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1.
Neurosci Res ; 170: 114-121, 2021 Sep.
Article in English | MEDLINE | ID: mdl-33316301

ABSTRACT

Spinal cord injury (SCI) induces severe motor and sensory dysfunction. We previously showed the neuroprotective effects of COA-Cl, a novel synthesized adenosine analog, in a rat stroke model. In this study, we evaluated the neuroprotective effects of COA-Cl in acute phase of SCI. SCI was induced in rats at the T9 vertebra by using a drop device. Rats were divided into acute and subacute groups. A 5-day dose of 6 mg/kg COA-Cl in saline was given to the acute group immediately after SCI and the subacute group 4 days after SCI. Motor function assessed by Basso-Beattie-Bresnahan scoring and inclined plane test improved significantly in the acute group while the subacute group did not. Histological evaluation and TUNEL staining revealed that both the cavity volume and apoptosis were significantly decreased in the acute group compared with the subacute group. In addition, pERK/ERK was increased in the acute group 7 days after SCI. These results suggest that COA-Cl exerts neuroprotective effects via the ERK pathway when administered in the acute phase after SCI, resulting in the recovery of motor function. COA-Cl could be a novel therapeutic agent for the acute phase of SCI.


Subject(s)
Neuroprotective Agents , Spinal Cord Injuries , Animals , Apoptosis , Coenzyme A/pharmacology , Disease Models, Animal , Neuroprotective Agents/pharmacology , Rats , Rats, Sprague-Dawley , Recovery of Function , Spinal Cord , Spinal Cord Injuries/drug therapy
2.
Neurorehabil Neural Repair ; 33(7): 538-552, 2019 07.
Article in English | MEDLINE | ID: mdl-31140375

ABSTRACT

Background. Although the effect of rehabilitation is influenced by aspects of the training protocol, such as initiation time and intensity of training, it is unclear whether training protocol modifications affect the corticospinal projections. Objective. The present study was designed to investigate how modification of initiation time (time-dependency) and affected forelimb use (use-dependency) influence the effects of rehabilitation on functional recovery and corticospinal projections. Methods. The time-dependency of rehabilitation was investigated in rats forced to use their impaired forelimb immediately, at 1 day, and 4 days after photothrombotic stroke. The use-dependency of rehabilitation was investigated by comparing rats with affected forelimb immobilization (forced nonuse), unaffected forelimb immobilization (forced use), and a combination of forced use and skilled forelimb training beginning at 4 days after stroke. Results. Although forced use beginning 1 day or 4 days after stroke caused significant functional improvement, immediate forced limb use caused no functional improvement. On the other hand, a combination of forced use and skilled forelimb training boosted functional recovery in multiple tasks compared to simple forced use treatment. Histological examination showed that no treatment caused brain damage. However, a retrograde tracer study revealed that immediate forced use and combination training, including forced use and skilled forelimb training, increased corticospinal projections from the contralesional and ipsilesional motor cortex, respectively. Conclusions. These results indicate that although both very early initiation time and enhanced skilled forelimb use increased corticospinal projections, premature initiation time hampers the functional improvement induced by poststroke rehabilitation.


Subject(s)
Exercise Therapy/methods , Forelimb/physiopathology , Motor Cortex/physiopathology , Stroke Rehabilitation/methods , Stroke/physiopathology , Animals , Disease Models, Animal , Exercise Therapy/standards , Male , Rats , Rats, Inbred F344 , Stroke Rehabilitation/standards , Time Factors
3.
Eur J Neurosci ; 50(1): 1700-1711, 2019 07.
Article in English | MEDLINE | ID: mdl-30687962

ABSTRACT

Ca2+ -induced Ca2+ release (CICR) via type-3 ryanodine receptor enhances neurotransmitter release in frog motor nerve terminals. To test a possible role of synaptic vesicle in CICR, we examined the effects of loading of EGTA, a Ca2+ chelator, into synaptic vesicles and depolymerization of actin fibers. Intravesicular EGTA loading via endocytosis inhibited the ryanodine sensitive enhancement of transmitter release induced by tetanic stimulation and the associated rises in intracellular-free Ca2+ ([Ca2+ ]i : Ca2+ transients). Latrunculin A, a depolymerizer of actin fibers, enhanced both spontaneous and stimulation-induced transmitter release, but inhibited the enhancement of transmitter release elicited by successive tetanic stimulation. The results suggest a possibility that the activation of CICR from mobilized synaptic vesicles caused the enhancement of neurotransmitter release.


Subject(s)
Actins/drug effects , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Calcium Chelating Agents/pharmacology , Calcium/metabolism , Electrophysiological Phenomena , Motor Neurons/metabolism , Presynaptic Terminals/metabolism , Ryanodine Receptor Calcium Release Channel/metabolism , Synaptic Transmission/drug effects , Synaptic Vesicles/metabolism , Thiazolidines/pharmacology , Animals , Egtazic Acid/pharmacology , Electric Stimulation , Ranidae
4.
Spine J ; 19(6): 1094-1105, 2019 06.
Article in English | MEDLINE | ID: mdl-30583107

ABSTRACT

BACKGROUND: The involvement of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) in functional recovery after spinal cord injury (SCI) by treadmill training has been suggested. The precise mechanism is poorly understood. However, muscle-derived bioactive molecules (myokines) are known to be produced by muscle contraction. Although BDNF is a myokine and is considered to be a potential mediator of neuroplasticity following exercise, its contribution to motor function recovery after SCI has not yet been described in detail. PURPOSE: To investigate the role of muscle contraction in motor function recovery after SCI, with a focus on BDNF. STUDY DESIGN: Male Sprague-Dawley rats (aged 8-9 weeks) were used to establish the SCI model. Percutaneous electrical muscle stimulation (10 mA, 2 Hz, 10 minutes) was applied to both hindlimbs of the rats immediately after SCI. The stimulation was performed once per day for 4 weeks. The sham, SCI only (SCI), and SCI with electrical muscle stimulation (SCI+ES) groups were compared. METHODS: Spinal cord injury was induced by dropping a 20 g rod with an apex diameter of 2 mm from a height of 25 mm onto the spine of an anesthetized rat at the T9 level. Motor function was assessed using the Basso-Beattie-Bresnahan Locomotor Scale, inclined plane test, and rotarod test. One week after injury, terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells were counted at the injury epicenter, and the level of BDNF was measured in both the spinal cord and the anterior tibial muscle. Four weeks after injury, the cavity volume of the epicenter and the level of phosphorylated growth-associated protein 43 in the spinal cord were measured. RESULTS: Significantly improved Basso-Beattie-Bresnahan scores and inclined plane test results were observed in the SCI+ES group compared with those in the SCI group at 4 weeks post-SCI. We also observed a decrease in the cavity volume and an increase in phosphorylated growth-associated protein 43 levels in the SCI+ES group. Electrical muscle stimulation decreased the numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells in the epicenter and increased the levels of BDNF in the spinal cord and lower limb muscles at 1 week post-SCI. CONCLUSIONS: Electrical muscle stimulation improved motor function and increased BDNF levels in both the muscles and the spinal cords of rats subjected to SCI. Muscle contraction-induced BDNF expression might be involved in motor recovery during rehabilitation. CLINICAL RELEVANCE: Our study provides experimental evidence for a possible therapeutic role of peripheral electrical muscle stimulation to enhance motor recovery after SCI.


Subject(s)
Electric Stimulation Therapy , Muscle Contraction/physiology , Muscle, Skeletal/physiopathology , Recovery of Function/physiology , Spinal Cord Injuries/therapy , Animals , Brain-Derived Neurotrophic Factor/metabolism , Exercise Test , Locomotion , Male , Muscle, Skeletal/metabolism , Rats , Rats, Sprague-Dawley , Spinal Cord/metabolism , Spinal Cord Injuries/metabolism , Spinal Cord Injuries/physiopathology
5.
Exp Neurol ; 305: 108-120, 2018 07.
Article in English | MEDLINE | ID: mdl-29653186

ABSTRACT

Descending spinal pathways (corticospinal, rubrospinal, and reticulospinal) are believed to contribute to functional recovery resulting from rehabilitative training after stroke. However, the contribution of each pathway remains unclear. In the current study, we investigated rehabilitation-induced functional recovery and remodelling of the descending spinal pathways after severe cortical stroke in rats followed by 3 weeks of various rehabilitation [constraint-induced movement therapy (CIMT), skilled forelimb reaching, rotarod, and treadmill exercise]. Following photothrombotic stroke, 96% of corticospinal neurons in the ipsilesional motor cortex were destroyed. Despite the preservation of 82% of total spinal projection neurons (e.g. rubrospinal and reticulospinal projection neurons), rats showed persistent and severe disability, especially in skilled motor function. In this severe stroke model, only CIMT promoted functional recovery, associated with increased corticospinal projections from the peri-infarct motor cortex. Rehabilitation-induced recovery was reversed when the restored corticospinal neurons were destroyed by a second stroke. These data indicate that training-induced functional recovery is dependent on ipsilesional corticospinal projections, which highlights the importance of using strategies to enhance survival, axonal remodelling, or regeneration of corticospinal neurons to effectively restore function in severely affected stroke patients.


Subject(s)
Motion Therapy, Continuous Passive/methods , Motor Cortex , Motor Skills/physiology , Psychomotor Performance/physiology , Pyramidal Tracts/physiology , Stroke/therapy , Animals , Humans , Male , Motor Cortex/pathology , Rats , Rats, Inbred F344 , Recovery of Function/physiology , Stroke/pathology , Treatment Outcome
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