Homeostatic regulation of the endoneurial microenvironment during development, aging and in response to trauma, disease and toxic insult

Mizisin, Andrew P.; Weerasuriya, Ananda

doi:10.1007/s00401-010-0783-x

Cited by 157 publications

(166 citation statements)

References 181 publications

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“…Diffusion of molecules injected into the midsciatic nerve has been shown up to 10 mm proximal and distal to the injection site, consistent with the flow of endoneurial fluid (20,21). The higher pressure in the intrathecal CSF space (∼10 mm Hg) compared with endoneural pressure in peripheral nerves (1-2 mm Hg) and DRG (3-5 mm Hg) supports the diffusion of particles from subarachnoid space into the peripheral nerves (22). In addition, expression in Schwann cells of the trigeminal nerve also indicates that viral infection following L5-6 intrathecal delivery is not confined to the lumbar roots, but may be widespread along the neuraxis following diffusion through the CSF.…”

Section: Discussionsupporting

confidence: 56%

Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy

Kagiava

Sargiannidou

Theophilidis

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Inherited demyelinating peripheral neuropathies are progressive incurable diseases without effective treatment. To develop a gene therapy approach targeting myelinating Schwann cells that can be translatable, we delivered a lentiviral vector using a single lumbar intrathecal injection and a myelin-specific promoter. The human gene of interest, GJB1, which is mutated in X-linked CharcotMarie-Tooth Disease (CMT1X), was delivered intrathecally into adult Gjb1-null mice, a genetically authentic model of CMT1X that develops a demyelinating peripheral neuropathy. We obtained widespread, stable, and cell-specific expression of connexin32 in up to 50% of Schwann cells in multiple lumbar spinal roots and peripheral nerves. Behavioral and electrophysiological analysis revealed significantly improved motor performance, quadriceps muscle contractility, and sciatic nerve conduction velocities. Furthermore, treated mice exhibited reduced numbers of demyelinated and remyelinated fibers and fewer inflammatory cells in lumbar motor roots, as well as in the femoral motor and sciatic nerves. This study demonstrates that a single intrathecal lentiviral gene delivery can lead to Schwann cell-specific expression in spinal roots extending to multiple peripheral nerves. This clinically relevant approach improves the phenotype of an inherited neuropathy mouse model and provides proof of principle for treating inherited demyelinating neuropathies.demyelinating neuropathy | Charcot-Marie-Tooth disease | connexin32 | peripheral nerve | gene therapy

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Section: Discussionsupporting

confidence: 56%

Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy

Kagiava

Sargiannidou

Theophilidis

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…This was noted mainly in the peri and epineurium, where strong and intact nerve appears as dense layers, which give the nerve support, cushioning and resistance to tension (Bové, 2008;Mizisin & Weerasuriya, 2011;Yegiyants et al). These factors contributed to integrating the most robust cross -sectional area identified in the Control Group.…”

Section: Groupsmentioning

confidence: 98%

Regenerative Capacity and Histomorphometric Changes in Rat Sciatic Nerve Following Experimental Neurotmesis

et al. 2015

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capacity and histomorphometric changes in rat sciatic nerve following experimental neurotmesis. Int. J. Morphol., 33(2):777-781, 2015. SUMMARY:Through a wide range of cellular and molecular events, the peripheral nervous system is endowed with great regenerative capacity, responding immediately to injuries that occur along the length of the nerve. The aim of this study was to histomorphometrically assess the degree of maturity of the nervous tissue and possible microscopic changes in newly formed nerve segments 60 days after experimental neurotmesis of the sciatic nerve in rats. Control Group (CG) and an Injury Group (IG) were used. IG underwent neurotmesis of the sciatic nerve of the right foot, with immediate surgical repair using the tubulization technique. 60 days following experimental surgery, animals from both groups had their sciatic nerves collected for histomorphometric analysis. Statistical analysis was performed, using the Student t-test for independent samples, expressed as mean ± standard deviation, with 5% significance. In the event of injury, peripheral nerve tissue is mobilized in an intrinsic self-healing process. 60 days following of nerve regeneration in neurotmesis injury, the peripheral nerve presents a segment joining the newly formed neural stump. The new stump has a number of regenerated axons compatible with an intact nerve, but which still show great immaturity in the axonal structural layers of the nerve.

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“…Osman, A., Dahlin, L. B., Thomsen Peripheral nerves may include one, two, or the three types of nerve fibers [3]. Axons in the peripheral nerves are the long process of neurons that carry nerve signals between the CNS and the innervated targets in both directions.…”

Section: List Of Papersmentioning

confidence: 99%

Autophagy in Peripheral Neuropathy

Osman¹

2017

Linköping University Medical Dissertations

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Peripheral neuropathy includes a wide range of diseases affecting millions around the world, and many of these diseases have unknown etiology. Peripheral neuropathy in diabetes represents a large proportion of peripheral neuropathies. Nerve damage can also be caused by trauma. Peripheral neuropathies are a significant clinical problem and efficient treatments are largely lacking. In the case of a transected nerve, different methods have been used to repair or reconstruct the nerve, including the use of nerve conduits, but functional recovery is usually poor. Autophagy, a cellular mechanism that recycles damaged proteins, is impaired in the brain in many neurodegenerative diseases affecting animals and humans. No research, however, has investigated the presence of autophagy in the human peripheral nervous system. In this study, I present the first structural evidence of autophagy in human peripheral nerves. I also show that the density of autophagy structures is higher in peripheral nerves of patients with chronic idiopathic axonal polyneuropathy (CIAP) and inflammatory neuropathy than in controls. The density of these structures increases with the severity of the neuropathy. In animal model, using Goto-Kakizaki (GK) rats with diabetes resembling human type 2 diabetes, activation of autophagy by local administration of rapamycin incorporated in collagen conduits that were used for reconnection of the transected sciatic nerve led to an increase in autophagy proteins LC3 and a decrease in p62 suggesting that the autophagic flux was activated. In addition, immunoreactivity of neurofilaments, which are parts of the cytoskeleton of axons, was increased indicating increased axonal regeneration. I also show that many proteins involved in axonal regeneration and cell survival were up-regulated by rapamycin in the injured sciatic nerve of GK rats four weeks after injury. Taken together, these findings provide new knowledge about the involvement of autophagy in neuropathy and after peripheral nerve injury and reconstruction using collagen conduits. 6 Populärvetenskaplig sammanfattningNervskador (neuropati) orsakade av sjukdomar eller olycksfall påverkar miljontals individer runt om i världen. Nervskador som orsakas av diabetes kallas diabetesneuropati och drabbar varannan patient med diabetes. Neuropati kan också orsakas av kronisk inflammation i nerven eller uppstå utan känd orsak, så kallad kronisk idiopatisk axonal polyneuropati. Patienterna som drabbas av neuropati uppvisar varierande symptom beroende på vilka nerver som drabbas men domningar, stickningar, smärta, känselbortfall och muskelsvaghet finns ofta i symptombilden. Nervskador efter trauma kräver oftast kirurgisk rekonstruktion. För närvarande finns det ingen behandling för diabetesneuropati. Allt fler människor i fysiskt aktiv ålder drabbas av åldersdiabetes (typ 2 diabetes). Detta leder till att fler patienter med diabetes drabbas av traumatiska nervskador som kräver nervreparation. Det är därför viktigt att utveckla reparationsmetoder som fungerar br...

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Homeostatic regulation of the endoneurial microenvironment during development, aging and in response to trauma, disease and toxic insult

Cited by 157 publications

References 181 publications

Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy

Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy

Regenerative Capacity and Histomorphometric Changes in Rat Sciatic Nerve Following Experimental Neurotmesis

Autophagy in Peripheral Neuropathy

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