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Polyethylene glycol fusion repair of severed rat sciatic nerves reestablishes axonal continuity and reorganizes sensory terminal fields in the spinal cord

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Neural regeneration research 2025年第7期20卷 2095-2107页

作者： Emily A.Hibbard Liwen Zhou Cathy Z.Yang Karthik Venkudusamy Yessenia Montoya Alexa Olivarez George D.Bittner dale r.sengelaub Program in Neuroscience Indiana UniversityBloomingtonINUSA Department of Neuroscience University of Texas at AustinAustinTXUSA

Peripheral nerve injuries result in the rapid degeneration of distal nerve segments and immediate loss of motor and sensory functions;behavioral recovery is typically *** used a plasmalemmal fusogen,polyethylene glycol(PEG),to immediately fuse closely apposed open ends of severed proximal and distal axons in rat sciatic *** have previously reported that sciatic nerve axons repaired by PEG-fusion do not undergo Wallerian degeneration,and PEG-fused animals exhibit rapid(within 2–6 weeks)and extensive locomotor ***,our previous report showed that PEG-fusion of severed sciatic motor axons was non-specific,i.e.,spinal motoneurons in PEG-fused animals were found to project to appropriate as well as inappropriate target *** this study,we examined the consequences of PEG-fusion for sensory axons of the sciatic *** adult male and female rats(Sprague–Dawley)received either a unilateral single cut or ablation injury to the sciatic nerve and subsequent repair with or without(Negative Control)the application of *** action potentials recorded immediately after PEG-fusion repair confirmed conduction across the injury *** success of PEG-fusion was confirmed through Sciatic Functional Index testing with PEG-fused animals showing improvement in locomotor function beginning at 35 days *** 2–42 days postoperatively,we anterogradely labeled sensory afferents from the dorsal aspect of the hindpaw following bilateral intradermal injection of wheat germ agglutinin conjugated horseradish ***-fusion repair reestablished axonal *** to unoperated animals,labeled sensory afferents ipsilateral to the injury in PEG-fused animals were found in the appropriate area of the dorsal horn,as well as inappropriate mediolateral and rostrocaudal ***,despite having intact peripheral nerves,similar reorganizations of labeled sensory afferents were also observed contralateral to the injury and repa

关键词： axotomy dorsal horn peripheral nerve injury plasticity polyethylene glycol(PEG) sciatic nerve sensory terminals wheat germ agglutinin horseradish peroxidase

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Exercise promotes recovery after motoneuron injury via hormonal mechanisms

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Neural regeneration research 2020年第8期15卷 1373-1376页

作者： Cory Chew dale r.sengelaub Psychological and Brain Sciences Indiana University

Injuries to spinal motoneurons manifest in a variety of forms,including damage to peripheral axons,neurodegenerative disease,or direct insult *** injuries produce a variety of negative structural and functional changes in both the directly affected and neighboring *** is a relatively simple behavioral intervention that has been demonstrated to protect against,and accelerate recovery from,these negative *** this article,we describe how exercise is neuroprotective for motoneurons,accelerating axon regeneration following axotomy and attenuating dendritic atrophy following the death of neighboring *** both of these injury models,the positive effects of exercise have been found to be dependent on gonadal hormone *** we describe a model in which exercise,hormones,and brain-derived neurotrophic factor might all interact to produce neuroprotective effects on motoneuron structure following neural injury.

关键词： axon regeneration axotomy dendritic morphology exercise hormones neuroprotection neurotrophins

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Protective effects of gonadal hormones on spinal motoneurons following spinal cord injury

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Neural regeneration research 2018年第6期13卷 971-976页

作者： dale r.sengelaub Xiao-Ming Xu Psychological and Brain Sciences Indiana University Spinal Cord and Brain Injury research Group Stark Neurosciences Research Institute Department of Neurological Surgery Indiana University School of Medicine

Spinal cord injury（SCI） results in lesions that destroy tissue and disrupt spinal tracts, producing deficits in locomotor and autonomic function. The majority of treatment strategies after SCI have concentrated on the damaged spinal cord, for example working to reduce lesion size or spread, or encouraging regrowth of severed descending axonal projections through the lesion, hoping to re-establish synaptic connectivity with caudal targets. In our work, we have focused on a novel target for treatment after SCI, surviving spinal motoneurons and their target musculature, with the hope of developing effective treatments to preserve or restore lost function following SCI. We previously demonstrated that motoneurons, and the muscles they innervate, show pronounced atrophy after SCI. Importantly, SCI-induced atrophy of motoneuron dendrites can be attenuated by treatment with gonadal hormones, testosterone and its active metabolites, estradiol and dihydrotestosterone. Similarly, SCI-induced reductions in muscle fiber cross-sectional areas can be prevented by treatment with androgens. Together, these findings suggest that regressive changes in motoneuron and muscle morphology seen after SCI can be ameliorated by treatment with gonadal hormones, further supporting a role for steroid hormones as neurotherapeutic agents in the injured nervous system.

关键词： testosterone dihydrotestosterone estradiol steroids atrophy neuroprotection morphology dendrites muscle fibers retrograde labeling

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Conundrums and confusions regarding how polyethylene glycol-fusion produces excellent behavioral recovery after peripheral nerve injuries

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Neural regeneration research 2018年第1期13卷 53-57页

作者： George D.Bittner dale r.sengelaub Cameron L.Ghergherehchi Department of Neuroscience University of Texas at Austin Department of Psychological and Brain Sciences Indiana University Department of Molecular Biosciences University of Texas at Austin

Current Neuroscience dogma holds that transections or ablations of a segment of peripheral nerves produce：（1） Immediate loss of axonal continuity, sensory signaling, and motor control; （2） Wallerian rapid （1-3 days） degeneration of severed distal axons, muscle atrophy, and poor behavioral recovery after many months （if ever, after ablations） by slowly-regenerating （1 mm/d）, proximal-stump outgrowths that must specifically reinnervate denervated targets; （3） Poor acceptance of microsutured nerve allografts, even if tissue-matched and immune-suppressed. repair of transections/ablations by neurorrhaphy and well-specified-sequences of PEG-fusion solutions （one containing polyethylene glycol, PEG） successfully address these problems. However, conundrums and confusions regarding unorthodox and dramatic results of PEG-fusion repair in animal model systems often lead to misunderstandings. For example, （1） Axonal continuity and signaling is re-established within minutes by non-specifically PEG-fusing （connecting） severed motor and sensory axons across each lesion site, but remarkable behavioral recovery to near-unoperated levels takes several weeks; （2） Many distal stumps of inappropriately-reconnected, PEG-fused axons do not ever （Wallerian） degenerate and continuously innervate muscle fibers that undergo much less atrophy than otherwise-denervated muscle fibers; （3） Host rats do not reject PEG-fused donor nerve allografts in a non-immuno-privileged environment with no tissue matching or immunosuppression; （4） PEG fuses apposed open axonal ends or seals each shut （thereby preventing PEG-fusion）, depending on the experimental protocol; （5） PEG-fusion protocols produce similar results in animal model systems and early human case studies. Hence, iconoclastic PEG-fusion data appropriately understood might provoke a re-thinking of some Neuroscience dogma and a paradigm shift in clinical treatment of peripheral nerve injuries.

关键词： axonal repair axotomy Wallerian degeneration polyethylene glycol allograft autograft nerve regeneration

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