Central Nervous System Trauma Research Articles

The fast‐aging killifish: A unique vertebrate model to identify molecular targets for neuroreparative strategies in the aged retina

AbstractThe rise in life expectancy in our modern societies concurs with an increasing prevalence of age‐associated neurodegenerative disorders and central nervous system (CNS) trauma. Despite many research attempts trying to unravel aging processes and their role in functional decline, the mechanisms underlying healthy CNS aging remain elusive. Moreover, the reparative approaches proposed to combat loss of neurons due to damage or (age‐associated) disease are failing. One of the reasons might be that the currently used animal models often lack the capability to properly recapitulate the aged environment in which these pathologies manifest and the repair processes need to occur. We introduce the African turquoise killifish as an opportune model to study CNS aging as well as neuroreparative strategies. Indeed, while sharing adult neuroregenerative potential with other teleost fish like zebrafish, the short‐lived killifish displays many of the human aging hallmarks, making it a promising biogerontology model.As vision decline manifests during human aging and in many neurodegenerative diseases, we performed a comprehensive characterization of the aged killifish visual system, comprising the retina, optic projections and optic tectum. Immunohistochemical, biochemical and molecular analyses revealed the presence of many aging traits in this system, including oxidative stress, genomic damage, cellular senescence, altered cellular communication, reduced neurogenic potential and even neurodegeneration. Specifically, microglia changed to a pro‐inflammatory secretion profile upon aging and macroglia became gliotic in the aging killifish visual system. Altogether, these age‐related changes led to a diminished visual performance in old killifish.Using an optic nerve injury model, we further disclosed an age‐related decline in functional circuit restoration, with different phases of the repair process being affected depending on the age. While young adult killifish were able to functionally recover after injury, old fish did not regain vision at all. Here we observed for the first time in a regenerative teleost fish model, a glial scar that formed a mechanical barrier physically preventing axonal regrowth. Moreover, in the optic tectum the inflammatory response shifted from acute to chronic upon aging. Macroglia, which showed a transient gliotic response after injury in young adult fish, displayed a permanent response in old animals. Overall, as in mammals, both a reduced intrinsic growth potential and a non‐supportive cellular environment, orchestrated by activated micro‐ and macroglia, were found to underlie the declined repair potential in aged killifish.To decode the cellular and molecular framework that defines visual system aging and the failed regenerative response in old fish, we are currently performing single‐cell RNA sequencing of the young adult and aged killifish retina. We envision our bioinformatic approaches to result in innovative druggable targets for future development of rejuvenative/curative therapies in the aged mammalian retina.In summary, our study highlights the importance of a neuron–glia crosstalk in health, disease and repair. It puts forward the strengths of the killifish as a vertebrate model with mammalian‐like characteristics upon aging, that offers unique opportunities to identify rejuvenating and neuroreparative strategies ensuring healthy aging.

Dental Pulp-Derived Stem Cells Preserve Astrocyte Health During Induced Gliosis by Modulating Mitochondrial Activity and Functions.

Astrocytes have been implicated in the onset and complication of various central nervous system (CNS) injuries and disorders. Uncontrolled astrogliosis (gliosis), while a necessary process for recovery after CNS trauma, also causes impairments in CNS performance and functions. The ability to preserve astrocyte health and better regulate the gliosis process could play a major role in controlling damage in the aftermath of acute insults and during chronic dysfunction. Here in, we demonstrate the ability of dental pulp-derived stem cells (DPSCs) in protecting the health of astrocytes during induced gliosis. First of all, we have characterized the expression of genes in primary astrocytes that are relevant to the pathological conditions of CNS by inducing gliosis. Subsequently, we found that astrocytes co-cultured with DPSCs reduced ROS production, NRF2 and GCLM expressions, mitochondrial membrane potential, and mitochondrial functions compared to the astrocytes that were not co-cultured with DPSCs in gliosis condition. In addition, hyperactive autophagy was also decreased in astrocytes that were co-cultured with DPSCs compared to the astrocytes that were not co-cultured with DPSCs during gliosis. This reversal and mitigation of gliosis in astrocytes were partly due to induction of neurogenesis in DPSCs through enhanced expressions of the neuronal genes like GFAP, NeuN, and Synapsin in DPSCs and by secretion of higher amounts of neurotropic factors, such as BDNF, GDNF, and TIMP-2. Protein-Protein docking analysis suggested that BDNF and GDNF can bind with CSPG4 and block the downstream signaling. Together these findings demonstrate novel functions of DPSCs to preserve astrocyte health during gliosis.

Triboelectric nanogenerators stimulated electroacupuncture (EA) treatment for promoting the functional recovery after spinal cord injury

Electroacupuncture (EA), as a particular type of electrostimulation treatment, has an extensive application in the field of biomedicine. Triboelectric nanogenerator (TENG) has sparked significant concern attributed to the high electrical output with low cost, whose electrical signals can also be directly usable for electrical stimulation. Here we propose a Chinese medicine EA treatment with the assistance of TENG technology, in which a bidirectional continuous current from a soft-contact freestanding rotary TENG (FR-TENG) is applied to two effective acupoints of rats by inserting electric needles. The TENG-driven EA treatment promotes the performance of gait 2 weeks after as well as the Basso–Beattie–Bresnahan (BBB) score. This elevation last as long as 4 weeks post injury. Moreover, the TENG-driven EA treatment enhances neuron survival in the ventral horn and inhibits astrocyte activation in the lesion site. Therefore, the TENG-driven EA treatment provides a significant neuroprotection effect on spinal cord contusion in rats. Our studies not only demonstrate the possibility of the TENG-driven EA treatment for traumatic central nervous system injuries but also provide an experimental basis for the prevention and treatment of diseases by traditional Chinese medicine treatment.

MiR-146a-5p-modified hUCMSC-derived exosomes facilitate spinal cord function recovery by targeting neurotoxic astrocytes

BackgroundAcute spinal cord injury (SCI) is a devastating result of neurological trauma with subsequent microenvironment dyshomeostasis that induces neurotoxic phenotype acquisition by astrocytes, exacerbating neurological function impairment. Exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSCs) have demonstrated essential therapeutic effects after central nervous system trauma. However, whether hUCMSC-derived exosomes exert therapeutic effects on neurotoxic astrocytes to facilitate SCI function recovery remains unclear. Additionally, the limited efficiency of single exosomes may restrict the optimization of exosomal biological functions.MethodsWe first determined that exosomes reduce the deleterious effects of neurotoxic astrocytes in vitro and in vivo. Then, we identified critical functional microRNAs (miRNAs). miR-146a-5p was overexpressed in exosomes, and then, miR-146a-5p-modified exosomes were used to investigate the ability of exosomes to reduce neurotoxic astrocyte effects, preserve neurons and promote neurological function recovery in rats with SCI.ResultsCell counting kit-8 and neurite length analyses revealed that exosomes partially reduced the negative effects of neurotoxic astrocytes on PC12 cell viability and neurites in vitro. The exosomes also attenuated inflammatory responses, reduced the number of neurotoxic astrocytes and preserved neural tissue in rats with SCI. Immunofluorescence assays suggested that the number of neurotoxic astrocytes was rapidly increased by injury, reaching a peak 5 days post-injury (dpi) and returning to the normal level 14dpi. Exosomal miR-146a-5p was identified as the critical functional miRNA. Overexpression of miR-146a-5p in exosomes strengthened the biological function of the exosomes. Therefore, the modified exosomes exerted more powerful therapeutic effects than the unmodified exosomes, reducing the deleterious effects of neurotoxic astrocytes both in vitro and in vivo and promoting locomotor function of the hindlimbs in the rats with SCI. Through a series of gain- and loss-of-function experiments, Traf6 and Irak1 were identified as targets of exosomal miR-146a-5p. Ultimately, we found that miR-146a-5p-modified exosomes exerted their function by targeting Traf6/Irak1/NFκB pathway in neurotoxic astrocytes.ConclusionsIn summary, miR-146a-5p-modified exosomes exerted a more powerful effect than unmodified exosomes to promote neurological function recovery in rats with SCI by targeting neurotoxic astrocytes. Therefore, miR-146a-5p-modified exosomes are promising therapeutics for SCI.

Melatonin Attenuates Spinal Cord Injury in Mice by Activating the Nrf2/ARE Signaling Pathway to Inhibit the NLRP3 Inflammasome.

Background: Spinal cord injury (SCI) is a central nervous system (CNS) trauma involving inflammation and oxidative stress, which play important roles in this trauma’s pathogenesis. Therefore, controlling inflammation is an effective strategy for SCI treatment. As a hormone, melatonin is capable of producing antioxidation and anti-inflammation effects. In the meantime, it also causes a neuroprotective effect in various neurological diseases. Nrf2/ARE/NLRP3 is a well-known pathway in anti-inflammation and antioxidation, and Nrf2 can be positively regulated by melatonin. However, how melatonin regulates inflammation during SCI is poorly explored. Therefore, it was investigated in this study whether melatonin can inhibit the NLRP3 inflammasome through the Nrf2/ARE signaling pathway in a mouse SCI model. Methods: A model of SCI was established in C57BL/6 mice and PC12 cells. The motor function of mice was detected by performing an open field test, and Nissl staining and terminal deoxynucleotidyl transferase dUTP nick end labeling were carried out to evaluate the survival of neurons. Mitochondrial dysfunction was detected by transmission electron microscopy (TEM) and by assessing the mitochondrial membrane potential. In addition, the expression of NLRP3 inflammasome and oxidative-stress-related proteins were detected through Western blot and immunofluorescence double staining. Results: By inhibiting neuroinflammation and reducing neuronal death, melatonin promotes the recovery of neuromotor function. Besides this, melatonin is able to reduce the damage that causes neuronal mitochondrial dysfunction, reduce the level of reactive oxygen species (ROS) and malondialdehyde, and enhance the activity of superoxide dismutase and the production of glutathione peroxidase. Mechanically, melatonin inhibits the activation of NLRP3 inflammasomes and reduces the secretion of pro-inflammatory factors through the Nrf2/ARE signaling. Conclusions: In conclusion, melatonin inhibits the NLRP3 inflammasome through stimulation of the Nrf2/ARE pathway, thereby suppressing neuroinflammation, reducing mitochondrial dysfunction, and improving the recovery of nerve function after SCI.

Modulation of Neuroinflammation via Selective Nanoparticle‐Mediated Drug Delivery to Activated Microglia/Macrophages in Spinal Cord Injury

AbstractInflammation after spinal cord injury (SCI) is characterized by immune cell invasion and activation, combined with inflammatory mediator release that worsens outcomes following primary trauma. Effective therapies targeting neuroinflammation remain an unmet need, and modulation of the injury microenvironment to induce a comprehensive pro‐regenerative response is an attractive therapeutic approach. Given its crucial role in cell stress and inflammation after SCI, the potential of pharmacologically targeting MAPK‐activated protein kinase‐2 (MK2) to modulate the response of microglia/macrophages after injury is focused. Nanoparticles (NPs) containing an MK2 inhibitor for specific targeting of microglia/macrophages is developed. NPs selectively target and modulate activated microglia/macrophages in vitro and in a rat model of SCI. NPs in the acute injury setting reduce the pro‐inflammatory cytokine IL‐6 and increase the anti‐inflammatory cytokine IL‐10. Importantly, NPs have a significant effect on microglia/macrophage distribution and accumulation, leading to ≈65% reduction of immune cells around the injury. Last, microglia/macrophage populations with activated morphology are significantly reduced compared to resting or ramified cells around the lesion site. This strategy exhibits potential therapeutic efficiency and specificity for local, pharmacologic manipulation of activated microglia/macrophages, and is a versatile tool to manage acute inflammation and glia plasticity after central nervous system trauma.

Immune dysfunction following severe trauma: A systems failure from the central nervous system to mitochondria.

When a traumatic injury exceeds the body’s internal tolerances, the innate immune and inflammatory systems are rapidly activated, and if not contained early, increase morbidity and mortality. Early deaths after hospital admission are mostly from central nervous system (CNS) trauma, hemorrhage and circulatory collapse (30%), and later deaths from hyperinflammation, immunosuppression, infection, sepsis, acute respiratory distress, and multiple organ failure (20%). The molecular drivers of secondary injury include damage associated molecular patterns (DAMPs), pathogen associated molecular patterns (PAMPs) and other immune-modifying agents that activate the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic stress response. Despite a number of drugs targeting specific anti-inflammatory and immune pathways showing promise in animal models, the majority have failed to translate. Reasons for failure include difficulty to replicate the heterogeneity of humans, poorly designed trials, inappropriate use of specific pathogen-free (SPF) animals, ignoring sex-specific differences, and the flawed practice of single-nodal targeting. Systems interconnectedness is a major overlooked factor. We argue that if the CNS is protected early after major trauma and control of cardiovascular function is maintained, the endothelial-glycocalyx will be protected, sufficient oxygen will be delivered, mitochondrial energetics will be maintained, inflammation will be resolved and immune dysfunction will be minimized. The current challenge is to develop new systems-based drugs that target the CNS coupling of whole-body function.

Consequences and mechanisms of myelin debris uptake and processing by cells in the central nervous system

Central nervous system (CNS) disorders and trauma involving changes to the neuronal myelin sheath have long been a topic of great interest. One common pathological change in these diseases is the generation of myelin debris resulting from the breakdown of the myelin sheath. Myelin debris contains many inflammatory and neurotoxic factors that inhibit remyelination and make its clearance a prerequisite for healing in CNS disorders. Many professional and semiprofessional phagocytes participate in the clearance of myelin debris in the CNS. These cells use various mechanisms for the uptake of myelin debris, and each cell type produces its own unique set of pathologic consequences resulting from the debris uptake. Examining these cells’ phagocytosis of myelin debris will contribute to a more complete understanding of CNS disease pathogenesis and help us conceptualize how the necessary clearance of myelin debris must be balanced with the detrimental consequences brought about by its clearance.

Fibrotic Scar in CNS Injuries: From the Cellular Origins of Fibroblasts to the Molecular Processes of Fibrotic Scar Formation.

Central nervous system (CNS) trauma activates a persistent repair response that leads to fibrotic scar formation within the lesion. This scarring is similar to other organ fibrosis in many ways; however, the unique features of the CNS differentiate it from other organs. In this review, we discuss fibrotic scar formation in CNS trauma, including the cellular origins of fibroblasts, the mechanism of fibrotic scar formation following an injury, as well as the implication of the fibrotic scar in CNS tissue remodeling and regeneration. While discussing the shared features of CNS fibrotic scar and fibrosis outside the CNS, we highlight their differences and discuss therapeutic targets that may enhance regeneration in the CNS.

Research progress on pharmacology of butylphthalide and its derivatives

The butylphthalide(NBP), a colorless or light yellow viscous oily component isolated from celery seeds, has the effects of anti-inflammation, anti-oxidative stress, protecting blood-brain barrier, improving cerebral microcirculation, and promoting angiogenesis. It can protect the neurological function of patients with ischemic stroke through a variety of mechanisms, improve the symptoms of patients, and contribute to the long-term recovery of them. Therefore, independently developed in China, NBP was approved by State Food and Drug Administration for the clinical treatment of stroke patients in 2002. At the same time, owing to the complex multi-target pharmacological mechanism, NBP has been frequently used in clinical practice. As frequently verified, it has obvious effects in the treatment of other neurological diseases such as Alzheimer's disease, vascular dementia, Parkinson's disease, autoimmune diseases, depression, traumatic central nervous system injury. Moreover, it demonstrates significant pharmacological effects on non-neurological diseases such as diabetes mellitus and myocardial infarction. Therefore, this study summarizes the research progress on roles of NBP in nervous system diseases and non-nervous system diseases, and the pharmacological characteristics and mechanisms of NBP, which is expected to lay a basis for research on related targets.

Functions and mechanisms of cytosolic phospholipase A2 in central nervous system trauma.

Central nervous system (CNS) trauma, including traumatic brain injury and spinal cord injury, has a high rate of disability and mortality, and effective treatment is currently lacking. Previous studies have revealed that neural inflammation plays a vital role in CNS trauma. As the initial enzyme in neuroinflammation, cytosolic phospholipase A2 (cPLA2) can hydrolyze membranous phosphatides at the sn-2 position in a preferential way to release lysophospholipids and ω3-polyunsaturated fatty acid dominated by arachidonic acid, thereby inducing secondary injuries. Although there is substantial fresh knowledge pertaining to cPLA2, in-depth comprehension of how cPLA2 participates in CNS trauma and the potential methods to ameliorate the clinical results after CNS trauma are still insufficient. The present review summarizes the latest understanding of how cPLA2 participates in CNS trauma, highlighting novel findings pertaining to how cPLA2 activation initiates the potential mechanisms specifically, neuroinflammation, lysosome membrane functions, and autophagy activity, that damage the CNS after trauma. Moreover, we focused on testing a variety of drugs capable of inhibiting cPLA2 or the upstream pathway, and we explored how those agents might be utilized as treatments to improve the results following CNS trauma. This review aimed to effectively understand the mechanism of cPLA2 activation and its role in the pathophysiological processes of CNS trauma and provide clarification and a new referential framework for future research.

Characterization of Ex Vivo and In Vitro Wnt Transcriptome Induced by Spinal Cord Injury in Rat Microglial Cells.

It is well known that inflammation is crucial in the onset and progression of neurodegenerative diseases and traumatic central nervous system (CNS) injuries, and that microglia and monocyte-derived macrophages (MDMs) play a pivotal role in neuroinflammation. Therefore, the exploration of molecular signaling pathways that are involved in the microglia/macrophage response might help us to shed light on their eventual therapeutic modulation. Interestingly, there is growing evidence showing that the Wnt family of proteins is involved in different neuropathologies that are characterized by a dysregulated neuroinflammatory response, including spinal cord injury (SCI). Here, we aimed to validate a methodology with competence to assess the physiologically relevant Wnt expression patterns of active microglia and MDMs in a rat model of SCI. For that purpose, we have selected and adapted an in vitro system of primary microglia culture that were stimulated with a lesioned spinal cord extract (SCE), together with an ex vivo protocol of flow cytometry sorting of rat microglia/MDMs at different time-points after contusive SCI. Our study demonstrates that the expression profile of Wnt-related genes in microglia/MDM cells exhibit important differences between these particular scenarios which would be in line with previous studies where similar discrepancies have been described for other molecules. Moreover, our results provide for a first experimental report of the Wnt transcriptome in rat microglia and MDMs after SCI which, together with the research platform that was used in the study, and considering its limitations, we expect might contribute to foster the research on Wnt-driven immunomodulatory therapies.

Secondary Mechanisms of Neurotrauma: A Closer Look at the Evidence.

Traumatic central nervous system injury is a leading cause of neurological injury worldwide. While initial neuroresuscitative efforts are focused on ameliorating the effects of primary injury through patient stabilization, secondary injury in neurotrauma is a potential cause of cell death, oxidative stress, and neuroinflammation. These secondary injuries lack defined therapy. The major causes of secondary injury in neurotrauma include endoplasmic reticular stress, mitochondrial dysfunction, and the buildup of reactive oxygen or nitrogenous species. Stress to the endoplasmic reticulum in neurotrauma results in the overactivation of the unfolded protein response with subsequent cell apoptosis. Mitochondrial dysfunction can lead to the release of caspases and the buildup of reactive oxygen species; several characteristics make the central nervous system particularly susceptible to oxidative damage. Together, endoplasmic reticulum, mitochondrial, and oxidative stress can have detrimental consequences, beginning moments and lasting days to months after the primary injury. Understanding these causative pathways has led to the proposal of various potential treatment options.

Compounds co-targeting kinases in axon regulatory pathways promote regeneration and behavioral recovery after spinal cord injury in mice

Recovery from spinal cord injury (SCI) and other central nervous system (CNS) trauma is hampered by limits on axonal regeneration in the CNS. Regeneration is restricted by the lack of neuron-intrinsic regenerative capacity and by the repressive microenvironment confronting damaged axons. To address this challenge, we have developed a therapeutic strategy that co-targets kinases involved in both extrinsic and intrinsic regulatory pathways. Prior work identified a kinase inhibitor (RO48) with advantageous polypharmacology (co-inhibition of targets including ROCK2 and S6K1), which promoted CNS axon growth in vitro and corticospinal tract (CST) sprouting in a mouse pyramidotomy model. We now show that RO48 promotes neurite growth from sensory neurons and a variety of CNS neurons in vitro, and promotes CST sprouting and/or regeneration in multiple mouse models of spinal cord injury. Notably, these in vivo effects of RO48 were seen in several independent experimental series performed in distinct laboratories at different times. Finally, in a cervical dorsal hemisection model, RO48 not only promoted growth of CST axons beyond the lesion, but also improved behavioral recovery in the rotarod, gridwalk, and pellet retrieval tasks. Our results provide strong evidence for RO48 as an effective compound to promote axon growth and regeneration. Further, they point to strategies for increasing robustness of interventions in pre-clinical models.

The human anti-ganglioside GM1 autoantibody response following traumatic and surgical central nervous system insults

Predictors of the central nervous system (CNS) directed autoantibody response after acute CNS injury are poorly understood. We analyzed titers of IgG and IgM autoantibodies to ganglioside GM1 in serial serum specimens collected from human patients following acute spinal cord injury (SCI), traumatic brain injury (TBI) and brain tumor resection. We also assessed putative predictors of the autoantibody titers. We enrolled 19 patients with acute SCI, 14 patients with acute severe TBI, and 19 patients undergoing brain tumor resection. We also enrolled 25 control subjects. Some SCI, TBI and tumor patients exhibited elevated IgG titers as compared with control values; some SCI and TBI patients exhibited an acute peak in IgG titers, most commonly 14 days after insult. Some clinical and radiographic measures of injury severity correlated with IgG titer elevation in SCI and TBI patients but not tumor patients. Our study demonstrates that diverse CNS insults are followed by increased IgG autoimmune antibody titers to the CNS antigen ganglioside GM1, however the response inherent to each insult type is unique. IgG autoimmune antibody titers to GM1 merit further study as a biomarker of traumatic injury severity that can be measured in delayed fashion after CNS insult. These human data help to inform which patients with CNS insults are at risk for CNS-directed autoimmunity as well as the time course of the response.

Оценка эффективности работы и перспектив развития санитарной авиации в условиях мегаполиса на примере г.Москвы

The objectives of the study are to develop a structural and functional model, principles and algorithms of organizational and methodological support of helicopter evacuation of patients to specialized medical organizations of megapolis; to evaluate their effectiveness analysing the results of treatment of patients with significant urgent pathology. Materials and research methods. The results of treatment of 241 patients with urgent pathology at the treatment facilities of the Moscow Health Department — City Clinical Hospital No.15 named after O.M. Filatov, S.S. Yudin State Clinical Hospital and N.S. Sklifosovskiy Research Institute of Emergency Medicine in 2016-2019 — were analyzed. Inclusion criteria: patients with bleeding (isolated or in combination with acute trauma) requiring surgical intervention; with acute coronary syndrome (unstable angina pectoris, myocardial infarction with and without ST-segment elevation); with vascular pathology of central nervous system or craniocerebral trauma, requiring emergency hospitalization of the patient in a specialized medical institution — provided that the time of delivery of all these patients to the hospital was at least 30 minutes from the time of call. Exclusion criteria: patients with mental illness, infectious-inflammatory processes, severe comorbid somatic diseases in decompensation stage (established by anamnesis, examination or autopsy reports); incurable cancer patients and any urgent patients whose delivery time to the specialized hospital was less than 30 minutes from the time of call. All patients included in the study were divided into 2 groups: The main — 1st group — included 112 patients delivered to the profile medical institution of the megapolis on a medical helicopter. The comparison group — 2nd group — consisted of 129 patients with similar urgent pathology, hospitalized to the specialized hospitals of the city by ground ambulance transport. Research results and their analysis. The analysis of the study results showed: – performance of air medical teams is comparable to or exceeds that of ground ambulance teams; – number of total bed-days in the group hospitalized by air ambulance was higher than in the comparison group; – inpatient outcomes and long-term outcomes were comparable in both groups; – pilot study of the use of mobile diagnostic ultrasound in providing emergency and urgent medical care allows us to consider this method as a promising one, but it requires further evidence accumulation. Thus, the performance of medical aviation is not inferior to the performance of ground ambulance teams, and in some aspects, even exceed them, which confirms the high potential of its use in megapolis conditions and in remote and hard-to-reach areas.

Cold protection allows local cryotherapy in a clinical-relevant model of traumatic optic neuropathy.

Therapeutic hypothermia (TH) is potentially an important therapy for central nervous system (CNS) trauma. However, its clinical application remains controversial, hampered by two major factors: (1) Many of the CNS injury sites, such as the optic nerve (ON), are deeply buried, preventing access for local TH. The alternative is to apply TH systemically, which significantly limits the applicable temperature range. (2) Even with possible access for 'local refrigeration', cold-induced cellular damage offsets the benefit of TH. Here we present a clinically translatable model of traumatic optic neuropathy (TON) by applying clinical trans-nasal endoscopic surgery to goats and non-human primates. This model faithfully recapitulates clinical features of TON such as the injury site (pre-chiasmatic ON), the spatiotemporal pattern of neural degeneration, and the accessibility of local treatments with large operating space. We also developed a computer program to simplify the endoscopic procedure and expand this model to other large animal species. Moreover, applying a cold-protective treatment, inspired by our previous hibernation research, enables us to deliver deep hypothermia (4 °C) locally to mitigate inflammation and metabolic stress (indicated by the transcriptomic changes after injury) without cold-induced cellular damage, and confers prominent neuroprotection both structurally and functionally. Intriguingly, neither treatment alone was effective, demonstrating that in situ deep hypothermia combined with cold protection constitutes a breakthrough for TH as a therapy for TON and other CNS traumas.

Emerging Mechanisms and Targeted Therapy of Pyroptosis in Central Nervous System Trauma.

Cell death can occur in different modes, ferroptosis, pyroptosis, apoptosis, and necroptosis. Recent studies have shown that pyroptosis can be effectively regulated and that like necroptosis, pyroptosis has been regarded as a type of programmed cell death. The mechanism of its occurrence can be divided into canonical inflammasome-induced pyroptosis and noncanonical inflammasome-induced pyroptosis. In the past research, pyroptosis has been shown to be closely related to various diseases, such as tumors, neurodegenerative diseases, and central nervous system trauma, and studies have pointed out that in central nervous system trauma, pyroptosis is activated. Furthermore, these studies have shown that the inhibition of pyroptosis can play a role in protecting nerve function. In this review, we summarized the mechanisms of pyroptosis, introduce treatment strategies for targeted pyroptosis in central nervous system trauma, and proposed some issues of targeted pyroptosis in the treatment of central nervous system injury.

Mesenchymal stromal cells: cell-based therapies for traumatic central nervous system injuries.

Traumatic central nervous system (CNS) injury often causes irreversible impairment, and new alternative therapies for the treatment of CNS injury and sequelae are expected to be developed. Recently, mesenchymal stromal cells (MSCs) have started being used as cell therapy for neurological disorders such as traumatic CNS injury based on their immunomodulatory, neuroprotective, and neurorestorative abilities. Based on the premise of basic research, numerous clinical trials using MSCs for the treatment of traumatic CNS injury have been performed, and the feasibility and efficacy of this therapy have been reported. In this review we aimed to shed light on the characteristics of MSCs and to discuss the basic and clinical research and recent progress in clinical studies using MSCs to treat various traumatic neurological injuries.

Stem Cell Therapies for Central Nervous System Trauma: The 4 Ws-What, When, Where, and Why.

Traumatic injury of the central nervous system (CNS) is a worldwide health problem affecting millions of people. Trauma of the CNS, that is, traumatic brain injury (TBI) and spinal cord injury (SCI), lead to massive and progressive cell loss and axonal degeneration, usually with very limited regeneration. At present, there are no treatments to protect injured CNS tissue or to replace the lost tissue. Stem cells are a cell type that by definition can self-renew and give rise to multiple cell lineages. In recent years, therapies using stem and progenitor cells have shown promising effects in experimental CNS trauma, particularly in the acute-subacute stage, but also in chronic injuries. However, the therapeutic mechanisms by which transplanted cells achieve the structural and/or functional improvements are often not clear. Stem cell therapies for CNS trauma can be categorized into 2 main concepts, transplantation of exogenous neural stem cells and neural progenitor cells and recruitment of endogenous stem and progenitor cells. In this review, focusing on the advances during the last decade, we will discuss the major cell therapies, the pros and cons of these 2 concepts for TBI and SCI, and the treatment strategies we believe will be successful.