Spontaneous and induced aberrant sprouting at the site of injury is irrelevant to motor function outcome in rats with spinal cord injury

Guı́zar-Sahagún, Gabriel; Grijalva, Israel; Salgado–Ceballos, Hermelinda; Espitia, A. L.; Orozco, Sandra; Ibarra, Antonio; Martínez, Angelina; Franco-Bourland, Rebecca E.; Madrazo, Ignacio

doi:10.1016/j.brainres.2004.03.062

Cited by 15 publications

(10 citation statements)

References 55 publications

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“…Neurons can extend compact neurites with many branches (arbors) or long solitary elongating axons with few branches (Smith and Skene, 1997). Therapies that induce an arborizing vs. elongating regeneration after injury/disease may have different effects on functional recovery (Guizar-Sahagun et al, 2004). For instance, pain is often associated with excess sprouting (arborization) while long distance regeneration will require elongating axon growth (Hofstetter et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Semi-automated Sholl analysis for quantifying changes in growth and differentiation of neurons and glia

Gensel

Schonberg

Alexander

et al. 2010

Journal of Neuroscience Methods

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There is a need to develop therapies that promote growth or remyelination of mammalian CNS axons. Although the feasibility of pre-clinical treatment strategies should be tested in animal models, in vitro assays are usually faster and less expensive. As a result, in vitro models are ideal for screening large numbers of potential therapeutics prior to use in more complex in vivo systems. In 1953, Sholl introduced a technique that is a reliable and sensitive method for quantifying indices of neurite outgrowth. However, application of the technique is limited because it is labor-intensive. Several methods have been developed to reduce the analysis time for the Sholl technique; but these methods require extensive pre-processing of digital images, they introduce user bias or they have not been compared to manual analysis to ensure accuracy. Here we describe a new, semi-automated Sholl technique for quantifying neuronal and glial process morphology. Using MetaMorph®, we developed an unbiased analysis protocol that can be performed ~3x faster than manual quantification with a comparable level of accuracy regardless of cell morphology. The laborious image processing typical of most computer-aided analysis is avoided by embedding image correction functions into the automated portion of the analysis. The sensitivity and validity of the technique was confirmed by quantifying neuron growth treated with growth factors or oligodendroglial maturation in the presence or absence of thyroid hormone. Thus, this technique provides a rapid and sensitive method for quantifying changes in cell morphology and screening for treatment effects in multiple cell types in vitro.

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Section: Discussionmentioning

confidence: 99%

Semi-automated Sholl analysis for quantifying changes in growth and differentiation of neurons and glia

Gensel

Schonberg

Alexander

et al. 2010

Journal of Neuroscience Methods

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“…This method does not, however, distinguish between the myelin status of spared, anatomically intact axons and the proximal stumps of injury-severed axons. Distal segments of severed axons undergo protracted Wallerian degeneration and proximal segments persist perilesionally with abortive, dystrophic endbulbs that likely provide no meaningful function (Coleman and Perry, 2002; Guizar-Sahagun et al, 2004; Tom et al, 2004). Previously, we developed an experimental approach to discriminate between severed and spared axons and found in the chronically injured mouse that intact axons are extensively remyelinated (Lasiene et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Axonal Thinning and Extensive Remyelination without Chronic Demyelination in Spinal Injured Rats

et al. 2012

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Remyelination following spinal cord injury (SCI) is thought to be incomplete; demyelination is reported to persist chronically and is proposed as a compelling therapeutic target. Yet most reports do not distinguish between the myelin status of intact axons and injury-severed axons whose proximal stumps persist but provide no meaningful function. We previously found full remyelination of spared, intact rubrospinal axons caudal to the lesion in chronic mouse SCI. However, the clinical concept of chronically demyelinated spared axons remains controversial. Since mouse models may have limitations in clinical translation, we asked whether the capacity for full remyelination is conserved in clinically relevant chronic rat SCI. We determined myelin status by examining paranodal protein distribution on anterogradely labeled, intact corticospinal and rubrospinal axons throughout the extent of the lesion. Demyelination was evident on proximal stumps of severed axons, but not on intact axons. For the first time, we demonstrate that a majority of intact axons exhibit remyelination (at least one abnormally short internode, < 100 μm). Remarkably, shortened internodes were significantly concentrated at the lesion epicenter and individual axons were thinned by 23% compared to their rostral and caudal zones. Mathematical modeling predicted a 25% decrease in conduction velocity at the lesion epicenter due to short internodes and axonal thinning. In conclusion, we do not find a large chronically demyelinated population to target with remyelination therapies. Interventions may be better focused on correcting structural or molecular abnormalities of regenerated myelin.

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“…In contrast, other steroids, such as prednisolone, inhibit aberrant sprouting in the injured rat spinal cord. 19 Perhaps in the present experiments progesterone facilitated the release of trophic factors from nearby Schwann cells. 31,32,[45][46][47] Nerve sectioning plays a fundamental role in aberrant innervation, since it occurred even in animals implanted with silicone tubes.…”

Section: Discussionmentioning

confidence: 51%

Aberrant gastrocnemius muscle innervation by tibial nerve afferents after implantation of chitosan tubes impregnated with progesterone favored locomotion recovery in rats with transected sciatic nerve

Sarabia-Estrada

Bañuelos-Pineda

Osuna-Carrasco³

et al. 2015

JNS

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obJect Transection of peripheral nerves produces loss of sensory and/or motor function. After complete nerve cutting, the distal and proximal segment ends retract, but if both ends are bridged with unaltered chitosan, progesteroneimpregnated chitosan, or silicone tubes, an axonal repair process begins. Progesterone promotes nerve repair and has neuroprotective effects thwarting regulation of neuron survival, inflammation, and edema. It also modulates aberrant axonal sprouting and demyelination. The authors compared the efficacy of nerve recovery after implantation of progesterone-loaded chitosan, unaltered chitosan, or silicone tubes after sciatic nerve transection in rats. methods After surgical removal of a 5-mm segment of the proximal sciatic nerve, rats were implanted with progesterone-loaded chitosan, unaltered chitosan, or silicone tubes in the transected nerve for evaluating progesterone and chitosan effects on sciatic nerve repair and ipsilateral hindlimb kinematic function, as well as on gastrocnemius electromyographic responses. In some experiments, tube implantation was performed 90 minutes after nerve transection. results At 90 days after sciatic nerve transection and tube implantation, rats with progesterone-loaded chitosan tubes showed knee angular displacement recovery and better outcomes for step length, velocity of locomotion, and normal hindlimb raising above the ground. In contrast, rats with chitosan-only tubes showed reduced normal raising and pendulum-like hindlimb movements. Aberrant fibers coming from the tibial nerve innervated the gastrocnemius muscle, producing electromyographic responses. Electrical responses in the gastrocnemius muscle produced by sciatic nerve stimulation occurred only when the distal nerve segment was stimulated; they were absent when the proximal or intratubular segment was stimulated. A clear sciatic nerve morphology with some myelinated fiber fascicles appeared in the tube section in rats with progesterone-impregnated chitosan tubes. Some gastrocnemius efferent fibers were partially repaired 90 days after nerve resection. The better outcome in knee angle displacement may be partially attributable to the aberrant neuromuscular synaptic effects, since nerve conduction in the gastrocnemius muscle could be blocked in the progesterone-impregnated chitosan tubes. In addition, in the region of the gap produced by the nerve resection, the number of axons and amount of myelination were reduced in the sciatic nerve implanted with chitosan, progesteroneloaded chitosan, and silicone tubes. At 180 days after sciatic nerve sectioning, the knee kinematic function recovered to a level observed in control rats of a similar age. In rats with progesterone-loaded chitosan tubes, stimulation of the proximal and intratubular sciatic nerve segments produced an electromyographic response. The axon morphology of the proximal and intratubular segments of the sciatic nerve resembled that of the contralateral nontransected nerve. coNclusioNs Progesterone-impregnated chitosan tubes produced...

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Spontaneous and induced aberrant sprouting at the site of injury is irrelevant to motor function outcome in rats with spinal cord injury

Cited by 15 publications

References 55 publications

Semi-automated Sholl analysis for quantifying changes in growth and differentiation of neurons and glia

Semi-automated Sholl analysis for quantifying changes in growth and differentiation of neurons and glia

Axonal Thinning and Extensive Remyelination without Chronic Demyelination in Spinal Injured Rats

Aberrant gastrocnemius muscle innervation by tibial nerve afferents after implantation of chitosan tubes impregnated with progesterone favored locomotion recovery in rats with transected sciatic nerve

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