Mesenchymal stem cell(MSC)therapy has attracted the attention of scientists and clinicians around the world.Basic and pre-clinical experimental studies have highlighted the positive effects of MSC treatment after spin...Mesenchymal stem cell(MSC)therapy has attracted the attention of scientists and clinicians around the world.Basic and pre-clinical experimental studies have highlighted the positive effects of MSC treatment after spinal cord and peripheral nerve injury.These effects are believed to be due to their ability to differentiate into other cell lineages,modulate inflammatory and immunomodulatory responses,reduce cell apoptosis,secrete several neurotrophic factors and respond to tissue injury,among others.There are many pre-clinical studies on MSC treatment for spinal cord injury(SCI)and peripheral nerve injuries.However,the same is not true for clinical trials,particularly those concerned with nerve trauma,indicating the necessity of more well-constructed studies showing the benefits that cell therapy can provide for individuals suffering the consequences of nerve lesions.As for clinical trials for SCI treatment the results obtained so far are not as beneficial as those described in experimental studies.For these reasons basic and pre-clinical studies dealing with MSC therapy should emphasize the standardization of protocols that could be translated to the clinical set with consistent and positive outcomes.This review is based on pre-clinical studies and clinical trials available in the literature from 2010 until now.At the time of writing this article there were 43 and 36 pre-clinical and 19 and 1 clinical trials on injured spinal cord and peripheral nerves,respectively.展开更多
The adaptability of the central nervous system has been revealed in several model systems.Of particular interest to central nervous system-injured individuals is the ability for neural components to be modified for re...The adaptability of the central nervous system has been revealed in several model systems.Of particular interest to central nervous system-injured individuals is the ability for neural components to be modified for regain of function.In both types of neurotrauma,traumatic brain injury and spinal cord injury,the primary parasympathetic control to the gastrointestinal tract,the vagus nerve,remains anatomically intact.However,individuals with traumatic brain injury or spinal cord injury are highly susceptible to gastrointestinal dysfunctions.Such gastrointestinal dysfunctions attribute to higher morbidity and mortality following traumatic brain injury and spinal cord injury.While the vagal efferent output remains capable of eliciting motor responses following injury,evidence suggests impairment of the vagal afferents.Since sensory input drives motor output,this review will discuss the normal and altered anatomy and physiology of the gastrointestinal vagal afferents to better understand the contributions of vagal afferent plasticity following neurotrauma.展开更多
Trauma is one of the most common surgical emergencies admitted in the acute care departments of hospitals in Guinea, West Africa. We carried a study to assess the epidemiological pattern and clinical care of neurotrau...Trauma is one of the most common surgical emergencies admitted in the acute care departments of hospitals in Guinea, West Africa. We carried a study to assess the epidemiological pattern and clinical care of neurotrauma in the emergency department of the Kindia regional hospital, a rural secondary hospital catering to the needs of western Guinea and nearby districts. Data were prospectively collected from December 2019 to March 2020 after receiving the required hospital authorization and informed consent from the patients or relatives. We recorded two hundred cases of neurotraumas (64.5% of traumatic brain injury cases and 14.5% of spinal cord injury). Neurotraumas represented 17.7% of all admitted patients in the department in the study period. The mean age was 25.34 ± 16.73, and the age range 16 to 30 was the most affected. The predominance was male, with a sex ratio of 3.43. Motor Vehicle Accident was the leading cause 68.5%, and 73.2% of them involved a motorcycle. Motorcycle-to-motorcycle collision was responsible for more than a third of neurotraumas. We classified the majority of the cases as mild and low risk neurotrauma representing 62.08%. All patients benefited from medical treatment, and 30.7% of patients received surgical treatment for associated abdominal, orthopedic, and minor procedures for scalp dilacerations. No patient was referred to a Neurosurgery department, and all living patients were discharged home during the study period with minimal disability. The mortality was 16.3%. Our results could be biased by the lack of interhospital networking and the fact that severe traumatic brain-injured patient dies before seeking medical attention.展开更多
Neutrophil extracellular traps are primarily composed of DNA and histones and are released by neutrophils to promote inflammation and thrombosis when stimulated by various inflammato ry reactions.Neutrophil extracellu...Neutrophil extracellular traps are primarily composed of DNA and histones and are released by neutrophils to promote inflammation and thrombosis when stimulated by various inflammato ry reactions.Neutrophil extracellular trap formation occurs through lytic and non-lytic pathways that can be further classified by formation mechanisms.Histones,von Willebrand factor,fibrin,and many other factors participate in the interplay between inflammation and thrombosis.Neuroimmunothrombosis summarizes the intricate interplay between inflammation and thrombosis during neural development and the pathogenesis of neurological diseases,providing cutting-edge insights into post-neurotrauma thrombotic events.The blood-brain barrier defends the brain and spinal cord against external assaults,and neutrophil extracellular trap involvement in blood-brain barrier disruption and immunothrombosis contributes substantially to secondary injuries in neurological diseases.Further research is needed to understand how neutrophil extracellular traps promote blood-brain barrier disruption and immunothrombosis,but recent studies have demonstrated that neutrophil extracellular traps play a crucial role in immunothrombosis,and identified modulators of neuro-immunothrombosis.However,these neurological diseases occur in blood vessels,and the mechanisms are unclear by which neutrophil extracellular traps penetrate the blood-brain barrier to participate in immunothrombosis in traumatic brain injury.This review discusses the role of neutrophil extracellular traps in neuro-immunothrombosis and explores potential therapeutic interventions to modulate neutrophil extracellular traps that may reduce immunothrombosis and improve traumatic brain injury outcomes.展开更多
Traumatic brain injury remains a global health crisis that spans all demographics,yet there exist limited treatment options that may effectively curtail its lingering symptoms.Traumatic brain injury pathology entails ...Traumatic brain injury remains a global health crisis that spans all demographics,yet there exist limited treatment options that may effectively curtail its lingering symptoms.Traumatic brain injury pathology entails a progression from primary injury to inflammation-mediated secondary cell death.Sequestering this inflammation as a means of ameliorating the greater symptomology of traumatic brain injury has emerged as an attractive treatment prospect.In this review,we recapitulate and evaluate the important developments relating to regulating traumatic brain injury-induced neuroinflammation,edema,and blood-brain barrier disintegration through pharmacotherapy and stem cell transplants.Although these studies of stand-alone treatments have yielded some positive results,more therapeutic outcomes have been documented from the promising area of combined drug and stem cell therapy.Harnessing the facilitatory properties of certain pharmaceuticals with the anti-inflammatory and regenerative effects of stem cell transplants creates a synergistic effect greater than the sum of its parts.The burgeoning evidence in favor of combined drug and stem cell therapies warrants more elaborate preclinical studies on this topic in order to pave the way for later clinical trials.展开更多
Sterile inflammatory processes are essential for the maintenance of central nervous system homeostasis,but they also contribute to various neurological disorders,including neurotrauma,stroke,and demyelinating or neuro...Sterile inflammatory processes are essential for the maintenance of central nervous system homeostasis,but they also contribute to various neurological disorders,including neurotrauma,stroke,and demyelinating or neurodegenerative diseases.Immune mechanisms in the central nervous system and periphery are regulated by a diverse group of endogenous proteins,which can be broadly divided into the pro-inflammatory damageassociated molecular patterns(DAMPs)and anti-inflammatory resolution-associated molecular patterns(RAMPs),even though there is notable overlap between the DAMPand RAMP-like activities for some of these molecules.Both groups of molecular patterns were initially described in peripheral immune processes and pathologies;however,it is now evident that at least some,if not all,of these immunomodulators also regulate neuroimmune processes and contribute to neuroinflammation in diverse central nervous system disorders.The review of recent literature demonstrates that studies on DAMPs and RAMPs of the central nervous system still lag behind the much broader research effort focused on their peripheral counterparts.Nevertheless,this review also reveals that over the last five years,significant advances have been made in our understanding of the neuroimmune functions of several well-established DAMPs,including high-mobility group box 1 protein and interleukin 33.Novel neuroimmune functions have been demonstrated for other DAMPs that previously were considered almost exclusively as peripheral immune regulators;they include mitochondrial transcription factor A and cytochrome C.RAMPs of the central nervous system are an emerging area of neuroimmunology with very high translational potential since some of these molecules have already been used in preclinical and clinical studies as candidate therapeutic agents for inflammatory conditions,such as multiple sclerosis and rheumatoid arthritis.The therapeutic potential of DAMP antagonists and neutralizing antibodies in central nervous system neuroinflammatory diseases is also supported by several of the identified studies.It can be concluded that further studies of DAMPs and RAMPs of the central nervous system will continue to be an important and productive field of neuroimmunology.展开更多
Hyponatremia is a common electrolyte disturbance usually observed in neurosurgical patients undergoing surgical management of traumatic, as well as, nontraumatic intracranial pathology. The spinal cord trauma is also ...Hyponatremia is a common electrolyte disturbance usually observed in neurosurgical patients undergoing surgical management of traumatic, as well as, nontraumatic intracranial pathology. The spinal cord trauma is also associated with occasional development of such hyponatremia;it usually occurs within the first two-weeks of the injury. Hyponatremia can lead to alterations of consciousness, convulsions, coma, cardiac arrhythmias and on rare occasions, death. Authors present a practical oriented review of the literature.展开更多
Evidence suggests that rapid changes to supporting glia may predispose individuals with spinal cord injury(SCI) to such comorbidities. Here, we interrogated the expression of astrocyte-and microglial-specific markers ...Evidence suggests that rapid changes to supporting glia may predispose individuals with spinal cord injury(SCI) to such comorbidities. Here, we interrogated the expression of astrocyte-and microglial-specific markers glial fibrillary acidic protein(GFAP) and ionized calcium binding adaptor molecule 1(Iba1) in the rat brain in the first 24 hours following SCI. Female Sprague-Dawley rats underwent thoracic laminectomy;half of the rats received a mild contusion injury at the level of the T10 vertebral body(SCI group), the other half did not(Sham group). Twenty-four hours post-surgery the amygdala, periaqueductal grey, prefrontal cortex, hypothalamus, lateral thalamus, hippocampus(dorsal and ventral) in rats were collected. GFAP and Iba1 m RNA and protein levels were measured by real-time quantitative polymerase chain reaction and Western blot. In SCI rats, GFAP m RNA and protein expression increased in the amygdala and hypothalamus. In contrast, gene and protein expression decreased in the thalamus and dorsal hippocampus. Interestingly, Iba1 transcripts and proteins were significantly diminished only in the dorsal and ventral hippocampus, where gene expression diminished. These findings demonstrate that as early as 24 hours post-SCI there are region-specific disruptions of GFAP and Iba1 transcript and protein levels in higher brain regions. All procedures were approved by the University of Technology Sydney Institutional Animal Care and Ethics Committee(UTS ACEC13-0069).展开更多
AIM: To illustrate the isoform-specific role and mechanism of c-Jun N-terminal kinases(JNKs) in mouse optic nerve axotomy induced neurotrauma. METHODS: We firstly investigated the expression of JNK1, JNK2, and JNK3 in...AIM: To illustrate the isoform-specific role and mechanism of c-Jun N-terminal kinases(JNKs) in mouse optic nerve axotomy induced neurotrauma. METHODS: We firstly investigated the expression of JNK1, JNK2, and JNK3 in the retinal ganglion cells(RGCs) by double-immunofluorescent staining. Then we created optic nerve axotomy model in wild type as well as JNK1, JNK2, JNK3, isoform specific gene deficiency mice. With that, we checked the protein expression profile of JNKs and its active form, and quantified the survival RGCs number by immunofluorescence staining. We further explored the molecules underlying isoform specific protective effect by real-time polymerase chain reaction(PCR) and Western blotting assay. RESULTS: We found that all the three isoforms of JNKs were expressed in the RGCs. Deficiency of JNK3, but not JNK1 or JNK2, significantly alleviated optic nerve axotomyinduced RGCs apoptosis. We further established that expression of Noxa, a pro-apoptotic member of BH3 family, was significantly suppressed only in JNK3 gene deficiency mice. But tumor necrosis factor receptor 1(TNFR1) and Fas, two key modulators of death receptor mediated apoptosis pathway, did not display obvious change in the expression. CONCLUSION: It is suggested that mitochondria mediated apoptosis, but not death receptor mediated apoptosis got involved in the JNK3 gene deficiency induced RGCs protection. Our study provides a novel insight into the isoform-specific role of JNKs in neurotrauma and indicates some cues for its therapeutics.展开更多
Lipid peroxidation-derived aldehydes,such as acrolein,the most reactive aldehyde,have emerged as key culprits in sustaining post-spinal cord injury(SCI)secondary pathologies leading to functional loss.Strong evidence ...Lipid peroxidation-derived aldehydes,such as acrolein,the most reactive aldehyde,have emerged as key culprits in sustaining post-spinal cord injury(SCI)secondary pathologies leading to functional loss.Strong evidence suggests that mitochondrial aldehyde dehydrogenase-2(ALDH2),a key oxidoreductase and powerful endogenous anti-aldehyde machinery,is likely important for protecting neurons from aldehydesmediated degeneration.Using a rat model of spinal cord contusion injury and recently discovered ALDH2 activator(Alda-1),we planned to validate the aldehyde-clearing and neuroprotective role of ALDH2.Over an acute 2 day period post injury,we found that ALDH2 expression was significantly lowered post-SCI,but not so in rats given Alda-1.This lower enzymatic expression may be linked to heightened acrolein-ALDH2 adduction,which was revealed in co-immunoprecipitation experiments.We have also found that administration of Alda-1 to SCI rats significantly lowered acrolein in the spinal cord,and reduced cyst pathology.In addition,Alda-1 treatment also resulted in significant improvement of motor function and attenuated post-SCI mechanical hypersensitivity up to 28 days post-SCI.Finally,ALDH2 was found to play a critical role in in vitro protection of PC12 cells from acrolein exposure.It is expected that the outcome of this study will broaden and enhance anti-aldehyde strategies in combating post-SCI neurodegeneration and potentially bring treatment to millions of SCI victims.All animal work was approved by Purdue Animal Care and Use Committee(approval No.1111000095)on January 1,2021.展开更多
Neural tissue engineering is premised on the integration of engineered living tissue with the host nervous system to directly restore lost function or to augment regenerative capacity following nervous system injury o...Neural tissue engineering is premised on the integration of engineered living tissue with the host nervous system to directly restore lost function or to augment regenerative capacity following nervous system injury or neurodegenerative disease.Disconnection of axon pathways – the long-distance fibers connecting specialized regions of the central nervous system or relaying peripheral signals – is a common feature of many neurological disorders and injury.However,functional axonal regeneration rarely occurs due to extreme distances to targets,absence of directed guidance,and the presence of inhibitory factors in the central nervous system,resulting in devastating effects on cognitive and sensorimotor function.To address this need,we are pursuing multiple strategies using tissue engineered "living scaffolds",which are preformed three-dimensional constructs consisting of living neural cells in a defined,often anisotropic architecture.Living scaffolds are designed to restore function by serving as a living labeled pathway for targeted axonal regeneration – mimicking key developmental mechanisms– or by restoring lost neural circuitry via direct replacement of neurons and axonal tracts.We are currently utilizing preformed living scaffolds consisting of neuronal clusters spanned by long axonal tracts as regenerative bridges to facilitate long-distance axonal regeneration and for targeted neurosurgical reconstruction of local circuits in the brain.Although there are formidable challenges in preclinical and clinical advancement,these living tissue engineered constructs represent a promising strategy to facilitate nervous system repair and functional recovery.展开更多
Blast overpressure has become an increasing cause of brain injuries in both military and civilian populations. Though blast's direct effects on the cochlea and vestibular organs are active areas of study, little a...Blast overpressure has become an increasing cause of brain injuries in both military and civilian populations. Though blast's direct effects on the cochlea and vestibular organs are active areas of study, little attention has been given to the ear's contribution to the overall spectrum of blast injury. Acute autonomic responses to blast exposure, including bradycardia and hypotension, can cause hypoxia and contribute to blast-induced neurotrauma. Existing literature suggests that these autonomic responses are elicited through blast impacting the thorax and lungs. We hypothesize that the unprotected ear also provides a vulnerable locus for blast to cause autonomic responses. We designed a blast generator that delivers controlled overpressure waves into the ear canal without impacting surrounding tissues in order to study the ear's specific contribution to blast injury. Anesthetized adult rats' left ears were exposed to a single blast wave ranging from 0 to 110 PSI(0-758 kPa). Blast exposed rats exhibited decreased heart rates and blood pressures with increased blast intensity, similar to results gathered using shock tubes and whole-body exposure in the literature. While rats exposed to blasts below 50 PSI(345 kPa) exhibited increased respiratory rate with increased blast intensity, some rats exposed to blasts higher than 50 PSI(345 kPa) stopped breathing immediately and ultimately died. These autonomic responses were significantly reduced in vagally denervated rats, again similar to whole-body exposure literature. These results support the hypothesis that the unprotected ear contributes to the autonomic responses to blast.展开更多
Studies have shown that a combined application of several ion channel inhibitors immediately after central nervous system injury can inhibit secondary degeneration. However, for clinical use, it is necessary to determ...Studies have shown that a combined application of several ion channel inhibitors immediately after central nervous system injury can inhibit secondary degeneration. However, for clinical use, it is necessary to determine how long after injury the combined treatment of several ion channel inhibitors can be delayed and efficacy maintained. In this study, we delivered Ca^(2+) entry-inhibiting P2X7 receptor antagonist oxidized-ATP and AMPA receptor antagonist YM872 to the optic nerve injury site via an iPRECIO~@ pump immediately, 6 hours, 24 hours and 7 days after partial optic nerve transection surgery. In addition, all of the ion channel inhibitor treated rats were administered with calcium channel antagonist lomerizine hydrochloride. It is important to note that as a result of implantation of the particular pumps required for programmable delivery of therapeutics directly to the injury site, seromas occurred in a significant proportion of animals, indicating infection around the pumps in these animals. Improvements in visual function were observed only when treatment was delayed by 6 hours; phosphorylated Tau was reduced when treatment was delayed by 24 hours or 7 days. Improvements in structure of node/paranode of Ranvier and reductions in oxidative stress indicators were also only observed when treatment was delayed for 6 hours, 24 hours, or 7 days. Benefits of ion channel inhibitors were only observed with time-delayed treatment, suggesting that delayed therapy of Ca^(2+) ion channel inhibitors produces better neuroprotective effects on secondary degeneration, at least in the presence of seromas.展开更多
文摘Mesenchymal stem cell(MSC)therapy has attracted the attention of scientists and clinicians around the world.Basic and pre-clinical experimental studies have highlighted the positive effects of MSC treatment after spinal cord and peripheral nerve injury.These effects are believed to be due to their ability to differentiate into other cell lineages,modulate inflammatory and immunomodulatory responses,reduce cell apoptosis,secrete several neurotrophic factors and respond to tissue injury,among others.There are many pre-clinical studies on MSC treatment for spinal cord injury(SCI)and peripheral nerve injuries.However,the same is not true for clinical trials,particularly those concerned with nerve trauma,indicating the necessity of more well-constructed studies showing the benefits that cell therapy can provide for individuals suffering the consequences of nerve lesions.As for clinical trials for SCI treatment the results obtained so far are not as beneficial as those described in experimental studies.For these reasons basic and pre-clinical studies dealing with MSC therapy should emphasize the standardization of protocols that could be translated to the clinical set with consistent and positive outcomes.This review is based on pre-clinical studies and clinical trials available in the literature from 2010 until now.At the time of writing this article there were 43 and 36 pre-clinical and 19 and 1 clinical trials on injured spinal cord and peripheral nerves,respectively.
基金the National Institutes of Health(NINDS 49177NINDS 105987)+1 种基金Craig H.Neilsen Foundation Senior Research award(295319)to GMHa grant from the National Institutes of Health(NINDS F31 NS 087834)to EMB。
文摘The adaptability of the central nervous system has been revealed in several model systems.Of particular interest to central nervous system-injured individuals is the ability for neural components to be modified for regain of function.In both types of neurotrauma,traumatic brain injury and spinal cord injury,the primary parasympathetic control to the gastrointestinal tract,the vagus nerve,remains anatomically intact.However,individuals with traumatic brain injury or spinal cord injury are highly susceptible to gastrointestinal dysfunctions.Such gastrointestinal dysfunctions attribute to higher morbidity and mortality following traumatic brain injury and spinal cord injury.While the vagal efferent output remains capable of eliciting motor responses following injury,evidence suggests impairment of the vagal afferents.Since sensory input drives motor output,this review will discuss the normal and altered anatomy and physiology of the gastrointestinal vagal afferents to better understand the contributions of vagal afferent plasticity following neurotrauma.
文摘Trauma is one of the most common surgical emergencies admitted in the acute care departments of hospitals in Guinea, West Africa. We carried a study to assess the epidemiological pattern and clinical care of neurotrauma in the emergency department of the Kindia regional hospital, a rural secondary hospital catering to the needs of western Guinea and nearby districts. Data were prospectively collected from December 2019 to March 2020 after receiving the required hospital authorization and informed consent from the patients or relatives. We recorded two hundred cases of neurotraumas (64.5% of traumatic brain injury cases and 14.5% of spinal cord injury). Neurotraumas represented 17.7% of all admitted patients in the department in the study period. The mean age was 25.34 ± 16.73, and the age range 16 to 30 was the most affected. The predominance was male, with a sex ratio of 3.43. Motor Vehicle Accident was the leading cause 68.5%, and 73.2% of them involved a motorcycle. Motorcycle-to-motorcycle collision was responsible for more than a third of neurotraumas. We classified the majority of the cases as mild and low risk neurotrauma representing 62.08%. All patients benefited from medical treatment, and 30.7% of patients received surgical treatment for associated abdominal, orthopedic, and minor procedures for scalp dilacerations. No patient was referred to a Neurosurgery department, and all living patients were discharged home during the study period with minimal disability. The mortality was 16.3%. Our results could be biased by the lack of interhospital networking and the fact that severe traumatic brain-injured patient dies before seeking medical attention.
基金supported by the National Natural Science Foundation of China,No.82271399(to XC)the Project of Tianjin Applied Basic and Multiple Support Research,No.21JCZDJC00910(to XC)+4 种基金the Scientific Research Program of Tianjin Education Commission(Natural Science)of China,No.2019ZD034(to QD)the Science&Technology Program of Tianjin for Cultivation of Innovative Talents,No.22JRRCRC00020(to QD)the Tianjin Medical University"Clinical Talent Training 123 Climbing Plan"(to XC)the Tianjin Health Care Elite Prominent Young Doctor Development Program(to XC)the Young and Middle-aged Backbone Innovative Talent Program(to XC)。
文摘Neutrophil extracellular traps are primarily composed of DNA and histones and are released by neutrophils to promote inflammation and thrombosis when stimulated by various inflammato ry reactions.Neutrophil extracellular trap formation occurs through lytic and non-lytic pathways that can be further classified by formation mechanisms.Histones,von Willebrand factor,fibrin,and many other factors participate in the interplay between inflammation and thrombosis.Neuroimmunothrombosis summarizes the intricate interplay between inflammation and thrombosis during neural development and the pathogenesis of neurological diseases,providing cutting-edge insights into post-neurotrauma thrombotic events.The blood-brain barrier defends the brain and spinal cord against external assaults,and neutrophil extracellular trap involvement in blood-brain barrier disruption and immunothrombosis contributes substantially to secondary injuries in neurological diseases.Further research is needed to understand how neutrophil extracellular traps promote blood-brain barrier disruption and immunothrombosis,but recent studies have demonstrated that neutrophil extracellular traps play a crucial role in immunothrombosis,and identified modulators of neuro-immunothrombosis.However,these neurological diseases occur in blood vessels,and the mechanisms are unclear by which neutrophil extracellular traps penetrate the blood-brain barrier to participate in immunothrombosis in traumatic brain injury.This review discusses the role of neutrophil extracellular traps in neuro-immunothrombosis and explores potential therapeutic interventions to modulate neutrophil extracellular traps that may reduce immunothrombosis and improve traumatic brain injury outcomes.
基金CVB was funded by National Institutes of Health(NIH)R01NS071956,NIH R01NS090962,NIH R21NS089851,NIH R21NS094087Veterans Affairs Merit Review I01 BX001407
文摘Traumatic brain injury remains a global health crisis that spans all demographics,yet there exist limited treatment options that may effectively curtail its lingering symptoms.Traumatic brain injury pathology entails a progression from primary injury to inflammation-mediated secondary cell death.Sequestering this inflammation as a means of ameliorating the greater symptomology of traumatic brain injury has emerged as an attractive treatment prospect.In this review,we recapitulate and evaluate the important developments relating to regulating traumatic brain injury-induced neuroinflammation,edema,and blood-brain barrier disintegration through pharmacotherapy and stem cell transplants.Although these studies of stand-alone treatments have yielded some positive results,more therapeutic outcomes have been documented from the promising area of combined drug and stem cell therapy.Harnessing the facilitatory properties of certain pharmaceuticals with the anti-inflammatory and regenerative effects of stem cell transplants creates a synergistic effect greater than the sum of its parts.The burgeoning evidence in favor of combined drug and stem cell therapies warrants more elaborate preclinical studies on this topic in order to pave the way for later clinical trials.
基金supported by grants from the Natural Sciences and Engineering Research Council of Canada and the Jack Brown and Family Alzheimer's Disease Research Foundation。
文摘Sterile inflammatory processes are essential for the maintenance of central nervous system homeostasis,but they also contribute to various neurological disorders,including neurotrauma,stroke,and demyelinating or neurodegenerative diseases.Immune mechanisms in the central nervous system and periphery are regulated by a diverse group of endogenous proteins,which can be broadly divided into the pro-inflammatory damageassociated molecular patterns(DAMPs)and anti-inflammatory resolution-associated molecular patterns(RAMPs),even though there is notable overlap between the DAMPand RAMP-like activities for some of these molecules.Both groups of molecular patterns were initially described in peripheral immune processes and pathologies;however,it is now evident that at least some,if not all,of these immunomodulators also regulate neuroimmune processes and contribute to neuroinflammation in diverse central nervous system disorders.The review of recent literature demonstrates that studies on DAMPs and RAMPs of the central nervous system still lag behind the much broader research effort focused on their peripheral counterparts.Nevertheless,this review also reveals that over the last five years,significant advances have been made in our understanding of the neuroimmune functions of several well-established DAMPs,including high-mobility group box 1 protein and interleukin 33.Novel neuroimmune functions have been demonstrated for other DAMPs that previously were considered almost exclusively as peripheral immune regulators;they include mitochondrial transcription factor A and cytochrome C.RAMPs of the central nervous system are an emerging area of neuroimmunology with very high translational potential since some of these molecules have already been used in preclinical and clinical studies as candidate therapeutic agents for inflammatory conditions,such as multiple sclerosis and rheumatoid arthritis.The therapeutic potential of DAMP antagonists and neutralizing antibodies in central nervous system neuroinflammatory diseases is also supported by several of the identified studies.It can be concluded that further studies of DAMPs and RAMPs of the central nervous system will continue to be an important and productive field of neuroimmunology.
文摘Hyponatremia is a common electrolyte disturbance usually observed in neurosurgical patients undergoing surgical management of traumatic, as well as, nontraumatic intracranial pathology. The spinal cord trauma is also associated with occasional development of such hyponatremia;it usually occurs within the first two-weeks of the injury. Hyponatremia can lead to alterations of consciousness, convulsions, coma, cardiac arrhythmias and on rare occasions, death. Authors present a practical oriented review of the literature.
基金The University of Technology Sydney(UTS)Start-up Research Grant 2018 funded this study(to AC)。
文摘Evidence suggests that rapid changes to supporting glia may predispose individuals with spinal cord injury(SCI) to such comorbidities. Here, we interrogated the expression of astrocyte-and microglial-specific markers glial fibrillary acidic protein(GFAP) and ionized calcium binding adaptor molecule 1(Iba1) in the rat brain in the first 24 hours following SCI. Female Sprague-Dawley rats underwent thoracic laminectomy;half of the rats received a mild contusion injury at the level of the T10 vertebral body(SCI group), the other half did not(Sham group). Twenty-four hours post-surgery the amygdala, periaqueductal grey, prefrontal cortex, hypothalamus, lateral thalamus, hippocampus(dorsal and ventral) in rats were collected. GFAP and Iba1 m RNA and protein levels were measured by real-time quantitative polymerase chain reaction and Western blot. In SCI rats, GFAP m RNA and protein expression increased in the amygdala and hypothalamus. In contrast, gene and protein expression decreased in the thalamus and dorsal hippocampus. Interestingly, Iba1 transcripts and proteins were significantly diminished only in the dorsal and ventral hippocampus, where gene expression diminished. These findings demonstrate that as early as 24 hours post-SCI there are region-specific disruptions of GFAP and Iba1 transcript and protein levels in higher brain regions. All procedures were approved by the University of Technology Sydney Institutional Animal Care and Ethics Committee(UTS ACEC13-0069).
文摘AIM: To illustrate the isoform-specific role and mechanism of c-Jun N-terminal kinases(JNKs) in mouse optic nerve axotomy induced neurotrauma. METHODS: We firstly investigated the expression of JNK1, JNK2, and JNK3 in the retinal ganglion cells(RGCs) by double-immunofluorescent staining. Then we created optic nerve axotomy model in wild type as well as JNK1, JNK2, JNK3, isoform specific gene deficiency mice. With that, we checked the protein expression profile of JNKs and its active form, and quantified the survival RGCs number by immunofluorescence staining. We further explored the molecules underlying isoform specific protective effect by real-time polymerase chain reaction(PCR) and Western blotting assay. RESULTS: We found that all the three isoforms of JNKs were expressed in the RGCs. Deficiency of JNK3, but not JNK1 or JNK2, significantly alleviated optic nerve axotomyinduced RGCs apoptosis. We further established that expression of Noxa, a pro-apoptotic member of BH3 family, was significantly suppressed only in JNK3 gene deficiency mice. But tumor necrosis factor receptor 1(TNFR1) and Fas, two key modulators of death receptor mediated apoptosis pathway, did not display obvious change in the expression. CONCLUSION: It is suggested that mitochondria mediated apoptosis, but not death receptor mediated apoptosis got involved in the JNK3 gene deficiency induced RGCs protection. Our study provides a novel insight into the isoform-specific role of JNKs in neurotrauma and indicates some cues for its therapeutics.
基金supported by a grant from National Institute of Neurological Disorders and Stroke R21(No.1R21NS115094-01)。
文摘Lipid peroxidation-derived aldehydes,such as acrolein,the most reactive aldehyde,have emerged as key culprits in sustaining post-spinal cord injury(SCI)secondary pathologies leading to functional loss.Strong evidence suggests that mitochondrial aldehyde dehydrogenase-2(ALDH2),a key oxidoreductase and powerful endogenous anti-aldehyde machinery,is likely important for protecting neurons from aldehydesmediated degeneration.Using a rat model of spinal cord contusion injury and recently discovered ALDH2 activator(Alda-1),we planned to validate the aldehyde-clearing and neuroprotective role of ALDH2.Over an acute 2 day period post injury,we found that ALDH2 expression was significantly lowered post-SCI,but not so in rats given Alda-1.This lower enzymatic expression may be linked to heightened acrolein-ALDH2 adduction,which was revealed in co-immunoprecipitation experiments.We have also found that administration of Alda-1 to SCI rats significantly lowered acrolein in the spinal cord,and reduced cyst pathology.In addition,Alda-1 treatment also resulted in significant improvement of motor function and attenuated post-SCI mechanical hypersensitivity up to 28 days post-SCI.Finally,ALDH2 was found to play a critical role in in vitro protection of PC12 cells from acrolein exposure.It is expected that the outcome of this study will broaden and enhance anti-aldehyde strategies in combating post-SCI neurodegeneration and potentially bring treatment to millions of SCI victims.All animal work was approved by Purdue Animal Care and Use Committee(approval No.1111000095)on January 1,2021.
基金support provided by the U.S.Army Medical Research and Materiel Command through the Joint Warfighter Medical Research Program(#W81XWH-13-13207004)Axonia Medical,Inc.+3 种基金Department of Veterans Affairs(RR&D Merit Review#B1097-I)National Institutes of Health(NINDS T32-NS043126)Penn Medicine Neuroscience Centerthe National Science Foundation(Graduate Research Fellowship DGE-1321851)
文摘Neural tissue engineering is premised on the integration of engineered living tissue with the host nervous system to directly restore lost function or to augment regenerative capacity following nervous system injury or neurodegenerative disease.Disconnection of axon pathways – the long-distance fibers connecting specialized regions of the central nervous system or relaying peripheral signals – is a common feature of many neurological disorders and injury.However,functional axonal regeneration rarely occurs due to extreme distances to targets,absence of directed guidance,and the presence of inhibitory factors in the central nervous system,resulting in devastating effects on cognitive and sensorimotor function.To address this need,we are pursuing multiple strategies using tissue engineered "living scaffolds",which are preformed three-dimensional constructs consisting of living neural cells in a defined,often anisotropic architecture.Living scaffolds are designed to restore function by serving as a living labeled pathway for targeted axonal regeneration – mimicking key developmental mechanisms– or by restoring lost neural circuitry via direct replacement of neurons and axonal tracts.We are currently utilizing preformed living scaffolds consisting of neuronal clusters spanned by long axonal tracts as regenerative bridges to facilitate long-distance axonal regeneration and for targeted neurosurgical reconstruction of local circuits in the brain.Although there are formidable challenges in preclinical and clinical advancement,these living tissue engineered constructs represent a promising strategy to facilitate nervous system repair and functional recovery.
基金supported by the United States National Institutes of Health[grant numbers:NIDCD R01DC014930(WZ),NIDCD R01DC012060(HZ)]
文摘Blast overpressure has become an increasing cause of brain injuries in both military and civilian populations. Though blast's direct effects on the cochlea and vestibular organs are active areas of study, little attention has been given to the ear's contribution to the overall spectrum of blast injury. Acute autonomic responses to blast exposure, including bradycardia and hypotension, can cause hypoxia and contribute to blast-induced neurotrauma. Existing literature suggests that these autonomic responses are elicited through blast impacting the thorax and lungs. We hypothesize that the unprotected ear also provides a vulnerable locus for blast to cause autonomic responses. We designed a blast generator that delivers controlled overpressure waves into the ear canal without impacting surrounding tissues in order to study the ear's specific contribution to blast injury. Anesthetized adult rats' left ears were exposed to a single blast wave ranging from 0 to 110 PSI(0-758 kPa). Blast exposed rats exhibited decreased heart rates and blood pressures with increased blast intensity, similar to results gathered using shock tubes and whole-body exposure in the literature. While rats exposed to blasts below 50 PSI(345 kPa) exhibited increased respiratory rate with increased blast intensity, some rats exposed to blasts higher than 50 PSI(345 kPa) stopped breathing immediately and ultimately died. These autonomic responses were significantly reduced in vagally denervated rats, again similar to whole-body exposure literature. These results support the hypothesis that the unprotected ear contributes to the autonomic responses to blast.
基金financial support from the National Health and Medical Research Council(NHMRC),Australia(APP1061791)an NHMRC Career Development Fellowship(APP1087114)
文摘Studies have shown that a combined application of several ion channel inhibitors immediately after central nervous system injury can inhibit secondary degeneration. However, for clinical use, it is necessary to determine how long after injury the combined treatment of several ion channel inhibitors can be delayed and efficacy maintained. In this study, we delivered Ca^(2+) entry-inhibiting P2X7 receptor antagonist oxidized-ATP and AMPA receptor antagonist YM872 to the optic nerve injury site via an iPRECIO~@ pump immediately, 6 hours, 24 hours and 7 days after partial optic nerve transection surgery. In addition, all of the ion channel inhibitor treated rats were administered with calcium channel antagonist lomerizine hydrochloride. It is important to note that as a result of implantation of the particular pumps required for programmable delivery of therapeutics directly to the injury site, seromas occurred in a significant proportion of animals, indicating infection around the pumps in these animals. Improvements in visual function were observed only when treatment was delayed by 6 hours; phosphorylated Tau was reduced when treatment was delayed by 24 hours or 7 days. Improvements in structure of node/paranode of Ranvier and reductions in oxidative stress indicators were also only observed when treatment was delayed for 6 hours, 24 hours, or 7 days. Benefits of ion channel inhibitors were only observed with time-delayed treatment, suggesting that delayed therapy of Ca^(2+) ion channel inhibitors produces better neuroprotective effects on secondary degeneration, at least in the presence of seromas.
