Spinal cord injury(SCI)is a highly devastating and com plex inj u ry with many seconda ry consequences.Finding a treatment for SCI has been a rollercoaster ride through exciting peaks and sobering valleys.As a matter ...Spinal cord injury(SCI)is a highly devastating and com plex inj u ry with many seconda ry consequences.Finding a treatment for SCI has been a rollercoaster ride through exciting peaks and sobering valleys.As a matter of fact,there are still no robust and reliable clinical treatments to minimize or repair spinal cord damage.展开更多
A substantial number of individuals have long-lasting adverse effects from a traumatic brain injury（TBI）. Depression is one of these long-term complications that influences many aspects of life. Depression can limit...A substantial number of individuals have long-lasting adverse effects from a traumatic brain injury（TBI）. Depression is one of these long-term complications that influences many aspects of life. Depression can limit the ability to return to work, and even worsen cognitive function and contribute to dementia. The mechanistic cause for the increased depression risk associated with a TBI remains to be defined. As TBI results in chronic neuroinflammation, and priming of glia to a secondary challenge, the inflammatory theory of depression provides a promising framework for investigating the cause of depression following a TBI. Increases in cytokines similar to those seen in depression in the general population are also increased following a TBI. Biomarker levels of cytokines peak within hours-to-days after the injury, yet pro-inflammatory cytokines may still be elevated above physiological levels months-to-years following TBI, which is the time frame in which post-TBI depression can persist. As tumor necrosis factor α and interleukin 1 can signal directly at the neuronal synapse, pathophysiological levels of these cytokines can detrimentally alter neuronal synaptic physiology. The purpose of this review is to outline the current evidence for the inflammatory hypothesis of depression specifically as it relates to depression following a TBI. Moreover, we will illustrate the potential synaptic mechanisms by which tumor necrosis factor α and interleukin 1 could contribute to depression. The association of inflammation with the development of depression is compelling; however, in the context of post-TBI depression, the role of inflammation is understudied. This review attempts to highlight the need to understand and treat the psychological complications of a TBI, potentially by neuroimmune modulation, as the neuropsychiatric disabilities can have a great impact on the rehabilitation from the injury, and overall quality of life.展开更多
The mitochondrion serves many functions in the central nervous system （CNS） and other organs beyond the well-recognized role of adenosine triphosphate （ATP） production. This includes calcium-dependent cell signali...The mitochondrion serves many functions in the central nervous system （CNS） and other organs beyond the well-recognized role of adenosine triphosphate （ATP） production. This includes calcium-dependent cell signaling, regulation of gene expression, synthesis and release of cytotoxic reactive oxygen species, and the release of cytochrome c and other apoptotic cell death factors. Traumatic injury to the CNS results in a rapid and, in some cases, sustained loss of mitochondrial function. One consequence of compromised mitochondrial function is induction of the mitochondrial permeability transition （mPT） state due to formation of the cyclosporine A sensitive permeability transition pore （mPTP）. In this mini-review, we summarize evidence supporting the involvement of the mPTP as a mediator of mitochondrial and cellular demise following CNS traumatic injury and discuss the beneficial effects and limitations of the current ex- perimental strategies targeting the mPTP.展开更多
To review the neuroprotective effects of minocycline in focal cerebral ischemia in animal models.By searching in the databases of PubMed,ScienceDirect,and Scopus,and considering the inclusion and exclusion criteria of...To review the neuroprotective effects of minocycline in focal cerebral ischemia in animal models.By searching in the databases of PubMed,ScienceDirect,and Scopus,and considering the inclusion and exclusion criteria of the study.Studies were included if focal cerebral ischemia model was performed in mammals and including a control group that has been compared with a minocycline group.Written in languages other than English;duplicate data;in vitro studies and combination of minocycline with other neuroprotective agents were excluded.Neurological function of patients was assessed by National Institute of Health Stroke Scale,modified Rankin Scale,and modified Barthel Index.Neuroprotective effects were assessed by detecting the expression of inflammatory cytokines.We examined 35 papers concerning the protective effects of minocycline in focal cerebral ischemia in animal models and 6 clinical trials which had evaluated the neuroprotective effects of minocycline in ischemic stroke.These studies revealed that minocycline increases the viability of neurons and decreases the infarct volume following cerebral ischemia.The mechanisms that were reported in these studies included anti-inflammatory,antioxidant,as well as anti-apoptotic effects.Minocycline also increases the neuronal regeneration following cerebral ischemia.Minocycline has considerable neuroprotective effects against cerebral ischemia-induced neuronal damages.However,larger clinical trials may be required before using minocycline as a neuroprotective drug in ischemic stroke.展开更多
MicroRNAs(miRNAs)are small non-coding RNA molecules that regulate post-transcriptional gene expression and contribute to all aspects of cellular function.We previously reported that the activities of several mitochond...MicroRNAs(miRNAs)are small non-coding RNA molecules that regulate post-transcriptional gene expression and contribute to all aspects of cellular function.We previously reported that the activities of several mitochondria-enriched miRNAs regulating inflammation(i.e.,miR-142-3p,miR-142-5p,and miR-146a)are altered in the hippocampus at 3–12 hours following a severe traumatic brain injury.In the present study,we investigated the temporal expression profile of these inflammatory miRNAs in mitochondria and cytosol fractions at more chronic post-injury times following severe controlled cortical impact injury in rats.In addition,several inflammatory genes were analyzed in the cytosol fractions.The analysis showed that while elevated levels were observed in cytoplasm,the mitochondria-enriched miRNAs,miR-142-3p and miR-142-5p continued to be significantly reduced in mitochondria from injured hippocampi for at least 3 days and returned to near normal levels at 7 days post-injury.Although not statistically significant,miR-146a also remained at reduced levels for up to 3 days following controlled cortical impact injury,and recovered by 7 days.In contrast,miRNAs that are not enriched in mitochondria,including miR-124a,miR-150,miR-19b,miR-155,and miR-223 were either increased or demonstrated no change in their levels in mitochondrial fractions for 7 days.The one exception was that miR-223 levels were reduced in mitochondria at 1 day following injury.No major alterations were observed in sham operated animals.This temporal pattern was unique to mitochondria-enriched miRNAs and correlated with injury-induced changes in mitochondrial bioenergetics as well as expression levels of several inflammatory markers.These observations suggested a potential compartmental re-distribution of the mitochondria-enriched inflammatory miRNAs and may reflect an intracellular mechanism by which specific miRNAs regulate injury-induced inflammatory signaling.To test this,we utilized a novel peptide-based nanoparticle strategy for in vitro and in vivo delivery of a miR-146a mimic as a potential therapeutic strategy for targeting nuclear factor-kappa B inflammatory modulators in the injured brain.Nanoparticle delivery of miR-146a to BV-2 or SH-SY5Y cells significantly reduced expression of TNF receptor-associated factor 6(TRAF6)and interleukin-1 receptor-associated kinase 1(IRAK1),two important modulators of the nuclear factor-kappa B(NF-κB)pro-inflammatory pathway.Moreover,injections of miR-146a containing nanoparticles into the brain immediately following controlled cortical impact injury significantly reduced hippocampal TNF receptor-associated factor 6 and interleukin-1 receptor-associated kinase 1 levels.Taken together,our studies demonstrate the subcellular alteration of inflammatory miRNAs after traumatic brain injury and establish proof of principle that nanoparticle delivery of miR-146a has therapeutic potential for modulating pro-inflammatory effectors in the injured brain.All of the studies performed were approved by the University of Kentucky Institutional Animal Care and Usage Committee(IACUC protocol#2014-1300)on August 17,2017.展开更多
The complex and variable nature of traumatic spinal cord inju- ry （SCI） presents a unique challenge for translational research. SCI is not bound by any demographic nor is it limited to specific injury biomechanics.
Commentary Most would agree that providing comprehensive detail in scientific reporting is critical for the development of mean- ingful therapies and treatments for diseases. Such stellar practices 1） allow for repro...Commentary Most would agree that providing comprehensive detail in scientific reporting is critical for the development of mean- ingful therapies and treatments for diseases. Such stellar practices 1） allow for reproduction of experiments to con- firm results, 2） promote thorough analyses of data, and 3） foster the incremental advancement of valid approaches. Unfortunately, most would also agree we have far to go to reach this vital goal （Hackam and Redelmeier, 2006; Prinz et al., 2011; Baker et al., 2014）.展开更多
Spinal cord injury(SCI)induces a robust inflammatory response largely mediated by resident microglia and infiltrating macrophages across the blood-brain barrier.While these cell populations are capable of promoting re...Spinal cord injury(SCI)induces a robust inflammatory response largely mediated by resident microglia and infiltrating macrophages across the blood-brain barrier.While these cell populations are capable of promoting repair and regenerative responses,in the days and weeks after SCI they predominately adopt pro-inflammatory profiles known to inhibit recovery and potentiate secondary injury pathways.展开更多
A recent demographic shift towards increased age at time of spinal cord injury (SCI), as well as decreased functional recovery following SCI in older populations, create the need to investigate how age effects SCI pat...A recent demographic shift towards increased age at time of spinal cord injury (SCI), as well as decreased functional recovery following SCI in older populations, create the need to investigate how age effects SCI pathology and repair (Scivoletto et al., 2003). While decreased neuroplasticity or physical strength with age may contribute to functional deficits, work from our lab and others have identified exacerbated acute inflammatory events as contributors to age-dependent secondary injury. Specifically, our recent paper identified that increased production of reactive oxygen species (ROS) from macrophage nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) with age exacerbates secondary injury after SCI (Zhang et al., 2019).展开更多
There is mounting evidence that targeting mitochondrial dysfunction following neurotrauma could be key in developing effective therapeutic strategies since mitochondria are known to play a major role in cellular bioen...There is mounting evidence that targeting mitochondrial dysfunction following neurotrauma could be key in developing effective therapeutic strategies since mitochondria are known to play a major role in cellular bioenergetics, function, and survival following traumatic spinal cord injury （SCI） （Rabchevsky et al., 2011）. Our research group is one of the pioneers in targeting mitochondrial dysfunction to foster functional neuroprotection, having documented that phar- macological maintenance of mitochondrial function acutely results in long-term neuroprotection and improved function- al recover. We have recently reported that treatment with the pleiotropic drug, pioglitazone, maintains acute mitochondrial integrity correlated with chronic tissue sparing and functional recovery after contusion SCI, but that this was not correlated with altered neuroinflammation （Patel et al., 2017）. We herein propose that the mechanism（s） by which pioglitazone confers neuroprotection may not be entirely dependent upon its activation of peroxisome proliferator activated receptor （PPAR）,展开更多
Dexamethasone has been widely used after various neurosurgical procedures due to its anti-inflammatory property and the abilities to restore vascular permeability,inhibit free radicals,and reduce cerebrospinal fluid p...Dexamethasone has been widely used after various neurosurgical procedures due to its anti-inflammatory property and the abilities to restore vascular permeability,inhibit free radicals,and reduce cerebrospinal fluid production.According to the latest guidelines for the treatment of traumatic brain injury in the United States,high-dose glucocorticoids cause neurological damage.To investigate the reason why high-dose glucocorticoids after traumatic brain injury exhibit harmful effect,rat controlled cortical impact models of traumatic brain injury were established.At 1 hour and 2 days after surgery,rat models were intraperitoneally administered dexamethasone 10 mg/kg.The results revealed that 31 proteins were significantly upregulated and 12 proteins were significantly downregulated in rat models of traumatic brain injury after dexamethasone treatment.The Ingenuity Pathway Analysis results showed that differentially expressed proteins were enriched in the mitochondrial dysfunction pathway and synaptogenesis signaling pathway.Western blot analysis and immunohistochemistry results showed that Ndufv2,Maob and Gria3 expression and positive cell count in the dexamethasone-treated group were significantly greater than those in the model group.These findings suggest that dexamethasone may promote a compensatory increase in complex I subunits(Ndufs2 and Ndufv2),increase the expression of mitochondrial enzyme Maob,and upregulate synaptic-transmission-related protein Gria3.These changes may be caused by nerve injury after traumatic brain injury treatment by dexamethasone.The study was approved by Institutional Ethics Committee of Beijing Neurosurgical Institute(approval No.201802001)on June 6,2018.展开更多
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 th...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.展开更多
The formation of axonal spheroid is a common feature following spinal cord injury.To further understand the source of Ca^(2+)that mediates axonal spheroid formation,we used our previously characterized ex vivo mouse s...The formation of axonal spheroid is a common feature following spinal cord injury.To further understand the source of Ca^(2+)that mediates axonal spheroid formation,we used our previously characterized ex vivo mouse spinal cord model that allows precise perturbation of extracellular Ca^(2+).We performed twophoton excitation imaging of spinal cords isolated from Thy1YFP+transgenic mice and applied the lipophilic dye,Nile red,to record dynamic changes in dorsal column axons and their myelin sheaths respectively.We selectively released Ca^(2+)from internal stores using the Ca^(2+)ionophore ionomycin in the presence or absence of external Ca^(2+).We reported that ionomycin dose-dependently induces pathological changes in myelin and pronounced axonal spheroid formation in the presence of normal 2 m M Ca^(2+)artificial cerebrospinal fluid.In contrast,removal of external Ca^(2+)significantly decreased ionomycin-induced myelin and axonal spheroid formation at 2 hours but not at 1 hour after treatment.Using mice that express a neuron-specific Ca^(2+)indicator in spinal cord axons,we confirmed that ionomycin induced significant increases in intra-axonal Ca^(2+),but not in the absence of external Ca^(2+).Periaxonal swelling and the resultant disruption in the axo-myelinic interface often precedes and is negatively correlated with axonal spheroid formation.Pretreatment with YM58483(500 n M),a well-established blocker of store-operated Ca^(2+)entry,significantly decreased myelin injury and axonal spheroid formation.Collectively,these data reveal that ionomycin-induced depletion of internal Ca^(2+)stores and subsequent external Ca^(2+)entry through store-operated Ca^(2+)entry contributes to pathological changes in myelin and axonal spheroid formation,providing new targets to protect central myelinated fibers.展开更多
The ex-copula penile dorsiflexion reflex(PDFR)is an established measure of sexual dysfunction in male rat models of spinal cord injury.Although the PDFR after complete spinal transection is well described,information ...The ex-copula penile dorsiflexion reflex(PDFR)is an established measure of sexual dysfunction in male rat models of spinal cord injury.Although the PDFR after complete spinal transection is well described,information regarding the more clinically relevant incomplete spinal contusion injury model is limited.This study examined,using two-dimensional(2D)kinematic analysis,the relationship between the PDFR and degree of white matter sparing(WMS).Male Wistar rats received a T9 contusion with varying degrees of impactor forces.Weekly kinematic recordings of the PDFR were made 3-8 weeks postinjury.Sexual reflex components examined included maximum angle of penile dorsiflexion,total penile event duration,and penile ascent speed.Post hoc comparison between animals grouped based upon injury severity(moderate-severe:13.33%-17.15%WMS vs moderate:20.85%-33.50%WMS)ndicated PDFR effects.Specifically,the numbers of animals with more moderate contusions having data points above the median n both maximum angle of penile dorsiflexion and penile ascent speed were significantly lower than animals with more severe njuries.Total penile event duration was also affected but only at more chronic time points(6-8 weeks).Thus,2D kinematic analysis of the PDFR allows for more consistent and quantifiable analysis of the subtle differences that can occur between injury severity groups in the rat contusion model.展开更多
Physical rehabilitation is an effective therapy to normalize weaknesses encountered with neurological disorders such as traumatic brain injury(TBI).However,the efficacy of exercise is limited during the acute period o...Physical rehabilitation is an effective therapy to normalize weaknesses encountered with neurological disorders such as traumatic brain injury(TBI).However,the efficacy of exercise is limited during the acute period of TBI because of metabolic dysfunction,and this may further compromise neuronal function.Here we discuss the possibility to normalize brain metabolism during the early post-injury convalescence period to support functional plasticity and prevent long-term functional deficits.Although BDNF possesses the unique ability to support molecular events involved with the transmission of information across nerve cells through activation of its TrkB receptor,the poor pharmacokinetic profile of BDNF has limited its therapeutic applicability.The flavonoid derivative,7,8-dihydroxyflavone(7,8-DHF),signals through the same TrkB receptors and results in the activation of BDNF signaling pathways.We discuss how the pharmacokinetic limitations of BDNF may be avoided by the use of 7,8-DHF,which makes it a promising pharmacological agent for supporting activity-based rehabilitation during the acute post-injury period after TBI.In turn,docosahexaenoic acid(C22:6n-3;DHA)is abundant in the phospholipid composition of plasma membranes in the brain and its action is important for brain development and plasticity.DHA is a major modulator of synaptic membrane fluidity and function,which is fundamental for supporting cell signaling and synaptic plasticity.Exercise influences DHA function by normalizing DHA content in the brain,such that the collaborative action of exercise and DHA can be instrumental to boost BDNF function with strong therapeutic potential for reducing the deleterious effects of TBI on synaptic plasticity and cognition.展开更多
Alzheimer's disease (AD) is the most common form of dementia,affecting millions worldwide.It is cha racterized by progressive cognitive decline and changes in behavior and personality,attributed to neuropathologic...Alzheimer's disease (AD) is the most common form of dementia,affecting millions worldwide.It is cha racterized by progressive cognitive decline and changes in behavior and personality,attributed to neuropathological changes,such as amyloid-beta (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein.展开更多
基金supported by NIH,Nos.NIH R01 NS116068(to JCG)and NIH T32 NS077889(to OHW)。
文摘Spinal cord injury(SCI)is a highly devastating and com plex inj u ry with many seconda ry consequences.Finding a treatment for SCI has been a rollercoaster ride through exciting peaks and sobering valleys.As a matter of fact,there are still no robust and reliable clinical treatments to minimize or repair spinal cord damage.
基金supported in part by a Kentucky Spinal and Head Injury Trust trainee fellowshipsupported by National Institutes of Health under award numbers R00 AG044445(to ADB)P30 GM110787(to ADB)
文摘A substantial number of individuals have long-lasting adverse effects from a traumatic brain injury（TBI）. Depression is one of these long-term complications that influences many aspects of life. Depression can limit the ability to return to work, and even worsen cognitive function and contribute to dementia. The mechanistic cause for the increased depression risk associated with a TBI remains to be defined. As TBI results in chronic neuroinflammation, and priming of glia to a secondary challenge, the inflammatory theory of depression provides a promising framework for investigating the cause of depression following a TBI. Increases in cytokines similar to those seen in depression in the general population are also increased following a TBI. Biomarker levels of cytokines peak within hours-to-days after the injury, yet pro-inflammatory cytokines may still be elevated above physiological levels months-to-years following TBI, which is the time frame in which post-TBI depression can persist. As tumor necrosis factor α and interleukin 1 can signal directly at the neuronal synapse, pathophysiological levels of these cytokines can detrimentally alter neuronal synaptic physiology. The purpose of this review is to outline the current evidence for the inflammatory hypothesis of depression specifically as it relates to depression following a TBI. Moreover, we will illustrate the potential synaptic mechanisms by which tumor necrosis factor α and interleukin 1 could contribute to depression. The association of inflammation with the development of depression is compelling; however, in the context of post-TBI depression, the role of inflammation is understudied. This review attempts to highlight the need to understand and treat the psychological complications of a TBI, potentially by neuroimmune modulation, as the neuropsychiatric disabilities can have a great impact on the rehabilitation from the injury, and overall quality of life.
基金supported by a grant from the Kentucky Spinal Cord and Head Injury Research Trust
文摘The mitochondrion serves many functions in the central nervous system （CNS） and other organs beyond the well-recognized role of adenosine triphosphate （ATP） production. This includes calcium-dependent cell signaling, regulation of gene expression, synthesis and release of cytotoxic reactive oxygen species, and the release of cytochrome c and other apoptotic cell death factors. Traumatic injury to the CNS results in a rapid and, in some cases, sustained loss of mitochondrial function. One consequence of compromised mitochondrial function is induction of the mitochondrial permeability transition （mPT） state due to formation of the cyclosporine A sensitive permeability transition pore （mPTP）. In this mini-review, we summarize evidence supporting the involvement of the mPTP as a mediator of mitochondrial and cellular demise following CNS traumatic injury and discuss the beneficial effects and limitations of the current ex- perimental strategies targeting the mPTP.
文摘To review the neuroprotective effects of minocycline in focal cerebral ischemia in animal models.By searching in the databases of PubMed,ScienceDirect,and Scopus,and considering the inclusion and exclusion criteria of the study.Studies were included if focal cerebral ischemia model was performed in mammals and including a control group that has been compared with a minocycline group.Written in languages other than English;duplicate data;in vitro studies and combination of minocycline with other neuroprotective agents were excluded.Neurological function of patients was assessed by National Institute of Health Stroke Scale,modified Rankin Scale,and modified Barthel Index.Neuroprotective effects were assessed by detecting the expression of inflammatory cytokines.We examined 35 papers concerning the protective effects of minocycline in focal cerebral ischemia in animal models and 6 clinical trials which had evaluated the neuroprotective effects of minocycline in ischemic stroke.These studies revealed that minocycline increases the viability of neurons and decreases the infarct volume following cerebral ischemia.The mechanisms that were reported in these studies included anti-inflammatory,antioxidant,as well as anti-apoptotic effects.Minocycline also increases the neuronal regeneration following cerebral ischemia.Minocycline has considerable neuroprotective effects against cerebral ischemia-induced neuronal damages.However,larger clinical trials may be required before using minocycline as a neuroprotective drug in ischemic stroke.
基金supported by a grant(15-12A)from the Kentucky Spinal Cord and Head Injury Research Trust to JES and WXW。
文摘MicroRNAs(miRNAs)are small non-coding RNA molecules that regulate post-transcriptional gene expression and contribute to all aspects of cellular function.We previously reported that the activities of several mitochondria-enriched miRNAs regulating inflammation(i.e.,miR-142-3p,miR-142-5p,and miR-146a)are altered in the hippocampus at 3–12 hours following a severe traumatic brain injury.In the present study,we investigated the temporal expression profile of these inflammatory miRNAs in mitochondria and cytosol fractions at more chronic post-injury times following severe controlled cortical impact injury in rats.In addition,several inflammatory genes were analyzed in the cytosol fractions.The analysis showed that while elevated levels were observed in cytoplasm,the mitochondria-enriched miRNAs,miR-142-3p and miR-142-5p continued to be significantly reduced in mitochondria from injured hippocampi for at least 3 days and returned to near normal levels at 7 days post-injury.Although not statistically significant,miR-146a also remained at reduced levels for up to 3 days following controlled cortical impact injury,and recovered by 7 days.In contrast,miRNAs that are not enriched in mitochondria,including miR-124a,miR-150,miR-19b,miR-155,and miR-223 were either increased or demonstrated no change in their levels in mitochondrial fractions for 7 days.The one exception was that miR-223 levels were reduced in mitochondria at 1 day following injury.No major alterations were observed in sham operated animals.This temporal pattern was unique to mitochondria-enriched miRNAs and correlated with injury-induced changes in mitochondrial bioenergetics as well as expression levels of several inflammatory markers.These observations suggested a potential compartmental re-distribution of the mitochondria-enriched inflammatory miRNAs and may reflect an intracellular mechanism by which specific miRNAs regulate injury-induced inflammatory signaling.To test this,we utilized a novel peptide-based nanoparticle strategy for in vitro and in vivo delivery of a miR-146a mimic as a potential therapeutic strategy for targeting nuclear factor-kappa B inflammatory modulators in the injured brain.Nanoparticle delivery of miR-146a to BV-2 or SH-SY5Y cells significantly reduced expression of TNF receptor-associated factor 6(TRAF6)and interleukin-1 receptor-associated kinase 1(IRAK1),two important modulators of the nuclear factor-kappa B(NF-κB)pro-inflammatory pathway.Moreover,injections of miR-146a containing nanoparticles into the brain immediately following controlled cortical impact injury significantly reduced hippocampal TNF receptor-associated factor 6 and interleukin-1 receptor-associated kinase 1 levels.Taken together,our studies demonstrate the subcellular alteration of inflammatory miRNAs after traumatic brain injury and establish proof of principle that nanoparticle delivery of miR-146a has therapeutic potential for modulating pro-inflammatory effectors in the injured brain.All of the studies performed were approved by the University of Kentucky Institutional Animal Care and Usage Committee(IACUC protocol#2014-1300)on August 17,2017.
文摘The complex and variable nature of traumatic spinal cord inju- ry （SCI） presents a unique challenge for translational research. SCI is not bound by any demographic nor is it limited to specific injury biomechanics.
文摘Commentary Most would agree that providing comprehensive detail in scientific reporting is critical for the development of mean- ingful therapies and treatments for diseases. Such stellar practices 1） allow for reproduction of experiments to con- firm results, 2） promote thorough analyses of data, and 3） foster the incremental advancement of valid approaches. Unfortunately, most would also agree we have far to go to reach this vital goal （Hackam and Redelmeier, 2006; Prinz et al., 2011; Baker et al., 2014）.
基金supported by National Institute of Neurological Disorders and Stroke(NINDS)R01NS091582,NINDS T32 NS077889,and NINDS F31 NS105443。
文摘Spinal cord injury(SCI)induces a robust inflammatory response largely mediated by resident microglia and infiltrating macrophages across the blood-brain barrier.While these cell populations are capable of promoting repair and regenerative responses,in the days and weeks after SCI they predominately adopt pro-inflammatory profiles known to inhibit recovery and potentiate secondary injury pathways.
文摘A recent demographic shift towards increased age at time of spinal cord injury (SCI), as well as decreased functional recovery following SCI in older populations, create the need to investigate how age effects SCI pathology and repair (Scivoletto et al., 2003). While decreased neuroplasticity or physical strength with age may contribute to functional deficits, work from our lab and others have identified exacerbated acute inflammatory events as contributors to age-dependent secondary injury. Specifically, our recent paper identified that increased production of reactive oxygen species (ROS) from macrophage nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) with age exacerbates secondary injury after SCI (Zhang et al., 2019).
基金funded by NIH R21NS096670(AGR)Craig H.Neilsen Foundation 476719(AGR)+3 种基金Kentucky Spinal Cord and Head Injury Research Trust#15-14A(PGS)Veterans Affairs Merit Review Award#I01BX003405(PGS)University of Kentucky Spinal Cord and Brain Injury Center Chair Endowments(AGR&PGS)NIH/NINDS 2P30NS051220
文摘There is mounting evidence that targeting mitochondrial dysfunction following neurotrauma could be key in developing effective therapeutic strategies since mitochondria are known to play a major role in cellular bioenergetics, function, and survival following traumatic spinal cord injury （SCI） （Rabchevsky et al., 2011）. Our research group is one of the pioneers in targeting mitochondrial dysfunction to foster functional neuroprotection, having documented that phar- macological maintenance of mitochondrial function acutely results in long-term neuroprotection and improved function- al recover. We have recently reported that treatment with the pleiotropic drug, pioglitazone, maintains acute mitochondrial integrity correlated with chronic tissue sparing and functional recovery after contusion SCI, but that this was not correlated with altered neuroinflammation （Patel et al., 2017）. We herein propose that the mechanism（s） by which pioglitazone confers neuroprotection may not be entirely dependent upon its activation of peroxisome proliferator activated receptor （PPAR）,
基金This study was supported by the National Natural Science Foundation of China,No.81771327(to BYL)the Platform Construction of Basic Research and Clinical Translation of Nervous System Injury,China,No.PXM2020_026280_000002(to BYL)the Scientific Research and Cultivation Fund of the Beijing Neurosurgical Institute,China,No.2020002(to FN).
文摘Dexamethasone has been widely used after various neurosurgical procedures due to its anti-inflammatory property and the abilities to restore vascular permeability,inhibit free radicals,and reduce cerebrospinal fluid production.According to the latest guidelines for the treatment of traumatic brain injury in the United States,high-dose glucocorticoids cause neurological damage.To investigate the reason why high-dose glucocorticoids after traumatic brain injury exhibit harmful effect,rat controlled cortical impact models of traumatic brain injury were established.At 1 hour and 2 days after surgery,rat models were intraperitoneally administered dexamethasone 10 mg/kg.The results revealed that 31 proteins were significantly upregulated and 12 proteins were significantly downregulated in rat models of traumatic brain injury after dexamethasone treatment.The Ingenuity Pathway Analysis results showed that differentially expressed proteins were enriched in the mitochondrial dysfunction pathway and synaptogenesis signaling pathway.Western blot analysis and immunohistochemistry results showed that Ndufv2,Maob and Gria3 expression and positive cell count in the dexamethasone-treated group were significantly greater than those in the model group.These findings suggest that dexamethasone may promote a compensatory increase in complex I subunits(Ndufs2 and Ndufv2),increase the expression of mitochondrial enzyme Maob,and upregulate synaptic-transmission-related protein Gria3.These changes may be caused by nerve injury after traumatic brain injury treatment by dexamethasone.The study was approved by Institutional Ethics Committee of Beijing Neurosurgical Institute(approval No.201802001)on June 6,2018.
基金supported by Hong Kong Spinal Cord Injury Fund (HKSCIF),China (to HZ)。
文摘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.
文摘The formation of axonal spheroid is a common feature following spinal cord injury.To further understand the source of Ca^(2+)that mediates axonal spheroid formation,we used our previously characterized ex vivo mouse spinal cord model that allows precise perturbation of extracellular Ca^(2+).We performed twophoton excitation imaging of spinal cords isolated from Thy1YFP+transgenic mice and applied the lipophilic dye,Nile red,to record dynamic changes in dorsal column axons and their myelin sheaths respectively.We selectively released Ca^(2+)from internal stores using the Ca^(2+)ionophore ionomycin in the presence or absence of external Ca^(2+).We reported that ionomycin dose-dependently induces pathological changes in myelin and pronounced axonal spheroid formation in the presence of normal 2 m M Ca^(2+)artificial cerebrospinal fluid.In contrast,removal of external Ca^(2+)significantly decreased ionomycin-induced myelin and axonal spheroid formation at 2 hours but not at 1 hour after treatment.Using mice that express a neuron-specific Ca^(2+)indicator in spinal cord axons,we confirmed that ionomycin induced significant increases in intra-axonal Ca^(2+),but not in the absence of external Ca^(2+).Periaxonal swelling and the resultant disruption in the axo-myelinic interface often precedes and is negatively correlated with axonal spheroid formation.Pretreatment with YM58483(500 n M),a well-established blocker of store-operated Ca^(2+)entry,significantly decreased myelin injury and axonal spheroid formation.Collectively,these data reveal that ionomycin-induced depletion of internal Ca^(2+)stores and subsequent external Ca^(2+)entry through store-operated Ca^(2+)entry contributes to pathological changes in myelin and axonal spheroid formation,providing new targets to protect central myelinated fibers.
文摘The ex-copula penile dorsiflexion reflex(PDFR)is an established measure of sexual dysfunction in male rat models of spinal cord injury.Although the PDFR after complete spinal transection is well described,information regarding the more clinically relevant incomplete spinal contusion injury model is limited.This study examined,using two-dimensional(2D)kinematic analysis,the relationship between the PDFR and degree of white matter sparing(WMS).Male Wistar rats received a T9 contusion with varying degrees of impactor forces.Weekly kinematic recordings of the PDFR were made 3-8 weeks postinjury.Sexual reflex components examined included maximum angle of penile dorsiflexion,total penile event duration,and penile ascent speed.Post hoc comparison between animals grouped based upon injury severity(moderate-severe:13.33%-17.15%WMS vs moderate:20.85%-33.50%WMS)ndicated PDFR effects.Specifically,the numbers of animals with more moderate contusions having data points above the median n both maximum angle of penile dorsiflexion and penile ascent speed were significantly lower than animals with more severe njuries.Total penile event duration was also affected but only at more chronic time points(6-8 weeks).Thus,2D kinematic analysis of the PDFR allows for more consistent and quantifiable analysis of the subtle differences that can occur between injury severity groups in the rat contusion model.
基金supported by the National Institutes of Health(grant numbers:NS111378,NS117148,NS050465,NS116838).
文摘Physical rehabilitation is an effective therapy to normalize weaknesses encountered with neurological disorders such as traumatic brain injury(TBI).However,the efficacy of exercise is limited during the acute period of TBI because of metabolic dysfunction,and this may further compromise neuronal function.Here we discuss the possibility to normalize brain metabolism during the early post-injury convalescence period to support functional plasticity and prevent long-term functional deficits.Although BDNF possesses the unique ability to support molecular events involved with the transmission of information across nerve cells through activation of its TrkB receptor,the poor pharmacokinetic profile of BDNF has limited its therapeutic applicability.The flavonoid derivative,7,8-dihydroxyflavone(7,8-DHF),signals through the same TrkB receptors and results in the activation of BDNF signaling pathways.We discuss how the pharmacokinetic limitations of BDNF may be avoided by the use of 7,8-DHF,which makes it a promising pharmacological agent for supporting activity-based rehabilitation during the acute post-injury period after TBI.In turn,docosahexaenoic acid(C22:6n-3;DHA)is abundant in the phospholipid composition of plasma membranes in the brain and its action is important for brain development and plasticity.DHA is a major modulator of synaptic membrane fluidity and function,which is fundamental for supporting cell signaling and synaptic plasticity.Exercise influences DHA function by normalizing DHA content in the brain,such that the collaborative action of exercise and DHA can be instrumental to boost BDNF function with strong therapeutic potential for reducing the deleterious effects of TBI on synaptic plasticity and cognition.
文摘Alzheimer's disease (AD) is the most common form of dementia,affecting millions worldwide.It is cha racterized by progressive cognitive decline and changes in behavior and personality,attributed to neuropathological changes,such as amyloid-beta (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein.
