Peripheral nerve mucoid degeneration involving the sciatic nerve.

Peripheral nerve mucoid degeneration (PNMD) is a rare non-neoplastic degenerative condition characterized by endoneural deposit of mucoid matrix. Herein, we report a case of PNMD involving the sciatic nerve with preoperative features, surgical treatment and pathological findings.

Neuro-regeneration therapy using human Muse cells is highly effective in a mouse intracerebral hemorrhage model.

A novel type of non-tumorigenic pluripotent stem cell, the Muse cell (multi-lineage, differentiating stress enduring cell), resides in the connective tissue and in cultured mesenchymal stem cells (MSCs) and is reported to differentiate into multiple cell types according to the microenvironment to repair tissue damage. We examined the efficiency of Muse cells in a mouse intracerebral hemorrhage (ICH) model. Seventy µl of cardiac blood was stereotactically injected into the left putamen of immunodeficient mice. Five days later, 2 × 105 of human bone marrow MSC-derived Muse cells (n = 6) or cells other than Muse cells in MSCs (non-Muse, n = 6) or the same volume of PBS (n = 11) was injected into the ICH cavity. Water maze and motor function tests were implemented for 68 days, and immunohistochemistry for NeuN, MAP2 and GFAP was done. The Muse group showed impressive recovery: Recovery was seen in the water maze after day 19, and motor functions after 5 days was compared with the other two groups, with a significant statistical difference (p < 0.05). The survival rate of the engrafted cells in the Muse group was significantly higher than in the non-Muse group (p < 0.05) at day 69, and those cells showed positivity for NeuN (~57%) and MAP-2 (~41.6%). Muse cells could remain in the ICH brain, differentiate into neural-lineage cells and restore functions without inducing them into neuronal cells by gene introduction and cytokine treatment prior to transplantation. A simple collection of Muse cells and their supply to the brain in naïve state facilitates regenerative therapy in ICH.

Mesenchymal stem cells attenuate peripheral neuronal degeneration in spinocerebellar ataxia type 1 knockin mice.

Spinocerebellar ataxia type 1 (SCA1) is a devastating neurodegenerative disorder in which an abnormally expanded polyglutamine tract is inserted into causative ataxin-1 proteins. We have previously shown that SCA1 knockin (SCA1-KI) mice over 6 months of age exhibit a degeneration of motor neuron axons and their encasing myelin sheaths, as reported in SCA1 patients. We examined whether axon degeneration precedes myelin degeneration or vice versa in SCA1-KI mice and then attempted to mitigate motor neuron degeneration by intrathecally administering mesenchymal stem cells (MSCs). Temporal examination of the diameters of motor neuron axons and their myelin sheaths revealed a decrease in diameter of the axon but not of the myelin sheaths in SCA1-KI mice as early as 1 month of age, which suggests secondary degeneration of the myelin sheaths. We injected MSCs into the intrathecal space of SCA1-KI mice at 1 month of age, which resulted in a significant suppression of degeneration of both motor neuron axons and myelin sheaths, even 6 months after the MSC injection. Thus, MSCs effectively suppressed peripheral nervous system degeneration in SCA1-KI mice. It has not yet been clarified how clinically administered MSCs exhibit significant therapeutic effects in patients with SCA1. The morphological evidence presented in this current mouse study might explain the mechanisms that underlie the therapeutic effects of MSCs that are observed in patients with SCA1.

Intravenous transplants of human adipose-derived stem cell protect the brain from traumatic brain injury-induced neurodegeneration and motor and cognitive impairments: cell graft biodistribution and soluble factors in young and aged rats.

Traumatic brain injury (TBI) survivors exhibit motor and cognitive symptoms from the primary injury that can become aggravated over time because of secondary cell death. In the present in vivo study, we examined the beneficial effects of human adipose-derived stem cells (hADSCs) in a controlled cortical impact model of mild TBI using young (6 months) and aged (20 months) F344 rats. Animals were transplanted intravenously with 4 × 10(6) hADSCs (Tx), conditioned media (CM), or vehicle (unconditioned media) at 3 h after TBI. Significant amelioration of motor and cognitive functions was revealed in young, but not aged, Tx and CM groups. Fluorescent imaging in vivo and ex vivo revealed 1,1' dioactadecyl-3-3-3',3'-tetramethylindotricarbocyanine iodide-labeled hADSCs in peripheral organs and brain after TBI. Spatiotemporal deposition of hADSCs differed between young and aged rats, most notably reduced migration to the aged spleen. Significant reduction in cortical damage and hippocampal cell loss was observed in both Tx and CM groups in young rats, whereas less neuroprotection was detected in the aged rats and mainly in the Tx group but not the CM group. CM harvested from hADSCs with silencing of either NEAT1 (nuclear enriched abundant transcript 1) or MALAT1 (metastasis associated lung adenocarcinoma transcript 1), long noncoding RNAs (lncRNAs) known to play a role in gene expression, lost the efficacy in our model. Altogether, hADSCs are promising therapeutic cells for TBI, and lncRNAs in the secretome is an important mechanism of cell therapy. Furthermore, hADSCs showed reduced efficacy in aged rats, which may in part result from decreased homing of the cells to the spleen.

Bone marrow cell transplantation restores olfaction in the degenerated olfactory bulb.

Bone marrow contains heterogeneous cell types including end-lineage cells, committed tissue progenitors, and multipotent stem/progenitor cells. The immense plasticity of bone marrow cells allows them to populate diverse tissues such as the encephalon, and give rise to a variety of cell types. This unique plasticity makes bone marrow-derived cells good candidates for cell therapy aiming at restoring impaired brain circuits. In the present study, bone marrow cells were transplanted into P20 mice that exhibit selective olfactory degeneration in adulthood between P60 and P150. These animals, the so-called Purkinje Cell Degeneration (PCD) mutant mice, suffer from a progressive and specific loss of a subpopulation of principal neurons of the olfactory bulb, the mitral cells (MCs), sparing the other principal neurons, the tufted cells. As such, PCD mice constitute an interesting model to evaluate the specific role of MCs in olfaction and to test the restorative function of transplanted bone marrow-derived cells. Using precision olfactometry, we revealed that mutant mice lacking MCs exhibited a deficit in odorant detection and discrimination. Remarkably, the transplantation of wild-type bone marrow-derived cells into irradiated PCD mutant mice generated a large population of microglial cells in the olfactory bulb and reduced the degenerative process. The alleviation of MC loss in transplanted mice was accompanied by functional recovery witnessed by significantly improved olfactory detection and enhanced odor discrimination. Together, these data suggest that: (1) bone marrow-derived cells represent an effective neuroprotective tool to restore degenerative brain circuits, and (2) MCs are necessary to encode odor concentration and odor identity in the mouse olfactory bulb.

Local self-renewal can sustain CNS microglia maintenance and function throughout adult life.

Microgliosis is a common response to multiple types of damage in the CNS. However, the origin of the cells involved in this process is still controversial and the relative importance of local expansion versus recruitment of microglia progenitors from the bloodstream is unclear. Here, we investigated the origin of microglia using chimeric animals obtained by parabiosis. We found no evidence of microglia progenitor recruitment from the circulation in denervation or CNS neurodegenerative disease, suggesting that maintenance and local expansion of microglia are solely dependent on the self-renewal of CNS resident cells in these models.

Management of chronic leg and knee pain following surgery or trauma related to saphenous nerve and knee neuromata.

Patients who present with lower extremity pain following surgery or trauma can occasionally have the saphenous nerve as the offending anatomic cause of their pain. Consistent with its anatomic course, the saphenous nerve can be the source of pain that manifests anywhere along its sensory distribution.Patients who presented to the Georgetown Peripheral Nerve Institute with lower extremity pain were evaluated, and those patients whose pain was suspected to be of saphenous nerve origin were offered surgical treatment. The surgical intervention included excision of the neuroma and/or nerve decompression, as clinically indicated. Patients were followed clinically and evaluated for both their pain as well as recovery in their ambulation and quality of life.Forty-two consecutive patients underwent surgery for pain of saphenous nerve origin from 2003 to 2008; 69% of these patients had concomitant surgery on another involved lower extremity peripheral nerve. Follow-up was achieved in 35 patients (83% response rate), with an average follow-up duration of 34.7 months. Using a 10-point pain scale, patients reported their preoperative pain as an 8.0 and their postoperative pain as a 2.37 (P < 0.001). Of the 35 patients, 30 (86%) were able to ambulate at the last follow-up encounter. Patients were asked to report their quality of life on a 10-point scale, and reported a 77% recovery of their baseline quality of life as a result of peripheral nerve surgery performed. Of the 35 patients, 29 reported that the surgery effectively resolved their pain, yielding a success rate of 82.8%.The saphenous nerve can be a source of lower extremity and knee pain following trauma or surgery. Accurate clinical diagnosis followed by surgical intervention can result in clinical resolution in the majority of patients, with improvement in ambulation and quality of life. This study reports the largest series of surgically-corrected saphenous neuropathy in the literature.

Hippocampal stem cell grafting-mediated recovery of injured hippocampus in the rat model of temporal lobe epilepsy.

Hippocampal stem cells (HSCs) are considered promising donor cells to promote reorganization of degenerated regions of the injured hippocampus in the epileptic brain. However, the efficacy of HSC grafting for repairing injured hippocampus remains unclear. To address this issue, we transplanted neonatal rat HSCs into the right hippocampus in rats with kainite acid (KA)-induced epilepsy. The activity of the hippocampus and amygdala nucleus was monitored with electroencephalogram (EEG) throughout 24 weeks posttransplantation. Rats with grafted HSCs exhibited reduced frequency of epileptic wave discharge and a 50% decrease in the amplitude of discharge. At 1, 4, 8, and 24 weeks posttransplantation, the aberrant mossy fiber sprouting (MFS) was evaluated with Timm's stain and the number of CA3 pyramidal neurons was analyzed with Nissl staining. Aberrant MFS induced by KA-lesion was notably suppressed by HSC grafts beginning 4 weeks posttransplantation, and was most effective by 8 weeks. In addition, the loss of CA3 pyramidal neurons was partially restored and reached the most recovery at 8 weeks. Taken together, these results suggest that HSCs derived from the postnatal hippocampus offer a promising reparative effect on KA-induced epileptic brain.

The effect of cerebellar transplantation and enforced physical activity on motor skills and spatial learning in adult Lurcher mutant mice.

Lurcher mutant mice represent a model of olivocerebellar degeneration. They are used to investigate cerebellar functions, consequences of cerebellar degeneration and methods of therapy influencing them. The aim of the work was to assess the effect of foetal cerebellar graft transplantation, repeated enforced physical activity and the combination of both these types of treatment on motor skills, spontaneous motor activity and spatial learning ability in adult B6CBA Lurcher mice. Foetal cerebellar grafts were applied into the cerebellum of Lurchers in the form of solid tissue pieces. Enforced motor activity was realised through rotarod training. Motor functions were examined using bar, ladder and rotarod tests. Spatial learning was tested in the Morris water maze. Spontaneous motor activity in the open field was observed. The presence of the graft was examined histologically. Enforced physical activity led to moderate improvement of some motor skills and to a significant amelioration of spatial learning ability in Lurchers. The transplantation of cerebellar tissue did not influence motor functions significantly but led to an improvement of spatial learning ability. Mutual advancement of the effects of both types of treatment was not observed. Spontaneous motor activity was influenced neither by physical activity nor by the transplantation. Physical activity did not influence the graft survival and development. Because nerve sprouting and cell migration from the graft to the host cerebellum was poor, the functional effects of the graft should be explained with regard to its trophic influence rather than with any involvement of the grafted cells into neural circuitries.

Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/ref-1) and DNA damage in the caudal region of acute and chronic spinal cord injured rats treated by embryonic neural stem cells.

The oxidative mechanisms of injury-induced damage of neurons within the spinal cord are not very well understood. We used a model of T8-T9 spinal cord injury (SCI) in the rat to induce neuronal degeneration. In this spinal cord injury model, unilateral avulsion of the spinal cord causes oxidative stress of neurons. We tested the hypothesis that apurinic/apyrimidinic endonuclease (or redox effector factor-1, APE/Ref-1) regulates this neuronal oxidation mechanism in the spinal cord region caudal to the lesion, and that DNA damage is an early upstream signal. The embryonic neural stem cell therapy significantly decreased DNA-damage levels in both study groups - acutely (followed up to 7 days after SCI), and chronically (followed up to 28 days after SCI) injured animals. Meanwhile, mRNA levels of APE/Ref-1 significantly increased after embryonic neural stem cell therapy in acutely and chronically injured animals when compared to acute and chronic sham groups. Our data has demonstrated that an increase of APE/Ref-1 mRNA levels in the caudal region of spinal cord strongly correlated with DNA damage after traumatic spinal cord injury. We suggest that DNA damage can be observed both in lesional and caudal regions of the acutely and chronically injured groups, but DNA damage is reduced with embryonic neural stem cell therapy.

A review of the role of epidural percutaneous neuroplasty.

Degeneration, whether from age or postsurgical, in the ventral and lateral epidural space can lead to irritation of both the nerve roots and of the nerves present in the epidural space, the peridural membrane and the posterior longitudinal ligament. This irritation is often accompanied by mild scarring. Neuroplasty is a specific procedure designed to relieve this irritation. The effectiveness of neuroplasty is not affected by the extent of spinal stenosis. Neuroplasty can be performed in the lumbar, thoracic and cervical spine, and using caudal, transforaminal and interlaminar approaches. Postprocedural home exercises are an integral part of the procedure. There are multiple high-grade studies positive for the effectiveness and safety of neuroplasty. Neuroplasty should be offered prior to surgery in patients with persistent back and/or extremity pain.

Human mesenchymal stem cell transplantation extends survival, improves motor performance and decreases neuroinflammation in mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a lethal disease affecting motoneurons. In familial ALS, patients bear mutations in the superoxide dismutase gene (SOD1). We transplanted human bone marrow mesenchymal stem cells (hMSCs) into the lumbar spinal cord of asymptomatic SOD1(G93A) mice, an experimental model of ALS. hMSCs were found in the spinal cord 10 weeks after, sometimes close to motoneurons and were rarely GFAP- or MAP2-positive. In females, where progression is slower than in males, astrogliosis and microglial activation were reduced and motoneuron counts with the optical fractionator were higher following transplantation. Motor tests (Rotarod, Paw Grip Endurance, neurological examination) were significantly improved in transplanted males. Therefore hMSCs are a good candidate for ALS cell therapy: they can survive and migrate after transplantation in the lumbar spinal cord, where they prevent astrogliosis and microglial activation and delay ALS-related decrease in the number of motoneurons, thus resulting in amelioration of the motor performance.

Reimplantation of avulsed lumbosacral ventral roots in the rat ameliorates injury-induced degeneration of primary afferent axon collaterals in the spinal dorsal columns.

Injuries to the cauda equina/conus medullaris portion of the spinal cord can result in motor, sensory, and autonomic dysfunction, and neuropathic pain. In rats, unilateral avulsion of the motor efferents from the lumbosacral spinal cord results in at-level allodynia, along with a corresponding glial and inflammatory response in the dorsal horn of the spinal cord segments immediately rostral to the lesion. Here, we investigated the fate of intramedullary primary sensory projections following a motor efferent lesion. The lumbosacral (L6 and S1) ventral roots were unilaterally avulsed from the rat spinal cord (VRA; n=9). A second experimental group had the avulsed roots acutely reimplanted into the lateral funiculus (Imp; n=5), as this neural repair strategy is neuroprotective, and promotes the functional reinnervation of peripheral targets. A laminectomy-only group served as controls (Lam; n=7). At 8 weeks post-lesion, immunohistochemical examination showed a 42% reduction (P<0.001) in the number of RT97-positive axons in the ascending tracts of the dorsal funiculus of the L4-5 spinal segment in VRA rats. Evidence for degenerating myelin was also present. Reimplantation of the avulsed roots ameliorated axon and myelin degeneration. Axons in the descending dorsal corticospinal tract were unaffected in all groups, suggesting a specificity of this lesion for spinal primary sensory afferents. These results show for the first time that a lesion restricted to motor roots can induce the degeneration of intramedullary sensory afferents. Importantly, reimplantation of the lesioned motor roots ameliorated sensory axon degeneration. These data further support the therapeutic potential for reimplantation of avulsed ventral roots following trauma to the cauda equina/conus medullaris.

Microanatomical evidences for potential of mesenchymal stem cells in amelioration of striatal degeneration.

Huntington's disease is an inherited neurodegenerative disorder, characterized by loss of spiny neurons in the striatum and cortex, which usually happens in the third or fourth decades of life. In advanced form of the disease, progressive striatum atrophy happens and medium spiny neurons, which occupy more than 80% of the striatum, become atrophic. Gradually, the atrophy expands to the neocortex and other regions of the brain. To our knowledge, there is no effective therapeutic strategy for diminishing the motor disorders of Huntington's disease. In recent years, cellular transplantation has been an effective therapeutic method for neurodegenerative diseases. In the present study, the potential of bone marrow derived mesenchymal stem cells in amelioration of striatal degeneration was assessed in animal model of Huntington's disease. After unilateral lesion in striatum was caused by quinolinic acid (QA), bone marrow derived mesenchymal stem cells, which were isolated and purified from 4-6 weeks old rats, were transplanted into the damaged striatum. After 9 weeks of transplantation, the volume of striatum, lateral ventricles and hemispheres were measured in control (normal) and test (QA injected + cell transplanted) groups. After volume determination, the atrophy percentage of both striatum and damaged hemisphere and volume extension of lateral ventricles were calculated. Histologic results showed significant difference in amount of striatum atrophy between sham (only QA injected) and test groups. These results confirm the potential of bone marrow derived mesenchymal stem cells in treatment of microanatomical defects in motor disorders of Huntington's disease. According to our results, cell therapy by means of bone marrow derived adult stem cells could be considered as a good candidate for treatment of neurodegenerative diseases, especially Huntington's disease.

The injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue.

Hypoxic-ischemic injury is a prototype for insults characterized by extensive tissue loss. Seeding neural stem cells (NSCs) onto a polymer scaffold that was subsequently implanted into the infarction cavities of mouse brains injured by hypoxia-ischemia allowed us to observe the multiple reciprocal interactions that spontaneously ensue between NSCs and the extensively damaged brain: parenchymal loss was dramatically reduced, an intricate meshwork of many highly arborized neurites of both host- and donor-derived neurons emerged, and some anatomical connections appeared to be reconstituted. The NSC-scaffold complex altered the trajectory and complexity of host cortical neurites. Reciprocally, donor-derived neurons were seemingly capable of directed, target-appropriate neurite outgrowth (extending axons to the opposite hemisphere) without specific external instruction, induction, or genetic manipulation of host brain or donor cells. These "biobridges" appeared to unveil or augment a constitutive reparative response by facilitating a series of reciprocal interactions between NSC and host, including promoting neuronal differentiation, enhancing the elaboration of neural processes, fostering the re-formation of cortical tissue, and promoting connectivity. Inflammation and scarring were also reduced, facilitating reconstitution.

Recurrent Neurological Deterioration after Conservative Treatment for Acute Traumatic Central Cord Syndrome without Bony Injury: Seventeen Operative Case Reports.

The mechanisms of late recurrent neurological deterioration after conservative treatment for acute traumatic central cord syndrome (ATCCS) remain unclear. Seventeen operative cases sustaining late recurrent neurological deterioration after conservative treatment for ATCCS were reviewed to investigate the mechanisms. The assessment of neurological status was based on International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). Gender, age, cause of injury, results of image, conservative treatment and operative data, and neurological status at different time points were recorded. The mean age of 17 patients was 43.8 ± 2.3 years old, and the causes of the cervical injury were 14 vehicle accidents and 3 falls. The neurological deficits of 17 patients on admission were not serious, and patients recovered quickly after conservative treatment. No fractures or dislocation were found in any patient's radiographs or CT scan images. All 17 patients performed first MRI test in 4 days and there was a slight or mild compression on the spinal cord in 16 patients. Eight patients had a second MRI scan ∼6 weeks later, which showed that there was aggravated compression on the spinal cord in six patients. All patients underwent an anterior approach to cervical decompression and internal fixation operation. During the operation, there were loose discs found in all 17 patients, obvious ruptures of disks found in 3 patients, obvious ruptures of anterior longitudinal ligaments (ALLs) found in 8 patients, and obvious ruptures of posterior longitudinal ligaments (PLLs) found in 7 patients. There was serious adhesion between PLLs and cervical disks in 12 patients. In five patients, partial ossification of PLLs was detected. All patients had a good neurological outcome at 6 month follow-up. Ruptures of ALLs, PLLs, and discs resulting in cervical instability and secondary compression on the spinal cord were important causes for recurrent neurological deterioration after conservative treatment for ATCCS. With timely spinal decompression after recurrent neurological deterioration, patients could achieve a good neurological outcome.

A new and simple transection knife for study of neurodegeneration and neuroregeneration in animal model.

BACKGROUND: The purpose of this study was to design and make a simple, inexpensive brain knife that could produce consistent results following transection in animal model. MATERIALS AND METHODS: After testing various materials including commercially available products, microelectrode recording needles as used in deep brain stimulation (DBS) surgery were selected as ideal candidates. They were modified to serve as type of wire-knife for the purposes of study. For this study, the major pathway for dopaminergic neuron from substantia nigra to striatum was selected for transection. A total of 40 Sprague-Dawley rats were assigned to 8 groups; normal, 1-4, 6, 8, and 10 weeks post-transection. Degree of cell death was determined and surviving neurons were counted by means of fluorescent microscopic examination, immunohistochemistry involving tyrosine hydroxylase (TH)-immunoreactive staining, and mapping to verify complete transection. RESULTS: Compared to control, percentage of remaining neurons in each group was 61.3, 36.8, 29.9, 5.1, 5.9, 7.0%, respectively. Completeness of lesion was correlated with the absence of TH-immunoreactivity in the striatum. CONCLUSION: Our model seems to provide complete cell death in early period after transection with consistent results. Thus, this type of brain knife can be very handy, without any extra cost, in any research model involving transection of fiber bundle for studies on neurodegeneration and neuroregeneration.