344 rats were exercised by treadmill running for five consecutive days. One group was killed immediately and a second group was killed 2h after the last training session. Exercise significantly elevated tyrosine hydroxylase messenger RNA equally in adrenals of both young and old rats. Training had no effect on dopamine beta-hydroxylase messenger RNA in adrenals of young, but levels were elevated in old rats. Binding activities of both activator protein-1 and cyclic AMP response element binding protein were diminished with age in the adrenal medulla. Exercise training had no significant effect on the binding activity of cyclic AMP response element binding protein in either young or old animals, whereas activator protein-1 binding activity increased equally in young and old animals. Exercise training revealed divergent changes in tyrosine hydroxylase messenger RNA in brain catecholaminergic neurons. In the locus coeruleus and the ventral tegmental areas, training elevated tyrosine hydroxylase messenger RNA levels only in young rats. In the substantia nigra, there was no change in young, but a 45% increase in tyrosine hydroxylase messenger RNA in old rats. In the ventral tegmental area, training increased tyrosine hydroxylase gene expression 80% in young but not in old rats. These results indicate that short-term exercise training increases tyrosine hydroxylase messenger RNA levels in young animals in the adrenals, the locus coeruleus and the ventral tegmental area. The responses for exercise training of aged animals differed from the young in brain noradrenergic and dopaminergic nuclei, especially in the substantia nigra, and to some extent in the locus coeruleus and the ventral tegmental area.

Exercise, heat shock proteins, and myocardial protection from I-R injury.

Heat shock proteins (HSPs) play a critical role in maintaining cellular homeostasis and protecting cells during episodes of acute stress. Specifically, HSPs of the 70 kDa family (i.e., HSP72) are important in preventing ischemia-reperfusion induced apoptosis, necrosis, and oxidative injury in a variety of cell types including the cardiac myocyte. Evidence indicates that HSP72 may contribute to cellular protection against a variety of stresses by preventing protein aggregation, assisting in the refolding of damaged proteins, and chaperoning nascent polypeptides along ribosomes. Endurance exercise is a physiological stress that can be used to elevate myocardial levels of HSP72. It is now clear that endurance exercise training can elevate myocardial HSP72 by 400-500% in young adult animals. Importantly, an exercise-induced elevation in myocardial HSPs is associated with a reduction in ischemia-reperfusion (I-R) injury in the heart. Although it seems likely that exercise-induced elevations in myocardial levels of HSPs play an important role in this protection against an I-R insult, new evidence suggests that other factors may also be involved. This is an important area for future research.

Primitive neuroectodermal tumor of cerebrum with adipose tissue.

Primitive neuroectodermal tumors (PNETs) of the central nervous system are uncommon embryonal neoplasms, rarely occurring in adults. Differentiation into specific mesenchymal tissues, such as cartilage, bone, skeletal muscle, smooth muscle, or adipose tissue, is rare. We report a case of a 51-year-old woman with a PNET of cerebrum that showed extensive mature adipose tissue differentiation. This is the second case, to our knowledge, of PNET of cerebrum with adipose tissue elements that has been described.

Improved cardiac performance after ischemia in aged rats supplemented with vitamin E and alpha-lipoic acid.

The purpose of these experiments was to examine the effects of dietary antioxidant supplementation with vitamin E (VE) and alpha-lipoic acid (alpha-LA) on biochemical and physiological responses to in vivo myocardial ischemia-reperfusion (I-R) in aged rats. Male Fischer-334 rats (18 mo old) were assigned to either 1) a control diet (CON) or 2) a VE and alpha-LA supplemented diet (ANTIOX). After a 14-wk feeding period, animals in each group underwent an in vivo I-R protocol (25 min of myocardial ischemia and 15 min of reperfusion). During reperfusion, peak arterial pressure was significantly higher (P < 0.05) in ANTIOX animals compared with CON diet animals. I-R resulted in a significant increase (P < 0.05) in myocardial lipid peroxidation in CON diet animals but not in ANTIOX animals. Compared with ANTIOX animals, heart homogenates from CON animals experienced significantly less (P < 0.05) oxidative damage when exposed to five different in vitro radical producing systems. These data indicate that dietary supplementation with VE and alpha-LA protects the aged rat heart from I-R-induced lipid peroxidation by scavenging numerous reactive oxygen species. Importantly, this protection is associated with improved cardiac performance during reperfusion.

Expression of a restrictive receptor for interleukin 13 is associated with glial transformation.

We have previously documented that the vast majority of high-grade gliomas over-express binding sites for interleukin 13 (IL13) in situ. We now extend this analysis to evaluate the distribution of the binding of IL13 among other brain tumors. Tumor specimens from patients with low-grade gliomas, oligodendrogliomas, ependymomas, pilocytic astrocytomas, gliosarcomas, medulloblastomas, meningiomas, and metastases to the brain were analyzed and compared to a new series of glioblastoma multiforme (GBM) samples. Serial tumor tissue sections were incubated with 125I-labeled (i) IL13, (ii) antibody against transferrin (Tf) receptor, and (iii) epidermal growth factor (EGF). Most (17/18) GBMs stained specifically for IL13 binding sites while sections from 3/11 low-grade gliomas, 5/5 high-grade gliomas (grade III), 3/5 oligodendrogliomas (all three were anaplastic), and 1/2 gliosarcomas also showed specific binding for IL13. We did not detect IL13 binding sites in medulloblastomas (0/4) and found them only in 2/20 meningiomas. Metastases to the brain (4/12, i.e., lung adenocarcinomas and renal cell carcinoma) showed some binding of 125I-IL13. The presence of receptors for Tf was ubiquitous among all studied tumors while EGF receptor expression was much more variable. Since it appears that primarily the least differentiated forms of gliomas possess IL13 binding sites in abundance, it is plausible that IL 13 receptor expressed in low-grade gliomas might be a prognostically significant marker associated with their progression to high-grade gliomas. Finally, we demonstrate that the glioma-associated IL13 receptor is truly more restrictive in nature also due to its selective representation among brain tumors of glial origin.

Optimal light dose for interstitial photodynamic therapy in treatment for malignant brain tumors.

BACKGROUND AND OBJECTIVE: The primary goal was to determine the maximal tolerable light dose that can be administered to patients undergoing multifiber interstitial photodynamic therapy (PDT) of malignant brain tumors at a fixed dose of photosensitizer. STUDY DESIGN/MATERIALS AND METHODS: Eighteen patients (12 glioblastomas, 5 anaplastic astrocytoma, and 1 malignant ependymoma) were included in this study. The total light dose delivered to the tumor was divided into three groups of six patients each: 1,500-3,700 J, 3,700-4,400 J, and 4,400-5,900 J. RESULTS: Five patients (all glioblastomas) demonstrated postoperative permanent neurologic deficits. None of the patients in 1,500-3,700 J, two patients in 3,700-4,400 J, and three patients in 4,400-5,900 J had neurologic deficits. Glioblastomas recurred more often than anaplastic astrocytomas. Increasing the light dose did not make a difference in local/regional control of glioblastomas. Patients with anaplastic astrocytomas survived (mean, 493 days) longer than patients with glioblastomas (mean, 116.5 days) after PDT. Four patients had prolonged survival (more than a year) after PDT. CONCLUSIONS: Increasing the total light dose delivered to the tumor increases the odds of having a permanent neurologic deficit but does not increase survival or time to tumor progression. There was no difference in local or marginal recurrence with increasing light dose. Recurrent anaplastic astrocytomas tend to do better than recurrent glioblastomas with PDT.