Recent research progress based on ferroptosis-related signaling pathways and the tumor microenvironment on it effects.

The existing therapies for cancer are not remote satisfactory due to drug-resistance in tumors that are malignant. There is a pressing necessity to take a step forward to develop innovative therapies that can complement current ones. Multiple investigations have demonstrated that ferroptosis therapy, a non-apoptotic modality of programmed cell death, has tremendous potential in face of multiple crucial events, such as drug resistance and toxicity in aggressive malignancies. Recently, ferroptosis at the crosswalk of chemotherapy, materials science, immunotherapy, tumor microenvironment, and bionanotechnology has been presented to elucidate its therapeutic feasibility. Given the burgeoning progression of ferroptosis-based nanomedicine, the newest advancements in this field at the confluence of ferroptosis-inducers, nanotherapeutics, along with tumor microenvironment are given an overview. Here, the signaling pathways of ferroptosis-related were first talked about briefly. The emphasis discussion was placed on the pharmacological mechanisms and the nanodrugs design of ferroptosis inducing agents based on multiple distinct metabolism pathways. Additionally, a comprehensive overview of the action mechanisms by which the tumor microenvironment influences ferroptosis was elaborately descripted. Finally, some limitations of current researches and future research directions were also deliberately discussed to provide details about therapeutic avenues for ferroptosis-related diseases along with the design of anti-drugs.

Dual-drug controllable co-assembly nanosystem for targeted and synergistic treatment of hepatocellular carcinoma.

The effectiveness of chemotherapeutic agents for hepatocellular carcinoma (HCC) is unsatisfactory because of tumor heterogeneity, multidrug resistance, and poor target accumulation. Therefore, multimodality-treatment with accurate drug delivery has become increasingly popular. Herein, a cell penetrating peptide-aptamer dual modified-nanocomposite (USILA NPs) was successfully constructed by coating a cell penetrating peptide and aptamer onto the surface of sorafenib (Sora), ursolic acid (UA) and indocyanine green (ICG) condensed nanodrug (USI NPs) via one-pot assembly for targeted and synergistic HCC treatment. USILA NPs showed higher cellular uptake and cytotoxicity in HepG2 and H22 cells, with a high expression of epithelial cell adhesion molecule (EpCAM). Furthermore, these NPs caused more significant mitochondrial membrane potential reduction and cell apoptosis. These NPs could selectively accumulate at the tumor site of H22 tumor-bearing mice and were detected with the help of ICG fluorescence; moreover, they retarded tumor growth better than monotherapy. Thus, USILA NPs can realize the targeted delivery of dual drugs and the integration of diagnosis and treatment. Moreover, the effects were more significant after co-administration of iRGD peptide, a tumor-penetrating peptide with better penetration promoting ability or programmed cell death ligand 1 (PD-L1) antibody for the reversal of the immunosuppressive state in the tumor microenvironment. The tumor inhibition rates of USILA NPs + iRGD peptide or USILA NPs + PD-L1 antibody with good therapeutic safety were 72.38 % and 67.91 % compared with control, respectively. Overall, this composite nanosystem could act as a promising targeted tool and provide an effective intervention strategy for enhanced HCC synergistic treatment.

An Adaptable Interface Conditioning Circuit Based on Triboelectric Nanogenerators for Self-Powered Sensors.

In order to solve the limited life problem of typical battery power supply, a self-powered method that is based on the environmental energy harvesting has emerged as an amazing power supply approach. The Tribo-electric-Nano-generator (TENG) has been widely studied because of its high efficiency, low fabrication cost, and high output voltage. However, low output power conversion efficiency has restricted its practical application because of its own extremely high output impedance. In order to match the high output impedance of TENG and increase the output power, this paper presents an adaptable interface conditioning circuit, which is composed of an impedance matching circuit, a synchronous rectifier bridge, a control circuit, and an energy storage device. In the impedance matching circuit, the energy loss of coupling inductance could be reduced by using the bi-directional switch to increase the frequency, and impedance matching circuit can be used to increase the output efficiency of TENG. Experimental results show that, in about 3.6 s, the storing capacitor voltage was basically stable at 5.5 V by using the proposed adapted interface conditioning circuit in this paper. The charging efficiency has increased by 50%.

The role of glutamate transporter-1 in the acquisition of brain ischaemic tolerance in rats induced by electro-acupuncture pre-treatment.

OBJECTIVE: To investigate whether electro-acupuncture can serve as a method of inducing brain ischaemic tolerance (BIT) by encouraging the expression of glutamate transporter-1 (GLT-1) and suppressing the release of glutamate (Glu). METHODS: Sprague-Dawley (SD) rats were divided into sham, ischaemia and EA groups. EA was performed on dazhui and baihui acupoints and the rat cerebral ischaemia model was achieved by occluding the middle cerebral artery (MCA) for 2 hours, followed by reperfusion. Dialysate was collected from the striatum in vivo to detect the concentration of Glu and the expression of Glutamate Transporter-1 (GLT-1) was examined. The changes of neurological deficit scores were evaluated at 24 hours after reperfusion, while the infarct volumes of brains were then measured with 2,3,5-triphenyltetrazolium chloride (TTC) staining. RESULTS: Compared with the ischaemia group, the concentration of Glu decreased and the expression of GLT-1 increased at most of the detective time points in the EA group; the neurological deficit scores were lower and the infarct volumes were smaller in the EA group. CONCLUSION: EA can up-regulate the expression of GLT-1 and inhibit the excessive release of Glu in the striatum in the process of subsequent ischaemic-reperfusion brain injury, which may be one of the mechanisms of inducing BIT and, thus, be neuroprotective for early ischaemic brain injury.

Constraint-induced movement therapy promotes motor function recovery and downregulates phosphorylated extracellular regulated protein kinase expression in ischemic brain tissue of rats.

Motor function impairment is a common outcome of stroke. Constraint-induced movement therapy (CIMT) involving intensive use of the impaired limb while restraining the unaffected limb is widely used to overcome the effects of 'learned non-use' and improve limb function after stroke. However, the underlying mechanism of CIMT remains unclear. In the present study, rats were randomly divided into a middle cerebral artery occlusion (model) group, a CIMT + model (CIMT) group, or a sham group. Restriction of the affected limb by plaster cast was performed in the CIMT and sham groups. Compared with the model group, CIMT significantly improved the forelimb functional performance in rats. By western blot assay, the expression of phosphorylated extracellular regulated protein kinase in the bilateral cortex and hippocampi of cerebral ischemic rats in the CIMT group was significantly lower than that in the model group, and was similar to sham group levels. These data suggest that functional recovery after CIMT may be related to decreased expression of phosphorylated extracellular regulated protein kinase in the bilateral cortex and hippocampi.

Autophagy suppression by exercise pretreatment and p38 inhibition is neuroprotective in cerebral ischemia.

Autophagy is a degradative mechanism for cellular proteins and organelles, but its role in the nervous system is still not clear. In the present study, we found that exercise pretreatment and p38 inhibition had influence on autophagic process after cerebral ischemia, contributing to their neuroprotective effects. We examined the levels of p62 and phosphorylated ERK1/2 as an autophagic marker and cell-survival marker respectively after cerebral ischemic injury. The brain infarction volume after ischemia was measured as well. Both treadmill training pretreatment and p38 inhibition decreased the degradation of p62, promoted the phosphorylation of ERK1/2, and alleviated the brain infarction, indicating that these treatments could provide neuroprotection in cerebral ischemic injury via autophagy suppression.

Long-term three-stage rehabilitation intervention alleviates spasticity of the elbows, fingers, and plantar flexors and improves activities of daily living in ischemic stroke patients: a randomized, controlled trial.

To investigate the effects of rehabilitation interventions on spasticity and activities of daily living (ADL) in ischemic stroke patients. A total of 165 ischemic stroke patients were recruited and assigned randomly to a control group (CG, n=82) or a therapeutic group (TG, n=83). Rehabilitation interventions were performed in the TG. The Modified Ashworth Scale was used to evaluate the severity of spasticity in the fingers, elbows, and plantar flexors, and the Modified Barthel Index (MBI) was used to measure ADL performance. Evaluations were performed at baseline (M0) and at the end of the first, third, and sixth months (M1, M3, M6) after enrollment. At M0, 20.8% (16/77) in the CG and 29.9% (23/77) in the TG developed spasticity, whereas at M6, the incidence of spasticity increased to 36.4% (28/77) in the TG and 42.9% (33/77) of patients in the CG. Fewer patients developed spasticity in the fingers, elbows, and ankles in the TG than CG, respectively. Both groups showed significant improvements in MBI scores (M6 vs. M0, P<0.01). MBI scores correlated negatively with the severity of spasticity in both groups at M6. Long-term standardized rehabilitation interventions alleviate spasticity and promote ADL with the presence of minor spasticity (Supplementary video, Supplemental digital content 1, http://links.lww.com/WNR/A291).

Exercise pretreatment promotes mitochondrial dynamic protein OPA1 expression after cerebral ischemia in rats.

Exercise training is a neuroprotective strategy in cerebral ischemic injury, but the underlying mechanisms are not yet clear. In the present study, we investigated the effects of treadmill exercise pretreatment on the expression of mitochondrial dynamic proteins. We examined the expression of OPA1/DLP1/MFF/Mfn1/Mfn2, which regulates mitochondrial fusion and fission, and cytochrome C oxidase subunits (COX subunits), which regulate mitochondrial functions, after middle cerebral artery occlusion (MCAO) in rats. T2-weighted magnetic resonance imaging (MRI) was evaluated as indices of brain edema after ischemia as well. Treadmill training pretreatment increased the expression levels of OPA1 and COXII/III/IV and alleviated brain edema, indicating that exercise pretreatment provided neuroprotection in cerebral ischemic injury via the regulation of mitochondrial dynamics and functions.

Treadmill pre-training ameliorates brain edema in ischemic stroke via down-regulation of aquaporin-4: an MRI study in rats.

OBJECTIVE: Treadmill pre-training can ameliorate blood brain barrier (BBB) dysfunction in ischemia-reperfusion injury, however, its role in ischemic brain edema remains unclear. This study assessed the neuroprotective effects induced by treadmill pre-training, particularly on brain edema in transient middle cerebral artery occluded model. METHODS: Transient middle cerebral artery occlusion to induce stroke was performed on rats after 2 weeks of treadmill pre-training. Magnetic resonance imaging (MRI) was used to evaluate the dynamic impairment of cerebral edema after ischemia-reperfusion injury. In addition, measurements of wet and dry brain weight, Evans Blue assay and Garcia scores were performed to investigate the cerebral water content, BBB permeability and neurologic deficit, respectively. Moreover, during ischemia-reperfusion injury, the expression of Aquaporin 4 (AQP4) was detected using immunofluorescence and Western bloting analyses. RESULTS: Treadmill pre-training improved the relative apparent diffusion coefficient (rADC) loss in the ipsilateral cortex and striatum at 1 hour and 2.5 hours after cerebral ischemia. In the treadmill pre-training group, T2W1 values of the ipsilateral cortex and striatum increased less at 7.5 hours, 1 day, and 2 days after stroke while the brain water content decreased at 2 days after ischemia. Regarding the BBB permeability, the semi-quantitative amount of contrast agent leakage of treadmill pre-training group significantly decreased. Less Evans Blue exudation was also observed in treadmill pre-training group at 2 days after stroke. In addition, treadmill pre-training mitigated the Garcia score deficits at 2 days after stroke. Immunofluorescence staining and Western blotting results showed a significant decrease in the expression of AQP4 after treadmill ischemia following pre-training. CONCLUSIONS: Treadmill pre-training may reduce cerebral edema and BBB dysfunction during cerebral ischemia/reperfusion injury via the down-regulation of AQP4.

The effect of different intensities of treadmill exercise on cognitive function deficit following a severe controlled cortical impact in rats.

Exercise has been proposed for the treatment of traumatic brain injury (TBI). However, the proper intensity of exercise in the early phase following a severe TBI is largely unknown. To compare two different treadmill exercise intensities on the cognitive function following a severe TBI in its early phase, rats experienced a controlled cortical impact (CCI) and were forced to treadmill exercise for 14 days. The results revealed that the rats in the low intensity exercise group had a shorter latency to locate a platform and a significantly better improvement in spatial memory in the Morris water maze (MWM) compared to the control group (p < 0.05). The high intensity exercise group showed a longer latency and a mild improvement in spatial memory compared to the control group rats in the MWM; however, this difference was not statistically significant (p > 0.05). The brain-derived neurotrophic factor (BDNF) and p-CREB protein levels in the contralateral hippocampus were increased significantly in the low intensity exercise group. Our results suggest that 2 weeks of low intensity of treadmill exercise is beneficial for improving cognitive function and increasing hippocampal BDNF expression after a severe TBI in its early phase.

Neuroprotective effects of prior exposure to enriched environment on cerebral ischemia/reperfusion injury in rats: the possible molecular mechanism.

Increasing evidence shows that exposure to an enriched environment (EE) after cerebral ischemia/reperfusion injury is neuroprotective in animal models. Recent studies have demonstrated that animals housed in an enriched environment condition after an experimental stroke obtained a better functional outcome than those housed in a standard condition. However, little is known about the underlying mechanisms of neuroprotective effects of enriched environment exposure prior to injury. The current study examined the neuroprotective effects of prior enriched environment exposure after transient middle cerebral artery occlusion (MCAO) in rats. Male Sprague Dawley (SD) rats, weighing 55-65g at the beginning of the experiment, were randomly assigned to a pre-ischemic enriched environment (PIEE) or pre-ischemic standard condition (PISC) group for 1 month. They were weighed on days1, 7, 18, and 28, and their locomotor activity was tracked during the period between 9:00am and 3:00pm daily. After 1 month, ischemia was induced by occluding the middle cerebral artery for 90min, followed by reperfusion. After approximately 24h of the operation, functional outcomes were assessed using the beam-walking test and a neurological evaluation scale in all rats. We measured the expression of extracellular signal regulated protein kinases1/2 (ERK1/2) by western blotting and gene expression levels of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthasen (iNOS) by Real-Time PCR in the cortical area affected by ischemia. Finally, we measured the level of malondialdehyde (MDA) content, which is a biomarker of oxidative stress. The results showed that rats in the PIEE group had lighter weight than those in the PISC group. The functional outcomes of rats in the PIEE group were better than those in the PISC group, and substances associated with inflammation, such as MDA, nNOS, iNOS, and phospho-ERK1/2, were lower in the PIEE group compared with the PISC group. These results indicate that enriched environment may provide neuroprotection via ischemic preconditioning and enhance resilience to cerebral ischemia.

Prior exposure to enriched environment reduces nitric oxide synthase after transient MCAO in rats.

Increasing evidence shows that exposure to an enriched environment (EE) after cerebral ischemia/reperfusion injury is neuroprotective in animal models. However, little is known about of the neuroprotective effects of EE exposure prior to injury. The current study examined the effects of prior EE exposure on inducible and neuronal nitric oxide syntheses (iNOS and nNOS) after transient middle cerebral artery occlusion (tMCAO) in rats. A total of 72 rats were exposed to EE or standard housing condition (SC) for 1 month, followed by 90-min MCAO and reperfusion or sham surgery, leading to the following three groups: (1) EE+MCAO (n=24), (2) SC+MCAO (n=24), (3) SC+sham (n=24). Rats were sacrificed at 1, 6, or 24h after MCAO (n=6/group) for iNOS and nNOS mRNA quantification by real-time PCR and at 24h after MCAO (n=6/group) for iNOS and nNOS protein quantification by Western blot or were evaluated for neurological function outcomes, then sacrificed to assess infarct volume (n=6/group). Results showed that prior exposure to EE reduced iNOS and nNOS mRNA and protein and improved neurological status after MCAO without affecting infarct volume, suggesting that EE may provide neuroprotection via ischemic preconditioning.

Early exercise training improves ischemic outcome in rats by cerebral hemodynamics.

This study examined whether very early initiated physical rehabilitation (VEIPR), as a recommended therapy for postischemia, could improve motor performance and cerebral blood flow (CBF). Adult male rats with ischemic injury caused by middle cerebral artery occlusion (MCAO) were trained to run on a treadmill for 30min per day at 12m/min. Through such exercise training for 3 days, the ischemic rats exhibited increased motor function and decreased infarct volume, as measured by a behavioral score and 2,3,5-triphenyltetrazolium chloride (TTC) staining method, as well as accelerated CBF, as detected with laser speckle imaging (LSI). Furthermore, to determine whether the observed improved CBF provided the protective factor for motor function recovery, we investigated the apoptosis of ischemic rat brain microvascular endothelial cells (rBMECs), which accepted the mechanical force of CBF directly, under flow intervention. The findings indicated that a modest flow decreased cell apoptosis in the ischemic condition and that this effect is magnitude dependent, as excessive flow increased apoptosis.

Early exercise protects the blood-brain barrier from ischemic brain injury via the regulation of MMP-9 and occludin in rats.

Early exercise within 24 h after stroke can reduce neurological deficits after ischemic brain injury. However, the mechanisms underlying this neuroprotection remain poorly understood. Ischemic brain injury disrupts the blood-brain barrier (BBB) and then triggers a cascade of events, leading to secondary brain injury and poor long-term outcomes. This study verified the hypothesis that early exercise protected the BBB after ischemia. Adult rats were randomly assigned to sham, early exercise (EE) or non-exercise (NE) groups. The EE and NE groups were subjected to ischemia induced by middle cerebral artery occlusion (MCAO). The EE group ran on a treadmill beginning 24 h after ischemia, 30 min per day for three days. After three-days' exercise, EB extravasation and electron microscopy were used to evaluate the integrity of the BBB. Neurological deficits, cerebral infarct volume and the expression of MMP-9, the tissue inhibitors of metalloproteinase-1 (TIMP-1), and occludin were determined. The data indicated that early exercise significantly inhibited the ischemia-induced reduction of occludin, and an increase in MMP-9 promoted TIMP-1 expression (p < 0.01), attenuated the BBB disruption (p < 0.05) and neurological deficits (p < 0.01) and diminished the infarct volume (p < 0.01). Our results suggest that the neuroprotection conferred by early exercise was likely achieved by improving the function of the BBB via the regulation of MMP-9 and occludin.

Demonstration of posturographic parameters of squat-stand activity in hemiparetic patients on a new multi-utility balance assessing and training system.

BACKGROUND: Quantitative evaluation of position control ability in stroke patients is needed. Here we report a demonstration of position control ability assessment and test-retest reliability during squat-stand activity on a new system in hemiparetic patients and controls. METHODS: Sixty-two healthy adults and thirty-four hemiparetics were enrolled. RESULTS: During partial weight support, the ICCs ranged from 0.77 to 0.91, which indicated a good reliability. During standard weight bearing and resistance, the ICCs varied from 0.64 to 0.86 and 0.54 to 0.84, respectively, indicating a fair reliability. Compared with the healthy adults, the stroke patients demonstrated poorer position control ability. CONCLUSIONS: The posturography of the squat-stand activity is a new and reliable measurement tool for position control. According to the methods proposed here, hemiparetics can be differentiated from healthy adults using the squat-stand activity. This activity will provide a new evaluation tool and therapy with visual feedback for the stroke patients. TRIAL REGISTRATION: Chinese clinical trial registry, ChiCTR-TRC-10000863.

Prospective, randomized controlled trial of physiotherapy and acupuncture on motor function and daily activities in patients with ischemic stroke.

OBJECTIVE: To assess the value of acupuncture for promoting the recovery of patients with ischemic stroke and to determine whether the outcomes of combined physiotherapy and acupuncture are superior to those with physiotherapy alone. DESIGN: Prospective randomized controlled trial. SETTING: Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, P. R. China. PARTICIPANTS: 120 inpatients and outpatients (84 men and 36 women). INTERVENTIONS: Acupuncture, physiotherapy, and physiotherapy combined with acupuncture. MAIN OUTCOME MEASURES: Motor function in the limbs was measured with the Fugl-Meyer assessment (FMA). The modified Barthel index (MBI) was used to rate activities of daily living. All evaluations were performed by assessors blinded to treatment group. RESULTS: On the first day of therapy (day 0, baseline), FMA and MBI scores did not significantly differ among the treatment groups. Compared with baseline, on the 28th day of therapy the mean FMA scores of the physiotherapy, acupuncture, and combined treatment groups had increased by 65.6%, 57.7%, and 67.2%, respectively; on the 56th day, FMA scores had increased by 88.1%, 64.5%, and 88.6%, respectively (p<0.05). The respective MBI scores in the three groups increased by 85.2%, 60.4%, and 63.4% at day 28 and by 108.0%, 71.2%, and 86.2% at day 56, respectively (p<0.05). However, FMA scores did not significantly differ among the three treatment groups on the 28th day. By the 56th day, the FMA and MBI scores of the physiotherapy group were 46.1% and 33.2% greater, respectively, than those in the acupuncture group p<0.05). No significant differences were seen between the combined treatment group and the other groups. In addition, the FMA subscores for the upper extremities did not reflect any significant improvement in any group on the 56th day. Although the FMA subscores for the upper and lower extremities and the MBI score in the combined treatment group were higher than those in the acupuncture group, the differences were not statistically significant. CONCLUSIONS: Acupuncture is less effective for the outcome measures studied than is physiotherapy. Moreover, the therapeutic effect of combining acupuncture with physiotherapy was not superior to that of physiotherapy alone. A larger-scale clinical trial is necessary to confirm these findings.

Early exercise improves cerebral blood flow through increased angiogenesis in experimental stroke rat model.

BACKGROUND: Early exercise after stroke promoted angiogenesis and increased microvessles density. However, whether these newly formatted vessels indeed give rise to functional vascular and improve the cerebral blood flow (CBF) in impaired brain region is still unclear. The present study aimed to determine the effect of early exercise on angiogenesis and CBF in ischemic region. METHODS: Adult male Sprague Dawley rats were subjected to 90 min middle cerebral artery occlusion(MCAO)and randomly divided into early exercise and non-exercised control group 24 h later. Two weeks later, CBF in ischemic region was determined by laser speckle flowmetry(LSF). Meantime, micro vessels density, the expression of tie-2, total Akt and phosphorylated Akt (p-Akt), and infarct volume were detected with immunohistochemistry, 2,3,5 triphenyltetrazolium chloride (TTC) staining and western blotting respectively. The function was evaluated by seven point's method. RESULTS: Our results showed that CBF, vessel density and expression of Tie-2, p-Akt in ischemic region were higher in early exercise group compared with those in non-exercise group. Consistent with these results, rats in early exercise group had a significantly reduced infarct volume and better functional outcomes than those in non-exercise group. CONCLUSIONS: Our results indicated that early exercise after MCAO improved the CBF in ischemic region, reduced infarct volume and promoted the functional outcomes, the underlying mechanism was correlated with angiogenesis in the ischemic cortex.

Cortical reorganization after motor imagery training in chronic stroke patients with severe motor impairment: a longitudinal fMRI study.

INTRODUCTION: Despite its clinical efficacy, few studies have examined the neural mechanisms of motor imagery training (MIT) in stroke. Our objective was to find the cortical reorganization patterns after MIT in chronic stroke patients. METHODS: Twenty stroke patients with severe motor deficits were randomly assigned to the MIT or conventional rehabilitation therapy (CRT) group, but two lost in the follow-up. All 18 patients received CRT 5 days/week for 4 weeks. Nine subjects in the MIT group received 30-min MIT 5 days/week for 4 weeks. Before and after the interventions, the upper limb section of the Fugl-Meyer Scale (FM-UL) was blindly evaluated, and functional magnetic resonance imaging was administered while the patients executed a passive fist clutch task. RESULTS: Two cortical reorganization patterns were found. One pattern consisted of the growth in activation in the contralateral sensorimotor cortex (cSMC) for most patients (six in the MIT group, five in the CRT group), and the other consisted of focusing of the activation in the cSMC with increasing of the laterality index of the SMC for a small portion of patients (three in the MIT group, one in the CRT group). When we applied correlation analyses to the variables of relative ΔcSMC and ΔFM-UL in the 11 patients who experienced the first pattern, a positive relationship was detected. CONCLUSIONS: Our results indicate that different cortical reorganization patterns (increases in or focusing of recruitment to the cSMC region) exist in chronic stroke patients after interventions, and patients may choose efficient patterns to improve their motor function.

Early Exercise Protects against Cerebral Ischemic Injury through Inhibiting Neuron Apoptosis in Cortex in Rats.

Early exercise is an effective strategy for stroke treatment, but the underlying mechanism remains poorly understood. Apoptosis plays a critical role after stroke. However, it is unclear whether early exercise inhibits apoptosis after stroke. The present study investigated the effect of early exercise on apoptosis induced by ischemia. Adult SD rats were subjected to transient focal cerebral ischemia by middle cerebral artery occlusion model (MCAO) and were randomly divided into early exercise group, non-exercise group and sham group. Early exercise group received forced treadmill training initiated at 24 h after operation. Fourteen days later, the cell apoptosis were detected by TdT-mediated dUTP-biotin nick-end labeling (TUNEL) and Fluoro-Jade-B staining (F-J-B). Caspase-3, cleaved caspase-3 and Bcl-2 were determined by western blotting. Cerebral infarct volume and motor function were evaluated by cresyl violet staining and foot fault test respectively. The results showed that early exercise decreased the number of apoptotic cells (118.74 ± 6.15 vs. 169.65 ± 8.47, p < 0.05, n = 5), inhibited the expression of caspase-3 and cleaved caspase-3 (p < 0.05, n = 5), and increased the expression of Bcl-2 (p < 0.05, n = 5). These data were consistent with reduced infarct volume and improved motor function. These results suggested that early exercise could provide neuroprotection through inhibiting neuron apoptosis.

Enriched environment preconditioning induced brain ischemic tolerance without reducing infarct volume and edema: the possible role of enrichment-related physical activity increase.

External stimuli, including environmental enrichment (EE) and physical activity, have been shown to significantly facilitate recovery from brain injury. However, whether EE can be used as a preconditioning method to induce cerebral ischemic tolerance has never been investigated. Furthermore, whether, and to what extent, such environmental stimuli regulate physical activity to promote neuroprotection is largely unclear. To examine the neuroprotective effects of pre-ischemic EE (PIEE) and to investigate the relationship between these effects and EE-induced physical activity, we tested neurobehavioral and morphological recovery of rats following transient focal cerebral ischemia. Our study showed that PIEE improved the recovery of motor function, spatial learning and memory without reduction in brain edema or infarct volume. We also found that PIEE robustly increased the level of physical activity of rats that positively correlated with the extent of neurobehavioral recovery. Our results suggest that PIEE may induce brain ischemic tolerance through, at least partially, increasing physical activity.