Functional recovery is the final goal in the treatment of spinal cord injury. However, to date, few treatment strategies have demonstrated significant locomotor improvement in animal experiments. By using tail nerve electrical stimulation (TANES) as an open-field locomotor training method combined with glial scar ablation and cell transplantation, we have successfully promoted locomotor recovery in rats with chronic spinal cord contusion injury. The purpose of the present study is to further investigate the mechanism of TANES and its effect on electrophysiology. Spinal cord segment T10 of female, adult Long-Evans rats was contused using the NYU impactor device with 25 mm height setting. After injury, rats were randomly divided into three groups. Group I was used as a control without any treatment, group II and group III were subjected to basic treatment including glial scar ablation and transplantation of olfactory lamina propria 6 weeks after injury, and group III received TANES-induced open-field locomotor training weekly after basic treatment. All animals were allowed to survive 22 weeks, except some rats which were transected. Basso, Beattie, and Bresnahan (BBB) open-field locomotor rating scale, horizontal ladder rung walking test, and electrophysiological tests were used to assess the restoration of functional behavior and conduction. Results showed that TANES significantly improves locomotor recovery and spinal cord conduction, reflex, as well as significantly reduces the occurrence of autophagia. Additionally, after transection, trained rats still maintained higher BBB score than that of control rats. This may be related to the activity-dependent plasticity promoted by TANES-induced locomotor training.

Schwann cells are glial cells of peripheral nervous system, responsible for axonal myelination and ensheathing, as well as tissue repair following a peripheral nervous system injury. They are one of several cell types that are widely studied and most commonly used for cell transplantation to treat spinal cord injury, due to their intrinsic characteristics including the ability to secrete a variety of neurotrophic factors. This mini review summarizes the recent findings of endogenous Schwann cells after spinal cord injury and discusses their role in tissue repair and axonal regeneration. After spinal cord injury, numerous endogenous Schwann cells migrate into the lesion site from the nerve roots, involving in the construction of newly formed repaired tissue and axonal myelination. These invading Schwann cells also can move a long distance away from the injury site both rostrally and caudally. In addition, Schwann cells can be induced to migrate by minimal insults (such as scar ablation) within the spinal cord and integrate with astrocytes under certain circumstances. More importantly, the host Schwann cells can be induced to migrate into spinal cord by transplantation of different cell types, such as exogenous Schwann cells, olfactory ensheathing cells, and bone marrow-derived stromal stem cells. Migration of endogenous Schwann cells following spinal cord injury is a common natural phenomenon found both in animal and human, and the myelination by Schwann cells has been examined effective in signal conduction electrophysiologically. Therefore, if the inherent properties of endogenous Schwann cells could be developed and utilized, it would offer a new avenue for the restoration of injured spinal cord.

To date, few treatment strategies applying cellular transplantation to the chronically injured spinal cord have yielded significant functional improvement in animal experiments. Here we report that significant improvement of locomotor function was achieved in rats with chronic spinal cord injury (SCI) by the application of combination treatments with tail nerve electrical stimulation (TANES), which can activate the central pattern generator, inducing active weight-supported stepping. Contusion injury (25 mm) to spinal cord T10 was produced by using the NYU impactor device in female, adult Long-Evans rats. Rats in 2 of 4 groups with SCI received basic treatments (scar ablation followed by transplantation of lamina propria of olfactory mucosa and cultured olfactory ensheathing cells into the lesion cavity) 6 weeks after SCI. Rats both with and without basic treatments were subjected to TANES one week after secondary surgery or 7 weeks after SCI. Sixteen weeks after secondary surgery or 22 weeks after SCI rats in two groups receiving TANES significantly improved their functional recovery compared with those without TANES, when evaluated with BBB open field rating scale (p<0.01). Among them, however, rats with basic treatments performed better than those without basic treatments. TANES may contribute to the activity-dependent plasticity below the injury level, which is critical for functional recovery. Additionally, TANES may promote axonal regeneration, including those from supraspinal level. Since TANES demonstrated considerable potential for achieving improvement of functional recovery in rat model, it would suggest a new strategy for chronic SCI.

Somatosensory evoked potentials (SSEPs) are a sensitive quantitative measure of conduction in somatosensory pathways of the central nervous system and are increasingly used in both clinical trials and animal experiments. SSEPs can be recorded in non-sedated rodents by magnetic stimulation (MS) of peripheral nerves. To overcome some disadvantages caused by using anesthesia and implanted recording electrodes, we used subdermal needle electrodes located on the midline of the skull to successfully record SSEPs in non-sedated rats, elicited by stimulating the tibial nerve with a magnetic stimulator. The wave form contains a typical P1 peak and N1 peak. Although there is a variation of P1 latency, N1 latency, and P1-N1 amplitude between right side and left side, it was not statistically significant. In addition, there is a significantly positive relationship between P1-N1 amplitude and MS strength, suggesting that the increase in magnetic stimulating strength resulted in the increase in P1-N1 amplitude. Results in the present study demonstrate that our modified method is a reliable and feasible paradigm for recording SSEPs in non-sedated rats. (C) 2012 Elsevier B.V. All rights reserved.

We have successfully removed an existing glial scar in chronically contused rat spinal cord using a rose Bengal-based phototoxic method. The purpose of this study is to examine if scar ablation benefits the anatomical recovery by cell/tissue transplantation, and thus provides a more permissive physical and biochemical environment for axonal growth, which may lead to functional recovery. Immediately after scar ablation, we transplanted lamina propria (LP) of the olfactory mucosa alone or in combination with cultured olfactory ensheathing cells (OEC) into the lesion cavity 6weeks after contusion injury (NYU impactor device, 25mm height setting) at spinal cord segment T10 of adult female Long–Evans rats. Sixteen weeks after scar ablation and transplantation, we found that the initial repaired tissue significantly expanded, companied by remarkable reduction or disappearance of the lesion cavity and integration of repaired tissue with the spared tissue, thus resulting in histological repair of damaged cord tissue at the injury epicenter. Glial scar reformation was effectively prevented after ablation due to the tissue repair. In addition, at the injury epicenter P0 (myelin glycoprotein P-zero)-positive myelination formed by Schwann cells, which are known to myelinate regenerating and demyelinated axons, were significantly increased in number compared with the control animals. However, when evaluated with BBB open-field scale a significant improvement of locomotor function was not observed in this study; the possible reasons were discussed.

The spinal cord has an intrinsic, limited ability of spontaneous repair; the endogenous repair of damaged tissue starts a few days after spinal cord injury (SCI). To date, however, detailed observation in histology at the injury site has not been well documented. In the present study we analyzed the histological structure of the repaired tissue from injury site of rats 6 or 14 weeks after contusion injury (NYU impactor device, 25 mm height setting) on T10, and rats 8 weeks after transplantation of lamina propria (LP) or acellular lamina propria. We found that the initial repaired tissue can be histologically divided into three different zones, i.e., fibrotic, cellular and axonal. The fibrotic zone consists of invading connective tissue, while the cellular zone is composed of invading, densely compacted Schwann cells. Schwann cells migrate from dorsal roots laterally toward and merge underneath the fibrotic zone, forming the U-shape shell of the cellular zone. The major component of the axonal zone is regenerating axons. Schwann cells myelinate regenerating axons in all three zones. In rats with combination treatments including scar ablation and LP transplantation, both cellular and axonal zones significantly expand in size, resulting in the disappearance of the lesion cavity and the integration of repaired tissue with spared tissue. Olfactory ensheathing cells from transplanted LP may promote the expansion of the cellular and axonal zones through stimulating host Schwann cells, indirectly contributing to tissue repair and axonal regeneration. The ependyma-derived cells may be directly involved in tissue repair, but not contribute to the formation of myelin sheaths.

Intrathecal infusion has been widely used to directly deliver drugs or neurotrophins to a lesion site following spinal cord injury. Evidence shows that intrathecal infusion is efficient for 7 days but is markedly reduced after 14 days, due to time dependent occlusion. In addition, extensive fibrotic scarring is commonly observed with intrathecal infusion. These anomalies need to be clearly elucidated in histology. In the present study, all adult Long-Evans rats received a 25 mm contusion injury on spinal cord T10 produced using the NYU impactor device. Immediately after injury, catheter tubing with an outer diameter of 0.38 mm was inserted through a small dural opening at L3 into the subdural space with the tubing tip positioned near the injury site. The tubing was connected to an Alzet mini pump, which was filled with saline solution and was placed subcutaneously. Injured rats without tubing served as control. Rats were behaviorally tested for 6 weeks using the BBB locomotor rating scale and histologically assessed for tissue scarring. Six weeks later, we found that the intrathecal tubing caused extensive scarring and inflammation, related to neutrophils, macrophages and plasma cells. The tubing's tip was occluded by scar tissue and inflammatory cells. The scar tissue surrounding the tubing consists of 20-70 layers of fibroblasts and densely compacted collagen fibers, seriously compressing and damaging the cord tissue. BBB scores of rats with intrathecal tubing were significantly lower than control rats (p<0.01) from 2 weeks after injury, implying serious impairment of functional recovery caused by the scarring.

Walking or stepping has been considered the result from the activation of the central pattern generator (CPG). In most patients with spinal cord injury (SCI) the CPG is undamaged. To date, there are no noninvasive approaches for activating the CPG. Recently we developed a noninvasive technique, tail nerve electrical stimulation (TANES), which can induce positive hind limb movement of SCI rats. The purpose of this study is to introduce the novel technique and examine the effect of TANES on CPG activation. A 25mm contusion injury was produced at spinal cord T10 of female, adult Long-Evans rats by using the NYU impactor device. Rats received TANES (∼40mA at 4kHz) 7 weeks after injury. During TANES all injured rats demonstrated active body weight-supported stepping of hind limbs with left–right alternation and occasional front–hind coordination, resulting in significant, temporary increase in BBB scores (p<0.01). However, there is no response to TANES from rats with L2 transection, consistent with other reports that the CPG may be located at L1–2. S1 transection negatively implies the key role of TANES in CPG activation. The TANES not only renders paralyzed rats with a technique-induced ability to walk via activating CPG, but also is likely to be used for locomotor training. It has more beneficial effects for physical training over other training paradigms including treadmill training and invasive functional electrical stimulation. Therefore the TANES may have considerable potential for achieving improvement of functional recovery in animal models and a similar method may be suggested for human study.

The excitatory neurotransmitter glutamate has been implicated in both migraine and persistent pain. The identification of the kainate receptor GLUK5 in dorsal root ganglia, the dorsal horn, and trigeminal ganglia makes it a target of interest for these indications. We examined the in vitro and in vivo pharmacology of the competitive GLUK5-selective kainate receptor antagonist LY466195 [(3S,4aR,6S,8aR)-6-[[(2S)-2-carboxy-4,4-difluoro-1-pyrrolidinyl]-methyl]decahydro-3-isoquinolinecarboxylic acid)], the most potent GLUK5 antagonist described to date. Comparisons were made to the competitive GLUK5/α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist LY293558 [(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]-decahydroisoquinoline-3-carboxylic acid], other decahydroisoquinoline GLUK5 receptor antagonists, and the noncompetitive AMPA receptor antagonist LY300168 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodi-azepine]. When characterized electrophysiologically in rat dorsal root ganglion neurons, LY466195 antagonized kainate (30 μM)-induced currents with an IC50 value of 0.045 ± 0.011 μM. In HEK293 cells transfected with GLUK5, GLUK2/GLUK5, or GLUK5/GLUK6 receptors, LY466195 produced IC50 values of 0.08 ± 0.02, 0.34 ± 0.17, and 0.07 ± 0.02 μM, respectively. LY466195 was efficacious in a dural plasma protein extravasation (PPE) model of migraine with an ID100 value of 100 μg/kg i.v. LY466195 was also efficacious in the c-fos migraine model, with a dose of 1 μg/kg i.v. significantly reducing the number of Fos-positive cells in the rat nucleus caudalis after electrical stimulation of the trigeminal ganglion. Furthermore, LY466195 showed no contractile activity in the rabbit saphenous vein in vitro. The diethyl ester prodrug of LY466195 was also efficacious in the same PPE and c-fos models after oral administration at doses of 10 and 100 μg/kg, respectively while having no N-methyl-d-aspartate antagonist-like behavioral effects at oral doses up to 100 mg/kg.

Glutamate is the major excitatory transmitter in the brain. Recent developments in the molecular biology and pharmacology of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid ( AMPA) subtype of glutamate receptors have led to the discovery of selective, potent, and systemically active AMPA receptor potentiators. These molecules enhance synaptic transmission and play important roles in plasticity and cognitive processes. In the present study, we first characterized a novel AMPA receptor potentiator, (R)-4'-[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)- ethyl]-biphenyl-4-carboxylic acid methylamide (LY503430), on recombinant human GLU(A1-4) and native preparations in vitro and then evaluated the potential neuroprotective effects of the molecule in rodent models of Parkinson's disease. Results indicated that submicromolar concentrations of LY503430 selectively enhanced glutamate-induced calcium influx into human embryonic kidney 293 cells transfected with human GLU(A1), GLU(A2), GLU(A3), or GLU(A4) AMPA receptors. The molecule also potentiated AMPA-mediated responses in native cortical, hippocampal, and substantia nigra neurons. We also report here that LY503430 provided dose-dependent functional and histological protection in animal models of Parkinson's disease. The neurotoxicity after unilateral infusion of 6-hydroxydopamine into either the substantia nigra or the striatum of rats and that after systemic 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine in mice were reduced. Interestingly, LY503430 also had neurotrophic actions on functional and histological outcomes when treatment was delayed until well after ( 6 or 14 days) the lesion was established. LY503430 also produced some increase in brain-derived neurotrophic factor in the substantia nigra and a dose-dependent increases in growth associated protein-43 (GAP-43) expression in the striatum. Therefore, we propose that AMPA receptor potentiators offer the potential of a new disease modifying therapy for Parkinson's disease.

Interest in kainate receptors has increased over the past few years. Our understanding of their physiology and pharmacology has improved markedly since their original cloning and expression in the early 1990s. For example, agonist profiles at recombinant kainate receptors have been used to identify and distinguish kainate receptors in neurons. Furthermore, the development of selective antagonists for kainate receptor subtypes has increased our understanding of the functional roles of kainate receptors in neurons and synaptic transmission. In this review we described the activity of agonists and antagonists at kainate receptors and their selectivity profiles at NMDA and non-NMDA receptors.

The present study describes the activity of two novel potent and selective AMPA receptor potentiator molecules LY392098 and LY404187. LY392098 and LY404187 enhance glutamate (100 microM) stimulated ion influx through recombinant homomeric human AMPA receptor ion channels, GluR1-4, with estimated EC(50) values of 1.77 microM (GluR1(i)), 0.22 microM (GluR2(i)), 0.56 microM (GluR2(o)), 1.89 microM (GluR3(i)) and 0.20 microM (GluR4(i)) for LY392098 and EC(50) values of 5.65 microM (GluR1(i)), 0.15 microM (GluR2(i)), 1.44 microM (GluR2(o)), 1.66 microM (GluR3(i)) and 0.21 microM (GluR4(i)) for LY404187. Neither compound affected ion influx in untransfected HEK293 cells or GluR transfected cells in the absence of glutamate. Both compounds were selective for activity at AMPA receptors, with no activity at human recombinant kainate receptors. Electrophysiological recordings demonstrated that glutamate (1 mM)-evoked inward currents in human GluR4 transfected HEK293 cells were potentiated by LY392098 and LY404187 at low concentrations (3-10 nM). In addition, both compounds removed glutamate-dependent desensitization of recombinant GluR4 AMPA receptors. These studies demonstrate that LY392098 and LY404187 allosterically potentiate responses mediated by human AMPA receptor ion channels expressed in HEK 293 cells in vitro.

ADVERTISEMENT RETURN TO ISSUEPREVLetterNEXT[3H]N-2-(4-(N-Benzamido)phenyl)propyl-2- propanesulfonamide: A Novel AMPA Receptor Potentiator and RadioligandHamideh Zarrinmayeh, David Bleakman, Mary R. Gates, Hong Yu, Dennis M. Zimmerman, Paul L. Ornstein, Tracey McKennon, M. Brian Arnold, William J. Wheeler, and Phil SkolnickView Author Information Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285 Cite this: J. Med. Chem. 2001, 44, 3, 302–304Publication Date (Web):January 25, 2001Publication History Received31 October 2000Published online25 January 2001Published inissue 1 February 2001https://pubs.acs.org/doi/10.1021/jm000462nhttps://doi.org/10.1021/jm000462nrapid-communicationACS PublicationsCopyright © 2001 American Chemical SocietyRequest reuse permissionsArticle Views342Altmetric-Citations28LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information SUBJECTS:Anions,Assays,Monomers,Peptides and proteins,Receptors Get e-Alerts

ADVERTISEMENT RETURN TO ISSUEPREVLetterNEXTBiarylpropylsulfonamides as Novel, Potent Potentiators of 2-Amino-3- (5-methyl-3-hydroxyisoxazol-4-yl)- propanoic Acid (AMPA) ReceptorsPaul L. Ornstein, Dennis M. Zimmerman, M. Brian Arnold, Thomas J. Bleisch, Buddy Cantrell, Richard Simon, Hamideh Zarrinmayeh, S. Richard Baker, Mary Gates, Joseph P. Tizzano, David Bleakman, Allan Mandelzys, Kieth R. Jarvie, Ken Ho, Michelle Deverill, and Rajender K. KambojView Author Information Lilly Research Laboratories A Division of Eli Lilly and Company Lilly Corporate Center, Indianapolis, Indiana 46285 NPS Allelix Corporation, 6850 Goreway Drive, Mississaugua, Ontario L4V 1V7, Canada Cite this: J. Med. Chem. 2000, 43, 23, 4354–4358Publication Date (Web):October 24, 2000Publication History Received29 June 2000Published online24 October 2000Published inissue 1 November 2000https://pubs.acs.org/doi/10.1021/jm0002836https://doi.org/10.1021/jm0002836rapid-communicationACS PublicationsCopyright © 2000 American Chemical SocietyRequest reuse permissionsArticle Views1072Altmetric-Citations63LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Alkyls,Anions,Aromatic compounds,Receptors,Structure activity relationship Get e-Alerts

The ability of synapses to modify their synaptic strength in response to activity is a fundamental property of the nervous system and may be an essential component of learning and memory 1 . There are three classes of ionotropic glutamate receptor, namely NMDA ( N -methyl- D -aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid) and kainate receptors 2 ; critical roles in synaptic plasticity have been identified for two of these. Thus, at many synapses in the brain, transient activation of NMDA receptors leads to a persistent modification in the strength of synaptic transmission mediated by AMPA receptors 3 , 4 . Here, to determine whether kainate receptors 5 , 6 , 7 are involved in synaptic plasticity, we have used a new antagonist, LY382884 ((3S, 4aR, 6S, 8aR)-6-((4-carboxyphenyl)methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid), which antagonizes kainate receptors at concentrations that do not affect AMPA or NMDA receptors. We find that LY382884 is a selective antagonist at neuronal kainate receptors containing the GluR5 subunit. It has no effect on long-term potentiation (LTP) that is dependent on NMDA receptors but prevents the induction of mossy fibre LTP, which is independent of NMDA receptors. Thus, kainate receptors can act as the induction trigger for long-term changes in synaptic transmission.