bims-empneu Biomed News
on Exercise and Molecular Pathways Involved in Neuroprotection
Issue of 2021–05–23
nine papers selected by
Navabeh Zare-Kookandeh, Victoria University



  1. Metab Brain Dis. 2021 May 18.
      Vascular endothelial growth factor (VEGF) regulates angio/neurogenesis and also tightly links to the pathogenesis of Alzheimer's disease (AD). Although exercise has a beneficial effect on neurovascular function and cognitive function, the direct effect of exercise on VEGF-related signaling and cognitive deficit in AD is incompletely understood. Therefore, the purpose of this study was to investigate the protective effect of exercise on angiostatin/VEGF cascade and cognitive function in AD model rats. Wistar male rats were randomly divided into five groups: control (CON), injection of DMSO (Sham-CON), CON-exercise (sham-EX), intrahippocampal injection of Aβ (Aβ), and Aβ-exercise (Aβ-EX). Rats in EX groups underwent treadmill exercise for 4 weeks, then the cognitive function was measured by the Morris Water Maze (MWM) test. mRNA levels of hypoxia-induced factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR2), and angiostatin were determined in hippocampus by RT-PCR. We found that spatial learning and memory were impaired in Aβ-injected rats, but exercise training improved it. Moreover, exercise training increased the reduced mRNA expression level of VEGF signaling, including HIF1α, VEGF, and VEGFR2 in the hippocampus from Aβ-injected rats. Also, the mRNA expression level of angiostatin was elevated in the hippocampus from Aβ-injected rats, and exercise training abrogated its expression. Our findings suggest that exercise training improves cognitive function in Aβ-injected rats, possibly through enhancing VEGF signaling and reducing angiostatin.
    Keywords:  Angiostatin; Cognitive dysfunction; Exercise; VEGF
    DOI:  https://doi.org/10.1007/s11011-021-00751-2
  2. J Exerc Rehabil. 2021 Apr;17(2): 81-87
      Dysfunctions of Parkinson disease (PD) are classified into motor dysfunction, autonomic nervous system dysfunction, and nonmotor dysfunction, and clinical symptoms such as muscle stiffness, tremors, speech disorders, balance disorders, and slow movements appear. Resistance exercise is a main compartment of exercise programs for PD patient. The effect of resistant exercise on short-term memory in PD mice was studied in relation to the activation of nuclear factor (NF)-κB pathway. PD was induced by subcutaneous injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. For resistance exercise, mice performed ladder climbing 5 days per week for 5 weeks. Step-down avoidance test for short-term memory, enzyme-linked immunoassay for tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β, Western bot for NF-κB, NF-κB inhibitor (IκB)-α, B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and Bcl-2, and immunohistochemistry for cleaved caspase-3 were done. Latency time was shortened, TNF-α, IL-6, and IL-1β concentration was increased, NF-κB expression and IκB-α phosphorylation were increased, cleaved caspase-3 and Bax expression was enhanced, and Bcl-2 expression was suppressed by PD induction. Latency time was lengthened, TNF-α, IL-6, and IL-1β concentration was decreased, NF-κB expression and IκB-α phosphorylation were suppressed, cleaved caspase-3 and Bax expression was decreased, and Bcl-2 expression was increased in PD mice by resistance exercise or levodopa treatment. Resistance exercise improved short-term memory by inhibiting secretion of proinflammatory cytokines and apoptosis through inactivation of NF-κB. These effects of resistance exercise were similar to levodopa treatment.
    Keywords:  Apoptosis; Nuclear factor-κB; Parkinson disease; Resistance exercise
    DOI:  https://doi.org/10.12965/jer.2142188.094
  3. Front Cell Neurosci. 2021 ;15 665867
      Perturbations in metabolism results in the accumulation of beta-amyloid peptides, which is a pathological feature of Alzheimer's disease. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate limiting enzyme responsible for beta-amyloid production. Obesogenic diets increase BACE1 while exercise reduces BACE1 activity, although the mechanisms are unknown. Brain-derived neurotropic factor (BDNF) is an exercise inducible neurotrophic factor, however, it is unknown if BDNF is related to the effects of exercise on BACE1. The purpose of this study was to determine the direct effect of BDNF on BACE1 activity and to examine neuronal pathways induced by exercise. C57BL/6J male mice were assigned to either a low (n = 36) or high fat diet (n = 36) for 10 weeks. To determine the direct effect of BDNF on BACE1, a subset of mice (low fat diet = 12 and high fat diet n = 12) were used for an explant experiment where the brain tissue was directly treated with BDNF (100 ng/ml) for 30 min. To examine neuronal pathways activated with exercise, mice remained sedentary (n = 12) or underwent an acute bout of treadmill running at 15 m/min with a 5% incline for 120 min (n = 12). The prefrontal cortex and hippocampus were collected 2-h post-exercise. Direct treatment with BDNF resulted in reductions in BACE1 activity in the prefrontal cortex (p < 0.05), but not the hippocampus. The high fat diet reduced BDNF content in the hippocampus; however, the acute bout of exercise increased BDNF in the prefrontal cortex (p < 0.05). These novel findings demonstrate the region specific differences in exercise induced BDNF in lean and obese mice and show that BDNF can reduce BACE1 activity, independent of other exercise-induced alterations. This work demonstrates a previously unknown link between BDNF and BACE1 regulation.
    Keywords:  Alzheimer’s disease; BDNF; beta-secretase; exercise; obesity
    DOI:  https://doi.org/10.3389/fncel.2021.665867
  4. Arch Phys Med Rehabil. 2021 May 13. pii: S0003-9993(21)00367-1. [Epub ahead of print]
       OBJECTIVE: To provide a novel overview of the literature and to summarise the evidence for the effects of aerobic exercise (AE) on serum biomarkers neuroplasticity and brain repair in stroke survivors.
    DATA SOURCE: We conducted a systematic review and searched MEDLINE, EMBASE and Cochrane CENTRAL using terms related to AE, neuroplasticity, brain repair, and stroke.
    STUDY SELECTION: Titles, abstracts, and selected full texts were screened by two independent reviewers against the following inclusion criteria: studies including adult stroke survivors, completing an AE intervention working within the AE capacity, with at least one blood biomarker outcome of interest measured.
    DATA EXTRACTION: Two independent reviewers extracted data and assessed risk of bias using Risk of Bias In Non-randomised Studies - of Interventions (ROBINS-I) and Cochrane's Risk of Bias 2 (RoB 2) tools.
    DATA SYNTHESIS: Nine studies (n=215 participants) were included, reporting on the following outcomes: brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), cortisol, interleukin-6 (IL-6) and myeloperoxidase (MPO). A single bout of high-intensity interval training significantly increased BDNF, IGF-1 and VEGF levels, and a 40-45-minute, 24-session, continuous eight-week AE training program significantly increased BDNF levels. No significant difference in response to any other AE intervention was found in other serum biomarkers.
    CONCLUSION: AE can significantly increase BDNF, IGF-1 and VEGF across different AE protocols in stroke survivors. However, more research is needed to determine the optimal exercise intensity and modalities, specifically in acute and subacute stroke survivors, and how this may relate to functional outcomes.
    Keywords:  HIIT; Stroke; aerobic exercise; brain repair; neuroplasticity; serum biomarkers
    DOI:  https://doi.org/10.1016/j.apmr.2021.04.010
  5. J Exerc Rehabil. 2021 Apr;17(2): 69-80
      The presence of apolipoprotein (Apo) E4 is a genetic risk factor in cognitive impairment. Physical exercise contributes to slowing cognitive impairment in older adults, but little is known about the influence of exercise on ApoE4 carriers and noncarriers. The objective of systematic review is to study the role of physical exercise in older adults' ApoE4 carriers and noncarriers. A systematic literature search was carried out in five international databases: PubMed, Web of Science, PeDro, Scopus, and SPORTDiscus. A total of nine randomized controlled trials were included with a sample size of 2,025 subjects (901 ApoE4 carriers). The exercise reported a significant improvement on cognitive performance in older adults' ApoE4 noncarriers (standardized mean difference [SMD]=0.653; 95% confidence interval [CI], 0.29-1.00; chi2=35.36; degrees of freedom [df ]=7; P<0.0001; l 2=80%). It was also reported that a total program duration greater than 50 sessions generated different and significant effects on cognitive performance in older adults' ApoE4 noncarriers (SMD=0.878; 95% CI, 0.14-1.61; chi2=31.82; df=3; P<0.0001; l 2=91%). The results reported that high intensity generated a differential effect on cognitive performance in older adults' ApoE4 carriers versus noncarriers (SMD=0.963; 95% CI, 0.25-1.67; chi2=18.11; df=3; P<0.0004; l 2=83%). The effect of physical exercise on cognitive performance in older adults is conditioned by the presence or not of ApoE4.
    Keywords:  Aged; Apolipoproteins E; Cognition; Exercise
    DOI:  https://doi.org/10.12965/jer.2142130.065
  6. Restor Neurol Neurosci. 2021 May 10.
       BACKGROUND: Physical exercise can improve cognitive dysfunction. Its specific mechanism remains unknown. Recent studies have indicated that elevating or peripherally overexpressing brain-derived neurotrophic factors (BDNF) improve cognitive impairment.
    OBJECTIVE: This meta-analysis aimed to investigate whether physical exercise improves cognitive performance in patients with cognitive dysfunction, such as mild cognitive impairment (MCI) or Alzheimer's disease (AD), by increasing peripheral BDNF.
    METHODS: PubMed, Embase, Cochrane Library, and Web of Science were searched up to June 2020 for studies that assayed the changes in peripheral BDNF levels in MCI and AD patients after exercise training.
    RESULTS: Peripheral BDNF levels were significantly elevated after a single exercise session (SMD = 0.469, 95% CI: 0.150-0.787, P = 0.004) or regular exercise interventions (SMD = 0.418, 95% CI: 0.105-0.731, P = 0.009). Subgroup analysis showed that only regular aerobic exercise interventions (SMD = 0.543, 95% CI: 0.038-1.049, P = 0.035) and intervention duration of 16 weeks or greater (SMD = 0.443, 95% CI: 0.154 -0.733, P = 0.003) significantly increased peripheral BDNF levels. Only plasma BDNF levels (SMD = 0.365, 95% CI:0.066-0.664, P = 0.017) were significantly increased after exercise interventions.
    CONCLUSIONS: Acute and chronic physical exercises may improve cognitive impairment by increasing peripheral BDNF levels. Aerobic exercises and a longer duration of exercising increased BDNF levels. These findings also suggest that BDNF may be a suitable biomarker for evaluating the effect of exercise in patients with cognitive impairment, such as AD or MCI.
    Keywords:  Alzheimer’s disease; Brain-derived neurotrophic factor; cognitive impairment; exercise; meta-analysis
    DOI:  https://doi.org/10.3233/RNN-201060
  7. J Diet Suppl. 2021 May 20. 1-13
      The accumulation of lactate in muscle and blood during high-intensity exercise is negatively correlated with the duration exercise can be sustained. Removal of lactate is a key component of acute recovery between consecutive bouts of such exercise. Low-intensity exercise enhances recovery by accelerating lactate turnover in metabolically active tissues, largely mediated by blood flow to these tissues. Therefore, the purpose of this research was to clarify if L-citrulline, a nutritional supplement purported to promote vasodilation via enhanced nitric oxide availability, would augment the removal of blood lactate during active recovery (AR). L-citrulline ingestion will augment the rate of blood lactate concentration decrease during AR, reduce the oxygen-cost of submaximal exercise, and increase time-to-exhaustion and peak oxygen uptake (V̇O2peak) during a test of maximal aerobic power. Healthy university students (five males & five females) participated in this double-blind, randomized, placebo-controlled study. Participants exercised on a cycle ergometer at submaximal steady-state intensities followed by progressively increasing intensity to exhaustion, 10 min of AR, and then supramaximal intensity exercise to exhaustion. Oxygen uptake was measured throughout the trial and blood lactate was sampled repeatedly during AR. The protocol elicited very high peak blood lactate concentrations after exercise (11.3 + 1.3 mmol/L). L-citrulline supplementation did not significantly alter blood lactate kinetics during AR, the oxygen cost of exercise, V̇O2peak, or time-to-exhaustion. Despite a strong theoretical basis by which L-citrulline could augment lactate removal from the blood, L-citrulline supplementation showed no effect as an exercise-recovery supplement.
    Keywords:  L-citrulline; L-citrulline supplementation; VO2peak; active recovery; aerobic power; amino acid; bicycle ergometry; blood lactate; blood-flow; cycling; dietary L-citrulline supplementation; ergogenic aids; exercise; exercise capacity; exercise metabolism; exercise physiology; exhaustive exercise; high-intensity exercise; human; lactate; lactate kinetics; metabolism; mitochondrial function; nitric oxide; nutrition; oral L-citrulline; oxygen consumption; oxygen cost; oxygen cost of exercise; oxygen uptake kinetics; performance; physiology; recovery; sport science; sports nutrition; steady-state exercise; submaximal exercise; supplementation; supramaximal exercise; total nitrate; vascular function; vasodilation; young adults
    DOI:  https://doi.org/10.1080/19390211.2021.1926392
  8. Neuroimage. 2021 May 18. pii: S1053-8119(21)00439-0. [Epub ahead of print] 118162
      Food-related inhibitory control, the ability to withhold a dominant response towards highly palatable foods, influences dietary decisions. Food-related inhibitory control abilities may increase following a bout of aerobic exercise; however, the impact of exercise intensity on both food-related inhibitory control and broader cognitive control processes is currently unclear. We used a high-powered, within-subjects, crossover design to test how relative intensity of aerobic exercise influenced behavioral (response time, accuracy) and neural (N2 and P3 components of the scalp-recorded event-related potential [ERP]) measures of food-related inhibitory and cognitive control. Two hundred and ten participants completed three separate conditions separated by approximately one week in randomized order: two exercise conditions (35% VO2max or 70% VO2max) and seated rest. Directly following exercise or rest, participants completed a food-based go/no-go task and a flanker task while electroencephalogram data were recorded. Linear mixed models showed generally faster response times (RT) and improved accuracy following 70% VO2max exercise compared to rest, but not 35% VO2max; RTs and accuracy did not differ between 35% VO2max exercise and rest conditions. N2 and P3 amplitudes were larger following 70% VO2max exercise for the food-based go/no-go task compared to rest and 35% VO2max exercise. There were no differences between exercise conditions for N2 amplitude during the flanker task; however, P3 amplitude was more positive following 70% VO2max compared to rest, but not 35% VO2max exercise. Biological sex did not moderate exercise outcomes. Results suggest improved and more efficient food-related recruitment of later inhibitory control and cognitive control processes following 70% VO2max exercise.
    Keywords:  Cognitive control; ERP; Event-related potential; Exercise; Inhibitory control
    DOI:  https://doi.org/10.1016/j.neuroimage.2021.118162
  9. Neurochem Res. 2021 May 20.
      The mechanisms underlying propofol-induced toxicity in developing neurons are still unclear. The aim of present study was to explore the role of Pink1 mediated mitochondria pathway in propofol-induced developmental neurotoxicity. The primary Neural Stem Cells (NSCs) were isolated from the hippocampus of E15.5 mice embryos and then treated with propofol. The effects of propofol on proliferation, differentiation, apoptosis, mitochondria ultrastructure and MMP of NSCs were investigated. In addition, the abundance of Pink1 and a group of mitochondria related proteins in the cytoplasm and/or mitochondria were investigated, which mainly included CDK1, Drp1, Parkin1, DJ-1, Mfn1, Mfn2 and OPA1. Moreover, the relationship between Pink1 and these molecules was explored using gene silencing, or pretreatment with protein inhibitors. Finally, the NSCs were pretreated with mitochondrial specific antioxidant (MitoQ) or Drp1 inhibitor (Mdivi-1), and then the toxic effects of propofol on NSCs were investigated. Our results indicated that propofol treatment inhibited NSCs proliferation and division, and promoted NSCs apoptosis. Propofol induced significant NSCs mitochondria deformation, vacuolization and swelling, and decreased MMP. Additional studies showed that propofol affected a group of mitochondria related proteins via Pink1 inhibition, and CDK1, Drp1, Parkin1 and DJ-1 are the important downstream proteins of Pink1. Finally, the effects of propofol on proliferation, differentiation, apoptosis, mitochondrial ultrastructure and MMP of NSCs were significantly attenuated by MitoQ or Mdivi-1 pretreatment. The present study demonstrated that propofol regulates the proliferation, differentiation and apoptosis of NSCs via Pink1mediated mitochondria pathway.
    Keywords:  Mitochondria; Neuron stem cell; Pink1; Propofol
    DOI:  https://doi.org/10.1007/s11064-021-03359-1