Treadmill exercise promotes neurogenesis and myelin repair via upregulating Wnt/ß­catenin signaling pathways in the juvenile brain following focal cerebral ischemia/reperfusion.

Physical exercise has a neuroprotective effect and is an important treatment after ischemic stroke. Promoting neurogenesis and myelin repair in the penumbra is an important method for the treatment of ischemic stroke. However, the role and potential mechanism of exercise in neurogenesis and myelin repair still needs to be clarified. The goal of the present study was to ascertain the possible effect of treadmill training on the neuroprotective signaling pathway in juvenile rats after ischemic stroke. The model of middle cerebral artery occlusion (MCAO) in juvenile rats was established and then the rats were randomly divided into 9 groups. XAV939 (an inhibitor of the Wnt/ß­catenin pathway) was used to confirm the effects of the Wnt/ß­catenin signaling pathway on exercise­mediated neurogenesis and myelin repair. Neurological deficits were detected by modified neurological severity score, the injury of brain tissue and the morphology of neurons was detected by hematoxylin­eosin staining and Nissl staining, and the infarct volume was detected by 2,3,5­triphenyl tetrazolium chloride staining. The changes in myelin were observed by Luxol fast blue staining. The neuron ultrastructure was observed by transmission electron microscopy. Immunofluorescence and western blots analyzed the molecular mechanisms. The results showed that treadmill exercise improved neurogenesis, enhanced myelin repair, promoted neurological function recovery and reduced infarct volume. These were the results of the upregulation of Wnt3a and nucleus ß­catenin, brain­derived neurotrophic factor (BDNF) and myelin basic protein (MBP). In addition, XAV939 inhibited treadmill exercise­induced neurogenesis and myelin repair, which was consistent with the downregulation of Wnt3a, nucleus ß­catenin, BDNF and MBP expression, and the deterioration of neurological function. In summary, treadmill exercise promotes neurogenesis and myelin repair by upregulating the Wnt/ß­catenin signaling pathway, to improve the neurological deficit caused by focal cerebral ischemia/reperfusion.

Treadmill exercise improves neurological function by inhibiting autophagy and the binding of HMGB1 to Beclin1 in MCAO juvenile rats.

AIMS: Treadmill exercise is a beneficial treatment following childhood stroke. Thus, studies focusing on the neuroprotective mechanism of exercise training during postischemic treatment in children with ischemic stroke are urgently needed. We evaluated the effects of treadmill exercise on autophagy after cerebral ischemia in young rats. MAIN METHODS: Rats (23-25 days old) underwent cerebral ischemia-reperfusion (CI/R) surgery. The experimental animals were divided into 5 groups, and some groups received either treadmill exercise, a rapamycin (RAPA) injection or combination therapy for 3 or 7 days. We performed a series of experimental tests including neurological scoring, hematoxylin-eosin staining (H&E), Nissl staining, triphenyl tetrazolium chloride (TTC) staining, Western blot analysis (WB), immunofluorescence (IF), enzyme-linked immunosorbent assay (ELISA), transmission electron microscopy (TEM) and Terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) fluorescence. KEY FINDINGS: The experimental data indicated that treadmill exercise inhibited autophagy in the ischemic penumbra, inhibited high mobility group box 1 (HMGB1) translocation and binding to Beclin1, reduced apoptosis, reduced infarct volumes, and aided in functional recovery. However, RAPA promoted the opposite effects of treadmill exercise. SIGNIFICANCE: We found that treadmill exercise improves the neurological deficits induced by CI/R by inhibiting autophagy and HMGB1 binding to Beclin1.

Metachromatic leukodystrophy: Characterization of two (p.Leu433Val, p.Gly449Arg) arylsulfatase A mutations.

Metachromatic leukodystrophy disorder (MLD) is an autosomal recessive lysosomal storage disease. The disease is primarily caused by a deficiency in the enzyme arylsulfatase A (ASA), which is encoded by the ARSA gene. A total of 254 mutations have been reported in different populations. The present study aimed to detect causative gene mutations in an atypical case presenting with attention deficit hyperactivity disorder through whole-exome sequencing. Of note, the patient's mother is from a consanguineous family. Compound heterozygous variants (c.1297C>G) + (c.1345G>A) [(p.Leu433Val) + (p.Gly449Arg)] were identified in exon 8 in the ARSA gene of the pediatric patient. The two missense mutations identified have not been previously reported, to the best of our knowledge. Furthermore, an in silico analysis and multiple phylogenetic tree analyses of ARSA homologs were performed to predict the effects of the two novel mutations. Serial changes were observed in the patient with MLD at follow-up visits over 6 years. However, brain MRI images demonstrated no notable progression and the number of ASA enzymes was stable. Also, the results of neurodevelopmental assessment showed that the patient was diagnose with ADHD. These data may offer a potential explanation of the genotype-phenotype correlation in MLD and enhance the spectrum of mutations associated with the condition.

Effects of Treadmill Exercise on Motor and Cognitive Function Recovery of MCAO Mice Through the Caveolin-1/VEGF Signaling Pathway in Ischemic Penumbra.

Exercise has been regarded as an effective rehabilitation strategy to facilitate motor and cognitive functional recovery after stroke, even though the complex effects associated with exercise-induced repair of cerebral ischemic injury are not fully elucidated. The enhancement of angiogenesis and neurogenesis, and the improvement of synaptic plasticity following moderate exercise are conducive to functional recovery after ischemic damage. Our previous studies have confirmed the angiogenesis and neurogenesis through the caveolin-1/VEGF pathway in MCAO rats. As an essential neurotrophic factor, BDNF has multiple effects on ischemic injury. In this study, we attempted to determine an additional mechanism of treadmill exercise-mediated motor and cognitive functional recovery through the caveolin-1/VEGF pathway associated with BDNF in the ischemic penumbra of MCAO mice. We found that mice exposed to treadmill exercise after the MCAO operation showed a significant up-regulation in expression of caveolin-1, VEGF, BDNF, synapsin I and CYFIP1 proteins, numbers of cells positive for BrdU/CD34, BDNF, BrdU/NeuN, BrdU/Synapsin I and CYFIP1 expression were increased, which support the reduction in neurological deficit and infarction volume, as well as improved synaptic morphology and spatial learning abilities, compared with the non-exercise mice. However, the caveolin-1 inhibitor, daidzein, resulted in increase in neurological deficit and infarction volume. The selective VEGFR2 inhibitor, PD173074, significantly induced larger infarction volume and neurological injury, and decreased the expression of BDNF in the ischemic penumbra. These findings indicate that exercise improves angiogenesis, neurogenesis and synaptic plasticity to ameliorate motor and cognitive impairment after stroke partially through the caveolin-1/VEGF pathway, which is associated with the coregulator factor, BDNF.

Treadmill exercise ameliorates focal cerebral ischemia/reperfusion-induced neurological deficit by promoting dendritic modification and synaptic plasticity via upregulating caveolin-1/VEGF signaling pathways.

Dendritic and synaptic plasticity in the penumbra are important processes and are considered to be therapeutic targets of ischemic stroke. Treadmill exercise is known to be a beneficial treatment following stroke. However, its effects and potential mechanism in promoting dendritic and synaptic plasticity remain unknown. We have previously demonstrated that the caveolin-1/VEGF signaling pathway plays a positive role in angiogenesis and neurogenesis. Here, we further investigated the effects of treadmill exercise on promoting dendritic and synaptic plasticity in the penumbra and whether they involve the caveolin-1/VEGF signaling pathway. A middle cerebral artery occlusion (MCAO) animal model was established, and rats were randomly divided into eleven groups. At 2 days after MCAO, rats were subjected to treadmill exercise for 7 or 28 days. Daidzein (a specific inhibitor of caveolin-1, 0.4 mg/kg) was used to confirm the effect of caveolin-1/VEGF signaling on exercise-mediated dendritic and synaptic plasticity. Neurobehavioral performance, tissue morphology and infarct volumes were detected by Modified Neurology Severity Score (mNSS), Hematoxylin-eosin (HE), and Nissl staining, while neural plasticity and its molecular mechanism were examined by Golgi-Cox staining, transmission electron microscopy, western blot analysis and immunofluorescence. We found that treadmill exercise promoted dendritic plasticity in the penumbra, consistent with the significant increase in caveolin-1 and VEGF expression; improved neurological recovery; and reduced infarct volume. In contrast to the positive effects of the treadmill, a caveolin-1 inhibitor abrogated the dendritic and synaptic plasticity. Furthermore, we observed that treadmill exercise-induced improved dendritic and synaptic plasticity were significantly inhibited by the caveolin-1 inhibitor, consistent with the lower expression of caveolin-1 and VEGF, as well as the worse neurobehavioral state. The findings indicate that treadmill exercise ameliorates focal cerebral ischemia/reperfusion-induced neurological deficit by promoting dendritic and synaptic plasticity via upregulating caveolin-1/VEGF signaling pathways.