A small molecule M1 promotes optic nerve regeneration to restore target-specific neural activity and visual function.

Axon regeneration is an energy-demanding process that requires active mitochondrial transport. In contrast to the central nervous system (CNS), axonal mitochondrial transport in regenerating axons of the peripheral nervous system (PNS) increases within hours and sustains for weeks after injury. Yet, little is known about targeting mitochondria in nervous system repair. Here, we report the induction of sustained axon regeneration, neural activities in the superior colliculus (SC), and visual function recovery after optic nerve crush (ONC) by M1, a small molecule that promotes mitochondrial fusion and transport. We demonstrated that M1 enhanced mitochondrial dynamics in cultured neurons and accelerated in vivo axon regeneration in the PNS. Ex vivo time-lapse imaging and kymograph analysis showed that M1 greatly increased mitochondrial length, axonal mitochondrial motility, and transport velocity in peripheral axons of the sciatic nerves. Following ONC, M1 increased the number of axons regenerating through the optic chiasm into multiple subcortical areas and promoted the recovery of local field potentials in the SC after optogenetic stimulation of retinal ganglion cells, resulting in complete recovery of the pupillary light reflex, and restoration of the response to looming visual stimuli was detected. M1 increased the gene expression of mitochondrial fusion proteins and major axonal transport machinery in both the PNS and CNS neurons without inducing inflammatory responses. The knockdown of two key mitochondrial genes, Opa1 or Mfn2, abolished the growth-promoting effects of M1 after ONC, suggesting that maintaining a highly dynamic mitochondrial population in axons is required for successful CNS axon regeneration.

Low-dose ionizing radiation promotes motor recovery and brain rewiring by resolving inflammatory response after brain injury and stroke.

Traumatic brain injury (TBI) and stroke share a common pathophysiology that worsens over time due to secondary tissue injury caused by sustained inflammatory response. However, studies on pharmacological interventions targeting the complex secondary injury cascade have failed to show efficacy. Here, we demonstrated that low-dose ionizing radiation (LDIR) reduced lesion size and reversed motor deficits after TBI and photothrombotic stroke. Magnetic resonance imaging demonstrated significant reduction of infarct volume in LDIR-treated mice after stroke. Systems-level transcriptomic analysis showed that genes upregulated in LDIR-treated stoke mice were enriched in pathways associated with inflammatory and immune response involving microglia. LDIR induced upregulation of anti-inflammatory- and phagocytosis-related genes, and downregulation of key pro-inflammatory cytokine production. These findings were validated by live-cell assays, in which microglia exhibited higher chemotactic and phagocytic capacities after LDIR. We observed substantial microglial clustering at the injury site, glial scar clearance and reversal of motor deficits after stroke. Cortical microglia/macrophages depletion completely abolished the beneficial effect of LDIR on motor function recovery in stroke mice. LDIR promoted axonal projections (brain rewiring) in motor cortex and recovery of brain activity detected by electroencephalography recordings months after stroke. LDIR treatment delayed by 8 h post-injury still maintained full therapeutic effects on motor recovery, indicating that LDIR is a promising therapeutic strategy for TBI and stroke.

Therapeutic benefits of maintaining mitochondrial integrity and calcium homeostasis by forced expression of Hsp27 in chemotherapy-induced peripheral neuropathy.

BACKGROUND: Vincristine, a widely used antineoplastic agent, is known to be neurotoxic and to lead to chemotherapy-induced peripheral neuropathy (CIPN), which is characterized by nerve damage. Growing evidence suggests that disruption of intracellular calcium homeostasis in peripheral neurons contributes largely to the pathological conditions of CIPN. Our previous study showed that forced expression of a peripheral nerve injury-induced small heat shock protein (Hsp), Hsp27, accelerates axon regeneration and functional recovery. In the current study, we examined whether neuronal expression of human Hsp27 (hHsp27) can prevent the inhibitory effects of vincristine in two mouse models of peripheral nerve injury, namely, sciatic nerve crush and CIPN. METHODS: The protective effects of hHsp27 against vincristine were examined in mouse models of both sciatic nerve crush and CIPN using multiple approaches, including animal behavioral tests, histology, electrophysiology, transmission electron microscopy and calcium imaging. RESULTS: Vincristine delayed functional recovery in littermate mice; however, hHsp27 Tg mice were unaffected after vincristine treatment and sciatic nerve crush. In CIPN mice, hHsp27 protected against vincristine-induced mechanical and cold allodynia by preventing axonal degeneration, demyelination, mitochondrial dysfunction, and apoptosis. Strikingly, vincristine-induced calcium influx was markedly attenuated in sensory neurons of hHsp27 Tg mice. CONCLUSIONS: Our findings suggest that preserving myelin and mitochondrial integrity as well as maintaining intracellular calcium homeostasis is beneficial for preventing CIPN, and these findings shed new light on the development of anti-CIPN drugs.

Probing for chemotherapy-induced peripheral neuropathy in live dorsal root ganglion neurons with atomic force microscopy.

Chemotherapy-induced peripheral neuropathy (CIPN) remains a major reason for cancer patients to withdraw from their lifesaving therapy. CIPN results in irreversible sensory and motor impairments; however, the epidemiology is largely unknown. Here, we report for the first time that chemotherapy drug vincristine not only reduced axonal regeneration in primary dorsal root ganglion neuron but also induced substantial changes in cell mechanical properties detected by atomic force microscopy (AFM). Confocal imaging analysis revealed vincristine-induced microtubule depolymerization. By using AFM for high-resolution live cell imaging and quantitative analysis, we observed significant changes in cell surface roughness and stiffness of vincristine-treated neurons. Elastic modulus was decreased (21-45%) with increasing dosage of vincristine. Further study with paclitaxel, another well-known CIPN drug, confirmed the link between cell mechanics and cytoskeleton organization. These data support that our system can be used for probing potential CIPN drugs that are of enormous benefit to new chemotherapy drug development. FROM THE CLINICAL EDITOR: This study concludes that reduced cell elasticity in dorsal root ganglion neurons accompanies the development of chemotherapy-induced peripheral neuropathy, providing a model system that enables testing of upcoming chemotherapy agents for this particularly inconvenient and often treatment-limiting complication.

Current understanding of the molecular mechanisms of chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is the most common off-target adverse effects caused by various chemotherapeutic agents, such as cisplatin, oxaliplatin, paclitaxel, vincristine and bortezomib. CIPN is characterized by a substantial loss of primary afferent sensory axonal fibers leading to sensory disturbances in patients. An estimated of 19-85% of patients developed CIPN during the course of chemotherapy. The lack of preventive measures and limited treatment options often require a dose reduction or even early termination of life-saving chemotherapy, impacting treatment efficacy and patient survival. In this Review, we summarized the current understanding on the pathogenesis of CIPN. One prominent change induced by chemotherapeutic agents involves the disruption of neuronal cytoskeletal architecture and axonal transport dynamics largely influenced by the interference of microtubule stability in peripheral neurons. Due to an ineffective blood-nerve barrier in our peripheral nervous system, exposure to some chemotherapeutic agents causes mitochondrial swelling in peripheral nerves, which lead to the opening of mitochondrial permeability transition pore and cytochrome c release resulting in degeneration of primary afferent sensory fibers. The exacerbated nociceptive signaling and pain transmission in CIPN patients is often linked the increased neuronal excitability largely due to the elevated expression of various ion channels in the dorsal root ganglion neurons. Another important contributing factor of CIPN is the neuroinflammation caused by an increased infiltration of immune cells and production of inflammatory cytokines. In the central nervous system, chemotherapeutic agents also induce neuronal hyperexcitability in the spinal dorsal horn and anterior cingulate cortex leading to the development of central sensitization that causes CIPN. Emerging evidence suggests that the change in the composition and diversity of gut microbiota (dysbiosis) could have direct impact on the development and progression of CIPN. Collectively, all these aspects contribute to the pathogenesis of CIPN. Recent advances in RNA-sequencing offer solid platform for in silico drug screening which enable the identification of novel therapeutic agents or repurpose existing drugs to alleviate CIPN, holding immense promises for enhancing the quality of life for cancer patients who undergo chemotherapy and improve their overall treatment outcomes.

Genome-wide study reveals novel roles for formin-2 in axon regeneration as a microtubule dynamics regulator and therapeutic target for nerve repair.

Peripheral nerves regenerate successfully; however, clinical outcome after injury is poor. We demonstrated that low-dose ionizing radiation (LDIR) promoted axon regeneration and function recovery after peripheral nerve injury (PNI). Genome-wide CpG methylation profiling identified LDIR-induced hypermethylation of the Fmn2 promoter, exhibiting injury-induced Fmn2 downregulation in dorsal root ganglia (DRGs). Constitutive knockout or neuronal Fmn2 knockdown accelerated nerve repair and function recovery. Mechanistically, increased microtubule dynamics at growth cones was observed in time-lapse imaging of Fmn2-deficient DRG neurons. Increased HDAC5 phosphorylation and rapid tubulin deacetylation were found in regenerating axons of neuronal Fmn2-knockdown mice after injury. Growth-promoting effect of neuronal Fmn2 knockdown was eliminated by pharmaceutical blockade of HDAC5 or neuronal Hdac5 knockdown, suggesting that Fmn2deletion promotes axon regeneration via microtubule post-translational modification. In silico screening of FDA-approved drugs identified metaxalone, administered either immediately or 24-h post-injury, accelerating function recovery. This work uncovers a novel axon regeneration function of Fmn2 and a small-molecule strategy for PNI.

Neuroinflammation, Microglia and Implications for Retinal Ganglion Cell Survival and Axon Regeneration in Traumatic Optic Neuropathy.

Traumatic optic neuropathy (TON) refers to a pathological condition caused by a direct or indirect insult to the optic nerves, which often leads to a partial or permanent vision deficit due to the massive loss of retinal ganglion cells (RGCs) and their axonal fibers. Retinal microglia are immune-competent cells residing in the retina. In rodent models of optic nerve crush (ONC) injury, resident retinal microglia gradually become activated, form end-to-end alignments in the vicinity of degenerating RGC axons, and actively internalized them. Some activated microglia adopt an amoeboid morphology that engulf dying RGCs after ONC. In the injured optic nerve, the activated microglia contribute to the myelin debris clearance at the lesion site. However, phagocytic capacity of resident retinal microglia is extremely poor and therefore the clearance of cellular and myelin debris is largely ineffective. The presence of growth-inhibitory myelin debris and glial scar formed by reactive astrocytes inhibit the regeneration of RGC axons, which accounts for the poor visual function recovery in patients with TON. In this Review, we summarize the current understanding of resident retinal microglia in RGC survival and axon regeneration after ONC. Resident retinal microglia play a key role in facilitating Wallerian degeneration and the subsequent axon regeneration after ONC. However, they are also responsible for producing pro-inflammatory cytokines, chemokines, and reactive oxygen species that possess neurotoxic effects on RGCs. Intraocular inflammation triggers a massive influx of blood-borne myeloid cells which produce oncomodulin to promote RGC survival and axon regeneration. However, intraocular inflammation induces chronic neuroinflammation which exacerbates secondary tissue damages and limits visual function recovery after ONC. Activated retinal microglia is required for the proliferation of oligodendrocyte precursor cells (OPCs); however, sustained activation of retinal microglia suppress the differentiation of OPCs into mature oligodendrocytes for remyelination after injury. Collectively, controlled activation of retinal microglia and infiltrating myeloid cells facilitate axon regeneration and nerve repair. Recent advance in single-cell RNA-sequencing and identification of microglia-specific markers could improve our understanding on microglial biology and to facilitate the development of novel therapeutic strategies aiming to switch resident retinal microglia's phenotype to foster neuroprotection.

Functional and Phenotypic Diversity of Microglia: Implication for Microglia-Based Therapies for Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease and is closely associated with the accumulation of ß-amyloid (Aß) and neurofibrillary tangles (NFTs). Apart from Aß and NFT pathologies, AD patients also exhibit a widespread microglial activation in various brain regions with elevated production of pro-inflammatory cytokines, a phenomenon known as neuroinflammation. In healthy central nervous system, microglia adopt ramified, "surveying" phenotype with compact cell bodies and elongated processes. In AD, the presence of pathogenic proteins such as extracellular Aß plaques and hyperphosphorylated tau, induce the transformation of ramified microglia into amoeboid microglia. Ameboid microglia are highly phagocytic immune cells and actively secrete a cascade of pro-inflammatory cytokines and chemokines. However, the phagocytic ability of microglia gradually declines with age, and thus the clearance of pathogenic proteins becomes highly ineffective, leading to the accumulation of Aß plaques and hyperphosphorylated tau in the aging brain. The accumulation of pathogenic proteins further augments the neuroinflammatory responses and sustains the activation of microglia. The excessive production of pro-inflammatory cytokines induces a massive loss of functional synapses and neurons, further worsening the disease condition of AD. More recently, the identification of a subset of microglia by transcriptomic studies, namely disease-associated microglia (DAM), the progressive transition from homeostatic microglia to DAM is TREM2-dependent and the homeostatic microglia gradually acquire the state of DAM during the disease progression of AD. Recent in-depth transcriptomic analysis identifies ApoE and Trem2 from microglia as the major risk factors for AD pathogenesis. In this review, we summarize current understandings of the functional roles of age-dependent microglial activation and neuroinflammation in the pathogenesis of AD. To this end, the exponential growth in transcriptomic data provides a solid foundation for in silico drug screening and gains further insight into the development of microglia-based therapeutic interventions for AD.

Clinically relevant small-molecule promotes nerve repair and visual function recovery.

Adult mammalian injured axons regenerate over short-distance in the peripheral nervous system (PNS) while the axons in the central nervous system (CNS) are unable to regrow after injury. Here, we demonstrated that Lycium barbarum polysaccharides (LBP), purified from Wolfberry, accelerated long-distance axon regeneration after severe peripheral nerve injury (PNI) and optic nerve crush (ONC). LBP not only promoted intrinsic growth capacity of injured neurons and function recovery after severe PNI, but also induced robust retinal ganglion cell (RGC) survival and axon regeneration after ONC. By using LBP gene expression profile signatures to query a Connectivity map database, we identified a Food and Drug Administration (FDA)-approved small-molecule glycopyrrolate, which promoted PNS axon regeneration, RGC survival and sustained CNS axon regeneration, increased neural firing in the superior colliculus, and enhanced visual target re-innervations by regenerating RGC axons leading to a partial restoration of visual function after ONC. Our study provides insights into repurposing of FDA-approved small molecule for nerve repair and function recovery.

Cerebellar glutamatergic system impacts spontaneous motor recovery by regulating Gria1 expression.

Peripheral nerve injury (PNI) often results in spontaneous motor recovery; however, how disrupted cerebellar circuitry affects PNI-associated motor recovery is unknown. Here, we demonstrated disrupted cerebellar circuitry and poor motor recovery in ataxia mice after PNI. This effect was mimicked by deep cerebellar nuclei (DCN) lesion, but not by damaging non-motor area hippocampus. By restoring cerebellar circuitry through DCN stimulation, and reversal of neurotransmitter imbalance using baclofen, ataxia mice achieve full motor recovery after PNI. Mechanistically, elevated glutamate-glutamine level was detected in DCN of ataxia mice by magnetic resonance spectroscopy. Transcriptomic study revealed that Gria1, an ionotropic glutamate receptor, was upregulated in DCN of control mice but failed to be upregulated in ataxia mice after sciatic nerve crush. AAV-mediated overexpression of Gria1 in DCN rescued motor deficits of ataxia mice after PNI. Finally, we found a correlative decrease in human GRIA1 mRNA expression in the cerebellum of patients with ataxia-telangiectasia and spinocerebellar ataxia type 6 patient iPSC-derived Purkinje cells, pointing to the clinical relevance of glutamatergic system. By conducting a large-scale analysis of 9,655,320 patients with ataxia, they failed to recover from carpal tunnel decompression surgery and tibial neuropathy, while aged-match non-ataxia patients fully recovered. Our results provide insight into cerebellar disorders and motor deficits after PNI.

Targeting Axon Integrity to Prevent Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is an irreversible off-target adverse effect of many chemotherapeutic agents such as paclitaxel, yet its mechanism is poorly understood and no preventative measure is available. CIPN is characterized by peripheral nerve damages resulting in permanent sensory function deficits. Our recent unbiased genome-wide analysis revealed that heat shock protein (Hsp) 27 is part of a transcriptional network induced by axonal injury and highly enriched for genes involved in adaptive neuronal responses, particularly axonal regeneration. To examine if Hsp27 could prevent the occurrence of CIPN, we first demonstrated that paclitaxel-induced allodynia was associated directly with axonal degeneration in sensory neurons in a mouse model of CIPN. We therefore hypothesize that by preventing axonal degeneration could prevent the development of CIPN. We drove expression of human Hsp27 (hHsp27) specifically in neurons. Development of mechanical and thermal allodynia was prevented completely in paclitaxel-treated hHsp27 transgenic mice. Strikingly, hHsp27 protected against paclitaxel-induced neurotoxicity in vivo including degeneration of afferent nerve fibers, demyelination, mitochondrial swelling, apoptosis, and restored sensory nerve action potential. Finally, we delineated signaling cascades that link CIPN development to caspase 3 and RhoA/cofilin activation in sensory neurons and peripheral nerves. hHsp27 exerted anti-apoptotic effect and maintained axon integrity by restoring caspase 3 and RhoA expression to basal levels. Taken together, our data suggest that by preventing axonal degeneration might prove beneficial as anti-CIPN drugs, which represents an emerging research area for therapeutic development.

Author Correction: Commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma.

The originally published version of this Article contained an error in Figure 4. The bar chart in panel f was inadvertently replaced with a duplicate of the bar chart in panel e. This error has now corrected in both the PDF and HTML versions of the Article.

Commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma.

Glaucoma is the most prevalent neurodegenerative disease and a leading cause of blindness worldwide. The mechanisms causing glaucomatous neurodegeneration are not fully understood. Here we show, using mice deficient in T and/or B cells and adoptive cell transfer, that transient elevation of intraocular pressure (IOP) is sufficient to induce T-cell infiltration into the retina. This T-cell infiltration leads to a prolonged phase of retinal ganglion cell degeneration that persists after IOP returns to a normal level. Heat shock proteins (HSP) are identified as target antigens of T-cell responses in glaucomatous mice and human glaucoma patients. Furthermore, retina-infiltrating T cells cross-react with human and bacterial HSPs; mice raised in the absence of commensal microflora do not develop glaucomatous T-cell responses or the associated neurodegeneration. These results provide compelling evidence that glaucomatous neurodegeneration is mediated in part by T cells that are pre-sensitized by exposure to commensal microflora.

Recent Advances in the Study of Bipolar/Rod-Shaped Microglia and their Roles in Neurodegeneration.

Microglia are the resident immune cells of the central nervous system (CNS) and they contribute to primary inflammatory responses following CNS injuries. The morphology of microglia is closely associated with their functional activities. Most previous research efforts have attempted to delineate the role of ramified and amoeboid microglia in the pathogenesis of neurodegenerative diseases. In addition to ramified and amoeboid microglia, bipolar/rod-shaped microglia were first described by Franz Nissl in 1899 and their presence in the brain was closely associated with the pathology of infectious diseases and sleeping disorders. However, studies relating to bipolar/rod-shaped microglia are very limited, largely due to the lack of appropriate in vitro and in vivo experimental models. Recent studies have reported the formation of bipolar/rod-shaped microglia trains in in vivo models of CNS injury, including diffuse brain injury, focal transient ischemia, optic nerve transection and laser-induced ocular hypertension (OHT). These bipolar/rod-shaped microglia formed end-to-end alignments in close proximity to the adjacent injured axons, but they showed no interactions with blood vessels or other types of glial cell. Recent studies have also reported on a highly reproducible in vitro culture model system to enrich bipolar/rod-shaped microglia that acts as a powerful tool with which to characterize this form of microglia. The molecular aspects of bipolar/rod-shaped microglia are of great interest in the field of CNS repair. This review article focuses on studies relating to the morphology and transformation of microglia into the bipolar/rod-shaped form, along with the differential gene expression and spatial distribution of bipolar/rod-shaped microglia in normal and pathological CNSs. The spatial arrangement of bipolar/rod-shaped microglia is crucial in the reorganization and remodeling of neuronal and synaptic circuitry following CNS injuries. Finally, we discuss the potential neuroprotective roles of bipolar/rod-shaped microglia, and the possibility of transforming ramified/amoeboid microglia into bipolar/rod-shaped microglia. This will be of considerable clinical benefit in the development of novel therapeutic strategies for treating various neurodegenerative diseases and promoting CNS repair after injury.

Acute Exposure to Pacific Ciguatoxin Reduces Electroencephalogram Activity and Disrupts Neurotransmitter Metabolic Pathways in Motor Cortex.

Ciguatera fish poisoning (CFP) is a common human food poisoning caused by consumption of ciguatoxin (CTX)-contaminated fish affecting over 50,000 people worldwide each year. CTXs are classified depending on their origin from the Pacific (P-CTXs), Indian Ocean (I-CTXs), and Caribbean (C-CTXs). P-CTX-1 is the most toxic CTX known and the major source of CFP causing an array of neurological symptoms. Neurological symptoms in some CFP patients last for several months or years; however, the underlying electrophysiological properties of acute exposure to CTXs remain unknown. Here, we used CTX purified from ciguatera fish sourced in the Pacific Ocean (P-CTX-1). Delta and theta electroencephalography (EEG) activity was reduced remarkably in 2 h and returned to normal in 6 h after a single exposure. However, second exposure to P-CTX-1 induced not only a further reduction in EEG activities but also a 2-week delay in returning to baseline EEG values. Ciguatoxicity was detected in the brain hours after the first and second exposure by mouse neuroblastoma assay. The spontaneous firing rate of single motor cortex neuron was reduced significantly measured by single-unit recording with high spatial resolution. Expression profile study of neurotransmitters using targeted profiling approach based on liquid chromatography-tandem mass spectrometry revealed an imbalance between excitatory and inhibitory neurotransmitters in the motor cortex. Our study provides a possible link between the brain oscillations and neurotransmitter release after acute exposure to P-CTX-1. Identification of EEG signatures and major metabolic pathways affected by P-CTX-1 provides new insight into potential biomarker development and therapeutic interventions.

The association between laminin and microglial morphology in vitro.

Microglia are immune cells in the central nervous system (CNS) that contribute to primary innate immune responses. The morphology of microglia is closely associated with their functional activities. The majority of microglial studies have focused on the ramified or amoeboid morphology; however, bipolar/rod-shaped microglia have recently received much attention. Bipolar/rod-shaped microglia form trains with end-to-end alignment in injured brains and retinae, which is proposed as an important mechanism in CNS repair. We previously established a cell culture model system to enrich bipolar/rod-shaped microglia simply by growing primary microglia on scratched poly-D-lysine (PDL)/laminin-coated surfaces. Here, we investigated the role of laminin in morphological changes of microglia. Bipolar/rod-shaped microglia trains were transiently formed on scratched surfaces without PDL/laminin coating, but the microglia alignment disappeared after 3 days in culture. Amoeboid microglia digested the surrounding laminin, and the gene and protein expression of laminin-cleaving genes Adam9 and Ctss was up-regulated. Interestingly, lipopolysaccharide (LPS)-induced transformation from bipolar/rod-shaped into amoeboid microglia increased the expression of Adam9 and Ctss, and the expression of these genes in LPS-treated amoeboid-enriched cultures remained unchanged. These results indicate a strong association between laminin and morphological transformation of microglia, shedding new light on the role of bipolar/rod-shaped microglia in CNS repair.

Ciguatoxin reduces regenerative capacity of axotomized peripheral neurons and delays functional recovery in pre-exposed mice after peripheral nerve injury.

Ciguatera fish poisoning (CFP) results from consumption of tropical reef fish containing ciguatoxins (CTXs). Pacific (P)-CTX-1 is among the most potent known CTXs and the predominant source of CFP in the endemic region responsible for the majority of neurological symptoms in patients. Chronic and persistent neurological symptoms occur in some CFP patients, which often result in incomplete functional recovery for years. However, the direct effects of exposure to CTXs remain largely unknown. In present study, we exposed mice to CTX purified from ciguatera fish sourced from the Pacific region. P-CTX-1 was detected in peripheral nerves within hours and persisted for two months after exposure. P-CTX-1 inhibited axonal regrowth from axotomized peripheral neurons in culture. P-CTX-1 exposure reduced motor function in mice within the first two weeks of exposure before returning to baseline levels. These pre-exposed animals exhibited delayed sensory and motor functional recovery, and irreversible motor deficits after peripheral nerve injury in which formation of functional synapses was impaired. These findings are consistent with reduced muscle function, as assessed by electromyography recordings. Our study provides strong evidence that the persistence of P-CTX-1 in peripheral nerves reduces the intrinsic growth capacity of peripheral neurons, resulting in delayed functional recovery after injury.

Pleiotropic molecules in axon regeneration and neuroinflammation.

Neuroinflammation is the foremost defense reaction of the nervous system to most if not all insults. Injuries to the central and peripheral nervous system (CNS and PNS) are followed by immediate activation of innate immune cells and infiltration of peripheral immune cells, amid waves of upregulation of numerous inflammatory mediators. Prolonged inflammation can lead to secondary tissue damage and prohibit regeneration of the injured nervous system. The regulation of inflammation and neuroregeneration are orchestrated through a complex network of signal transduction. Interestingly, many molecules play pleiotropic roles in both processes. Growing evidence implicates a handful of axon regeneration regulators in the processes of neuroinflammation, among which are the myelin and glial scar associated axon growth inhibitors and their axonal receptors. In this article, we will review the roles of these canonical axon regeneration regulators in neuroinflammation.

A lysosome-specific two-photon phosphorescent binuclear cyclometalated platinum(II) probe for in vivo imaging of live neurons.

Real-time tracking of fast axonal transport of acidic vesicles in live adult mouse dorsal root ganglion (DRG) and cortical neurons in brain slices was visualized by the use of binuclear cycloplatinated complexes, {[Pt(L1)]2(µ-dppm)}(2+) (1) and {[Pt(L2)]2(µ-dppm)}(2+) (2), as lysosome-specific two-photon imaging probes.