Nanoscale water-polymer interactions tune macroscopic diffusivity of water in aqueous poly(ethylene oxide) solutions.

The separation and anti-fouling performance of water purification membranes is governed by both macroscopic and molecular-scale water properties near polymer surfaces. However, even for poly(ethylene oxide) (PEO) - ubiquitously used in membrane materials - there is little understanding of whether or how the molecular structure of water near PEO surfaces affects macroscopic water diffusion. Here, we probe both time-averaged bulk and local water dynamics in dilute and concentrated PEO solutions using a unique combination of experimental and simulation tools. Pulsed-Field Gradient NMR and Overhauser Dynamic Nuclear Polarization (ODNP) capture water dynamics across micrometer length scales in sub-seconds to sub-nanometers in tens of picoseconds, respectively. We find that classical models, such as the Stokes-Einstein and Mackie-Meares relations, cannot capture water diffusion across a wide range of PEO concentrations, but that free volume theory can. Our study shows that PEO concentration affects macroscopic water diffusion by enhancing the water structure and altering free volume. ODNP experiments reveal that water diffusivity near PEO is slower than in the bulk in dilute solutions, previously not recognized by macroscopic transport measurements, but the two populations converge above the polymer overlap concentration. Molecular dynamics simulations reveal that the reduction in water diffusivity occurs with enhanced tetrahedral structuring near PEO. Broadly, we find that PEO does not simply behave like a physical obstruction but directly modifies water's structural and dynamic properties. Thus, even in simple PEO solutions, molecular scale structuring and the impact of polymer interfaces is essential to capturing water diffusion, an observation with important implications for water transport through structurally complex membrane materials.

Design of Polymeric Zwitterionic Solid Electrolytes with Superionic Lithium Transport.

Progress toward durable and energy-dense lithium-ion batteries has been hindered by instabilities at electrolyte-electrode interfaces, leading to poor cycling stability, and by safety concerns associated with energy-dense lithium metal anodes. Solid polymeric electrolytes (SPEs) can help mitigate these issues; however, the SPE conductivity is limited by sluggish polymer segmental dynamics. We overcome this limitation via zwitterionic SPEs that self-assemble into superionically conductive domains, permitting decoupling of ion motion and polymer segmental rearrangement. Although crystalline domains are conventionally detrimental to ion conduction in SPEs, we demonstrate that semicrystalline polymer electrolytes with labile ion-ion interactions and tailored ion sizes exhibit excellent lithium conductivity (1.6 mS/cm) and selectivity (t + ≈ 0.6-0.8). This new design paradigm for SPEs allows for simultaneous optimization of previously orthogonal properties, including conductivity, Li selectivity, mechanics, and processability.

Stacking Faults Assist Lithium-Ion Conduction in a Halide-Based Superionic Conductor.

In the pursuit of urgently needed, energy dense solid-state batteries for electric vehicle and portable electronics applications, halide solid electrolytes offer a promising path forward with exceptional compatibility against high-voltage oxide electrodes, tunable ionic conductivities, and facile processing. For this family of compounds, synthesis protocols strongly affect cation site disorder and modulate Li+ mobility. In this work, we reveal the presence of a high concentration of stacking faults in the superionic conductor Li3YCl6 and demonstrate a method of controlling its Li+ conductivity by tuning the defect concentration with synthesis and heat treatments at select temperatures. Leveraging complementary insights from variable temperature synchrotron X-ray diffraction, neutron diffraction, cryogenic transmission electron microscopy, solid-state nuclear magnetic resonance, density functional theory, and electrochemical impedance spectroscopy, we identify the nature of planar defects and the role of nonstoichiometry in lowering Li+ migration barriers and increasing Li site connectivity in mechanochemically synthesized Li3YCl6. We harness paramagnetic relaxation enhancement to enable 89Y solid-state NMR and directly contrast the Y cation site disorder resulting from different preparation methods, demonstrating a potent tool for other researchers studying Y-containing compositions. With heat treatments at temperatures as low as 333 K (60 °C), we decrease the concentration of planar defects, demonstrating a simple method for tuning the Li+ conductivity. Findings from this work are expected to be generalizable to other halide solid electrolyte candidates and provide an improved understanding of defect-enabled Li+ conduction in this class of Li-ion conductors.

A stable cathode-solid electrolyte composite for high-voltage, long-cycle-life solid-state sodium-ion batteries.

Rechargeable solid-state sodium-ion batteries (SSSBs) hold great promise for safer and more energy-dense energy storage. However, the poor electrochemical stability between current sulfide-based solid electrolytes and high-voltage oxide cathodes has limited their long-term cycling performance and practicality. Here, we report the discovery of the ion conductor Na3-xY1-xZrxCl6 (NYZC) that is both electrochemically stable (up to 3.8 V vs. Na/Na+) and chemically compatible with oxide cathodes. Its high ionic conductivity of 6.6 × 10-5 S cm-1 at ambient temperature, several orders of magnitude higher than oxide coatings, is attributed to abundant Na vacancies and cooperative MCl6 rotation, resulting in an extremely low interfacial impedance. A SSSB comprising a NaCrO2 + NYZC composite cathode, Na3PS4 electrolyte, and Na-Sn anode exhibits an exceptional first-cycle Coulombic efficiency of 97.1% at room temperature and can cycle over 1000 cycles with 89.3% capacity retention at 40 °C. These findings highlight the immense potential of halides for SSSB applications.

Glass Transition Temperature and Ion Binding Determine Conductivity and Lithium-Ion Transport in Polymer Electrolytes.

Polymer electrolytes with high Li+-ion conductivity provide a route toward improved safety and performance of Li+-ion batteries. However, most polymer electrolytes suffer from low ionic conduction and an even lower Li+-ion contribution to the conductivity (the transport number, t+), with the anion typically transporting over 80% of the charge. Here, we show that subtle and potentially undetected associations within a polymer electrolyte can entrain both the anion and the cation. When removed, the conductivity performance of the electrolyte can be improved by almost 2 orders of magnitude. Importantly, while some of this improvement can be attributed to a decreased glass transition temperature, Tg, the removal of the amide functional group reduces interactions between the polymer and the Li+ cations, doubling the Li+ t+ to 0.43, as measured using pulsed-field-gradient NMR. This work highlights the importance of strategic synthetic design and emphasizes the dual role of Tg and ion binding for the development of polymer electrolytes with increased total ionic conductivity and the Li+ ion contribution to it.

The Detection and Reactivity of Silanols and Silanes Using Hyperpolarized 29 Si Nuclear Magnetic Resonance.

Silanols and silanes are key precursors and intermediates for the synthesis of silicon-based materials. While their characterization and quantification by 29 Si NMR spectroscopy has received significant attention, it is a technique that is limited by the low natural abundance of 29 Si and its low sensitivity. Here, we describe a method using p-H2 to hyperpolarize 29 Si. The observed signal enhancements, approaching 3000-fold at 11.7 T, would take many days of measurement for comparable results under Boltzmann conditions. The resulting signals were exploited to monitor the rapid reaction of tris(tert-butoxy)silanol with triflic anhydride in a T1 -corrected process that allows for rapid quantification. These results demonstrate a novel route to quantify dynamic processes and intermediates in the synthesis of silicon materials.

Understanding substrate substituent effects to improve catalytic efficiency in the SABRE hyperpolarisation process.

The use of parahydrogen based hyperpolarisation in NMR is becoming more widespread due to the rapidly expanding range of suitable target molecules and low-cost of parahydrogen production. Hyperpolarisation via SABRE catalysis employs a metal complex to transfer polarisation from parahydrogen into a substrate whilst they are bound. In this paper we present a quantitative study of substrate-iridium ligation effects by reference to the substrates 4-chloropyridine (A), 4-pyridinecarboxaldehyde methyl hemiacetal (B), 4-methylpyridine (C) and 4-methoxypyridine (D), and evaluate the role they play in the SABRE catalysis. Substrates whose substituents enable stronger associations yield slower substrate dissociation rates (k d). A series of variable temperature studies link these exchange rates to optimal SABRE performance and reveal the critical impact of NMR relaxation times (T 1). Longer catalyst residence times are shown to result in shorter substrate T 1 values in solution as binding to iridium promotes relaxation thereby not only reducing SABRE efficiency but decreasing the overall level of achieved hyperpolarisation. Based on these data, a route to achieve more optimal SABRE performance is defined.

In Situ SABRE Hyperpolarization with Earth's Field NMR Detection.

Hyperpolarization methods, which increase the sensitivity of nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI), have the potential to expand the range of applications of these powerful analytical techniques and to enable the use of smaller and cheaper devices. The signal amplification by reversible exchange (SABRE) method is of particular interest because it is relatively low-cost, straight-forward to implement, produces high-levels of renewable signal enhancement, and can be interfaced with low-cost and portable NMR detectors. In this work, we demonstrate an in situ approach to SABRE hyperpolarization that can be achieved using a simple, commercially-available Earth's field NMR detector to provide 1H polarization levels of up to 3.3%. This corresponds to a signal enhancement over the Earth's magnetic field by a factor of ε > 2 × 108. The key benefit of our approach is that it can be used to directly probe the polarization transfer process at the heart of the SABRE technique. In particular, we demonstrate the use of in situ hyperpolarization to observe the activation of the SABRE catalyst, the build-up of signal in the polarization transfer field (PTF), the dependence of the hyperpolarization level on the strength of the PTF, and the rate of decay of the hyperpolarization in the ultra-low-field regime.

Reaction Monitoring Using SABRE-Hyperpolarized Benchtop (1 T) NMR Spectroscopy.

The conversion of [IrCl(COD)(IMes)] (COD = cis, cis-1,5-cyclooctadiene, IMes = 1,3-bis(2,4,6-trimethyl-phenyl)imidazole-2-ylidene) in the presence of an excess of para-hydrogen ( p-H2) and a substrate (4-aminopyridine (4-AP) or 4-methylpyridine (4-MP)) into [Ir(H)2(IMes)(substrate)3]Cl is monitored by 1H NMR spectroscopy using a benchtop (1 T) spectrometer in conjunction with the p-H2-based hyperpolarization technique signal amplification by reversible exchange (SABRE). A series of single-shot 1H NMR measurements are used to monitor the chemical changes that take place in solution through the lifetime of the hyperpolarized response. Non-hyperpolarized high-field 1H NMR control measurements were also undertaken to confirm that the observed time-dependent changes relate directly to the underlying chemical evolution. The formation of [Ir(H)2(IMes)(substrate)3]Cl is further linked to the hydrogen isotope exchange (HIE) reaction, which leads to the incorporation of deuterium into the ortho positions of 4-AP, where the source of deuterium is the solvent, methanol- d4. Comparable reaction monitoring results are achieved at both high-field (9.4 T) and low-field (1 T). It is notable that the low sensitivity of the benchtop (1 T) NMR enables the use of protio solvents, which when used here allows the effects of catalyst formation and substrate deuteration to be separated. Collectively, these methods illustrate how low-cost low-field NMR measurements provide unique insight into a complex catalytic process through a combination of hyperpolarization and relaxation data.

Rapid 13C NMR hyperpolarization delivered from para-hydrogen enables the low concentration detection and quantification of sugars.

Monosaccharides, such as glucose and fructose, are important to life. In this work we highlight how the rapid delivery of improved 13C detectability for sugars by nuclear magnetic resonance (NMR) can be achieved using the para-hydrogen based NMR hyperpolarization method SABRE-Relay (Signal Amplification by Reversible Exchange-Relay). The significant 13C signal enhancements of 250 at a high field of 9.4 T, and 3100 at a low field of 1 T, enable the detection of trace amounts of these materials as well as the quantification of their tautomeric makeup. Using studies on 13C and 2H isotopically labelled agents we demonstrate how hyperpolarization lifetime (T 1) values can be extended, and how singlet states with long lifetimes can be created. The precise quantification of d-glucose-13C6-d 7 at the millimolar concentration level is shown to be possible within minutes in conjunction with a linear hyperpolarized response as a function of concentration. In addition to the measurements using labelled materials, low concentration detection is also illustrated for millimolar samples with natural abundance 13C where isomeric form quantification can be achieved with a single transient.

Quantitative In Situ Monitoring of Parahydrogen Fraction Using Raman Spectroscopy.

Raman spectroscopy has been used to provide a rapid, noninvasive, and nondestructive quantification method for determining the parahydrogen fraction of hydrogen gas. The basis of the method is the measurement of the ratio of the first two rotational bands of hydrogen at 355 cm-1 and 586 cm-1 corresponding to parahydrogen and orthohydrogen, respectively. The method has been used to determine the parahydrogen content during a production process and a reaction. In the first example, the performance of an in-house liquid nitrogen cooled parahydrogen generator was monitored both at-line and on-line. The Raman measurements showed that it took several hours for the generator to reach steady state and, hence, for maximum parahydrogen production (50%) to be reached. The results obtained using Raman spectroscopy were compared to those obtained by at-line low-field nuclear magnetic resonance (NMR) spectroscopy. While the results were in good agreement, Raman analysis has several advantages over NMR for this application. The Raman method does not require a reference sample, as both spin isomers (ortho and para) of hydrogen can be directly detected, which simplifies the procedure and eliminates some sources of error. In the second example, the method was used to monitor the fast conversion of parahydrogen to orthohydrogen in situ. Here the ability to acquire Raman spectra every 30 s enabled a conversion process with a rate constant of 27.4×10-4 s-1 to be monitored. The Raman method described here represents an improvement on previously reported work, in that it can be easily applied on-line and is approximately 500 times faster. This offers the potential of an industrially compatible method for determining parahydrogen content in applications that require the storage and usage of hydrogen.

Quantification of hyperpolarisation efficiency in SABRE and SABRE-Relay enhanced NMR spectroscopy.

para-Hydrogen (p-H2) induced polarisation (PHIP) is an increasingly popular method for sensitivity enhancement in NMR spectroscopy. Its growing popularity is due in part to the introduction of the signal amplification by reversible exchange (SABRE) method that generates renewable hyperpolarisation in target analytes in seconds. A key benefit of PHIP and SABRE is that p-H2 can be relatively easily and cheaply produced, with costs increasing with the desired level of p-H2 purity. In this work, the efficiency of the SABRE polarisation transfer is explored by measuring the level of analyte hyperpolarisation as a function of the level of p-H2 enrichment. A linear relationship was found between p-H2 enrichment and analyte 1H hyperpolarisation for a range of molecules, polarisation transfer catalysts, NMR detection fields and for both the SABRE and SABRE-Relay transfer mechanisms over the range 29-99% p-H2 purity. The gradient of these linear relationships were related to a simple theoretical model to define an overall efficiency parameter, E, that quantifies the net fraction of the available p-H2 polarisation that is transferred to the target analyte. We find that the efficiency of SABRE is independent of the NMR detection field and exceeds E = 20% for methyl-4,6-d2-nicotinate when using a previously optimised catalyst system. For the SABRE-Relay transfer mechanism, efficiencies of up to E = 1% were found for 1H polarisation of 1-propanol, when ammonia was used as the polarisation carrier.

SABRE hyperpolarization enables high-sensitivity 1H and 13C benchtop NMR spectroscopy.

Benchtop NMR spectrometers operating with low magnetic fields of 1-2 T at sub-ppm resolution show great promise as analytical platforms that can be used outside the traditional laboratory environment for industrial process monitoring. One current limitation that reduces the uptake of benchtop NMR is associated with the detection fields' reduced sensitivity. Here we demonstrate how para-hydrogen (p-H2) based signal amplification by reversible exchange (SABRE), a simple to achieve hyperpolarization technique, enhances agent detectability within the environment of a benchtop (1 T) NMR spectrometer so that informative 1H and 13C NMR spectra can be readily recorded for low-concentration analytes. SABRE-derived 1H NMR signal enhancements of up to 17 000-fold, corresponding to 1H polarization levels of P = 5.9%, were achieved for 26 mM pyridine in d4-methanol in a matter of seconds. Comparable enhancement levels can be achieved in both deuterated and protio solvents but now the SABRE-enhanced analyte signals dominate due to the comparatively weak thermally-polarized solvent response. The SABRE approach also enables the acquisition of 13C NMR spectra of analytes at natural isotopic abundance in a single scan as evidenced by hyperpolarized 13C NMR spectra of tens of millimolar concentrations of 4-methylpyridine. Now the associated signal enhancement factors are up to 45 500 fold (P = 4.0%) and achieved in just 15 s. Integration of an automated SABRE polarization system with the benchtop NMR spectrometer framework produces renewable and reproducible NMR signal enhancements that can be exploited for the collection of multi-dimensional NMR spectra, exemplified here by a SABRE-enhanced 2D COSY NMR spectrum.

A simple hand-held magnet array for efficient and reproducible SABRE hyperpolarisation using manual sample shaking.

Signal amplification by reversible exchange (SABRE) is a hyperpolarisation technique that catalytically transfers nuclear polarisation from parahydrogen, the singlet nuclear isomer of H2 , to a substrate in solution. The SABRE exchange reaction is carried out in a polarisation transfer field (PTF) of tens of gauss before transfer to a stronger magnetic field for nuclear magnetic resonance (NMR) detection. In the simplest implementation, polarisation transfer is achieved by shaking the sample in the stray field of a superconducting NMR magnet. Although convenient, this method suffers from limited reproducibility and cannot be used with NMR spectrometers that do not have appreciable stray fields, such as benchtop instruments. Here, we use a simple hand-held permanent magnet array to provide the necessary PTF during sample shaking. We find that the use of this array provides a 25% increase in SABRE enhancement over the stray field approach, while also providing improved reproducibility. Arrays with a range of PTFs were tested, and the PTF-dependent SABRE enhancements were found to be in excellent agreement with comparable experiments carried out using an automated flow system where an electromagnet is used to generate the PTF. We anticipate that this approach will improve the efficiency and reproducibility of SABRE experiments carried out using manual shaking and will be particularly useful for benchtop NMR, where a suitable stray field is not readily accessible. The ability to construct arrays with a range of PTFs will also enable the rapid optimisation of SABRE enhancement as function of PTF for new substrate and catalyst systems.

Intraneural Injection of ATP Stimulates Regeneration of Primary Sensory Axons in the Spinal Cord.

Injury to the peripheral axons of sensory neurons strongly enhances the regeneration of their central axons in the spinal cord. It remains unclear on what molecules that initiate such conditioning effect. Because ATP is released extracellularly by nerve and other tissue injury, we hypothesize that injection of ATP into a peripheral nerve might mimic the stimulatory effect of nerve injury on the regenerative state of the primary sensory neurons. We found that a single injection of 6 µl of 150 µm ATP into female rat sciatic nerve quadrupled the number of axons growing into a lesion epicenter in spinal cord after a concomitant dorsal column transection. A second boost ATP injection 1 week after the first one markedly reinforced the stimulatory effect of a single injection. Single ATP injection increased expression of phospho-STAT3 and GAP43, two markers of regenerative activity, in sensory neurons. Double ATP injections sustained the activation of phospho-STAT3 and GAP43, which may account for the marked axonal growth across the lesion epicenter. Similar studies performed on P2X7 or P2Y2 receptor knock-out mice indicate P2Y2 receptors are involved in the activation of STAT3 after ATP injection or conditioning lesion, whereas P2X7 receptors are not. Injection of ATP at 150 µm caused little Wallerian degeneration and behavioral tests showed no significant long-term adverse effects on sciatic nerve functions. The results in this study reveal possible mechanisms underlying the stimulation of regenerative programs and suggest a practical strategy for stimulating axonal regeneration following spinal cord injury.SIGNIFICANCE STATEMENT Injury of peripheral axons of sensory neurons has been known to strongly enhance the regeneration of their central axons in the spinal cord. In this study, we found that injection of ATP into a peripheral nerve can mimic the effect of peripheral nerve injury and significantly increase the number of sensory axons growing across lesion epicenter in the spinal cord. ATP injection increased expression of several markers for regenerative activity in sensory neurons, including phospho-STAT3 and GAP43. ATP injection did not cause significant long-term adverse effects on the functions of the injected nerve. These results may lead to clinically applicable strategies for enhancing neuronal responses that support regeneration of injured axons.

Promoting survival, migration, and integration of transplanted Schwann cells by over-expressing polysialic acid.

The poor survival and migration of transplanted Schwann cells (SCs) are major drawbacks for their clinical application in cell therapy for neurotrauma. To overcome such drawbacks we genetically modified SCs to over-express polysialic acid (PSA) by lentiviral delivery of polysialyltransferase (PST) to study whether over-expression of PSA could enhance their survival, migration, and integration when transplanted into the spinal cord. It was found that more PSA-expressing SCs (PST/SCs) survived than GFP-expressing SCs (GFP/SCs) after transplantation, although cell loss was still quite significant. PSA expression did not enhance the motility of transplanted SCs in uninjured spinal cord. However, in a spinal cord crush injury model PST/SCs transplanted caudal to the lesion showed that increased number of PST/SCs migrated to the injury site compared with that of GFP/SCs. Induced expression of PSA in spinal cord can further facilitate the infiltration of PST/SCs into the lesion site. PST/SCs were also shown to intermingle well with host spinal cells while GFP/SCs formed boundaries with host tissue. This was confirmed by an in vitro confrontation assay showing that more PST/SCs crossed over to astrocyte territory than GFP/SCs. Furthermore, PST/SCs induced much less expression of glial fibrillary acidic protein and chondroitin sulfate proteoglycan in the surrounding tissues than GFP/SCs, indicating that expression of PSA on SCs do not cause significant stress response of astrocytes. These results demonstrate that expression of PSA on SCs significantly changes their biological properties and makes them more feasible for neural repair after neurotrauma.

Responses of the nerve cell body to axotomy.

OBJECTIVE: Peripheral nerve injury causes retrograde changes in the damaged neurons, which are beneficial to axonal regeneration. Better understanding of the mechanisms of induction and mediation of these conditioning responses would help to design strategies to invoke stronger regenerative responses in neurons in situations when these responses are inadequate. METHODS: Relevant literature is reviewed. RESULTS: Experimental preparations that measure the influence of peripheral axotomy on regeneration in the central axons of primary sensory neurons are useful to examine mechanisms of conditioning neurons. Despite 4 decades of speculation, the nature of the damage signals from injured nerves that initiate axonal signals to the nerve cell body remains elusive. Members of the family of neuropoietic cytokines are clearly implicated, but what induces them is unknown. Multiple changes in gene regulation in axotomized neurons have been described, and dozens of growth-associated genes have been identified: neurotrophic factors, transcription factors, molecules participating in axonal transport, and molecules active in the growth cone. The mechanisms of interaction of a few regeneration-associated molecules with the signaling cascades that lead to actin and tubulin remodeling at the growth cone are understood in some detail. In animals, viral gene therapy to deliver regeneration-associated genes to neurons or other local measures to induce these genes can improve regeneration. A few pharmacological agents, administered systemically, have small beneficial effects on axonal regeneration. CONCLUSION: Advances in laboratory research have provided knowledge of cell body responses to axotomy with clinical relevance.

Targeting a dominant negative rho kinase to neurons promotes axonal outgrowth and partial functional recovery after rat rubrospinal tract lesion.

Many axonal growth inhibitors that contribute to the usual failure of axon regeneration in the central nervous system (CNS) exert their effects via the RhoA-Rho kinase (ROCK) signal pathway. In this study, we investigated whether lentiviral vector (LV)-mediated neuron-specific expression of a dominant negative mutant of ROCK (DNROCK) could promote axon outgrowth in vitro and in vivo. Dissociated adult rat dorsal root ganglion (DRG) neurons were seeded on solubilized myelin proteins and transduced with either LV/DNROCK or LV/green fluorescent protein (GFP). DNROCK-expressing neurons were shown to have a greater chance of generating neurites and a longer mean length of neurite than GFP-expressing neurons. In the in vivo studies, lentiviruses were injected into the adult rat red nucleus followed by unilateral rubrospinal tract (RST) transection at the fourth cervical level. Rats in the DNROCK group showed better functional recovery in the affected hindlimbs and forelimbs than those in the GFP group. Examination of the spinal cord sections revealed more rubrospinal axonal profiles growing to the spinal cord caudal to the lesion in the DNROCK group than in the GFP group. These results indicate that blocking the RhoA-ROCK signal pathway by expressing DNROCK can enhance regenerative axonal sprouting and lead to partial recovery of limb function.

Observations on the function of nuclear factor kappa B (NF-kappaB) in the survival of adult primary sensory neurons after nerve injury.

Peripheral nerve transections cause much more neuronal death in embryonic and neonatal dorsal root ganglia (DRG) than in adult DRG. Here we used transgenic approaches to examine the hypothesis that NF-kappaB is an important intrinsic factor of adult DRG neurons for their in vivo capacity to survive after nerve injury. We generated transgenic mice expressing the NF-kappaB super-inhibitor (IkappaBalpha-SI), a multi-mutant form of IkappaBalpha, specifically in adult neurons. Adult DRG neurons in these transgenic animals are not abnormally susceptible to apoptosis after peripheral nerve injury, although there is a significant inhibition in the ability of NF-kappaB to translocate into their nucleus. We investigated the observed lack of NF-kappaB neuroprotective function at the level of NF-kappaB transcriptional activity using transgenic NF-kappaB/LacZ reporter mice. We show that the expression of the NF-kappaB reporter transgene is restricted in naïve and injured DRG neurons. However, NF-kappaB transcriptional activity in adult DRG neurons is evident upon exposure to Trichostatin A (TSA) which is a specific inhibitor of histone deacetylases. Taken together our results illustrate that the functions of NF-kappaB are limited in adult primary sensory neurons due to a transcriptional repression mechanism mediated by histone deacetylases, and that intrinsic neuroprotective factors other than NF-kappaB are responsible for the resistance of adult DRG neurons to apoptosis in response to nerve injury.

Cell adhesion molecules of the immunoglobulin superfamily in axonal regeneration and neural repair.

Cell adhesion molecules (CAMs) play important roles in cell-cell and cell-extracellular matrix interactions in both mature and developing nervous system. During development, they are involved in cell migration, axon guidance, target recognition, and synapse formation; while in the mature nervous system, they maintain synaptic connections, cell-cell contacts, and neuron-glial interactions. Injuries to the nervous systems break the stable state of the tissues and the repair of damaged tissues and regeneration of axons require the participation of CAMs both as adhesion molecules and as signal transduction molecules. One group of the well-studied CAMs in the nervous system is the immunoglobulin superfamily including L1 and neural cell adhesion molecule (NCAM). This review will be focussed on the involvement of L1, NCAM, and polysialylated NCAM in neural repair and axon regeneration after nerve injury and their potential applications in the treatment of CNS injury.