Axonal remodeling of the corticospinal tract during neurological recovery after stroke

Stroke remains the leading cause of long-term disability.Hemiparesis is one of the most common post-stroke motor deficits and is largely attributed to loss or disruption of the motor signals from the affected motor cortex.As the only direct descending motor pathway,the corticospinal tract(CST)is the primary pathway to innervate spinal motor neurons,and thus,forms the neuroanatomical basis to control the peripheral muscles for voluntary movements.Here,we review evidence from both experimental animals and stroke patients,regarding CST axonal damage,functional contribution of CST axonal integrity and remodeling to neurological recovery,and therapeutic approaches aimed to enhance CST axonal remodeling after stroke.The new insights gleaned from preclinical and clinical studies may encourage the development of more rational therapeutics with a strategy targeted to promote axonal rewiring for corticospinal innervation,which will significantly impact the current clinical needs of subacute and chronic stroke treatment.

Reactive astrocytes promote axonal remodeling and neurological recovery after stroke

Stroke is a leading cause of death and disability in adults worldwide. For decades, the primary approach and goal of therapy for stroke has focused on neuroprotection, namely treating the injured tissue, with interventions designed to reduce the volume of cerebral infarction. Enormous effort in the laboratory has been devoted to the development of neuroprotective agents in an attempt to salvage ischemic neurons in the brain from irreversible injury; however, all these efforts have failed to demonstrate efficacy in clinical trials of stroke. In order to treat stroke, we have to re-con- ceptualize and redefine our therapeutic targets. Acute neu- roprotective treatments for stroke fight a temporal battle of salvaging cerebral tissue before the onset of death, as well as a physiological impediment of delivery of therapy to tissue which has inadequate blood flow.

Can lithium enhance the extent of axon regeneration and neurological recovery following peripheral nerve trauma?

The clinical"gold standard"technique for attempting to restore function to nerves with a gap is to bridge the gap with sensory autografts.However,autografts induce good to excellent recovery only across short nerve gaps,in young patients,and when repairs are performed a short time post nerve trauma.Even under the best of conditions,<50%of patients recover good recovery.Although many alternative techniques have been tested,none is as effective as autografts.Therefore,alternative techniques are required that increase the percentage of patients who recover function and the extent of their recovery.This paper examines the actions of lithium,and how it appears to trigger all the cellular and molecular events required to promote axon regeneration,and how both in animal models and clinically,lithium administration enhances both the extent of axon regeneration and neurological recovery.The paper proposes more extensive clinical testing of lithium for its ability and reliability to increase the extent of axon regeneration and functional recovery.

Surgical intervention combined with weight-bearing walking training promotes recovery in patients with chronic spinal cord injury:a randomized controlled study

For patients with chronic spinal cord injury,the co nventional treatment is rehabilitation and treatment of spinal cord injury complications such as urinary tract infection,pressure sores,osteoporosis,and deep vein thrombosis.Surgery is rarely perfo rmed on spinal co rd injury in the chronic phase,and few treatments have been proven effective in chronic spinal cord injury patients.Development of effective therapies fo r chronic spinal co rd injury patients is needed.We conducted a randomized controlled clinical trial in patients with chronic complete thoracic spinal co rd injury to compare intensive rehabilitation(weight-bearing walking training)alone with surgical intervention plus intensive rehabilitation.This clinical trial was registered at ClinicalTrials.gov(NCT02663310).The goal of surgical intervention was spinal cord detethering,restoration of cerebrospinal fluid flow,and elimination of residual spinal cord compression.We found that surgical intervention plus weight-bearing walking training was associated with a higher incidence of American Spinal Injury Association Impairment Scale improvement,reduced spasticity,and more rapid bowel and bladder functional recovery than weight-bearing walking training alone.Overall,the surgical procedures and intensive rehabilitation were safe.American Spinal Injury Association Impairment Scale improvement was more common in T7-T11 injuries than in T2-T6 injuries.Surgery combined with rehabilitation appears to have a role in treatment of chronic spinal cord injury patients.

miR-181b promotes angiogenesis and neurological function recovery after ischemic stroke

Promotion of new blood vessel formation is a new strategy for treating ischemic stroke.Non-coding miRNAs have been recently considered potential therapeutic targets for ischemic stroke.miR-181b has been shown to promote angiogenesis in hypoxia and traumatic brain injury model,while its effect on ischemic stroke remains elusive.In this study,we found that overexpression of miR-181b in brain microvascular endothelial cells subjected to oxygen-glucose deprivation in vitro restored cell prolife ration and enhanced angiogenesis.In rat models of focal cerebral ischemia,ove rexpression of miR-181b reduced infarction volume,promoted angiogenesis in ischemic penumbra,and improved neurological function.We further investigated the molecular mechanism by which miR-181b participates in angiogenesis after ischemic stroke and found that miR-181b directly bound to the 3’-UTR of phosphatase and tensin homolog(PTEN) mRNA to induce PTEN downregulation,leading to activation of the protein kinase B(Akt) pathway,upregulated expression of vascular endothelial growth facto rs,down-regulated expression of endostatin,and promoted angiogenesis.Taken togethe r,these results indicate that exogenous miR-181b exhibits neuroprotective effects on ischemic stro ke through activating the PTEN/Akt signal pathway and promoting angiogenesis.

Injectable collagen scaffold with human umbilical cordderived mesenchymal stem cells promotes functional recovery in patients with spontaneous intracerebral hemorrhage:phase Ⅰ clinical trial

Animal expe riments have shown that injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells can promote recovery from spinal cord injury.To investigate whether injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells can be used to treat spontaneous intracerebral hemorrhage,this non-randomized phase I clinical trial recruited patients who met the inclusion criteria and did not meet the exclusion crite ria of spontaneous intracerebral hemorrhage treated in the Characteristic Medical Center of Chinese People’s Armed Police Force from May 2016 to December 2020.Patients were divided into three groups according to the clinical situation and patient benefit:control(n=18),human umbilical cord-derived mesenchymal stem cells(n=4),and combination(n=8).The control group did not receive any transplantation.The human umbilical cord-derived mesenchymal stem cells group received human umbilical cord-derived mesenchymal stem cell transplantation.The combination group received injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells.Patients who received injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells had more remarkable improvements in activities of daily living and cognitive function and smaller foci of intra cerebral hemorrhage-related encephalomalacia.Severe adve rse events associated with cell transplantation were not observed.Injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells appears to have great potential treating spontaneous intracerebral hemorrhage.

Effects of professional rehabilitation training on the recovery of neurological function in young stroke patients

Young stroke patients have a strong desire to return to the society, but few studies have been conducted on their rehabilitation training items, intensity, and prognosis. We analyzed clinical data of young and middle-aged/older stroke patients hospitalized in the Department of Neurological Rehabilitation, China Rehabilitation Research Center, Capital Medical University, China from February 2014 to May 2015. Results demonstrated that hemorrhagic stroke （59.6%） was the primary stroke type found in the young group, while ischemic stroke （60.0%） was the main type detected in the middle-aged/older group. Compared with older stroke patients, education level and incidence of hyperhomocysteinemia were higher in younger stroke patients, whereas, incidences of hypertension, diabetes, and heart disease were lower. The average length of hospital stay was longer in the young group than in the middle-aged/older group. The main risk factors observed in the young stroke patients were hypertension, drinking, smoking, hyperlipidemia, hyperhomocysteinemia, diabetes, previous history of stroke, and heart disease. The most accepted rehabilitation program consisted of physiotherapy, occupational therapy, speech therapy, acupuncture and moxibustion. Average rehabilitation training time was 2.5 hours/day. Barthel Index and modified Rankin Scale scores were increased at discharge. Six months after discharge, the degree of occupational and economic satisfaction declined, and there were no changes in family life satisfaction. The degrees of other life satisfaction （such as friendship） improved. The degree of disability and functional status improved significantly in young stroke patients after professional rehabilitation, but the number of patients who returned to society within 6 months after stroke was still small.

Erythropoietin inhibits ferroptosis and ameliorates neurological function after spinal cord injury

Ferroptosis is one of the critical pathological events in spinal cord injury.Erythropoietin has been reported to improve the recovery of spinal cord injury.However,whether ferroptosis is involved in the neuroprotective effects of erythropoietin on spinal cord injury has not been examined.In this study,we established rat models of spinal cord injury by modified Allen’s method and intraperitoneally administered 1000 and 5000 IU/kg erythropoietin once a week for 2 successive weeks.Both low and high doses of erythropoietin promoted recovery of hindlimb function,and the high dose of erythropoietin led to better outcome.High dose of erythropoietin exhibited a stronger suppressive effect on ferroptosis relative to the low dose of erythropoietin.The effects of erythropoietin on inhibiting ferroptosis-related protein expression and restoring mitochondrial morphology were similar to those of Fer-1(a ferroptosis suppressor),and the effects of erythropoietin were largely diminished by RSL3(ferroptosis activator).In vitro experiments showed that erythropoietin inhibited RSL3-induced ferroptosis in PC12 cells and increased the expression of xCT and Gpx4.This suggests that xCT and Gpx4 are involved in the neuroprotective effects of erythropoietin on spinal cord injury.Our findings reveal the underlying anti-ferroptosis role of erythropoietin and provide a potential therapeutic strategy for treating spinal cord injury.

JNK3 involvement in nerve cell apoptosis and neurofunctional recovery after traumatic brain injury

Increasing evidence has revealed that the activation of the JNK pathway participates In apoptosis o1 nerve cells and neurological function recovery after traumatic brain injury. However, which genes inI the JNK family are activated and their role in traumatic brain injury remain unclear. Therefore, in this study, in situ end labeling, reverse transcription-PCR and neurological function assessment were adopted to investigate the alteration of JNK1, JNK2 and JNK3 gene expression in cerebral injured rats, and their role in celt apoptosis and neurological function restoration. Results showed that JNK3 expression significantly decreased at 1 and 6 hours and 1 and 7 days post injury, but that JNK1 and JNK2 expression remained unchanged. In addition, the number of apoptotic nerve cells surrounding the injured cerebral cortex gradually reduced over time post injury. The Neurological Severity Scores gradually decreased over 1,3, 5, 14 and 28 days post injury. These findings suggested that JNK3 expression was downregulated at early stages of brain injury, which may be associated with apoptosis of nerve cells. Downregulation of JNK3 expression may promote the recovery of neurological function following traumatic brain injury.

Neural stem cell-derived exosome as a nano-sized carrier for BDNF delivery to a rat model of ischemic stroke

Our previo us study demonstrated the potential therapeutic role of human neural stem cell-derived exosomes(hNSC-Exo)in ischemic stroke.Here,we loaded brain-derived neurotrophic factor(BDNF)into exosomes derived from NSCs to construct engineered exosomes(BDNF-hNSC-Exo)and compared their effects with those of hNSC-Exo on ischemic stroke both in vitro and in vivo.In a model of H_(2)O_(2)-induced oxidative stress in NSCs,BDNF-hNSC-Exo markedly enhanced cell survival.In a rat middle cerebral arte ry occlusion model,BDNF-hNSC-Exo not only inhibited the activation of microglia,but also promoted the differentiation of endogenous NSCs into neurons.These results suggest that BDNF can improve the function of NSC-derived exosomes in the treatment of ischemic stro ke.Our research may support the clinical use of other neurotrophic factors for central nervous system diseases.

Effects of durotomy versus myelotomy in the repair of spinal cord injury

Current management for spinal cord injury aims to reduce secondary damage and recover sensation and movement.Acute spinal cord injury is often accompanied by spinal cord compartment syndrome.Decompression by durotomy and/or myelotomy attempts to relieve secondary damage by completelyrelieving the compression of the spinal cord,removing the necrotic tissue,decreasing edema,reducing hemorrhage,and improving blood circulation in the spinal cord.However,it is controversial whether durotomy and/or myelotomy after spinal cord injury are beneficial to neurological recovery.This review compares the clinical effects of durotomy with those of myelotomy in the treatment of spinal cord injury.We found that durotomy has been performed more than myelotomy in the clinic,and that durotomy may be safer and more effective than myelotomy.Durotomy performed in humans had positive effects on neurological function in 92.3% of studies in this review,while durotomy in animals had positive effects on neurological function in 83.3% of studies.Myelotomy procedures were effective in 80% of animal studies,but only one clinical study of myelotomy has reported positive results,of motor and sensory improvement,in humans.However,a number of new animal studies have reported that durotomy and myelotomy are ineffective for spinal cord injury.More clinical data,in the form of a randomized controlled study,are needed to understand the effectiveness of durotomy and myelotomy.

The translational importance of establishing biomarkers of human spinal cord injury

The evaluation of such novel therapies for acute spinal cord injury in clinical trials is extremely challenging.Our current dependence upon the clinical assessment of neurologic impairment renders many acute SCI patients ineligible for trials because they are not examinable.Furthermore,the difficulty in predicting neurologic recovery based on the early clinical assessment forces investigators to recruit large cohorts to have sufficient power.Biomarkers that objectively classify injury severity and better predict neurologic outcome would be valuable tools for translational research.As such,the objective of the present review was to describe some of the translational challenges in acute spinal cord injury research and examine the potential utility of neurochemical biomarkers found within cerebrospinal fluid and blood.We focus on published efforts to establish biological markers for accurately classifying injury severity and precisely predict neurological outcome.

A three-dimensional matrix system containing melatonin and neural stem cells repairs damage from traumatic brain injury in rats

Brain lesions can cause neural stem cells to activate,proliferate,diffe rentiate,and migrate to the injured area.However,after traumatic brain injury,brain tissue defects and microenvironment changes greatly affect the survival and growth of neural stem cells;the resulting reduction in the number of neural stem cells impedes effective repair of the injured area.Melatonin can promote the survival,proliferation,and differentiation of neural stem cells under adverse conditions such as oxidative stress or hypoxia that can occur after traumatic brain injury.Therefore,we investigated the therapeutic effects of melatonin combined with neural stem cells on traumatic brain injury in rats.First,in vitro studies confirmed that melatonin promoted the survival of neural stem cells deprived of oxygen and glucose.Then,we established a three-dimensional Matrigel-based transplantation system containing melatonin and neural stem cells and then used it to treat traumatic brain injury in rats.We found that treatment with the Matrigel system containing melatonin and neural stem cells decreased brain lesion volume,increased the number of surviving neuro ns,and improved recove ry of neurological function compared with treatment with Matrigel alone,neural stem cells alone,Matrigel and neural stem cells combined,and Matrigel and melatonin combined.Our findings suggest that the three-dimensional Matrigelbased transplantation system containing melatonin and neural stem cells is a potential treatment for traumatic brain injury.