Neurons in the CNS lose regenerative potential with maturity, leading to minimal corticospinal tract (CST) axon regrowth after spinal cord injury (SCI). In young rodents, knockdown of PTEN, which antagonizes PI3K signaling by hydrolyzing PIP3, promotes axon regeneration following SCI. However, this effect diminishes in adults, potentially due to lower PI3K activation leading to reduced PIP3. This study explores whether increased PIP3 generation can promote long-distance regeneration in adults. We used a hyperactive PI3K, PI3Kδ (PIK3CD), to boost PIP3 levels in mature cortical neurons and assessed CST regeneration after SCI. Adult rats received AAV1-PIK3CD and AAV1-eGFP, or AAV1-eGFP alone, in the sensorimotor cortex concurrent with a C4 dorsal SCI. Transduced neurons showed increased pS6 levels, indicating elevated PI3K/Akt/mTOR signaling. CST regeneration, confirmed with retrograde tracing, was evaluated up to 16 weeks post injury. At 12 weeks, ∼100 axons were present at lesion sites, doubling to 200 by 16 weeks, with regeneration indices of 0.1 and 0.2, respectively. Behavioral tests showed significant improvements in paw reaching, grip strength, and ladder-rung walking in PIK3CD-treated rats, corroborated by electrophysiological recordings of cord dorsum potentials and distal flexor muscle electromyography. Thus, PI3Kδ upregulation in adult cortical neurons enhances axonal regeneration and functional recovery post SCI.

• MeSH
• axony metabolismus   fyziologie   MeSH
• Dependovirus genetika   MeSH
• fosfatidylinositol-3-kinasy třídy I metabolismus   genetika   MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• genetické vektory genetika   MeSH
• krysa rodu rattus MeSH
• modely nemocí na zvířatech MeSH
• neurony metabolismus   MeSH
• obnova funkce MeSH
• poranění míchy * metabolismus   terapie   genetika   MeSH
• pyramidové dráhy * metabolismus   MeSH
• regenerace nervu * MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

CXCL12 and CXCR4 proteins and mRNAs were monitored in the dorsal root ganglia (DRGs) of lumbar (L4-L5) and cervical (C7-C8) spinal segments of naïve rats, rats subjected to sham operation, and those undergoing unilateral complete sciatic nerve transection (CSNT) on post-operation day 7 (POD7). Immunohistochemical, Western blot, and RT-PCR analyses revealed bilaterally increased levels of CXCR4 protein and mRNA in both lumbar and cervical DRG neurons after CSNT. Similarly, CXCL12 protein levels increased, and CXCL12 mRNA was upregulated primarily in lumbar DRGs ipsilateral to the nerve lesion. Intrathecal application of the CXCR4 inhibitor AMD3100 following CSNT reduced CXCL12 and CXCR4 protein levels in cervical DRG neurons, as well as the length of afferent axons regenerated distal to the ulnar nerve crush. Furthermore, treatment with the CXCR4 inhibitor decreased levels of activated Signal Transducer and Activator of Transcription 3 (STAT3), a critical transforming factor in the neuronal regeneration program. Administration of IL-6 increased CXCR4 levels, whereas the JAK2-dependent STAT3 phosphorylation inhibitor (AG490) conversely decreased CXCR4 levels. This indicates a link between the CXCL12/CXCR4 signaling axis and IL-6-induced activation of STAT3 in the sciatic nerve injury-induced pro-regenerative state of cervical DRG neurons. The role of CXCR4 signaling in the axon-promoting state of DRG neurons was confirmed through in vitro cultivation of primary sensory neurons in a medium supplemented with CXCL12, with or without AMD3100. The potential involvement of conditioned cervical DRG neurons in the induction of neuropathic pain is discussed.

• MeSH
• benzylaminy MeSH
• chemokin CXCL12 * metabolismus   MeSH
• cyklamy farmakologie   MeSH
• heterocyklické sloučeniny farmakologie   MeSH
• interleukin-6 metabolismus   MeSH
• krysa rodu rattus MeSH
• nemoci sedacího nervu metabolismus   MeSH
• nervové receptory * metabolismus   MeSH
• nervus ischiadicus * zranění   metabolismus   MeSH
• potkani Sprague-Dawley MeSH
• receptory CXCR4 * metabolismus   MeSH
• regenerace nervu * MeSH
• signální transdukce * MeSH
• spinální ganglia * metabolismus   MeSH
• transkripční faktor STAT3 * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Mammalian neurons lose the ability to regenerate their central nervous system axons as they mature during embryonic or early postnatal development. Neuronal maturation requires a transformation from a situation in which neuronal components grow and assemble to one in which these components are fixed and involved in the machinery for effective information transmission and computation. To regenerate after injury, neurons need to overcome this fixed state to reactivate their growth programme. A variety of intracellular processes involved in initiating or sustaining neuronal maturation, including the regulation of gene expression, cytoskeletal restructuring and shifts in intracellular trafficking, have been shown to prevent axon regeneration. Understanding these processes will contribute to the identification of targets to promote repair after injury or disease.

• MeSH
• axony * fyziologie   MeSH
• lidé MeSH
• neurogeneze * fyziologie   MeSH
• neurony fyziologie   MeSH
• regenerace nervu * fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Dual nerve transfer of the spinal accessory nerve to the suprascapular nerve (SAN-SSN) and the radial nerve to the axillary nerve is considered to be the most feasible method of restoration of shoulder abduction in brachial plexus injuries. Supraspinatus muscle plays an important role in the initiation of abduction and its functional restoration is crucial for shoulder movements. There are two possible approaches for the SAN-SSN transfer: the more conventional anterior approach and the posterior approach in the area of scapular spine, which allows more distal neurotization. Although the dual nerve transfer is a widely used method, it is unclear which approach for the SAN-SSN transfer results in better outcomes. We conducted a search of English literature from January 2001 to December 2021 using the PRISMA guidelines. Twelve studies with a total 142 patients met our inclusion criteria. Patients were divided into two groups depending on the approach used: Group A included patients who underwent the anterior approach, and Group B included patients who underwent the posterior approach. Abduction strength using the Medical Research Scale (MRC) and range of motion (ROM) were assessed. The average MRC grade was 3.57 ± 1.08 in Group A and 4.0 ± 0.65 (p = 0.65) in Group B. The average ROM was 114.6 ± 36.7 degrees in Group A and 103.4 ± 37.2 degrees in Group B (p = 0.247). In conclusion, we did not find statistically significant differences between SAN-SSN transfers performed from the anterior or posterior approach in patients undergoing dual neurotization technique for restoration of shoulder abduction.

• MeSH
• kognice MeSH
• lidé MeSH
• nervový transfer * MeSH
• nervus radialis MeSH
• rameno * chirurgie   MeSH
• regenerace nervu MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• systematický přehled MeSH

Spinal cord injuries have devastating consequences for humans, as mammalian neurons of the central nervous system (CNS) cannot regenerate. In the peripheral nervous system (PNS), however, neurons may regenerate to restore lost function following injury. While mammalian CNS tissue softens after injury, how PNS tissue mechanics changes in response to mechanical trauma is currently poorly understood. Here we characterised mechanical rat nerve tissue properties before and after in vivo crush and transection injuries using atomic force microscopy-based indentation measurements. Unlike CNS tissue, PNS tissue significantly stiffened after both types of tissue damage. This nerve tissue stiffening strongly correlated with an increase in collagen I levels. Schwann cells, which crucially support PNS regeneration, became more motile and proliferative on stiffer substrates in vitro, suggesting that changes in tissue stiffness may play a key role in facilitating or impeding nervous system regeneration.

• MeSH
• axony fyziologie   MeSH
• centrální nervový systém MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• nervová tkáň * MeSH
• neurony MeSH
• poranění míchy * MeSH
• regenerace nervu fyziologie   MeSH
• savci MeSH
• Schwannovy buňky fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Spinal cord injuries (SCI), for which there are limited effective treatments, result in enduring paralysis and hypoesthesia, in part because of the inhibitory microenvironment that develops and limits regeneration/sprouting, especially during chronic stages. Recently, we discovered that targeted enzymatic removal of the inhibitory chondroitin sulfate proteoglycan (CSPG) component of the extracellular and perineuronal net (PNN) matrix via Chondroitinase ABC (ChABC) rapidly restored robust respiratory function to the previously paralyzed hemi-diaphragm after remarkably long times post-injury (up to 1.5 years) following a cervical level 2 lateral hemi-transection. Importantly, ChABC treatment at cervical level 4 in this chronic model also elicited improvements in gross upper arm function. In the present study, we focused on arm and hand function, seeking to highlight and optimize crude as well as fine motor control of the forearm and digits at lengthy chronic stages post-injury. However, instead of using ChABC, we utilized a novel and more clinically relevant systemic combinatorial treatment strategy designed to simultaneously reduce and overcome inhibitory CSPGs. Following a 3-month upper cervical spinal hemi-lesion using adult female Sprague Dawley rats, we show that the combined treatment had a profound effect on functional recovery of the chronically paralyzed forelimb and paw, as well as on precision movements of the digits. The regenerative and immune system related events that we describe deepen our basic understanding of the crucial role of CSPG-mediated inhibition via the PTPσ receptor in constraining functional synaptic plasticity at lengthy time points following SCI, hopefully leading to clinically relevant translational benefits.

• MeSH
• chondroitinasa ABC farmakologie   MeSH
• chondroitinsulfát proteoglykany * farmakologie   MeSH
• krysa rodu rattus MeSH
• mícha MeSH
• poranění míchy * MeSH
• potkani Sprague-Dawley MeSH
• přední končetina MeSH
• regenerace nervu fyziologie   MeSH
• tyrosinfosfatasy receptorového typu, třída 2 MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The peripheral branch of sensory dorsal root ganglion (DRG) neurons regenerates readily after injury unlike their central branch in the spinal cord. However, extensive regeneration and reconnection of sensory axons in the spinal cord can be driven by the expression of α9 integrin and its activator kindlin-1 (α9k1), which enable axons to interact with tenascin-C. To elucidate the mechanisms and downstream pathways affected by activated integrin expression and central regeneration, we conducted transcriptomic analyses of adult male rat DRG sensory neurons transduced with α9k1, and controls, with and without axotomy of the central branch. Expression of α9k1 without the central axotomy led to upregulation of a known PNS regeneration program, including many genes associated with peripheral nerve regeneration. Coupling α9k1 treatment with dorsal root axotomy led to extensive central axonal regeneration. In addition to the program upregulated by α9k1 expression, regeneration in the spinal cord led to expression of a distinctive CNS regeneration program, including genes associated with ubiquitination, autophagy, endoplasmic reticulum (ER), trafficking, and signaling. Pharmacological inhibition of these processes blocked the regeneration of axons from DRGs and human iPSC-derived sensory neurons, validating their causal contributions to sensory regeneration. This CNS regeneration-associated program showed little correlation with either embryonic development or PNS regeneration programs. Potential transcriptional drivers of this CNS program coupled to regeneration include Mef2a, Runx3, E2f4, and Yy1. Signaling from integrins primes sensory neurons for regeneration, but their axon growth in the CNS is associated with an additional distinctive program that differs from that involved in PNS regeneration.SIGNIFICANCE STATEMENT Restoration of neurologic function after spinal cord injury has yet to be achieved in human patients. To accomplish this, severed nerve fibers must be made to regenerate. Reconstruction of nerve pathways has not been possible, but recently, a method for stimulating long-distance axon regeneration of sensory fibers in rodents has been developed. This research uses profiling of messenger RNAs in the regenerating sensory neurons to discover which mechanisms are activated. This study shows that the regenerating neurons initiate a novel CNS regeneration program which includes molecular transport, autophagy, ubiquitination, and modulation of the endoplasmic reticulum (ER). The study identifies mechanisms that neurons need to activate to regenerate their nerve fibers.

• MeSH
• axony * fyziologie   MeSH
• integriny metabolismus   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• mícha metabolismus   MeSH
• nervové receptory fyziologie   MeSH
• poranění míchy * terapie   metabolismus   MeSH
• potkani Sprague-Dawley MeSH
• regenerace nervu fyziologie   MeSH
• spinální ganglia metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

• MeSH
• dítě MeSH
• dospělí MeSH
• fyzikální stimulace MeSH
• komplikace porodu MeSH
• lidé MeSH
• novorozenec MeSH
• paréza rehabilitace   MeSH
• pohybová aktivita fyziologie   MeSH
• poporodní paréza brachiálního plexu * etiologie   klasifikace   rehabilitace   vrozené   MeSH
• poranění nervového systému etiologie   MeSH
• prognóza MeSH
• ramenní kloub patofyziologie   MeSH
• reflexní terapie metody   MeSH
• regenerace nervu fyziologie   MeSH
• rozsah kloubních pohybů fyziologie   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• novorozenec MeSH

OBJECTIVES: To investigate the anatomical feasibility of the infraspinatus branch of the suprascapular nerve (IB-SSN) reconstruction by lower subscapular nerve (LSN) transfer. METHODS: The morphological study was performed on 18 adult human cadavers. The length of the distal stump of the IB-SSN, the length of the LSN available for reconstruction and diameter of both stumps were measured. The feasibility study of the LSN to IB-SSN transfer was performed. RESULTS: The mean length of the IB-SSN to the end of its first branch was 40.9 mm (±4.6). Its mean diameter was 2.3 mm (±0.3). The mean length of the LSN stump, which was mobilized from its original course and transferred to reach the distal stump of the IB-SSN was 66.5 mm (±11.8). Its mean diameter was 2.1 mm (±0.3). The mean ratio between LSN and IB-SSN diameters was 0.9 (±0.1). The nerve transfer was feasible in 17 out of 18 cases (94.4%). CONCLUSION: This study demonstrates that direct LSN to IB-SSN transfer is anatomically feasible in most cases in the adult population. It may be used in cases of complex scapular fractures resulting in severe suprascapular nerve injury.

• MeSH
• dospělí MeSH
• lidé MeSH
• nervový transfer * metody   MeSH
• plexus brachialis * chirurgie   MeSH
• regenerace nervu fyziologie   MeSH
• rotátorová manžeta MeSH
• studie proveditelnosti MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The aim of this study was to assess 17-β-estradiol (E2) influence on sciatic nerve regeneration after injury followed by a repair with chitosan conduit in ovariectomized female rats. The study was performed in 2 groups (n = 16) of rats: OVChit - after excision of a fragment of the sciatic nerve, a chitosan conduit was implanted; OVChitE10 group - additionally to chitosan conduit, shape-memory terpolymer rods based on poly(L-lactide-co-glycolide- co-trimethylene carbonate) releasing 17-β-estradiol for 20 weeks were implanted. The mean number of regenerating axons and mean fiber area were significantly greater in 17-β-estradiol-treated animals. In this group, the infiltrate of leukocytes was diminished. The presence of 17-β-estradiol receptors alpha and beta in motoneurons in the spinal cord were discovered. This may indicate the location where 17-β-estradiol affects the regeneration of the injured nerve. Estradiol released from the terpolymer rods for 20 weeks could enhance, to some extent, sciatic nerve regeneration after injury, and diminish the inflammatory reaction. In the future, 17-β-estradiol entrapped in terpolymer rods could be used in the repair of injured peripheral nerves, but there is a need for further studies.

• MeSH
• chitosan * farmakologie   MeSH
• estradiol farmakologie   MeSH
• krysa rodu rattus MeSH
• nervus ischiadicus chirurgie   MeSH
• potkani Wistar MeSH
• receptory estradiolu MeSH
• regenerace nervu MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH