Non-viral Vector Mediated RNA Interference Technology for Central Nervous System Injury

AbstractNeuronal axons damaged by traumatic injury are unable to spontaneously regenerate in the mammalian adult central nervous system (CNS), causing permanent motor, sensory, and cognitive deficits. Regenerative failure in the adult CNS results from a complex pathology presenting multiple barriers, both the presence of growth inhibitors in the extrinsic microenvironment and intrinsic deficiencies in neuronal biochemistry, to axonal regeneration and functional recovery. There are many strategies for axonal regeneration after CNS injury including antagonism of growth-inhibitory molecules and their receptors, manipulation of cyclic nucleotide levels, and delivery of growth-promoting stimuli through cell transplantation and neurotrophic factor delivery. While all of these approaches have achieved varying degrees of improvement in plasticity, regeneration, and function, there is no clinically effective therapy for CNS injury. RNA interference technology offers strategies for improving regeneration by overcoming the aspects of the injured CNS environment that inhibit neurite growth. This occurs through the knockdown of growth-inhibitory molecules and their receptors. In this review, we discuss the current state of RNAi strategies for the treatment of CNS injury based on non-viral vector mediated delivery.

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Nogo-A Represses Anatomical and Synaptic Plasticity in the Central Nervous System

Physiology ◽

10.1152/physiol.00052.2012 ◽

2013 ◽

Vol 28 (3) ◽

pp. 151-163 ◽

Cited By ~ 31

Author(s):

Anissa Kempf ◽

Martin E. Schwab

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Synaptic Plasticity ◽

Axonal Regeneration ◽

Current Knowledge ◽

Cns Injury ◽

Inhibitory Protein ◽

Growth Inhibitory ◽

The Central Nervous System ◽

Regulation Of Growth

Nogo-A was initially discovered as a myelin-associated growth inhibitory protein limiting axonal regeneration after central nervous system (CNS) injury. This review summarizes current knowledge on how myelin and neuronal Nogo-A and its receptors exert physiological functions ranging from the regulation of growth suppression to synaptic plasticity in the developing and adult intact CNS.

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Acellularized spinal cord scaffolds incorporating bpV(pic)/PLGA microspheres promote axonal regeneration and functional recovery after spinal cord injury

RSC Advances ◽

10.1039/d0ra02661a ◽

2020 ◽

Vol 10 (32) ◽

pp. 18677-18686

Author(s):

Jia Liu ◽

Kai Li ◽

Ke Huang ◽

Chengliang Yang ◽

Zhipeng Huang ◽

...

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Spinal Cord Injury ◽

Nervous System ◽

Axonal Regeneration ◽

Traumatic Injury ◽

High Rate ◽

Plga Microspheres ◽

Cord Injury ◽

The Central Nervous System

Spinal cord injury (SCI) is a traumatic injury to the central nervous system (CNS) with a high rate of disability and a low capability of self-recovery.

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Regenerative Nerve Fiber Growth in the Adult Central Nervous System

Physiology ◽

10.1152/physiologyonline.1998.13.6.294 ◽

1998 ◽

Vol 13 (6) ◽

pp. 294-298 ◽

Cited By ~ 1

Author(s):

Martin E. Schwab

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Neutralizing Antibody ◽

Neurite Growth ◽

Long Distance ◽

Adult Rats ◽

Adult Central Nervous System ◽

Growth Inhibitory ◽

Output System

Neurite growth and regeneration in the adult central nervous system (CNS) is extremely limited. An important factor contributing to these restrictions is specific growth inhibitory proteins associated with oligodendrocytes and CNS myelin. A major inhibitory factor is the antigen of a monoclonal antibody; the application of this neutralizing antibody to spinal cord- or brain-lesioned adult rats induces long-distance regeneration of lesioned axons, as well as a specific increase in sprouting and rewiring of the cortical output system to the brain stem and the spinal cord. These anatomic changes are paralleled by important functional recoveries of locomotion and precision movements.

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The natural history of the myelin-derived nerve growth inhibitor Nogo-A

Neuron Glia Biology ◽

10.1017/s1740925x09990147 ◽

2008 ◽

Vol 4 (2) ◽

pp. 83-89 ◽

Cited By ~ 11

Author(s):

Rüdiger Schweigreiter

Keyword(s):

Central Nervous System ◽

Endoplasmic Reticulum ◽

Nervous System ◽

Teleost Fish ◽

Growth Inhibitor ◽

Neurite Growth ◽

Nerve Growth ◽

Growth Inhibitory ◽

History Of ◽

Nogo Gene

Nogo-A is possibly the best characterized myelin-derived inhibitor of nerve growth in the adult central nervous system (CNS). It is a member of the ancient reticulon family of mainly endoplasmic reticulum resident proteins with representatives found throughout the eukaryotic domain. Orthologs of the nogo gene were identified in tetrapods and teleost fish but none have been detected in invertebrates. Evolution of the nogo gene has been non-homogeneous. The exon–intron arrangement is conserved from amphibians (Xenopus) to mammals, but partly deviates from that found in several teleost fish species, indicating that the recruitment of nogo exons proceeded along at least two independent lines during early vertebrate evolution. This might have far-reaching consequences. Tetrapod nogo orthologs encode two neurite growth inhibitory domains whereas in fish nogo only one of the inhibitory domains is present. These distinct paths in nogo evolution have potentially contributed to the regeneration permissive CNS in fish as opposed to the non-regenerating CNS in higher vertebrates.

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Glioblastoma infiltration into central nervous system tissue in vitro: involvement of a metalloprotease.

The Journal of Cell Biology ◽

10.1083/jcb.107.6.2281 ◽

1988 ◽

Vol 107 (6) ◽

pp. 2281-2291 ◽

Cited By ~ 68

Author(s):

P A Paganetti ◽

P Caroni ◽

M E Schwab

Keyword(s):

Central Nervous System ◽

Nervous System ◽

White Matter ◽

Optic Nerve ◽

Cell Attachment ◽

Neurite Growth ◽

Cell Spreading ◽

C6 Cells ◽

3T3 Fibroblasts

Differentiated oligodendrocytes and central nervous system (CNS) myelin are nonpermissive substrates for neurite growth and for cell attachment and spreading. This property is due to the presence of membrane-bound inhibitory proteins of 35 and 250 kD and is specifically neutralized by monoclonal antibody IN-1 (Caroni, P., and M. E. Schwab. 1988. Neuron. 1:85-96). Using rat optic nerve explants, CNS frozen sections, cultured oligodendrocytes or CNS myelin, we show here that highly invasive CNS tumor line (C6 glioblastoma) was not inhibited by these myelin-associated inhibitory components. Lack of inhibition was due to a specific mechanism as the metalloenzyme blocker 1,10-phenanthroline and two synthetic dipeptides containing metalloprotease-blocking sequences (gly-phe, tyr-tyr) specifically impaired C6 cell spreading on CNS myelin. In the presence of these inhibitors, C6 cells were affected by the IN-1-sensitive inhibitors in the same manner as control cells, e.g., 3T3 fibroblasts or B16 melanomas. Specific blockers of the serine, cysteine, and aspartyl protease classes had no effect. C6 cell spreading on inhibitor-free substrates such as CNS gray matter, peripheral nervous system myelin, glass, or poly-D-lysine was not sensitive to 1,10-phenanthroline. The nonpermissive substrate properties of CNS myelin were strongly reduced by incubation with a plasma membrane fraction prepared from C6 cells. This reduction was sensitive to the same inhibitors of metalloproteases. In our in vitro model for CNS white matter invasion, cell infiltration of optic nerve explants, which occurred with C6 cells but not with 3T3 fibroblasts or B16 melanomas, was impaired by the presence of the metalloprotease blockers. These results suggest that C6 cell infiltrative behavior in CNS white matter in vitro occurs by means of a metalloproteolytic activity, which probably acts on the myelin-associated inhibitory substrates.

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Understanding Neuropathic Pain

CNS Spectrums ◽

10.1017/s1092852900022628 ◽

2005 ◽

Vol 10 (4) ◽

pp. 298-308 ◽

Cited By ~ 38

Author(s):

Walter Zieglgänsberger ◽

Achim Berthele ◽

Thomas R. Tölle

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Neuropathic Pain ◽

Neuronal Excitability ◽

Traumatic Injury ◽

Nerve Fibers ◽

Cellular Events ◽

Excitatory Neurotransmitters ◽

The Central Nervous System ◽

Activity Dependent

AbstractNeuropathic pain is defined as a chronic pain condition that occurs or persists after a primary lesion or dysfunction of the peripheral or central nervous system. Traumatic injury of peripheral nerves also increases the excitability of nociceptors in and around nerve trunks and involves components released from nerve terminals (neurogenic inflammation) and immunological and vascular components from cells resident within or recruited into the affected area. Action potentials generated in nociceptors and injured nerve fibers release excitatory neurotransmitters at their synaptic terminals such as L-glutamate and substance P and trigger cellular events in the central nervous system that extend over different time frames. Short-term alterations of neuronal excitability, reflected for example in rapid changes of neuronal discharge activity, are sensitive to conventional analgesics, and do not commonly involve alterations in activity-dependent gene expression. Novel compounds and new regimens for drug treatment to influence activity-dependent long-term changes in pain transducing and suppressive systems (pain matrix) are emerging.

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