Nerve Fiber Growth Research Articles

Biomimetic Approaches for Separated Regeneration of Sensory and Motor Fibers in Amputee People: Necessary Conditions for Functional Integration of Sensory-Motor Prostheses With the Peripheral Nerves.

The regenerative capacity of the peripheral nervous system after an injury is limited, and a complete function is not recovered, mainly due to the loss of nerve tissue after the injury that causes a separation between the nerve ends and to the disorganized and intermingled growth of sensory and motor nerve fibers that cause erroneous reinnervations. Even though the development of biomaterials is a very promising field, today no significant results have been achieved. In this work, we study not only the characteristics that should have the support that will allow the growth of nerve fibers, but also the molecular profile necessary for a specific guidance. To do this, we carried out an exhaustive study of the molecular profile present during the regeneration of the sensory and motor fibers separately, as well as of the effect obtained by the administration and inhibition of different factors involved in the regeneration. In addition, we offer a complete design of the ideal characteristics of a biomaterial, which allows the growth of the sensory and motor neurons in a differentiated way, indicating (1) size and characteristics of the material; (2) necessity to act at the microlevel, on small groups of neurons; (3) combination of molecules and specific substrates; and (4) temporal profile of those molecules expression throughout the regeneration process. The importance of the design we offer is that it respects the complexity and characteristics of the regeneration process; it indicates the appropriate temporal conditions of molecular expression, in order to obtain a synergistic effect; it takes into account the importance of considering the process at the group of neuron level; and it gives an answer to the main limitations in the current studies.

Brief Report: Demographic and Genetic Associations With Markers of Small and Large Fiber Sensory Neuropathy in HIV Patients Treated Without Stavudine.

Neurotoxic antiretroviral therapy (ART) such as stavudine has been now replaced with safer therapies, reducing the prevalence of neuropathy from 34% to 15% in HIV+ Indonesians. However, it is unclear whether the residual cases display damage to small or large nerve fibers and whether both are influenced by known risk factors, including alleles of CAMKK2 associated with neuropathy in HIV patients. The encoded protein influences the growth and repair of nerve fibers. HIV-positive adults on ART for >12 months without exposure to stavudine were screened for neuropathy using the AIDS Clinical Trials Group Brief Peripheral Neuropathy Screen (BPNS). Large fiber neuropathy was assessed by nerve conduction (NC) and small fiber neuropathy using stimulated skin wrinkling (SSW) applied to the fingers. CAMKK2 alleles were assessed by TaqMan OpenArray technology. Neuropathy diagnoses were more common with SSW than BPNS (49/173 vs 26/185, χ; P = 0.0009), with poor alignment between these outcomes (P = 0.60). NC and BPNS diagnosed neuropathy at similar frequencies (29/151 vs 26/185; P = 0.12) and were aligned (P < 0.0001). In bivariate analyses, all diagnoses were associated with patients' age and persistent HIV replication, with minor effects from CD4 T-cell counts and time on ART. CAMKK2 alleles associated with neuropathy diagnosed with BPNS and SSW but not NC. Multivariable analyses confirmed the importance of age and HIV replication, with distinct CAMKK2 polymorphisms affecting BPNS and SSW. Paradoxically, height was protective against skin wrinkling. Overall the data link CAMKK2 genotypes with small rather than large fiber damage. SSW may reflect pathology distinct from that identified using BPNS.

Combined Atoh1 and Neurod1 Deletion Reveals Autonomous Growth of Auditory Nerve Fibers.

Ear development requires the transcription factors ATOH1 for hair cell differentiation and NEUROD1 for sensory neuron development. In addition, NEUROD1 negatively regulates Atoh1 gene expression. As we previously showed that deletion ofthe Neurod1 gene in the cochlea results in axonguidance defects and excessive peripheral innervation of the sensory epithelium, we hypothesized that some of the innervation defects may be a result of abnormalities in NEUROD1 and ATOH1 interactions. To characterize the interdependency of ATOH1 and NEUROD1 in inner ear development, we generated a new Atoh1/Neurod1 double null conditional deletion mutant. Through careful comparison of the effects of single Atoh1 or Neurod1 gene deletion with combined double Atoh1 and Neurod1 deletion, we demonstrate that NEUROD1-ATOH1 interactions are not important for the Neurod1 null innervation phenotype. We report that neurons lacking Neurod1 can innervate the flat epithelium without any sensory hair cells or supporting cells left after Atoh1 deletion, indicating that neurons with Neurod1 deletion do not require the presence of hair cells for axon growth. Moreover, transcriptome analysis identified genes encoding axon guidance and neurite growth molecules that aredysregulated in the Neurod1 deletion mutant. Taken together, we demonstrate that much of the projections of NEUROD1-deprived inner ear sensory neurons are regulated cell-autonomously.

Efficacy of Electrical Stimulation on Nerve Fiber Growth in Small Fiber Neuropathy.

To define whether electrical nerve stimulation (ENS) therapy would promote intraepidermal nerve growth and nerve regeneration in patients with small fiber neuropathy (SFN). This was a prospective study conducted on 8 subjects with previously diagnosed SFN. Nerve conduction testing, punch biopsies, and clinical examinations with a calculation of revised total neuropathy score were conducted on subjects before beginning ENS therapy and at 30 and 60 days after the start of ENS therapy. Clinical examination findings and intraepidermal nerve fiber density measurements on day 30 and day 60 did not show statistically significant changes in the treated group compared with the untreated group. Despite the success of previous animal studies, no meaningful nerve growth and regeneration in SFN was demonstrated with ENS therapy in this study. Studies of larger subject larger populations with longer duration of ENS treatment are warranted to confirm our findings.

Fabrication and transplantation of chitosan-selenium biodegradable nanocomposite conduit on transected sciatic nerve: a novel study in rat model

ABSTRACTPurpose: The improvement of techniques using conduits that connects the ends of damaged nerves and guides the growth of nerve fibers between the stumps, including adoption of natural or synthetic materials still is a challenge in peripheral nerve repair. The aim of the present novel study was to fabricate and transplant chitosan-selenium biodegradable nanocomposite conduit on transected sciatic nerve in rat model.Methods: In NORMAL group, the left sciatic nerve was exposed through a gluteal muscle incision and after careful hemostasis skin was closed. In TRANSECTED group left sciatic nerve was transected and stumps were fixed in adjacent muscle. In CHITOSAN and CSBNC groups, 10-mm sciatic nerve defects were bridged using a chitosan and chitosan-selenium biodegradable nanocomposite conduits, respectively. The regenerated fibers were studied 4, 8 and 12 weeks after surgery. Assessment of nerve regeneration was based on behavioral, functional, biomechanical, histomorphometric and immunohistochemical criteria.Results: The behavioral, functional and biomechanical studies confirmed significant recovery of regenerated axons in CSBNC group (P < 0.05). Quantitative morphometric analyses of regenerated fibers showed the number and diameter of myelinated fibers in CSBNC group were significantly higher than in the CHITOSAN group (P < 0.05).Discussion: This demonstrates the potential of using CSBNC in peripheral nerve regeneration without limitations of donor-site morbidity associated with isolation autograft. It is also cost saving and may have clinical implications for the surgical management of patients after facial nerve transection.

3D-engineered GelMA conduit filled with ECM promotes regeneration of peripheral nerve.

Autologous transplantation remains the golden standard for peripheral nerve repair. However, many drawbacks, such as the risk of reoperation or nerve injury remain associated with this method. To date, commercially available artificial nerve conduits comprise hollow tubes. By providing physical guiding and biological cues, tissue engineered conduits are promising for bridging peripheral nerve defects. The present study focuses on the preparation of artificial composite nerve conduits by 3D bio-printing. 3D-printed molds with a tubular cavity were filled with an Engelbreth-Holm-Swarm (EHS) Hydrogel mimicking the extracellular matrix (ECM) basement membrane. Chemically cross-linked gelatin methacryloyl (GelMA) was used to form the conduit backbone, while EHS Hydrogels improved nerve fiber growth while shortening repair time. Statistical significant difference had been found between the blank conduit and the composite conduit group on compound muscle action potential after 4 months. On the other hand, results between the composite conduit group and the autograft group were of no statistical differences. All results above showed that the composite conduit filled with EHS Hydrogel can promote the repair of peripheral nerve and may become a promising way to treat peripheral nerve defects.

The Impact of Lactoferrin on the Growth of Intestinal Inhabitant Bacteria.

Lactoferrin (Lf) is an iron-binding milk glycoprotein that promotes the growth of selected probiotic strains. The effect of Lf on the growth and diversification of intestinal microbiota may have an impact on several issues, including (i) strengthening the permeability of the epithelial cell monolayer, (ii) favoring the microbial antagonism that discourages the colonization and proliferation of enteric pathogens, (iii) enhancing the growth and maturation of cell-monolayer components and gut nerve fibers, and (iv) providing signals to balance the anti- and pro-inflammatory responses resulting in gut homeostasis. Given the beneficial role of probiotics, this contribution aims to review the current properties of bovine and human Lf and their derivatives in in vitro probiotic growth and Lf interplay with microbiota described in the piglet model. By using Lf as a component in pharmacological products, we may enable novel strategies that promote probiotic growth while conferring antimicrobial activity against multidrug-resistant microorganisms that cause life-threatening diseases, especially in neonates.

Computational Simulation Expands Understanding of Electrotransfer-Based Gene Augmentation for Enhancement of Neural Interfaces

The neural interface is a critical factor in governing efficient and safe charge transfer between a stimulating electrode and biological tissue. The interface plays a crucial role in the efficacy of electric stimulation in chronic implants and both electromechanical properties and biological properties shape this. In the case of cochlear implants, it has long been recognized that neurotrophins can stimulate growth of the target auditory nerve fibers into a favorable apposition with the electrode array, and recently such arrays have been re-purposed to enable electrotransfer (electroporation)-based neurotrophin gene augmentation to improve the “bionic ear.” For both this acute bionic array-directed electroporation and for chronic conventional cochlear implant arrays, the electric fields generated in target tissue during pulse delivery are central to efficacy, but are challenging to map. We present a computational model for predicting electric fields generated by array-driven DNA electrotransfer in the cochlea. The anatomically realistic model geometry was reconstructed from magnetic resonance images of the guinea pig cochlea and an eight-channel electrode array embedded within this geometry. The model incorporates a description of both Faradaic and non-Faradaic mechanisms occurring at the electrode-electrolyte interface with frequency dependency optimized to match experimental impedance spectrometry measurements. Our simulations predict that a tandem electrode configuration with four ganged cathodes and four ganged anodes produces three to fourfold larger area in target tissue where the electric field is within the range for successful gene transfer compared to an alternate paired anode-cathode electrode configuration. These findings matched in vivo transfection efficacy of a green fluorescent protein (GFP) reporter following array-driven electrotransfer of the reporter-encoding plasmid DNA. This confirms utility of the developed model as a tool to optimize the safety and efficacy of electrotransfer protocols for delivery of neurotrophin growth factors, with the ultimate aim of using gene augmentation approaches to improve the characteristics of the electrode-neural interfaces in chronically implanted neurostimulation devices.

LINGO-1 deficiency promotes nerve regeneration through reduction of cell apoptosis, inflammation, and glial scar after spinal cord injury in mice

Leucine-rich repeat and immunoglobulin domain-containing protein 1 (LINGO-1) is a transmembrane protein that negatively regulates neural regeneration in the central nervous system. LINGO-1 expression is up-regulated after central nerve injury, and is accompanied by cell death. Both LINGO-1 and cell death in the injury microenvironment are thought to limit neural regeneration, but the relationship between LINGO-1 and cell death has not been characterized. To investigate whether LINGO-1 deletion improves the spinal cord microenvironment after spinal cord injury (SCI) and contributes to cell survival, we generated LINGO-1 knockout (KO) mice. These mice and wild-type control mice were subjected to spinal cord transection. Fourteen days after spinal cord transection, cell apoptosis, inflammation, glial scar, and growth of nerve fibers were evaluated by immunostaining. The results showed that LINGO-1 KO mice demonstrated a profound reduction in expression of caspase-3, transferase-mediated deoxyuridine triphosphate biotin nick end labeling (TUNEL), ionized calcium binding adapter molecule 1 (IBA1), glial fibrillary acidic protein (GFAP), and chondroitin sulfate proteoglycans (CSPGs) compared to controls. In contrast, expression of neurofilament (NF) at the SCI site in LINGO-1 KO mice was markedly increased compared to that in wild-type mice. These results suggested that LINGO-1 plays a critical role in the injury microenvironment in processes such as cell death, inflammatory response, and glial scar formation. Importantly, LINGO-1 deletion and a positive microenvironment may exert synergistic effects to promote nerve fiber regeneration. Therefore, inhibition of LINGO-1 may be a therapeutic strategy to promote neural regeneration following SCI.

Sequence‐Optimized Peptide Nanofibers as Growth Stimulators for Regeneration of Peripheral Neurons

AbstractThere is an urgent need for biomaterials that support tissue healing, particularly neuronal regeneration. In a medium throughput screen novel self‐assembling peptide (SAP) sequences that form fibrils and stimulated nerve fiber growth of peripheral nervous system (PNS)‐derived neurons are identified. Based on the peptide sequences and fibril morphologies and by applying rational data‐mining, important structural parameters stimulating neuronal activity are elucidated. Three SAPs (SAP1e, SAP2e, and SAP5c) enhance adhesion and growth of PNS neurons. These SAPs form 2D and 3D matrices that serve as bioactive scaffolds stimulating cell adhesion and growth. The newly discovered SAPs also support the growth of CNS neurons and glia cells. Subsequently, the potential of SAPs to enhance PNS regeneration in vivo is analyzed. For this, the facial nerve driving whisker movement in mice is injured. Notably, SAPs persist for up to 3 weeks in the injury site indicating highly adhesive properties and stability. After SAP administration, more motor neurons incorporating markers for successive regeneration are observed. Recovery of whisker movement is elevated in SAP‐injected mice. In summary, short peptides that form fibrils are identified and the adhesion, growth, and regeneration of neurons have been efficiently enhanced without the necessity to attach hormones or growth factors.

Behavioral Compensations and Neuronal Remodeling in a Rodent Model of Chronic Intervertebral Disc Degeneration

Low back pain is associated with degeneration of the intervertebral disc, but specific mechanisms of pain generation in this pathology remain unknown. Sensory afferent nerve fiber growth into the intervertebral disc after injury-induced inflammation may contribute to discogenic pain. We describe a clinically relevant behavioral phenotype in a rodent model of chronic intervertebral disc degeneration which provides a means to map sensory neuron changes to a single affected lumbar intervertebral disc. Unilateral disc puncture of one lumbar intervertebral disc revealed a bilateral behavioral phenotype characterized by gait changes and decreased activity. Moreover, neurons extracted from the dorsal root ganglia in animals with intervertebral disc injury demonstrated altered TRPV1 activation in vitro independent of exogenous NGF administration. Finally, neuronal nuclear hypertrophy and elevated expression of p75NTR provide evidence of active adaptation of innervating sensory neurons in chronic intervertebral disc degeneration. Therefore, this model and findings provide the template for future studies to establish specific mechanisms of nociceptive pain in chronic intervertebral disc degeneration.

Devising micro/nano-architectures in multi-channel nerve conduits towards a pro-regenerative matrix for the repair of spinal cord injury

Multi-channel nerve conduits have shown significant advantages in guidance of axonal growth and functional restoration after spinal cord injury (SCI). It was realized that the micro/nano-architectures of these implanted conduits can effectively tune the lesion-induced biological responses, including inflammation and scar formation. In this work, two PLLA multi-channel conduits were fabricated with ladder-like porous channel wall (labelled as LNCs) and nano-fibrous channel wall (labelled as NNCs), respectively, and transferred into complete spinal cord transected injury model in rats. The implantation of such two scaffolds significantly alleviated the infiltration of macrophages/microglia and accumulation of astrocyte and collagen scar, especially in the NNCs group. Meanwhile, recruitment of endogenous stem cells and axonal growth was observed in both of the multi-channel conduits. Compared to the LNCs, the extracellular matrix (ECM) – mimicry nanostructures in the NNCs promoted directional nerve fiber growth within the channels. Moreover, a relatively denser nano-architecture in the channel wall confined the nerve fiber extension within the channels. These results from in vivo evaluations suggested that the NNCs implants possess a great potential in future application for SCI treatment and nerve regeneration. Statements of SignificanceThe implantation of biocompatible and degradable polymeric scaffolds holds great potential in clinical treatment and tissue regeneration after spinal cord injury (SCI). In this work, the ladder-like nerve conduits (LNCs) and nano-fibrous nerve conduits (NNCs) were fabricated and implanted into completely spinal cord transected rats, respectively. In vivo characteristics showed significant reduction in post-injury inflammation and scar formation, with elevated nerve stem cells (NSCs) recruitment and nerve fiber growth, hence both conduits resulted in significant functional restoration after implantation. Remarkably, we noticed that not only the multi-channels in the conduits can guide nerve fiber regeneration, their micro-/nano-structured walls also played a critical role in modulating the post-implantation biological responses.

Pelvic organ cross-talk: A new paradigm for endometriosis-related pelvic pain?

Endometriosis patients often complain about pelvic and abdominal pain with varying bowel and bladder symptoms unrelated to the location and extent of the disease. The pathophysiology can be multifactorial, but one possibility is that pelvic organ cross-talk may play a role. The aim of this review was to evaluate the scientific support for this hypothesis. A search was performed in PubMed to identify relevant experimental and clinical studies. Data achieved in animal models and clinical evidence suggest that endometriosis-related pain may implicate interactions between pelvic structures like the urinary tract, the bowel and the vagina, mediated by the autonomous nervous system. Such pelvic organ cross-talk with involvement of nerve fibre outgrowth into endometriosis lesions, peripheral sensitisation and convergence of afferent nerve fibres could be an explanation for the varying pain problems in endometriosis, but the precise mechanisms are still poorly understood. Some patients with chronic pelvic pain, including those with endometriosis, also seem to have a more general somatic, musculoskeletal hyperalgesia, indicating a potential viscero-somatic convergence. This might be due to continuous nociceptive input to the brain, resulting in changes in brain structures and finally leading to central sensitisation. Thus, pelvic organ cross-talk seems to represent a new paradigm for endometriosis-related pain with novel possibilities for the development of therapeutic strategies.

The Expression and Cellular Localisation of Neurotrophin and Neural Guidance Molecules in Peritoneal Ectopic Lesions.

Endometriosis is a gynaecological disorder characterised by the presence of endometrial-like tissue outside the uterus. It affects 10-15% of women during their reproductive age. The existence of close and complex relationship between chronic pelvic pain and endometriosis are widely recognised. However, the mechanisms of pain generation in women with endometriosis remain poorly understood. Immunohistochemistry was used to assess the density of nerve fibres stained with protein gene product 9.5 (PGP9.5) and the expression of various neurotrophins including glial cell derived neurotrophic factor (GDNF), persephin, neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) and neuronal guidance molecules semaphorin 3E and Slit-2 and their receptors Plexin-D1 and Robo4 in peritoneal ectopic lesions from women with endometriosis and uninvolved peritoneum samples. Neurotrophins and neuronal guidance molecules and their receptors are synthesised in situ within peritoneal ectopic lesion which suggest their role in facilitating and maintaining the growth of nerve fibres. These molecules were found to be overall most highly expressed in the glands of endometriotic peritoneal lesions. In addition, the presence of ectopic lesions within the peritoneal cavity may affect the environment; in turn, the peritoneum altered appeared to play a role in the growth of nerve fibres and their development and maintenance in peritoneal lesions. Through exploring different neuronally active factors in and around ectopic lesions which may be contributing to pain generation, this study provides an insight and better understanding of the pain mechanisms associated with peritoneal endometriosis.

ЛІКУВАННЯ СОБАК З УРАХУВАННЯМ ОСОБЛИВОСТЕЙ ПАТОГЕНЕЗУ ХРЕБЕТНО-СПИННОМОЗКОВИХ ТРАВМ

ЛІКУВАННЯ СОБАК З УРАХУВАННЯМ ОСОБЛИВОСТЕЙ ПАТОГЕНЕЗУ ХРЕБЕТНО-СПИННОМОЗКОВИХ ТРАВМ

Water‐Dispersible Polydopamine‐Coated Nanofibers for Stimulation of Neuronal Growth and Adhesion

Hybrid nanomaterials have shown great potential in regenerative medicine due to the unique opportunities to customize materials properties for effectively controlling cellular growth. The peptide nanofiber-mediated auto-oxidative polymerization of dopamine, resulting in stable aqueous dispersions of polydopamine-coated peptide hybrid nanofibers, is demonstrated. The catechol residues of the polydopamine coating on the hybrid nanofibers are accessible and provide a platform for introducing functionalities in a pH-responsive polymer analogous reaction, which is demonstrated using a boronic acid modified fluorophore. The resulting hybrid nanofibers exhibit attractive properties in their cellular interactions: they enhance neuronal cell adhesion, nerve fiber growth, and growth cone area, thus providing great potential in regenerative medicine. Furthermore, the facile modification by pH-responsive supramolecular polymer analog reactions allows tailoring the functional properties of the hybrid nanofibers in a reversible fashion.

Pain Mechanisms in Peritoneal Diseases Might Be Partially Regulated by Estrogen.

To identify factors influencing the differential pain pathogenesis in peritoneal endometriosis (pEM) and peritoneal carcinomatosis in ovarian cancer (pOC), we undertook an experimental study. Tissue samples of 18 patients with pEM, 15 patients with pOC, and 15 unaffected peritoneums as controls were collected during laparoscopy or laparotomy. Immunohistochemical stainings were conducted to identify nerve fibers and neurotrophins in the tissue samples. Additionally, 23 pEM fluids, 25 pOC ascites fluids, and 20 peritoneal fluids of patients with myoma uteri as controls were collected. In these fluids, the expression of neurotrophins was evaluated. The effects of peritoneal fluids and ascites on the neurite outgrowth of chicken sensory ganglia were estimated by using a neuronal growth assay. An electrochemiluminescence immunoassay was carried out to determine the expression of estrogen in the peritoneal fluids and ascites. The total and sensory nerve fiber density was significantly higher in pEM than in pOC ( P < .001 and P < .01). All neurotrophins tested were present in tissue and fluid samples of pEM and pOC. Furthermore, the neurotrophic properties of pEM and pOC fluids were demonstrated, leading to sensory nerve fiber outgrowth. Estrogen concentration in the peritoneal fluids of pEM was significantly higher compared to ascites of pOC ( P < .001). The total and sensory nerve fiber density in the tissue samples as well as the estrogen expression in the peritoneal fluid of pEM was considerably higher than that in pOC, representing the most notable difference found in both diseases. This might explain the differential pain perception in pEM and pOC. Therefore, estrogen might be a key factor in influencing the genesis of pain in endometriosis.

Stress During Development of Experimental Endometriosis Influences Nerve Growth and Disease Progression.

We have previously shown that stress prior to induction worsens clinical presentation and inflammatory parameters in a rat model of endometriosis. This study was designed to examine whether stress during the development of endometriosis can affect the growth of endometriotic implants through nerve growth and immune alterations. Endometriosis was surgically induced in female Sprague-Dawley rats by suturing uterine horn implants onto the small intestine mesentery. Two weeks later, one group of rats (endo-stress) was subjected to a 10-day swim stress protocol. Controls had no stress (endo-no stress) or sutures only and stress (sham-stress). On day 60, all rats were killed and examined for the presence of endometriotic vesicles. The size of each vesicle was measured. The uterus and colon were removed and assessed for damage, cell infiltration, and expression of nerve growth factor (NGF), its receptors (p75 and Tropomyosin receptor kinase A (Trk-A)/pTrk-A), and calcitonin gene-related peptide, a sensory fiber marker. A differential analysis of peritoneal fluid white blood cell count was performed. Stress significantly increased endometriotic vesicle size but not colonic damage and increased infiltration of mast cells. Significantly increased expression of NGF and its receptors was found in the uterus of animals with endometriosis receiving stress. Stress stimulates the development of ectopic endometrial vesicles in an animal model of endometriosis and increases inflammatory cell recruitment to the peritoneum. In addition, stress promotes nerve fiber growth in the uterus.

The Comprehensive Therapy of Electroacupuncture Promotes Regeneration of Nerve Fibers and Motor Function Recovery in Rats after Spinal Cord Injury.

The present study aimed to evaluate the role of the combination treatment of methylprednisolone (MP) and electroacupuncture (EA) in regeneration of nerve fibers and functional recovery in rats with spinal cord injury (SCI). Female Wistar rats were used for an SCI model by using a weight-drop hammer at levels T10 (spinal cord segment corresponding to the 10th thoracic vertebra). Four groups received different treatments for the study: SCI control, MP, MP and EA, and Sham. The growth of nerve fibers was examined by counting fluorescein positive nerve fibers. The motor functional recovery was evaluated by Basso, Beattie, Bresnahan (BBB) score, and electrophysiology analysis. We found that, compared to MP groups, there were more well-oriented and paralleled fluorescein positive nerve fibers in MP and EA group. Both latencies and amplitudes of the Motor Evoked Potential (MEP) in the combination therapy of MP and EA were higher than MP group. Additionally, recovered hindlimb movements were sustained in most rats in the MP and EA group. Our study indicated that combination therapies could become a powerful treatment for SCI in rats.

Involvement of the Urokinase Receptor and Its Endogenous Ligands in the Development of the Brain and the Formation of Cognitive Functions

Studies in recent years have shown that the urokinase receptor (uPAR) and its ligands – urokinase (uPA) and protein SRPX2 – play important roles in the processes underlying the formation and functioning of the brain. Human studies have demonstrated an interaction between a polymorphism of the uPAR gene and the development of autism. Patients with autism, incurable epilepsy, verbal dyspraxia, and perisylvian polymicrogyria show changes in uPAR expression. Studies using mice with knockout of the uPAR gene showed a tendency to develop epilepsy and impairments to behavioral reactions. Data have also been obtained on the involvement of uPAR ligands – uPA and protein SRPX2 – in the development of pathological brain states associated with autism, cognitive disorders, and speech disorders. The urokinase system has been shown to be able to regulate not only the rate of growth of vessels and nerve fibers by remodeling the matrix and activating neurotrophic and angiogenic factors, but also to function as a system of navigation molecules determining the direction of vessel and nerve growth in tissue regeneration processes. This article summarizes and analyzes results from recent studies of the role of uPAR and its endogenous ligands in the development of the brain and the formation of the cognitive functions.