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PURPOSE: To investigate the impact of early and continuous postoperative inpatient rehabilitation during chemoradiotherapy on functional outcomes and overall survival (OS) in patients with glioblastoma (GBM), particularly in different age groups. METHODS: This retrospective cohort study at a university hospital (2011-2016) included 75 of 119 consecutive patients newly diagnosed with GBM who underwent standardized treatment and postoperative rehabilitation. Patients were divided into older (≥ 65 years, n = 45) and younger (< 65 years, n = 30) groups, engaging in a 50-day rehabilitation program. We assessed rehabilitation progress, Barthel Index (BI), Brunnstrom Recovery Stage (BRS), adverse events, and OS. BI at discharge and survival were analyzed using multivariate and Cox regression models, respectively. RESULTS: The mean age was 72.5 ± 6.3 and 52.4 ± 7.8 years in the older and younger groups, respectively. Both groups demonstrated significant improvements in BI and BRS. Despite more adverse events in the older group, no significant difference existed in median OS (older group: 18.7 months vs. younger group: 18.3 months, p = 0.87). Early walking training, reduced fatigue during chemoradiotherapy, and high Karnofsky Performance Status at admission significantly impacted the BI at discharge. Cox regression analysis identified the BI at discharge as a significant predictor of survival (hazard ratio [HR] 0.98, 95% confidence interval [CI] 0.97-0.99, p = 0.008). CONCLUSION: Integrated rehabilitation improves functional outcomes, and enhanced ADL at discharge is associated with improved survival outcomes in patients with GBM, regardless of age. This highlights the need for personalized rehabilitation in treatment protocols. Further prospective studies are warranted to confirm these findings.
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We aimed to minimize the frequency of exercise intervention and test the efficacy of pain relief. We also investigated the mechanism of neuropathic pain to determine the best frequency of pain relief for neuropathic pain. The chronic constriction injury (CCI) rat model was randomly divided into three groups: exercise (Ex), No-Ex, and normal. The treadmill exercise intervention was administered, and the 50% withdrawal threshold was assessed using the Von Frey Test. Ionized calcium-binding adaptor molecule 1 (IBA1), glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF), C-C chemokine receptor type 2 (CCR2), and tumor necrosis factor receptor-associated factor 6 (TRAF6) activation was determined through immunohistochemistry. In the brain, we examined the increased expression of ß-endorphin/met-enkephalin in the gray matter of the midbrain aqueduct. Co-expression of CCR2, IBA1, and Neu-N was observed in the spinal cord dorsal horn by immunofluorescence staining. The 50% pain response threshold was significantly lower in the Ex group than in the No-Ex group at five weeks post-CCI, indicating a high analgesic effect. In the dorsal horn of the spinal cord, IBA1 and GFAP were significantly decreased in the Ex group than in the No-Ex group at five weeks post-CCI. However, no significant difference in activation of BDNF, CCR2, and TRAF6 was observed. In the midbrain, the Ex group showed a significant increase compared to the No-Ex group. In summary, our results suggest that in minimal-exercise intervention, neuropathic pain relief is achieved by activation of the descending pain inhibitory system in the midbrain.
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Fatigue can lead to several health issues and is particularly prevalent among elderly individuals with chronic inflammatory conditions. Ninjin'yoeito, a traditional Japanese herbal medicine, is used to address fatigue and malaise, anorexia, and anemia. This study aimed to examine whether relieving inflammation in the brain and skeletal muscle of senescence-accelerated mice prone 8 (SAMP8) could reduce fatigue-like conditions associated with aging. First, SAMP8 mice were divided into two groups, with and without ninjin'yoeito treatment. The ninjin'yoeito-treated group received a diet containing 3% ninjin'yoeito for a period of 4 months starting at 3 months of age. At 7 months of age, all mice underwent motor function, treadmill fatigue, and behavioral tests. They were then euthanized and the skeletal muscle weight, muscle cross-sectional area, and concentration of interleukin (IL)-1ß and IL-1 receptor antagonist (IL-1RA) in both the brain and skeletal muscle were measured. The results showed that the ninjin'yoeito-treated group had higher motor function and spontaneous locomotor activity than the untreated group did and ran for significantly longer in the treadmill fatigue test. Moreover, larger muscle cross-sectional area, lower IL-1ß concentrations, and higher IL-1RA concentrations were observed in both the brain and skeletal muscle tissues of the ninjin'yoeito-treated group than in the untreated group. The results suggest that ninjin'yoeito improves age-related inflammatory conditions in both the central and peripheral tissues and reduces fatigue.
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Envejecimiento , Encéfalo , Medicamentos Herbarios Chinos , Fatiga , Inflamación , Músculo Esquelético , Animales , Ratones , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Envejecimiento/efectos de los fármacos , Fatiga/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Masculino , Inflamación/tratamiento farmacológico , Inflamación/patología , Interleucina-1beta/metabolismoRESUMEN
Introduction: Cerebral white matter hyperintensities (WMHs) are commonly found in the aging brain and have been implicated in the initiation and severity of many central nervous system diseases. Furthermore, an increased WMH volume indicates reduced brain health in older adults. This study investigated the association between WMH volume and physical activity in older adults with depressive symptoms (DS) and mild memory impairment (MMI). Factors associated with the WMH volume were also investigated. Methods: A total of 57 individuals aged over 65 years with DS and MMI were included in this study. The participants underwent magnetic resonance imaging to quantify WMH volumes. After WMH volume was accumulated, normalized to the total intracranial volume (TIV), the percentage of WMH volume was calculated. In addition, all participants wore a triaxial accelerometer for 2 weeks, and the average daily physical activity and number of steps were measured. The levels of blood biomarkers including cortisol, interleukin-6 (IL-6), brain-derived insulin-like growth factor-1, and brain-derived neurotrophic factor were measured. Motor and cognitive functions were also assessed. Results: Faster maximum walking speed and longer time spent engaged in moderate physical activity were associated with a smaller percent of WMH volume, whereas higher serum IL-6 levels were associated with a larger percent of WMH volume. The number of steps per day, time spent engaged in low levels of physical activity, cognitive function, and all other measured biomarkers were not significantly associated with percent of WMH volume. Discussion: Higher blood inflammatory cytokine levels, shorter duration of moderate physical activity, and lower maximum walking speed were associated with a higher percent of WMH volume. Our results provide useful information for maintaining brain health in older adults at a high risk of developing dementia and may contribute to the development of preventive medicine for brain health.
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5'-Adenosine monophosphate-activated protein kinase (AMPK) is a metabolic sensor that serves as a cellular housekeeper; it also controls energy homeostasis and stress resistance. Thus, correct regulation of this factor can enhance health and survival. AMPK signaling may have a critical role in aging-associated brain diseases. Some in vitro studies have shown that 1,5-anhydro-D-fructose (1,5-AF) induces AMPK activation. In the present study, we experimentally evaluated the effects of 1,5-AF on aging-associated brain diseases in vivo using an animal model of acute ischemic stroke (AIS), stroke-prone spontaneously hypertensive rats (SHRSPs), and the spontaneous senescence-accelerated mouse-prone 8 (SAMP8) model. In the AIS model, intraperitoneal injection of 1,5-AF reduced cerebral infarct volume, neurological deficits, and mortality. In SHRSPs, oral administration of 1,5-AF reduced blood pressure and prolonged survival. In the SAMP8 model, oral administration of 1,5-AF alleviated aging-related decline in motor cognitive function. Although aging reduced the expression levels of peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α) and brain-derived neurotrophic factor (BDNF), we found that 1,5-AF activated AMPK, which led to upregulation of the PGC-1α/BDNF pathway. Our results suggest that 1,5-AF can induce endogenous neurovascular protection, potentially preventing aging-associated brain diseases. Clinical studies are needed to determine whether 1,5-AF can prevent aging-associated brain diseases.
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Accidente Cerebrovascular Isquémico , Factores de Transcripción , Ratas , Ratones , Animales , Factores de Transcripción/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Adenosina Monofosfato , PPAR gamma/metabolismo , Envejecimiento , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismoRESUMEN
BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease associated with aging, which often leads to joint stiffness and disability. Exercise is one of the most important non-pharmacological treatments and is prescribed as an indispensable treatment for OA. However, whether physical exercise is beneficial for preventing the progression of OA symptoms with age is poorly understood. We investigated the effects of exercise on spontaneously developed knee OA using male senescence-accelerated mouse prone 8 (SAMP8). METHODS: To examine age-related changes in the knee joints of SAMP8, knee articular cartilage changes, synovitis, knee joint flexion and extension angles, swelling, walking ability, and quadriceps muscle atrophy were analyzed at 3, 5, 7, and 9 months. SAMP8 were required to run at a speed of 10 m/min for 15 min/day from 7 to 9 months of age. The knee joint pathologies and symptoms of exercising and non-exercising mice were compared by histological, immunohistochemical, and morphometrical analyses. RESULTS: The mice presented with various histological changes, including cartilage destruction, osteocyte formation, synovitis, declined joint angles, and swelling. Notably, medial and posterior cartilage destruction was more severe than that of the lateral and anterior cartilage. Knee joint angles were significantly correlated with the histological scores (modified Mankin and OARSI, osteophyte formation and synovial lining cell layer). Exercise did not attenuate cartilage degeneration in the medial and posterior tibial plateau, although the articular cartilage of the anterior and lateral tibial plateau and its histological scores was remained and significantly improved, respectively, by exercise. Exercise suppressed the age-related decline of collagen type II-positive areas in the remaining articular cartilage and improved the OA symptoms. Exercise reduced the expression of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-α positive macrophages in the synovium. CONCLUSION: This study revealed that SAMP8 developed spontaneous knee OA with age, which resembled the disease symptoms in humans. Low-intensity exercise temporarily alleviated degeneration of the remaining cartilage, synovitis, and age-related decreases in knee flexion angle, stride length, and muscle atrophy in SAMP8. However, exercise during OA progression with age may cause mechanical stress that could be both beneficial and detrimental to joint health.
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Cartílago Articular , Osteoartritis de la Rodilla , Sinovitis , Humanos , Ratones , Masculino , Animales , Lactante , Osteoartritis de la Rodilla/terapia , Articulación de la Rodilla , CaminataRESUMEN
Physical exercise is beneficial for preventing Alzheimer's disease (AD) and cognitive decline through several mechanisms, including suppression of neuroinflammation and neuronal loss in the hippocampus. Despite these exercise-induced benefits in AD pathology, less attention has been paid to the importance of maintaining exercise and the consequences of detraining. This study aimed to investigate the effects of early exercise intervention and detraining on age-related cognitive decline and its protective mechanisms using senescence-accelerated mouse prone 8 (SAMP8). These mice were divided to four groups: no-exercise (No-Ex, n = 9), 4 months (4 M)-detraining (n = 11), 2 months (2 M)-detraining (n = 11), and long-term exercise (LT-Ex, n = 13). Age-related cognitive decline was prevented in the LT-Ex group compared with the No-Ex group through the suppression of neuronal loss, enhanced brain-derived neurotrophic factor (BDNF), and inhibition of neuroinflammation corresponding to reduced M1 and increased M2 microglia in the hippocampus. No significant differences were observed in cognitive function between the detraining and No-Ex groups. However, the 2 M-detraining group showed increased BDNF positive area in the CA1 region and the enhancement of anti-inflammatory M2 phenotype microglia. In contrast, no statistically beneficial exercise-induced changes in the hippocampus were observed in the 4 M-detrainig group. These results showed that early exercise intervention prevented age-related cognitive deficits in AD progression by suppressing neuronal loss and neuroinflammation in the hippocampus. Exercise-induced benefits, including the anti-inflammation in the hippocampus, may be retained after exercise cessation, even if exercise-induced beneficial effects decline in a time-dependent manner.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Ratones , Animales , Humanos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Enfermedades Neuroinflamatorias , Disfunción Cognitiva/prevención & control , Disfunción Cognitiva/patología , Cognición , Hipocampo , Enfermedad de Alzheimer/patología , Terapia por Ejercicio , Modelos Animales de EnfermedadRESUMEN
Remote ischemic perconditioning (RIPerC) is a novel neuroprotective method against cerebral infarction that has shown efficacy in animal studies but has not been consistently neuroprotective in clinical trials. We focused on the temporal regulation of ischemia-reperfusion by RIPerC to establish an optimal method for RIPerC. Rats were assigned to four groups: 10 min ischemia, 5 min reperfusion; 10 min ischemia, 10 min reperfusion; 5 min ischemia, 10 min reperfusion; and no RIPerC. RIPerC interventions were performed during ischemic stroke, which was induced by a 60-min left middle cerebral artery occlusion. Infarct volume, sensorimotor function, neurological deficits, and cellular expressions of brain-derived neurotrophic factor (BDNF), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), and caspase 3 were evaluated 48 h after the induction of ischemia. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) was also performed. RIPerC of 10 min ischemia/10 min reperfusion, and 5 min ischemia/10 min reperfusion decreased infarct volume, improved sensorimotor function, decreased Bax, caspase 3, and TUNEL-positive cells, and increased BDNF and Bcl-2 expressions. Our findings suggest RIPerC with a reperfusion time of approximately 10 min exerts its neuroprotective effects via an anti-apoptotic mechanism. This study provides important preliminary data to establish more effective RIPerC interventions.
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Isquemia Encefálica , Daño por Reperfusión , Ratas , Animales , Ratas Sprague-Dawley , Factor Neurotrófico Derivado del Encéfalo , Caspasa 3 , Proteína X Asociada a bcl-2 , Isquemia , Infarto , Infarto Cerebral , Daño por Reperfusión/patología , Apoptosis , Infarto de la Arteria Cerebral MediaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Ninjin'yoeito (NYT), a traditional Japanese Kampo medicine consisting of 12 herbs, has been reported to improve cognitive dysfunction, depression, and neurological recovery in patients with neurovascular diseases such as Alzheimer's disease and stroke. Several studies have reported that the NYT components exert neurotrophic, neurogenic, and neuroprotective effects. In addition, exercise enhances neuroprotection and functional recovery after stroke. Rehabilitative exercises and pharmacological agents induce neurophysiological plasticity, leading to functional recovery in stroke patients. These reports indicate that NYT treatment and exercise may promote functional recovery following stroke through their beneficial effects. However, no study has determined the effects of NYT and the possible mechanisms of neurorepair and functional recovery after stroke. AIM OF THE STUDY: This study aimed to investigate the combined effects of NYT and exercise on neuroprotection and functional recovery and the underlying mechanisms in a rat ischemic stroke model. MATERIALS AND METHODS: Stroke was induced with 60-min middle cerebral artery occlusion (MCAO) followed by reperfusion in adult male Sprague-Dawley rats. After stroke, the rats were assigned to four groups: ischemia reperfusion (IR), NYT, exercise (Ex), and NYT + Ex. NYT-treated rats were fed a diet containing 1% NYT one day after stroke. Exercise was performed using a motorized treadmill for 5 days a week (8-15 m/min, 20 min/day), starting 3 days after stroke. The NYT treatment and exercise were continued for 4 weeks after the stroke. Infarct volume, neurological deficits, sensorimotor functions, expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase A (TrkA) and B (TrkB), caspase-3 activity, and the p-Akt/Akt ratio were examined by immunohistochemistry and western blotting. RESULTS: Compared to the IR group, all treated groups indicated reduced infarct volumes. The NYT + Ex group showed significantly improved waking time and beam walking score compared with the IR group. The expression of NGF/TrkA/p-TrkA and BDNF/TrkB was significantly increased in the NYT + Ex group compared with those in the IR group, whereas the number of caspase-3 positive cells around the lesion was significantly lower in the NYT + Ex group than in the IR group. In addition, the ratio of p-Akt/Akt was significantly higher in the NYT + Ex group than in the IR group. CONCLUSIONS: This study suggests that NYT in combination with exercise provides neuroprotective effects and improves sensorimotor function by stimulating NGF/TrkA and BDNF/TrkB, and by activating the Akt pathway in ischemic stroke of rats. NYT may be an effective adjunctive agent in post-stroke rehabilitation.
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Accidente Cerebrovascular Isquémico , Medicina Kampo , Fármacos Neuroprotectores , Condicionamiento Físico Animal , Animales , Masculino , Ratas , Factor Neurotrófico Derivado del Encéfalo , Caspasa 3 , Infarto , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Factor de Crecimiento Nervioso , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Proteínas Proto-Oncogénicas c-akt , Ratas Sprague-DawleyRESUMEN
Physical frailty is an aging-related clinical syndrome involving decreases in body weight, mobility, activity, and walking speed that occurs in individuals with sarcopenia and is accelerated by increased oxidative stress. Ninjin'yoeito, a traditional Japanese Kampo medicine, is used for treating conditions, including anemia and physical weakness. Here, we investigated whether ninjin'yoeito could improve physical frailty by controlling oxidative stress in the senescence-accelerated mouse prone 8 (SAMP8) model. First, SAMP8 mice were divided into two groups, ninjin'yoeito treated and untreated, with the former consuming a diet containing 3% ninjin'yoeito from 3 months of age. At 7 months of age, body weight, motor function, locomotor activity, and mean walking speed were measured. Subsequently, mice were euthanized and measured for muscle weight, 8-hydroxy-2'-deoxyguanosine levels in muscle and brain, and cleaved caspase-3 expression in brain. The results showed reductions in weight, locomotor function, locomotion, and average walking speed in the untreated group, which were significantly improved by ninjin'yoeito. Furthermore, 8-hydroxy-2'-deoxyguanosine levels were reduced in muscle and brain from ninjin'yoeito-treated mice, compared with the levels in untreated mice; cleaved caspase-3 expression was similarly reduced in brain from the treated mice, indicating reduced apoptosis. Our findings suggest that ninjin'yoeito inhibits sarcopenia-based physical frailty through its antioxidant effects.
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Fragilidad , Sarcopenia , 8-Hidroxi-2'-Desoxicoguanosina , Animales , Antioxidantes , Peso Corporal , Caspasa 3 , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos , Ratones , Sarcopenia/tratamiento farmacológicoRESUMEN
Purpose: Pain disrupts the daily and social lives of patients with neuropathic pain. Effective treatment of neuropathic pain is difficult. Pharmacological treatments for neuropathic pain are limited, and 40-60% of patients do not achieve even partial relief of their pain. This study created a chronic constriction injury (CCI) model in rats to examine the effects of regular exercise on neuropathic pain relief, elucidate the mechanism, and determine the effects of neuropathic pain in the hippocampus. Methods: CCI model rats were randomly divided into exercise (Ex) and no exercise (No-Ex) groups. Normal rats (Normal group) were used as controls. The Ex group exercised on a treadmill at 20 m/min for 30 min, 5 days per week for 5 weeks post-CCI. The 50% pain response threshold was assessed by mechanical stimulation. Using immunohistochemistry, we examined activation of glial cells (microglia and astrocytes) by CCR2 and TRAF6 expression in the spinal cord dorsal horn and DCX and PROX1 expression in the hippocampal dentate gyrus. Results: The 50% pain response threshold was significantly lower in the Ex than in the No-Ex group at 5 weeks post-CCI, indicating pain relief. In the spinal cord dorsal horn, IBA1, CCR2, and TRAF6 expression was markedly lower in the Ex group than in the No-Ex group at 3 weeks post-CCI. IBA1, GFAP, CCR2, and TRAF6 expression was markedly lower in the Ex group than in the No-Ex group at 5 weeks post-CCI. In the hippocampus, DCX, but not PROX1, expression was significantly higher in the Ex group than in the No-Ex group at 3 weeks post-CCI. At 5 weeks post-CCI, both DCX and PROX1 expression was markedly increased in the Ex group compared to the No-Ex group. Conclusion: Our findings suggest that regular exercise can improve the neuropathic pain-induced neurogenic dysfunction in the hippocampal dentate gyrus.
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Knee arthrofibrosis is a common complication of knee surgery, caused by excessive scar tissue, which results in functional disability. However, no curative treatment has been established. E8002 is an anti-adhesion material that contains L-ascorbic acid, an antioxidant. We aimed to evaluate the efficacy of E8002 for the prevention of knee arthrofibrosis in a rat model, comprising injury to the surface of the femur and quadriceps muscle 1 cm proximal to the patella. Sixteen male, 8-week-old Sprague Dawley rats were studied: in the Adhesion group, haemorrhagic injury was induced to the quadriceps and bone, and in the E8002 group, an adhesion-preventing film was implanted between the quadriceps and femur after injury. Six weeks following injury, the restriction of knee flexion owing to fibrotic scarring had not worsened in the E8002 group but had worsened in the Adhesion group. The area of fibrotic scarring was smaller in the E8002 group than in the Adhesion group (p < 0.05). In addition, the numbers of fibroblasts (p < 0.05) and myofibroblasts (p < 0.01) in the fibrotic scar were lower in the E8002 group. Thus, E8002 reduces myofibroblast proliferation and fibrotic scar formation and improves the range of motion of the joint in a model of knee injury.
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Ácido Ascórbico/farmacología , Cicatriz/prevención & control , Fibrosis/tratamiento farmacológico , Artropatías/tratamiento farmacológico , Traumatismos de la Rodilla/tratamiento farmacológico , Articulación de la Rodilla/efectos de los fármacos , Poliésteres/farmacología , Adherencias Tisulares/prevención & control , Animales , Cicatriz/metabolismo , Cicatriz/patología , Fibrosis/metabolismo , Fibrosis/patología , Artropatías/metabolismo , Artropatías/patología , Traumatismos de la Rodilla/metabolismo , Traumatismos de la Rodilla/patología , Articulación de la Rodilla/metabolismo , Articulación de la Rodilla/patología , Masculino , Membranas Artificiales , Rango del Movimiento Articular , Ratas , Ratas Sprague-Dawley , Adherencias Tisulares/metabolismo , Adherencias Tisulares/patologíaRESUMEN
Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor. To identify the factors influencing the improvement of the activities of daily living (ADL) in newly diagnosed patients with GBM, we investigated the characteristics and variable factors and overall survival. A total of 105 patients with GBM were retrospectively analyzed and categorized into the following three groups according to the quartile of change of their Barthel index score from admission to discharge: deterioration (n = 25), no remarkable change (n = 55), and good recovery (n = 25). A statistical difference was observed in the pre-operative, intra-operative, post-operative, and rehabilitation-related factors between the deterioration and good recovery groups. Multiple regression analysis identified the following significant factors that may influence the improvement of ADL after surgery: the improvement of motor paralysis after surgery, mild fatigue during radio and chemotherapy, and length up to early walking training onset. The median overall survival was significantly different between the deterioration (10.6 months) and good recovery groups (18.9 months, p = 0.025). Our findings identified several factors that may be associated with post-operative functional improvement in patients with GBM. The inpatient rehabilitation during radio and chemotherapy may be encouraged without severe adverse events and can promote functional outcomes, which may contribute to the overall survival of newly diagnosed patients with GBM.
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Subarachnoid hemorrhage (SAH) is a catastrophic form of stroke responsible for significant morbidity and mortality. Oxidative stress, inflammation, and neuronal apoptosis are important in the pathogenesis of early brain injury (EBI) following SAH. Preconditioning exercise confers neuroprotective effects, mitigating EBI; however, the basis for such protection is unknown. We investigated the effects of preconditioning exercise on brain damage and sensorimotor function after SAH. Male rats were assigned to either a sham-operated (Sham) group, exercise (Ex) group, or no-exercise (No-Ex) group. After a 3-week exercise program, they underwent SAH by endovascular perforation. Consciousness level, neurological score, and sensorimotor function were studied. The expression of nuclear factor erythroid 2 p45-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), 4-hydroxynonenal (4HNE), nitrotyrosine (NT), ionized calcium-binding adaptor molecule 1 (Iba1), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 1ß (IL-1ß), 14-3-3γ, p-ß-catenin Ser37, Bax, and caspase-3 were evaluated by immunohistochemistry or western blotting. The terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick end labeling (TUNEL) assay was also performed. After SAH, the Ex group had significantly reduced neurological deficits, sensorimotor dysfunction, and consciousness disorder compared with the No-Ex group. Nrf2, HO-1, and 14-3-3γ were significantly higher in the Ex group, while 4HNE, NT, Iba1, TNF-α, IL-6, IL-1ß, Bax, caspase-3, and TUNEL-positive cells were significantly lower. Our findings suggest that preconditioning exercise ameliorates EBI after SAH. The expression of 4HNE and NT was reduced by Nrf2/HO-1 pathway activation; additionally, both oxidative stress and inflammation were reduced. Furthermore, preconditioning exercise reduced apoptosis, likely via the 14-3-3γ/p-ß-catenin Ser37/Bax/caspase-3 pathway.
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Daño Encefálico Crónico/prevención & control , Neuronas/patología , Condicionamiento Físico Animal , Hemorragia Subaracnoidea/complicaciones , Proteínas 14-3-3/fisiología , Animales , Apoptosis , Daño Encefálico Crónico/diagnóstico por imagen , Daño Encefálico Crónico/etiología , Daño Encefálico Crónico/metabolismo , Citocinas/biosíntesis , Citocinas/genética , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Procesamiento de Imagen Asistido por Computador , Etiquetado Corte-Fin in Situ , Masculino , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Enfermedades Neuroinflamatorias/etiología , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/prevención & control , Estrés Oxidativo , Condicionamiento Físico Animal/fisiología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Factores de Tiempo , Microtomografía por Rayos XRESUMEN
Preconditioning exercise prior to stroke exerts neuroprotection, which is an endogenous strategy that leads the brain cells to express several intrinsic factors and inhibits their apoptosis. However, it is unclear how long these benefits last after exercise cessation. The aim of this study was to investigate the effects of detraining on preconditioning exercise-induced neuroprotective potential after stroke. Rats were trained using a treadmill for aerobic exercise 5 days each week for 3 weeks, and their neuroprotective effects were examined until 3 weeks after exercise cessation. Stroke was induced by 60 min of left middle cerebral artery occlusion at 3 days, 1, 2, and 3 weeks after exercise cessation. Infarct volume, neurological deficits, sensorimotor function, expression levels of brain-derived neurotrophic factor (BDNF), hypoxia-induced factor-1α (HIF-1α), glial fibrillary acidic protein (GFAP), and P2X7 receptors, and apoptosis activity were examined using immunohistochemical and western blot analyses. Preconditioning exercise significantly reduced infarct volume and ameliorated sensorimotor function after stroke, and its beneficial effects were observed until 2 weeks after exercise cessation. The expression level of BDNF in the ischemic brain was significantly upregulated at 3 days after exercise cessation; however, the expression levels of HIF-1α, GFAP, and P2X7 receptor were significantly increased until 2 weeks after exercise cessation; thereby, significant anti-apoptotic effects were lost at 3 weeks of detraining. Our findings suggest that preconditioning exercise-induced neuroprotective potential may be lost shortly after exercise cessation. Neuroprotection through intrinsic protective factors, such as BDNF and HIF-1α, may provide different neuroprotective mechanisms in a time-dependent manner during detraining.
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Accidente Cerebrovascular Isquémico , Animales , Factor Neurotrófico Derivado del Encéfalo , Modelos Animales de Enfermedad , Infarto de la Arteria Cerebral Media , Neuroprotección , Ratas , Ratas Sprague-DawleyRESUMEN
It is well known that physical exercise reduces the risk of Alzheimer's disease (AD) and age-related cognitive decline. However, its mechanisms are still not fully understood. This study aimed to investigate the effect of aging and rotarod exercise (Ex) on cognitive function and AD pathogenesis in the hippocampus using senescence-accelerated mice prone 8 (SAMP8). Cognitive functions clearly declined at 9-months of age. Amyloid-beta (Aß) deposition, neuronal loss, and glia activation-induced neuroinflammation increased with aging. The rotarod Ex prevented the decline of cognitive functions corresponding to the suppression of Aß deposition, neuroinflammation, neuronal loss, inducible nitric oxide synthase (NOS) activities, and neuronal NOS activities. In addition, the rotarod Ex suppressed proinflammatory M1 phenotype microglia and A1 phenotype astrocytes. Our findings suggest that low-intensity motor balance and coordination exercise prevented age-related cognitive decline in the early stage of AD progression, possibly through the suppression of hippocampal Aß deposition, neuronal loss, oxidative stress, and neuroinflammation, including reduced M1 and A1 phenotypes microglia and astrocytes.
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Enfermedad de Alzheimer/terapia , Precursor de Proteína beta-Amiloide/metabolismo , Cognición/fisiología , Hipocampo/metabolismo , Inflamación/terapia , Neuronas/patología , Estrés Oxidativo , Condicionamiento Físico Animal , Equilibrio Postural , Desempeño Psicomotor , Enfermedad de Alzheimer/metabolismo , Animales , Astrocitos , Hipocampo/patología , Inflamación/patología , Activación de Macrófagos , Masculino , Memoria , Ratones , Actividad Motora , Neuroglía , Óxido Nítrico Sintasa de Tipo II/metabolismo , Reconocimiento en PsicologíaRESUMEN
The present study investigates the diurnal profiles of locomotive and household activities in older adults with musculoskeletal disorders (MSDs) using an accelerometer. Furthermore, we examined the effect of chronic pain on their diurnal profiles in both activities. Seventy-one older adults with MSDs (73-89 years) were included in this cross-sectional survey, and 25 age-matched older adults (75-86 years) were selected as healthy older adults. The daily physical activities, including steps walked and locomotive and household activity intensities, were recorded using a triaxial accelerometer in terms of metabolic equivalent task-hours per week (MET-h/week). The diurnal profiles of steps and locomotive activities in older adults with MSDs were considerably lower than those of healthy older adults. In contrast, there was no significant decline in household activity. However, the locomotive and household activities were reduced by severe chronic pain. This survey demonstrated that the diurnal profiles of household activity in older people with MSDs as well as those in age-matched healthy older adults were maintained. Furthermore, severe chronic pain influenced both activities. Therefore, the maintenance of household activity throughout the day, as well as the management of chronic pain, may be important strategies for the promotion of physical activity in older people with MSDs.
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Acelerometría , Actividades Cotidianas , Vida Independiente , Enfermedades Musculoesqueléticas , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Humanos , Masculino , Encuestas y CuestionariosRESUMEN
Perineural adhesions leading to neuropathy are one of the most undesirable consequences of peripheral nerve surgery. However, there are currently no widely used compounds with anti-adhesive effects in the field of peripheral nerve surgery. E8002 is a novel, anti-adhesive, multi-layer membrane that contains L-ascorbic acid (AA). Here, we investigated the effect and mechanism of E8002 in a rat sciatic nerve adhesion model. A total of 21 rats were used. Six weeks after surgery, macroscopic adhesion scores were significantly lower in the E8002 group (adhesion procedure followed by nerve wrapping with E8002) compared to the E8002 AA(-) group (adhesion procedure followed by nerve wrapping with the E8002 membrane excluding AA) and adhesion group (adhesion procedure but no treatment). Correspondingly, a microscopic examination revealed prominent scar tissue in the E8002 AA(-) and adhesion groups. Furthermore, an in vitro study using human blood samples showed that AA enhanced tissue-type, plasminogen activator-mediated fibrinolysis. Altogether, these results suggest that E8002 may exert an anti-adhesive action via AA and the regulation of fibrinolysis.
Asunto(s)
Ácido Ascórbico/química , Poliésteres/química , Nervio Ciático/efectos de los fármacos , Adherencias Tisulares/prevención & control , Cicatrización de Heridas/efectos de los fármacos , Adulto , Animales , Antioxidantes/química , Materiales Biocompatibles/química , Cicatriz , Femenino , Fibrinólisis , Humanos , Masculino , Membranas Artificiales , Persona de Mediana Edad , Polímeros/química , Ratas , Ratas Sprague-Dawley , Terapia TrombolíticaRESUMEN
BACKGROUND: Midkine (MK) is a multifunctional cytokine found upregulated in the brain in the presence of different disorders characterized by neuroinflammation, including neurodegenerative disorders and ischemia. The neuroinflammatory response to traumatic brain injury (TBI) represents a key secondary injury factor that can result in further neuronal injury. In the present study, we investigated the role of endogenous MK in secondary injury, including neuroinflammation, immune response, and neuronal apoptosis activity, after TBI. METHODS: Wild type (Mdk+/+) and MK gene deficient (Mdk-/-) mice were subjected to fluid percussion injury for TBI models and compared at 3, 7, and 14 days after TBI, in terms of the following: brain tissue loss, neurological deficits, microglia response, astrocytosis, expression of proinflammatory M1 and anti-inflammatory M2 microglia/macrophage phenotype markers, and apoptotic activity. RESULTS: As opposed to Mdk+/+ mice, Mdk-/- mice reported a significantly reduced area of brain tissue loss and an improvement in their neurological deficits. The ratios of the Iba1-immunoreactive microglia/macrophages in the perilesional site were significantly decreased in Mdk-/- than in the Mdk+/+ mice at 3 days after TBI. However, the ratios of the glial fibrillary acidic protein immunoreactive area were similar between the two groups. The M1 phenotype marker (CD16/32) immunoreactive areas were significantly reduced in Mdk-/- than in the Mdk+/+ mice. Likewise, the mRNA levels of the M1 phenotype markers (TNF-α, CD11b) were significantly decreased in Mdk-/- mice than in Mdk+/+ mice. Furthermore, flow cytometry analysis identified the M2 markers, i.e., CD163+ macrophages cells and arginase-1+ microglia cells, to be significantly higher in Mdk-/- than in Mdk+/+ mice. Finally, the ratios of apoptotic neurons were significantly decreased in the area surrounding the lesion in Mdk-/- than in Mdk+/+ mice following TBI. CONCLUSION: Our findings suggest that MK-deficiency reduced tissue infiltration of microglia/macrophages and altered their polarization status thereby reducing neuroinflammation, neuronal apoptosis, and tissue loss and improving neurological outcomes after TBI. Therefore, targeting MK to modulate neuroinflammation may represent a potential therapeutic strategy for TBI management.
Asunto(s)
Lesiones Traumáticas del Encéfalo/genética , Lesiones Traumáticas del Encéfalo/patología , Encefalitis/genética , Encefalitis/patología , Midkina/genética , Animales , Apoptosis/genética , Astrocitos/patología , Encéfalo/patología , Proteínas de Unión al Calcio/metabolismo , Polaridad Celular/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Microfilamentos/metabolismo , Microglía/patología , ARN Mensajero/biosíntesis , ARN Mensajero/genéticaRESUMEN
The objective of this study was to examine the interactive effects of exercise and low-level inhibition of GABAA receptors on the recovery of motor function and BDNF expression in the primary motor cortex (M1) of a stroke rat model. Male Sprague-Dawley rats were divided into five groups: sham (SHAM), control (CON), exercise (EX), bicuculline (BIC), and bicuculline plus exercise (BICEX) groups. All rats, except those in the SHAM group, underwent middle cerebral artery occlusion (MCAO) surgery to induce an ischemic stroke. GABAA receptor antagonist, bicuculline (0.25â¯mg/kg, i.p.), was administered to the BIC and BICEX groups. The EX and BICEX groups exercised on a treadmill (11â¯m/min for 30â¯min). Each intervention started 3â¯days after the MCAO surgery and was carried out every day for 2â¯weeks. Following the intervention, bilateral M1 BDNF mRNA and protein expression levels were assessed using qRT-PCR and ELISA. Marginal recovery was found in the EX and BIC groups, whereas motor function recovery was enhanced with exercise in the presence of BIC administration specifically in the BICEX group. Furthermore, BDNF protein level in the ipsilateral M1 was significantly higher in the BICEX group than in other groups. This study indicated that exercise combined with low-level inhibition of GABAA receptors after stroke could facilitate the recovery of motor function accompanied by BDNF upregulation in the ipsilateral M1. Therefore, this study provides a novel insight of pharmacological neuromodulation into stroke rehabilitation.