Physical Activity Attenuates Brain Irradiation-Associated Skeletal Muscle Damage in the Rat.

PURPOSE: Radiation therapy for brain tumors increases patient survival. Nonetheless, side effects are increasingly reported such as cognitive deficits and fatigue. The etiology of fatigue remains poorly described. Our hypothesis is that the abscopal effects of radiation therapy on skeletal muscle may be involved in fatigue. The present study aims to assess the effect of brain irradiation on skeletal muscles and its relationship with fatigue and to analyze whether physical activity could counteract brain radiation-induced side effects. METHODS AND MATERIALS: Adult Wistar rats were randomly distributed between 4 groups: control (CTL), irradiated (IR), nonirradiated with physical activity (PA), and irradiated with physical activity (IR+PA). IR rats were exposed to a whole-brain irradiation (WBI) of 30 Gy (3 × 10 Gy). Rats subjected to PA underwent sessions of running on a treadmill, 3 times/week for 6 months. The effects of WBI on muscles were evaluated by complementary approaches: behavioral tests (fatigue, locomotion activity), magnetic resonance imaging, and histologic analyses. RESULTS: IR rats displayed a significant fatigue and a reduced locomotor activity at short term compared with the CTL group, which were attenuated with PA at 6 months after WBI. The IR rat's gastrocnemius mass decreased compared with CTL rats, which was reversed by physical activity at 14 days after WBI. Multiparametric magnetic resonance imaging of the skeletal muscle highlighted an alteration of the fiber organization in IR rats as demonstrated by a significant decrease of the mean diffusivity in the gastrocnemius at short term. Alteration of fibers was confirmed by histologic analyses: the number of type I fibers was decreased, whereas that of type IIa fibers was increased in IR animals but not in the IR+PA group. CONCLUSIONS: The data show that WBI induces skeletal muscle damage, which is attenuated by PA. This muscle damage may explain, at least in part, the fatigue of patients treated with radiation therapy.

Assessment of hypoxia and oxidative-related changes in a lung-derived brain metastasis model by [64Cu][Cu(ATSM)] PET and proteomic studies.

BACKGROUND: Brain metastases (BM) are the most frequent malignant brain tumors. The aim of this study was to characterize the tumor microenvironment (TME) of BM and particularly hypoxia and redox state, known to play a role in tumor growth and treatment resistance with multimodal PET and MRI imaging, immunohistochemical and proteomic approaches in a human lung cancer (H2030-BrM3)-derived BM model in rats. RESULTS: First, in vitro studies confirmed that H2030-BrM3 cells respond to hypoxia with increasing expression of HIF-1, HIF-2 and their target genes. Proteomic analyses revealed, among expression changes, proteins associated with metabolism, oxidative stress, metal response and hypoxia signaling in particular in cortical BM. [64Cu][Cu(ATSM)] PET revealed a significant uptake by cortical BM (p < 0.01), while no uptake is observed in striatal BM 23 days after tumor implantation. Pimonidazole, HIF-1α, HIF-2α, CA-IX as well as GFAP, CTR1 and DMT1 immunostainings are positive in both BM. CONCLUSION: Overall, [64Cu][Cu(ATSM)] imaging and proteomic results showed the presence of hypoxia and protein expression changes linked to hypoxia and oxidative stress in BM, which are more pronounced in cortical BM compared to striatal BM. Moreover, it emphasized the interest of [64Cu][Cu(ATSM)] PET to characterize TME of BM and depict inter-metastasis heterogeneity that could be useful to guide treatments.

Magnetic resonance imaging of hypoxia in acute stroke compared with fluorine-18 fluoromisonidazole-positron emission tomography: A cross-validation study?

Acute ischemic stroke results in an ischemic core surrounded by a tissue at risk, named the penumbra, which is potentially salvageable. One way to differentiate the tissues is to measure the hypoxia status. The purpose of the current study is to correlate the abnormal brain tissue volume derived from magnetic resonance-based imaging of brain oxygen saturation (St O2 -MRI) to the fluorine-18 fluoromisonidazole ([18 F]FMISO) positron emission tomography (PET) volume for hypoxia imaging validation, and to analyze the ability of St O2 -MRI to depict the different hypoxic tissue types in the acute phase of stroke. In a pertinent model of stroke in the rat, the volume of tissue with decreased St O2 -MRI signal and that with increased uptake of [18 F]FMISO were equivalent and correlated (r = 0.706; p = 0.015). The values of St O2 in the tissue at risk were significantly greater than those quantified in the core of the lesion, and were less than those for healthy tissue (52.3% ± 2.0%; 43.3% ± 1.9%, and 67.9 ± 1.4%, respectively). A threshold value for St O2 of ≈60% as the cut-off for the identification of the tissue at risk was calculated. Tissue volumes with reduced St O2 -MRI correlated with the final lesion (r = 0.964, p < 0.0001). The findings show that the St O2 -MRI approach is sensitive for the detection of hypoxia and for the prediction of the final lesion after stroke. Once validated in acute clinical settings, this approach might be used to enhance the stratification of patients for potential therapeutic interventions.

VCAM-1 targeted alpha-particle therapy for early brain metastases.

BACKGROUND: Brain metastases (BM) develop frequently in patients with breast cancer. Despite the use of external beam radiotherapy (EBRT), the average overall survival is short (6 months from diagnosis). The therapeutic challenge is to deliver molecularly targeted therapy at an early stage when relatively few metastatic tumor cells have invaded the brain. Vascular cell adhesion molecule 1 (VCAM-1), overexpressed by nearby endothelial cells during the early stages of BM development, is a promising target. The aim of this study was to investigate the therapeutic value of targeted alpha-particle radiotherapy, combining lead-212 (212Pb) with an anti-VCAM-1 antibody (212Pb-αVCAM-1). METHODS: Human breast carcinoma cells that metastasize to the brain, MDA-231-Br-GFP, were injected into the left cardiac ventricle of nude mice. Twenty-one days after injection, 212Pb-αVCAM-1 uptake in early BM was determined in a biodistribution study and systemic/brain toxicity was evaluated. Therapeutic efficacy was assessed using MR imaging and histology. Overall survival after 212Pb-αVCAM-1 treatment was compared with that observed after standard EBRT. RESULTS: 212Pb-αVCAM-1 was taken up into early BM with a tumor/healthy brain dose deposition ratio of 6 (5.52e108 and 0.92e108) disintegrations per gram of BM and healthy tissue, respectively. MRI analyses showed a statistically significant reduction in metastatic burden after 212Pb-αVCAM-1 treatment compared with EBRT (P < 0.001), translating to an increase in overall survival of 29% at 40 days post prescription (P < 0.01). No major toxicity was observed. CONCLUSIONS: The present investigation demonstrates that 212Pb-αVCAM-1 specifically accumulates at sites of early BM causing tumor growth inhibition.

Modification of apparent intracerebral hematoma volume on T2∗-weighted images during normobaric oxygen therapy may contribute to false diagnosis.

It was previously reported that normobaric oxygen therapy (NBO) significantly affected T2∗-weighted imaging in a mouse model of intracerebral hemorrhage (ICH). However, it is unclear whether a similar phenomenon exists in large volume ICH as seen in human pathology. We investigated the effects of NBO on T2∗-weighted images in a pig model of ICH. Our data show that NBO makes disappear a peripheral crown of the hematoma, which in turn decreases the apparent volume of ICH by 18%. We hypothesized that this result could be translated to ICH in human, and subsequently could lead to inaccurate diagnostic.

Two-kidney one-clip is a pertinent approach to integrate arterial hypertension in animal models of stroke: Serial magnetic resonance imaging studies of brain lesions before and during cerebral ischemia.

Although chronic arterial hypertension (CAH) represents the major comorbid factor in stroke, it is rarely integrated in preclinical studies of stroke. The majority of those investigations employ spontaneously hypertensive rats (SHR) which display a susceptibility to ischemic damage independent of hypertension. Here, we used a renovascular model of hypertension (RH) to examine, with magnetic resonance imaging (MRI), brain alterations during the development of hypertension and after brain ischemia. We also examined whether MRI-derived parameters predict the extent of ischemia-induced brain damage. RH was induced according to the two-kidney one-clip model and multiparametric MRI was performed at 3, 6, 9, and 12 weeks after hypertension and also at 10, 50, and 60 min following stroke. Blood pressure values increased progressively and reached a plateau at 6 weeks after RH induction. At 12 weeks, all hypertensive animals displayed spontaneous brain lesions (hemorrhages, deep and cortical lesions, ventricular dilatation), increased apparent diffusion coefficient (ADC) values in the corpus callosum and higher fractional anisotropy in the cortex. Following ischemia, these animals showed larger brain lesions (406 ± 82 vs. 179 ± 36 mm3, p < 0.002) which correlated with ADC values at chronic stage of hypertension. This model of hypertension displays many characteristics of the neuropathology of human CAH. The use of this model in stroke studies is relevant and desirable.

Thirty-five Day Fluoxetine Treatment Limits Sensory-Motor Deficit and Biochemical Disorders in a Rat Model of Decompression Sickness.

According to the OECD statistical base for 2014, anti-depressants will, on average, be distributed at a rate of 62 daily doses per 1,000 inhabitants for the 25 countries surveyed (Health at a glance: Europe 2014; OECD Health Statistics; World Health Organization and OECD Health Statistics, 2014). Divers must be concerned. On another hand, divers are potentially exposed to decompression sickness including coagulation inflammation and ischemia, which can result in neurological lesions or even death. The purpose of this study is to assess whether chronic treatment with anti-depressants may represent a contraindication to the practice of an at-risk activity, such as, scuba diving, or even presents a benefit by attenuating the severity of the symptoms. We study for the first time the effect of a 35-day fluoxetine treatment (20 mg/kg) on the occurrence of decompression sickness in laboratory rats (n = 79). Following exposure to the hazardous protocol, there is a significant correlation between the type of treatment and the clinical status of the rats in favor of a better clinical prognosis for the rats treated with fluoxetine with a significantly higher number of No DCS status and a lower number of Severe DCS status in the Flux, compared to Controls. The treatment modifies the rat performances both significantly and favorably during the physical and behavioral tests, just like their biological and biochemical constants. After decompression, rats under treatment display lower sensory-motor deficit and lowers biochemical disorders. From a biological point of view, we conclude fluoxetine should not be seen as a contraindication for diving on the basis of anticipated increased physiological risk.

Hyperbaric oxygen increases tissue-plasminogen activator-induced thrombolysis in vitro, and reduces ischemic brain damage and edema in rats subjected to thromboembolic brain ischemia.

Recent data have shown that normobaric oxygen (NBO) increases the catalytic and thrombolytic efficiency of recombinant tissue plasminogen activator (rtPA) in vitro, and is as efficient as rtPA at restoring cerebral blood flow in rats subjected to thromboembolic brain ischemia. Therefore, in the present study, we studied the effects of hyperbaric oxygen (HBO) (i) on rtPA-induced thrombolysis in vitro and (ii) in rats subjected to thromboembolic middle cerebral artery occlusion-induced brain ischemia. HBO increases rtPA-induced thrombolysis in vitro to a greater extent than NBO; in addition, HBO treatment of 5-minute duration, but not of 25-minute duration, reduces brain damage and edema in vivo. In line with the facilitating effect of NBO on cerebral blood flow, our findings suggest that 5-minute HBO could have provided neuroprotection by promoting thrombolysis. The lack of effect of HBO exposure of longer duration is discussed.

Effects of normobaric versus hyperbaric oxygen on cell injury induced by oxygen and glucose deprivation in acute brain slices.

Normobaric oxygen (NBO) and hyperbaric oxygen (HBO) are emerging as a possible co-treatment of acute ischemic stroke. Both have been shown to reduce infarct volume, to improve neurologic outcome, to promote endogenous tissue plasminogen activator-induced thrombolysis and cerebral blood flow, and to improve tissue oxygenation through oxygen diffusion in the ischemic areas, thereby questioning the interest of HBO compared to NBO. In the present study, in order to investigate and compare the oxygen diffusion effects of NBO and HBO on acute ischemic stroke independently of their effects at the vascular level, we used acute brain slices exposed to oxygen and glucose deprivation, an ex vivo model of brain ischemia that allows investigating the acute effects of NBO (partial pressure of oxygen (pO2) = 1 atmospheres absolute (ATA) = 0.1 MPa) and HBO (pO2 = 2.5 ATA = 0.25 MPa) through tissue oxygenation on ischemia-induced cell injury as measured by the release of lactate dehydrogenase. We found that HBO, but not NBO, reduced oxygen and glucose deprivation-induced cell injury, indicating that passive tissue oxygenation (i.e. without vascular support) of the brain parenchyma requires oxygen partial pressure higher than 1 ATA.

Prospective versus retrospective ECG-gating for 64-detector computed tomography of the coronary venous system in pigs.

BACKGROUND: Multidetector computed tomography (MDCT) provides a non-invasive anatomic description of the coronary veins that may be useful in patients candidates to cardiac resynchronization. Prospective gating reduces radiation exposure but its impact on image quality is unknown is this setting. AIMS: This study compared image quality and reliability of MDCT angiography of the coronary veins between prospective and retrospective gating. METHODS: Seven anaesthetized pigs underwent 64-detector row MDCT with prospective and retrospective ECG-gating. MDCT scans were evaluated for visibility of the veins, estimated radiation dose and vein characteristics. Inter- and intra-observer reproducibility was calculated. RESULTS: Visibility grades of all veins were significantly decreased in prospective (0.82 ± 0.6) compared to retrospective gating (1.68 ± 0.9; P<0.001), the lateral vein being missed in two cases when using prospective vs. retrospective gating. The maximal vein length was significantly increased when using retrospective gating (P=0.015). Inter-observer but not intra-observer reproducibility was dependent on the gating technique for the maximal length and contrast-to-noise ratio (P=0.003 for both). Heart rate was 82 ± 13 bpm and 86 ± 11 bpm during retrospective and prospective ECG-gating (P=ns) despite full dose of atenolol titration. CONCLUSION: Retrospective gating seems to be superior to prospective gating MDCT to describe the coronary venous system but the conclusions of our study should be confined to high heart rate condition.

Thrombotic stroke in the anesthetized monkey (Macaca mulatta): characterization by MRI--a pilot study.

BACKGROUND: The lack of a relevant stroke model in large nonhuman primates hinders the development of innovative diagnostic/therapeutic approaches concerned with this cerebrovascular disease. Our objective was to develop a novel and clinically relevant model of embolic stroke in the anesthetized monkey that incorporates readily available clinical imaging techniques and that would allow the possibility of drug delivery including strategies of reperfusion. METHODS: Thrombin was injected into the lumen of the middle cerebral artery (MCA) in 12 anesthetized (sevoflurane) male rhesus macaques (Macaca mulatta). Sequential MRI studies (including angiography, FLAIR, PWI, DWI, and gadolinium-enhanced T1W imaging) were performed in a 3T clinical MRI. Physiological and biochemical parameters were monitored throughout the investigations. RESULTS: Once standardized, the surgical procedure induced transient occlusion of the middle cerebral artery in all operated animals. All animals studied showed spontaneous reperfusion, which occurred some time between 2 h and 7 days post-ictus. Eighty percent of the studied animals showed diffusion/perfusion mismatch. The ischemic lesions at 24 h spared both superficial and profound territories of the MCA. Some animals presented hemorrhagic transformation at 7 days post-ictus. CONCLUSION: In this study, we developed a pre-clinically relevant model of embolic stroke in the anesthetized nonhuman primate.

Moderately delayed post-insult treatment with normobaric hyperoxia reduces excitotoxin-induced neuronal degeneration but increases ischemia-induced brain damage.

BACKGROUND: The use and benefits of normobaric oxygen (NBO) in patients suffering acute ischemic stroke is still controversial. RESULTS: Here we show for the first time to the best of our knowledge that NBO reduces both NMDA-induced calcium influxes in vitro and NMDA-induced neuronal degeneration in vivo, but increases oxygen and glucose deprivation-induced cell injury in vitro and ischemia-induced brain damage produced by middle cerebral artery occlusion in vivo. CONCLUSIONS: Taken together, these results indicate that NBO reduces excitotoxin-induced calcium influx and subsequent neuronal degeneration but favors ischemia-induced brain damage and neuronal death. These findings highlight the complexity of the mechanisms involved by the use of NBO in patients suffering acute ischemic stroke.

Post-ischemic helium provides neuroprotection in rats subjected to middle cerebral artery occlusion-induced ischemia by producing hypothermia.

During the past decade, studies on the manipulation of various inhaled inert gases during ischemia and/or reperfusion have led to the conclusion that inert gases may be promising agents for treating acute ischemic stroke and perinatal hypoxia-ischemia insults. Although there is a general consensus that among these gases xenon is a golden standard, the possible widespread clinical use of xenon experiences major obstacles, namely its availability and cost of production. Interestingly, recent findings have shown that helium, which is a cost-efficient inert gas with no anesthetic properties, can provide neuroprotection against acute ischemic stroke in vivo when administered during ischemia and early reperfusion. We have investigated whether helium provides neuroprotection in rats subjected to middle cerebral artery occlusion (MCAO) when administered after reperfusion, a condition prerequisite for the therapeutic viability and possible clinical use of helium. In this study, we show that helium at 75 vol% produces neuroprotection and improvement of neurologic outcome in rats subjected to transient MCAO by producing hypothermia on account of its high specific heat as compared with air.

Behavioral deficits after distal focal cerebral ischemia in mice: Usefulness of adhesive removal test.

Distal occlusion of the middle cerebral artery (dMCAo), which closely mimics human stroke, is one of the most used animal models. However, although assessment of histological and functional outcome is increasingly recommended for preclinical studies, the latter is often excluded because of the high difficulties to estimate, especially in mice, behavioral impairments. The aim of our study was to deeply screen functional consequences of distal permanent MCAo in mice to target relevant behaviors for future studies. A set of sensorimotor and cognitive tests were performed during 3 weeks postsurgery in 2 groups of mice. Afterward, brain infarctions were estimated by histological staining or magnetic resonance imaging. Overall, while no long-term functional impairments could be detected, the adhesive removal was the only test showing a deficit. Interestingly, this sensorimotor impairment was correlated to cortical damage 3 weeks after surgery. In conclusion, despite the fact that dMCAo-induced deficits could not be evidenced by most of our behavioral tests, the authors showed that the adhesive removal test was the only one, sensitive enough, to highlight a long-term deficit. This result suggests therefore that this mouse model of ischemia is relevant to efficiently assess therapeutic strategies with histological but also behavioral analysis, provided that relevant tests are used.

Neuroprotection by nitrous oxide: facts and evidence.

BACKGROUND AND OBJECTIVE: Preliminary studies have shown that nitrous oxide, like xenon, may possess potentially neuroprotective properties. However, because of its possible neurotoxic and proneurotoxic effects (obtained under particular conditions) and its bad reputation at anesthetic concentrations, no thorough investigations have been performed on the potentially neuroprotective properties of nitrous oxide. The aim of this study was to investigate the possible neuroprotective effects of nitrous oxide at nonanesthetic concentrations on different models of excitotoxic insult and brain ischemia. MEASUREMENTS AND MAIN RESULTS: Here, we show using multiple models of ex vivo and in vivo excitotoxic insults and brain ischemia that nitrous oxide, administered alone at nonanesthetic doses, offers global neuroprotection from reduction of neurotransmitter release induced by ischemia to reduction of subsequent cell injury. In vivo, in rats subjected to transient cerebral ischemia, nitrous oxide at 50 vol% offers full neuroprotection at both the histologic and neurologic outcome levels when administered up to 2 hrs, but not 3 hrs, after ischemia onset. CONCLUSIONS: These data provide experimental evidence that nitrous oxide, which is a cost-efficient and easily available gas, has potentially neuroprotective properties in rodents when given alone at nonanesthetic concentrations. Therefore, because there is a lot at stake for the affected patients and society--in terms of easy access to treatment, profound impact of brain damage, cost of treatment, and subsequent financial cost on society--we believe that further studies should investigate thoroughly the possible potential clinical interest of nitrous oxide for the treatment of ischemic stroke in terms of optimal indications, type of ischemic injury, duration and time points for treatment, and the optimal concentration of gas to be used in clinical circumstances.

Effects of urotensin-II on cerebral blood flow and ischemia in anesthetized rats.

Urotensin-II (U-II) is a cyclic peptide identified recently in many mammalian species including man. U-II and its receptor are expressed in the central nervous system, in the cardiovascular system and in other peripheral tissues. Although this peptide has been reported initially to be a potent vasoconstrictor, increasing evidence shows that its vascular actions strongly depend on species and vascular beds. Here we analyzed the effects of U-II administration on cerebral blood flow (CBF) under physiological conditions and following cerebral ischemia in rats. Although intravenous injection of U-II had minimal effects on CBF as measured by the technique of laser Doppler flowmetry, its administration (10 nmol) into the lateral cerebral ventricle induced gradual and long lasting increase in CBF (+61% at 1 h post-injection, p<0.05). These U-II-mediated CBF increases were not related to the transient systemic pressor actions of the peptide and were reduced by nitric oxide synthase inhibition (61 vs 17%, p<0.05). Intracerebroventricular administration of U-II following the induction of cerebral ischemia, failed to alter residual CBF in the affected cerebral hemisphere. Nonetheless, following reperfusion (90 min after ischemia), U-II-treated animals displayed a remarkable hyperperfusion compared to vehicle-treated rats (+168%, p<0.05). The volume of infarction was significantly increased in U-II-treated rats (+40%, p<0.05). These results provide the first evidence that U-II increases cerebral blood flow when administered into the cerebral ventricle and exacerbates brain damage following an ischemic insult.

Neuroprotective effects of xenon: a therapeutic window of opportunity in rats subjected to transient cerebral ischemia.

Brain insults are a major cause of acute mortality and chronic morbidity. Given the largely ineffective current therapeutic strategies, the development of new and efficient therapeutic interventions is clearly needed. A series of previous investigations has shown that the noble and anesthetic gas xenon, which has low-affinity antagonistic properties at the N-methyl-D-aspartate (NMDA) receptor, also exhibits potentially neuroprotective properties with no proven adverse side effects. Surprisingly and in contrast with most drugs that are being developed as therapeutic agents, the dose-response neuroprotective effect of xenon has been poorly studied, although this effect could be of major critical importance for its clinical development as a neuroprotectant. Here we show, using ex vivo and in vivo models of excitotoxic insults and transient brain ischemia, that xenon, administered at subanesthetic doses, offers global neuroprotection from reduction of neurotransmitter release induced by ischemia, a critical event known to be involved in excitotoxicity, to reduction of subsequent cell injury and neuronal death. Maximal neuroprotection was obtained with xenon at 50 vol%, a concentration at which xenon further exhibited significant neuroprotective effects in vivo even when administered up to 4 h after intrastriatal NMDA injection and up to at least 2 h after induction of transient brain ischemia.

Spontaneously hypertensive rats are highly vulnerable to AMPA-induced brain lesions.

BACKGROUND AND PURPOSE: Whereas the effects of chronic arterial hypertension on the cerebral vasculature have been widely studied, its effects on brain tissue have been studied less so. Here we examined if spontaneously hypertensive rats (SHRs) or the normotensive control Wistar Kyoto rats (WKYs) made hypertensive by renal artery stenosis (R-WKYs) are vulnerable to an excitotoxic brain lesion provoked by an overactivation of glutamate receptors. METHODS: Lesion volumes were quantified by histology in WKYs and SHRs subjected to striatal administration of N-methyl-d-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA). The expression of AMPA receptors subunits and calcium/calmodulin kinase-II alpha was analyzed by real-time polymerase chain reaction and Western blot. RESULTS: NMDA (50 and 75 nmol) induced similar lesions in both SHRs (10+/-2 mm(3) and 16+/-4 mm(3), respectively) and WKYs (11+/-2 mm(3) and 19+/-7 mm(3), respectively). However, AMPA-induced (2.5 and 5 nmol) lesions were significantly greater in 14-week-old SHRs (14+/-3 mm(3) and 20+/-5 mm(3), respectively) than WKYs (4+/-2 mm(3), P<0.05 and 7+/-4 mm(3), P<0.001, respectively). Furthermore, normotensive 7-week-old SHRs also displayed an aggravated AMPA-induced lesion compared with age-matched WKYs (10+/-3 mm(3) vs 6+/-3 mm(3); P<0.05). Neither NMDA nor AMPA produced increased lesion volumes in R-WKYs (12+/-3 mm(3) and 5+/-4 mm(3), respectively) compared with WKYs. Striatal levels of AMPA receptors subunits, GluR1 and GluR2, were not different between SHRs and WKYs. However, SHRs displayed an increase in phosphorylated form of GluR1 at Ser-831 (P<0.05), as well as in calcium/calmodulin kinase-II alpha (P<0.002). Selective inhibition of this kinase by KN-93 reduced AMPA-induced damage in SHRs (P<0.01 vs vehicle). CONCLUSIONS: These findings show that an increase in phosphorylated GluR1, which increases AMPA receptor conductance, may be involved in the vulnerability of SHRs to AMPA.

Delayed administration of deferoxamine reduces brain damage and promotes functional recovery after transient focal cerebral ischemia in the rat.

The mechanisms underlying functional recovery after stroke are poorly understood. Brain-adaptive responses to the hypoxic stress elicited by ischemia could contribute to these mechanisms. Indeed, hypoxia-inducible factor-1 (HIF-1), one of the main transcriptional factors regulated by oxygen level, increases the expression of several beneficial genes such as erythropoietin, glucose transporter-1 and vascular endothelial growth factor. In order to strengthen the expression of these hypoxia-inducible factors, we administered deferoxamine, an iron chelator known to stabilize HIF-1alpha protein expression, and examined its effects on the functional deficits induced by ischemia. Anesthetized Sprague-Dawley rats were subjected to 60 min of intraluminal occlusion of the middle cerebral artery. Chronic deferoxamine treatment (300 mg/kg, s.c.), or its vehicle, started 24 h after ischemia and was continued bi-weekly until the animals were killed. Sensorimotor deficits were periodically assessed over 2 months, and at this end point, the lesion volume was determined by histology. Treatment with deferoxamine significantly decreased the size of brain damage (-28%) after ischemia and improved behavioral recovery. Indeed, neurological score and sensorimotor performances in the adhesive removal test recovered earlier in the deferoxamine-treated animals. Moreover, the long-lasting skilled forepaw reaching deficits were attenuated by deferoxamine. Although an antioxidant effect of deferoxamine cannot be excluded, the hypothesis that its beneficial effects could be mediated by an increase in HIF-1 target genes merits further investigations. Our data suggest that delayed administration of deferoxamine could represent an interesting therapeutical approach to treat focal cerebral ischemia.