Chemogenetics Modulation of Electroacupuncture Analgesia in Mice Spared Nerve Injury-Induced Neuropathic Pain through TRPV1 Signaling Pathway.

Neuropathic pain, which is initiated by a malfunction of the somatosensory cortex system, elicits inflammation and simultaneously activates glial cells that initiate neuroinflammation. Electroacupuncture (EA) has been shown to have therapeutic effects for neuropathic pain, although with uncertain mechanisms. We suggest that EA can reliably cure neuropathic disease through anti-inflammation and transient receptor potential V1 (TRPV1) signaling pathways from the peripheral to the central nervous system. To explore this, we used EA to treat the mice spared nerve injury (SNI) model and explore the underlying molecular mechanisms through novel chemogenetics techniques. Both mechanical and thermal pain were found in SNI mice at four weeks (mechanical: 3.23 ± 0.29 g; thermal: 4.9 ± 0.14 s). Mechanical hyperalgesia was partially attenuated by 2 Hz EA (mechanical: 4.05 ± 0.19 g), and thermal hyperalgesia was fully reduced (thermal: 6.22 ± 0.26 s) but not with sham EA (mechanical: 3.13 ± 0.23 g; thermal: 4.58 ± 0.37 s), suggesting EA's specificity. In addition, animals with Trpv1 deletion showed partial mechanical hyperalgesia and no significant induction of thermal hyperalgesia in neuropathic pain mice (mechanical: 4.43 ± 0.26 g; thermal: 6.24 ± 0.09 s). Moreover, we found increased levels of inflammatory factors such as interleukin-1 beta (IL1-ß), IL-3, IL-6, IL-12, IL-17, tumor necrosis factor alpha, and interferon gamma after SNI modeling, which decreased in the EA and Trpv1-/- groups rather than the sham group. Western blot and immunofluorescence analysis showed similar tendencies in the dorsal root ganglion, spinal cord dorsal horn, somatosensory cortex (SSC), and anterior cingulate cortex (ACC). In addition, a novel chemogenetics method was used to precisely inhibit SSC to ACC activity, which showed an analgesic effect through the TRPV1 pathway. In summary, our findings indicate a novel mechanism underlying neuropathic pain as a beneficial target for neuropathic pain.

High-voltage pulsed radiofrequency improves ultrastructure of DRG and enhances spinal microglial autophagy to ameliorate neuropathic pain induced by SNI.

Neuropathic pain (NeP) is intractable for which many therapies are ineffective. High-voltage pulsed radiofrequency (HVPRF) on dorsal root ganglion (DRG) is considered an effective treatment for NeP. The aim of this study is to explore the therapeutic voltage for the optimal efficacy of PRF and the underlying mechanisms. The radiofrequency electrode was placed close to the L5 DRG of rats with spared nerve injury (SNI) and emitted current by the corresponding voltage in different groups. Four different voltages (45 V, 65 V, 85 V, and 100 V) of PRF on DRG significantly alleviated the SNI-induced NeP, reduced the levels of activating transcription factor 3 (ATF3) in DRG, improved the ultrastructure of DRG, and promoted autophagy in spinal microglia to varying degrees and partially reversed the increased expression of TNF-α and the reduced expression of IL-10 in spinal cord dorsal horn (SCDH). The beneficial effect of 85V-PRF was superior to those of other three PRF treatments. The underlying mechanisms may be related to repairing the DRG damage and improving the DRG ultrastructure while regulating spinal microglial autophagy and thereby alleviating neuroinflammation.

A Single Injection of rAAV-shmTOR in Peripheral Nerve Persistently Attenuates Nerve Injury-Induced Mechanical Allodynia.

Activation of mammalian target of rapamycin (mTOR) has been known as one of the contributing factors in nociceptive sensitization after peripheral injury. Its activation followed by the phosphorylation of downstream effectors causes hyperexcitability of primary sensory neurons in the dorsal root ganglion. We investigated whether a single injection of rAAV-shmTOR would effectively downregulate both complexes of mTOR in the long-term and glial activation as well. Male SD rats were categorized into shmTOR (n = 29), shCON (n = 23), SNI (n = 13), and Normal (n = 8) groups. Treatment groups were injected with rAAV-shmTOR or rAAV-shCON, respectively. DRG tissues and sciatic nerve were harvested for Western blot and immunohistochemical analyses. Peripheral sensitization was gradually attenuated in the shmTOR group, and it reached a peak on PID 21. Western blot analysis showed that both p-mTORC1 and p-mTORC2 were downregulated in the DRG compared to shCON and SNI groups. We also found decreased expression of phosphorylated p38 and microglial activation in the DRG. We first attempted a therapeutic strategy for neuropathic pain with a low dose of AAV injection by interfering with the mTOR signaling pathway, suggesting its potential application in pain treatment.

Characterisation of GFAP-Expressing Glial Cells in the Dorsal Root Ganglion after Spared Nerve Injury.

Satellite glial cells (SGCs), enveloping primary sensory neurons' somas in the dorsal root ganglion (DRG), contribute to neuropathic pain upon nerve injury. Glial fibrillary acidic protein (GFAP) serves as an SGC activation marker, though its DRG satellite cell specificity is debated. We employed the hGFAP-CFP transgenic mouse line, designed for astrocyte studies, to explore its expression within the peripheral nervous system (PNS) after spared nerve injury (SNI). We used diverse immunostaining techniques, Western blot analysis, and electrophysiology to evaluate GFAP+ cell changes. Post-SNI, GFAP+ cell numbers increased without proliferation, and were found near injured ATF3+ neurons. GFAP+ FABP7+ SGCs increased, yet 75.5% of DRG GFAP+ cells lacked FABP7 expression. This suggests a significant subset of GFAP+ cells are non-myelinating Schwann cells (nmSC), indicated by their presence in the dorsal root but not in the ventral root which lacks unmyelinated fibres. Additionally, patch clamp recordings from GFAP+ FABP7-cells lacked SGC-specific Kir4.1 currents, instead displaying outward Kv currents expressing Kv1.1 and Kv1.6 channels specific to nmSCs. In conclusion, this study demonstrates increased GFAP expression in two DRG glial cell subpopulations post-SNI: GFAP+ FABP7+ SGCs and GFAP+ FABP7- nmSCs, shedding light on GFAP's specificity as an SGC marker after SNI.

Extracellular Vesicles: Therapeutic Potential in Central Nervous System Trauma by Regulating Cell Death.

CNS (central nervous system) trauma, which is classified as SCI (spinal cord injury) and TBI (traumatic brain injury), is gradually becoming a major cause of accidental death and disability worldwide. Many previous studies have verified that the pathophysiological mechanism underlying cell death and the subsequent neuroinflammation caused by cell death are pivotal factors in the progression of CNS trauma. Simultaneously, EVs (extracellular vesicles), membrane-enclosed particles produced by almost all cell types, have been proven to mediate cell-to-cell communication, and cell death involves complex interactions among molecules. EVs have also been proven to be effective carriers of loaded bioactive components to areas of CNS trauma. Therefore, EVs are promising therapeutic targets to cure CNS trauma. However, the link between EVs and various types of cell death in the context of CNS trauma remains unknown. Therefore, in this review, we summarize the mechanism underlying EV effects, the relationship between EVs and cell death and the pathophysiology underlying EV effects on the CNS trauma based on information in published papers. In addition, we discuss the prospects of applying EVs to the CNS as feasible therapeutic strategies for CNS trauma in the future.

Epigenetic Up-Regulation of ADAMTS4 in Sympathetic Ganglia is Involved in the Maintenance of Neuropathic Pain Following Nerve Injury.

Sympathetic axonal sprouting into dorsal root ganglia is a major phenomenon implicated in neuropathic pain, and sympathetic ganglia blockage may relieve some intractable chronic pain in animal pain models and clinical conditions. These suggest that sympathetic ganglia participated in the maintenance of chronic pain. However, the molecular mechanism underlying sympathetic ganglia-mediated chronic pain is not clear. Here, we found that spared nerve injury treatment upregulated the expression of ADAMTS4 and AP-2α protein and mRNA in the noradrenergic neurons of sympathetic ganglia during neuropathic pain maintenance. Knockdown the ADAMTS4 or AP-2α by injecting specific retro scAAV-TH (Tyrosine Hydroxylase)-shRNA ameliorated the mechanical allodynia induced by spared nerve injury on day 21 and 28. Furthermore, chromatin immunoprecipitation and coimmunoprecipitation assays found that spared nerve injury increased the recruitment of AP-2α to the ADAMTS4 gene promoter, the interaction between AP-2α and histone acetyltransferase p300 and the histone H4 acetylation on day 28. Finally, knockdown the AP-2α reduced the acetylation of H4 on the promoter region of ADAMTS4 gene and suppressed the increase of ADAMTS4 expression induced by spared nerve injury. Together, these results suggested that the enhanced interaction between AP-2α and p300 mediated the epigenetic upregulation of ADAMTS4 in sympathetic ganglia noradrenergic neurons, which contributed to the maintenance of spared nerve injury induced neuropathic pain.

Intraperitoneal 5-Azacytidine Alleviates Nerve Injury-Induced Pain in Rats by Modulating DNA Methylation.

To investigate the role of DNA methylation in modulating chronic neuropathic pain (NPP), identify possible target genes of DNA methylation involved in this process, and preliminarily confirm the medicinal value of the DNA methyltransferases (DNMTs) inhibitor 5-azacytidine (5-AZA) in NPP by targeting gene methylation. Two rat NPP models, chronic constriction injury (CCI) and spinal nerve ligation (SNL), were used. The DNA methylation profiles in the lumbar spinal cord were assayed using an Arraystar Rat RefSeq Promoter Array. The underlying genes with differential methylation were then identified and submitted to Gene Ontology and pathway analysis. Methyl-DNA immunoprecipitation quantitative PCR (MeDIP-qPCR) and quantitative reverse transcription-PCR (RT-qPCR) were used to confirm gene methylation and expression. The protective function of 5-AZA in NPP and gene expression were evaluated via behavioral assays and RT-qPCR, respectively. Analysis of the DNA methylation patterns in the lumbar spinal cord indicated that 1205 differentially methylated fragments in CCI rats were located within DNA promoter regions, including 638 hypermethylated fragments and 567 hypomethylated fragments. The methylation levels of Grm4, Htr4, Adrb2, Kcnf1, Gad2, and Pparg, which are associated with long-term potentiation (LTP) and glutamatergic synapse pathways, were increased with a corresponding decrease in their mRNA expression, in the spinal cords of CCI rats. Moreover, we found that the intraperitoneal injection of 5-AZA (4 mg/kg) attenuated CCI- or SNL-induced mechanical allodynia and thermal hyperalgesia. Finally, the mRNA expression of hypermethylated genes such as Grm4, Htr4, Adrb2, Kcnf1, and Gad2 was reversed after 5-AZA treatment. CCI induced widespread methylation changes in the DNA promoter regions in the lumbar spinal cord. Intraperitoneal 5-AZA alleviated hyperalgesia in CCI and SNL rats, an effect accompanied by the reversed expression of hypermethylated genes. Thus, DNA methylation inhibition represents a promising epigenetic strategy for protection against chronic NPP following nerve injury. Our study lays a theoretical foundation for 5-AZA to become a clinical targeted drug.

Expression and Kinetics of Endogenous Cannabinoids in the Brain and Spinal Cord of a Spare Nerve Injury (SNI) Model of Neuropathic Pain.

The role of endogenous cannabinoids in neuropathic pain has been actively studied, among which 2-arachidonoyl glycerol (2-AG) has received the most attention. However, owing to its chemical properties, direct detection of 2-AG distribution in tissues is difficult. Moreover, although desorption electrospray ionization mass spectrometry imaging (DESI-MSI) has enabled the detection of 2-AG, its distribution in the brain and spinal cord of neuropathic pain models has not been reported. In this study, the expression and distribution of 2-AG in the brain and spinal cord of a spare nerve injury (SNI) mice model of neuropathic pain was examined using DESI-MSI. The brain and lumbar spinal cord were collected and analyzed on days 3, 7, and 21 after treatment. On days 3 and 7 after treatment, 2-AG expression in the SNI model was decreased in the hypothalamus, midbrain, and especially in the periaqueductal gray (PAG) region but increased in the lumbar spinal cord. On day 21, the SNI model showed decreased 2-AG expression in the hypothalamus, but the difference from the control was not significant. Furthermore, there were no differences in 2-AG expression between the lumbar spinal cord, midbrain, or PAG. These data suggest that 2-AG might be involved in pain control.

Retinal ganglion cell expression of cytokine enhances occupancy of NG2 cell-derived astrocytes at the nerve injury site: Implication for axon regeneration.

Following injury in the central nervous system, a population of astrocytes occupy the lesion site, form glial bridges and facilitate axon regeneration. These astrocytes originate primarily from resident astrocytes or NG2+ oligodendrocyte progenitor cells. However, the extent to which these cell types give rise to the lesion-filling astrocytes, and whether the astrocytes derived from different cell types contribute similarly to optic nerve regeneration remain unclear. Here we examine the distribution of astrocytes and NG2+ cells in an optic nerve crush model. We show that optic nerve astrocytes partially fill the injury site over time after a crush injury. Viral mediated expression of a growth-promoting factor, ciliary neurotrophic factor (CNTF), in retinal ganglion cells (RGCs) promotes axon regeneration without altering the lesion size or the degree of lesion-filling GFAP+ cells. Strikingly, using inducible NG2CreER driver mice, we found that CNTF overexpression in RGCs increases the occupancy of NG2+ cell-derived astrocytes in the optic nerve lesion. An EdU pulse-chase experiment shows that the increase in NG2 cell-derived astrocytes is not due to an increase in cell proliferation. Lastly, we performed RNA-sequencing on the injured optic nerve and reveal that CNTF overexpression in RGCs results in significant changes in the expression of distinct genes, including those that encode chemokines, growth factor receptors, and immune cell modulators. Even though CNTF-induced axon regeneration has long been recognized, this is the first evidence of this procedure affecting glial cell fate at the optic nerve crush site. We discuss possible implication of these results for axon regeneration.

The Role of miR-20 in Health and Disease of the Central Nervous System.

Current understanding of the mechanisms underlying central nervous system (CNS) injury is limited, and traditional therapeutic methods lack a molecular approach either to prevent acute phase or secondary damage, or to support restorative mechanisms in the nervous tissue. microRNAs (miRNAs) are endogenous, non-coding RNA molecules that have recently been discovered as fundamental and post-transcriptional regulators of gene expression. The capacity of microRNAs to regulate the cell state and function through post-transcriptionally silencing hundreds of genes are being acknowledged as an important factor in the pathophysiology of both acute and chronic CNS injuries. In this study, we have summarized the knowledge concerning the pathophysiology of several neurological disorders, and the role of most canonical miRNAs in their development. We have focused on the miR-20, the miR-17~92 family to which miR-20 belongs, and their function in the normal development and disease of the CNS.

Roles of neuronal toll-like receptors in neuropathic pain and central nervous system injuries and diseases.

Toll-like receptors (TLRs) are innate immune receptors that are expressed in immune cells as well as glia and neurons of the central and peripheral nervous systems. They are best known for their role in the host defense in response to pathogens and for the induction of inflammation in infectious and non-infectious diseases. In the central nervous system (CNS), TLRs modulate glial and neuronal functions as well as innate immunity and neuroinflammation under physiological or pathophysiological conditions. The majority of the studies on TLRs in CNS pathologies investigated their overall contribution without focusing on a particular cell type, or they analyzed TLRs in glia and infiltrating immune cells in the context of neuroinflammation and cellular activation. The role of neuronal TLRs in CNS diseases and injuries has received little attention and remains underappreciated. The primary goal of this review is to summarize findings demonstrating the pivotal and unique roles of neuronal TLRs in neuropathic pain, Alzheimer's disease, Parkinson's disease and CNS injuries. We discuss how the current findings warrant future investigations to better define the specific contributions of neuronal TLRs to these pathologies. We underline the paucity of information regarding the role of neuronal TLRs in other neurodegenerative, demyelinating, and psychiatric diseases. We draw attention to the importance of broadening research on neuronal TLRs in view of emerging evidence demonstrating their distinctive functional properties.

C/EBPß Participates in Nerve Trauma-Induced TLR7 Upregulation in Primary Sensory Neurons.

Nerve trauma-induced toll-like receptor 7 (TLR7) expression level increases in primary sensory neurons in injured dorsal root ganglion (DRG) avails to neuropathic pain, but the reason is still unknown. In the current study, we showed that unilateral lumbar 4 (L4) spinal nerve ligation (SNL) upregulated CCAAT/enhancer-binding protein-ß (C/EBPß) expression in ipsilateral L4 DRG. Preventing this elevation attenuated the SNL-induced upregulation of TLR7 in the ipsilateral L4 DRG and inhibited cold/thermal hyperalgesia and mechanical allodynia. In injected DRG, mimicking nerve trauma-induced C/EBPß upregulation increased TLR7 levels, augmented responses to cold/thermal/mechanical stimuli, and caused ipsilateral spontaneous pain with no SNL. Mechanistically, SNL upregulated binding of increased C/EBPß to Tlr7 promoter in ipsilateral L4 DRG. Accorded that C/EBPß could trigger the activation of Tlr7 promoter and co-expressed with Tlr7 mRNA in individual DRG neurons, our findings strongly suggest the role of C/EBPß in nerve trauma-mediated TLR7 upregulation in injured primary sensory neurons.

The Role of Lipids, Lipid Metabolism and Ectopic Lipid Accumulation in Axon Growth, Regeneration and Repair after CNS Injury and Disease.

Axons in the adult mammalian nervous system can extend over formidable distances, up to one meter or more in humans. During development, axonal and dendritic growth requires continuous addition of new membrane. Of the three major kinds of membrane lipids, phospholipids are the most abundant in all cell membranes, including neurons. Not only immature axons, but also severed axons in the adult require large amounts of lipids for axon regeneration to occur. Lipids also serve as energy storage, signaling molecules and they contribute to tissue physiology, as demonstrated by a variety of metabolic disorders in which harmful amounts of lipids accumulate in various tissues through the body. Detrimental changes in lipid metabolism and excess accumulation of lipids contribute to a lack of axon regeneration, poor neurological outcome and complications after a variety of central nervous system (CNS) trauma including brain and spinal cord injury. Recent evidence indicates that rewiring lipid metabolism can be manipulated for therapeutic gain, as it favors conditions for axon regeneration and CNS repair. Here, we review the role of lipids, lipid metabolism and ectopic lipid accumulation in axon growth, regeneration and CNS repair. In addition, we outline molecular and pharmacological strategies to fine-tune lipid composition and energy metabolism in neurons and non-neuronal cells that can be exploited to improve neurological recovery after CNS trauma and disease.

α-Synuclein in traumatic and vascular diseases of the central nervous system.

α-Synuclein (α-Syn) is a small, soluble, disordered protein that is widely expressed in the nervous system. Although its physiological functions are not yet fully understood, it is mainly involved in synaptic vesicle transport, neurotransmitter synthesis and release, cell membrane homeostasis, lipid synthesis, mitochondrial and lysosomal activities, and heavy metal removal. The complex and inconsistent pathological manifestations of α-Syn are attributed to its structural instability, mutational complexity, misfolding, and diverse posttranslational modifications. These effects trigger mitochondrial dysfunction, oxidative stress, and neuroinflammatory responses, resulting in neuronal death and neurodegeneration. Several recent studies have discovered the pathogenic roles of α-Syn in traumatic and vascular central nervous system diseases, such as traumatic spinal cord injury, brain injury, and stroke, and in aggravating the processes of neurodegeneration. This review aims to highlight the structural and pathophysiological changes in α-Syn and its mechanism of action in traumatic and vascular diseases of the central nervous system.

Axon growth and synaptic function: A balancing act for axonal regeneration and neuronal circuit formation in CNS trauma and disease.

Axons in the adult mammalian central nervous system (CNS) fail to regenerate inside out due to intrinsic and extrinsic neuronal determinants. During CNS development, axon growth, synapse formation, and function are tightly regulated processes allowing immature neurons to effectively grow an axon, navigate toward target areas, form synaptic contacts and become part of information processing networks that control behavior in adulthood. Not only immature neurons are able to precisely control the expression of a plethora of genes necessary for axon extension and pathfinding, synapse formation and function, but also non-neuronal cells such as astrocytes and microglia actively participate in sculpting the nervous system through refinement, consolidation, and elimination of synaptic contacts. Recent evidence indicates that a balancing act between axon regeneration and synaptic function may be crucial for rebuilding functional neuronal circuits after CNS trauma and disease in adulthood. Here, we review the role of classical and new intrinsic and extrinsic neuronal determinants in the context of CNS development, injury, and disease. Moreover, we discuss strategies targeting neuronal and non-neuronal cell behaviors, either alone or in combination, to promote axon regeneration and neuronal circuit formation in adulthood.

Modelling human CNS injury with human neural stem cells in 2- and 3-Dimensional cultures.

The adult human central nervous system (CNS) has very limited regenerative capability, and injury at the cellular and molecular level cannot be studied in vivo. Modelling neural damage in human systems is crucial to identifying species-specific responses to injury and potentially neurotoxic compounds leading to development of more effective neuroprotective agents. Hence we developed human neural stem cell (hNSC) 3-dimensional (3D) cultures and tested their potential for modelling neural insults, including hypoxic-ischaemic and Ca2+-dependent injury. Standard 3D conditions for rodent cells support neuroblastoma lines used as human CNS models, but not hNSCs, but in all cases changes in culture architecture alter gene expression. Importantly, response to damage differs in 2D and 3D cultures and this is not due to reduced drug accessibility. Together, this study highlights the impact of culture cytoarchitecture on hNSC phenotype and damage response, indicating that 3D models may be better predictors of in vivo response to damage and compound toxicity.

Systemic Immune Response to Traumatic CNS Injuries-Are Extracellular Vesicles the Missing Link?

Inflammation following traumatic injury to the central nervous system (CNS) persists long after the primary insult and is known to exacerbate cell death and worsen functional outcomes. Therapeutic interventions targeting this inflammation have been unsuccessful, which has been attributed to poor bioavailability owing to the presence of blood-CNS barrier. Recent studies have shown that the magnitude of the CNS inflammatory response is dependent on systemic inflammatory events. The acute phase response (APR) to CNS injury presents an alternative strategy to modulating the secondary phase of injury. However, the communication pathways between the CNS and the periphery remain poorly understood. Extracellular vesicles (EVs) are membrane bound nanoparticles that are regulators of intercellular communication. They are shed from cells of the CNS including microglia, astrocytes, neurons and endothelial cells, and are able to cross the blood-CNS barrier, thus providing an attractive candidate for initiating the APR after acute CNS injury. The purpose of this review is to summarize the current evidence that EVs play a critical role in the APR following CNS injuries.

Stretch-Induced Deformation as a Model to Study Dopaminergic Dysfunction in Traumatic Brain Injury.

Traumatic brain injury (TBI) is defined as damage to the brain that consequently disrupts normal function. Neuronal death, a hallmark of TBI, has been related to the development of neurodegenerative disorders like Parkinson's disease (PD), where loss of dopaminergic neurons and dopaminergic dysfunction are observed. To date, no in vitro model exists in which the dopaminergic damage observed in TBI is replicated. In this study, we evaluated the effects of in vitro simulated TBI on human dopaminergic neurons. To simulate TBI, neurons were subjected to 0%, 5%, 10%, 15%, 25% and 50% deformation. 24 h after injury, cell viability and apoptosis were determined by lactate dehydrogenase (LDH) release and DNA fragmentation, as well as ethidium homodimer and caspase 3/7 staining. Dopamine (DA) levels were determined by ELISA. Levels of tyrosine hydroxylase (TH) and DA transporter (DAT) were determined by western blot. Only 50% stretch increased LDH release and ethidium homodimer staining, suggesting the induction of necrosis. On the contrary, 25% and 50% stretch increased DNA fragmentation while 15%, 25% and 50% increased caspase 3/7 staining, suggesting that moderate and severe TBI promote apoptosis. Levels of intracellular DA decreased in a stretch-dependent manner with 15%, 25% and 50% stretch, which were related with a decrease in TH expression. Extracellular DA levels increased only at 50%. Levels of DAT remained unchanged regardless of treatment. These data support the use of stretch as a model to simulate TBI in vitro in human dopaminergic neurons, replicating the acute effects of TBI in the dopaminergic system.

Autophagy in Neurotrauma: Good, Bad, or Dysregulated.

Autophagy is a physiological process that helps maintain a balance between the manufacture of cellular components and breakdown of damaged organelles and other toxic cellular constituents. Changes in autophagic markers are readily detectable in the spinal cord and brain following neurotrauma, including traumatic spinal cord and brain injury (SCI/TBI). However, the role of autophagy in neurotrauma remains less clear. Whether autophagy is good or bad is under debate, with strong support for both a beneficial and detrimental role for autophagy in experimental models of neurotrauma. Emerging data suggest that autophagic flux, a measure of autophagic degradation activity, is impaired in injured central nervous systems (CNS), and interventions that stimulate autophagic flux may provide neuroprotection in SCI/TBI models. Recent data demonstrating that neurotrauma can cause lysosomal membrane damage resulting in pathological autophagosome accumulation in the spinal cord and brain further supports the idea that the impairment of the autophagy-lysosome pathway may be a part of secondary injury processes of SCI/TBI. Here, we review experimental work on the complex and varied responses of autophagy in terms of both the beneficial and detrimental effects in SCI and TBI models. We also discuss the existing and developing therapeutic options aimed at reducing the disruption of autophagy to protect the CNS after injuries.