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Short-term inhibition of fibrinolytic system restores locomotor function after spinal cord injury in mice.

ABSTRACT: Spinal cord injury (SCI) is caused by an initial mechanical insult followed by a series of deleterious events that promote the progressive damage of affected tissues. Fibrinolysis, the process by which plasmin degrades cross-linked fibrin clots, has numerous functions in the central nervous system. However, the roles of the fibrinolytic system in SCI pathophysiology remain unknown. We investigated the roles of fibrinolysis in SCI, and explored therapeutic applications targeting fibrinolysis. Plasminogen-deficient (Plg^-/-) mice exhibited significantly improved locomotor function in the early phase of SCI (the first 7 days post injury), with significant inhibition of bleeding and vascular permeability, but failed to demonstrate conclusive functional recovery. Consistent with these findings, the short-term administration of tranexamic acid (TXA) in wild-type mice over the first 3 days post injury significantly improved locomotor function after SCI, whereas prolonged TXA administration did not. Prolonged TXA administration resulted in significantly lower levels of matrix metalloproteinase activities in the spinal cord, suggesting that inhibition of the fibrinolytic system impaired tissue remodeling. Our results indicate that the fibrinolytic system has time-dependent biphasic actions following SCI. The temporally optimised modulation of fibrinolytic activity may thus be a novel therapeutic strategy to improve functional outcomes after SCI.

SUBMITTER: Shiraishi Y

PROVIDER: S-EPMC6831600 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Short-term inhibition of fibrinolytic system restores locomotor function after spinal cord injury in mice.

Shiraishi Yasuyuki Y Kimura Atsushi A Matsuo Osamu O Sakata Yoichi Y Takeshita Katsushi K Ohmori Tsukasa T

Scientific reports 20191105 1

Spinal cord injury (SCI) is caused by an initial mechanical insult followed by a series of deleterious events that promote the progressive damage of affected tissues. Fibrinolysis, the process by which plasmin degrades cross-linked fibrin clots, has numerous functions in the central nervous system. However, the roles of the fibrinolytic system in SCI pathophysiology remain unknown. We investigated the roles of fibrinolysis in SCI, and explored therapeutic applications targeting fibrinolysis. Pla ...[more]

PMID: 31690812

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Project description:Background and purposeFor rehabilitation strategies to be effective, training should be based on principles of motor learning, such as feedback-error learning, that facilitate adaptive processes in the nervous system by inducing errors and recalibration of sensory and motor systems. This case report suggests that locomotor resistance training can enhance somatosensory and corticospinal excitability and modulate resting-state brain functional connectivity in a patient with motor-incomplete spinal cord injury (SCI).Case descriptionThe short-term cortical plasticity of a 31-year-old man who had sustained an incomplete SCI 9.5 years previously was explored in response to body-weight-supported treadmill training with velocity-dependent resistance applied with a robotic gait orthosis. The following neurophysiological and neuroimaging measures were recorded before and after training. Sensory evoked potentials were elicited by electrical stimulation of the tibial nerve and recorded from the somatosensory cortex. Motor evoked potentials were generated with transcranial magnetic stimulation applied over the tibialis anterior muscle representation in the primary motor cortex. Resting-state functional magnetic resonance imaging was performed to evaluate short-term changes in patterns of brain activity associated with locomotor training.OutcomesSomatosensory excitability and corticospinal excitability were observed to increase after locomotor resistance training. Motor evoked potentials increased (particularly at higher stimulation intensities), and seed-based resting-state functional magnetic resonance imaging analyses revealed increased functional connectivity strength in the motor cortex associated with the less affected side after training.DiscussionThe observations suggest evidence of short-term cortical plasticity in 3 complementary neurophysiological measures after one session of locomotor resistance training. Future investigation in a sample of people with incomplete SCI will enhance the understanding of potential neural mechanisms underlying the behavioral response to locomotor resistance training.

Project description:Transcutaneous spinal cord or transspinal stimulation over the thoracolumbar enlargement, the spinal location of motoneurons innervating leg muscles, modulates neural circuits engaged in the control of movement. The extent to which daily sessions (e.g. repeated) of transspinal stimulation affects soleus H-reflex excitability in individuals with chronic spinal cord injury (SCI) remains largely unknown. In this study, we established the effects of repeated cathodal transspinal stimulation on soleus H-reflex excitability and spinal inhibition in individuals with and without chronic SCI. Ten SCI and 10 healthy control subjects received monophasic transspinal stimuli of 1-ms duration at 0.2 Hz at subthreshold and suprathreshold intensities of the right soleus transspinal evoked potential (TEP). SCI subjects received an average of 16 stimulation sessions, while healthy control subjects received an average of 10 stimulation sessions. Before and one or two days post intervention, we used the soleus H reflex to assess changes in motoneuron recruitment, homosynaptic depression following single tibial nerve stimuli delivered at 0.1, 0.125, 0.2, 0.33 and 1.0 Hz, and postactivation depression following paired tibial nerve stimuli at the interstimulus intervals of 60, 100, 300, and 500 ms. Soleus H-reflex excitability was decreased in both legs in motor incomplete and complete SCI but not in healthy control subjects. Soleus H-reflex homosynaptic and postactivation depression was present in motor incomplete and complete SCI but was of lesser strength to that observed in healthy control subjects. Repeated transspinal stimulation increased homosynaptic depression in all SCI subjects and remained unaltered in healthy controls. Postactivation depression remained unaltered in all subject groups. Lastly, transspinal stimulation decreased the severity of spasms and ankle clonus. The results indicate decreased reflex hyperexcitability and recovery of spinal inhibitory control in the injured human spinal cord with repeated transspinal stimulation. Transspinal stimulation is a noninvasive neuromodulation method for restoring spinally-mediated afferent reflex actions after SCI in humans.

Project description:Microtubule stabilization through epothilones is a promising preclinical therapy for functional recovery following spinal cord injury that stimulates axon regeneration, reduces growth-inhibitory molecule deposition and promotes functional improvements. Rehabilitation therapy is the only clinically validated approach to promote functional improvements following spinal cord injury. However, whether microtubule stabilization can augment the beneficial effects of rehabilitation therapy or act in concert with it to further promote repair remains unknown. Here, we investigated the pharmacokinetic, histological and functional efficacies of epothilone D, epothilone B and ixabepilone alone or in combination with rehabilitation following a moderate contusive spinal cord injury. Pharmacokinetic analysis revealed that ixabepilone only weakly crossed the blood-brain barrier and was subsequently excluded from further investigations. In contrast, epothilones B and D rapidly distributed to CNS compartments displaying similar profiles after either subcutaneous or intraperitoneal injections. Following injury and subcutaneous administration of epothilone B or D, rats were subjected to 7 weeks of sequential bipedal and quadrupedal training. For all outcome measures, epothilone B was efficacious compared with epothilone D. Specifically, epothilone B decreased fibrotic scaring which was associated with a retention of fibronectin localized to perivascular cells in sections distal to the lesion. This corresponded to a decreased number of cells present within the intralesional space, resulting in less axons within the lesion. Instead, epothilone B increased serotonergic fibre regeneration and vesicular glutamate transporter 1 expression caudal to the lesion, which was not affected by rehabilitation. Multiparametric behavioural analyses consisting of open-field locomotor scoring, horizontal ladder, catwalk gait analysis and hindlimb kinematics revealed that rehabilitation and epothilone B both improved several aspects of locomotion. Specifically, rehabilitation improved open-field locomotor and ladder scores, as well as improving the gait parameters of limb coupling, limb support, stride length and limb speed; epothilone B improved these same gait parameters but also hindlimb kinematic profiles. Functional improvements by epothilone B and rehabilitation acted complementarily on gait parameters leading to an enhanced recovery in the combination group. As a result, principal component analysis of gait showed the greatest improvement in the epothilone B plus rehabilitation group. Thus, these results support the combination of epothilone B with rehabilitation in a clinical setting.

Dataset Information

Short-term inhibition of fibrinolytic system restores locomotor function after spinal cord injury in mice.

Publications

Short-term inhibition of fibrinolytic system restores locomotor function after spinal cord injury in mice.

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