The angiogenesis and functional recovery effect after spinal cord injury by newly synthesized nucleotide analog, COA-Cl

　2-chloro-carbocyclic oxetanocin A（COA-Cl）はアデノシン類似体合成化合物であり in vitro にて血管新生作用が報告されており，またラットの脳卒中モデルに対する投与で神経保護，血管新生および機能回復効果が示されている．本研究ではこれらの効果が脊髄損傷モデルにおいても発揮されるか否かを評価した．荷重装置により T9レベルの脊髄損傷モデルラットを作製し，損傷直後から COA-Cl を５日間腹腔内投与した COA-Cl 群と，同量の生理食塩水を投与した vehicle群に分けた．脊髄損傷14日後に運動機能を Basso-Beattie-Bresnahan Locomotor Rating Scale スコア（BBB スコア）と傾斜台試験にて，血管新生をラミニンの免疫染色により後索の血管数と血管面積を測定することで評価した．運動機能は BBB スコアと傾斜台試験ともに COA-Cl 群でvehicle 群に比べて有意に改善した．血管新生は COA-Cl 群で血管数および血管面積ともに有意に増加した．これらの結果から，COA-Cl の脊髄損傷後急性期における投与は運動機能改善および血管新生をもたらし，脊髄損傷急性期の新規治療薬としての可能性が示された．　2-chloro-carbocyclic oxetanocin A (COA-Cl), a novel synthesized adenosine analog, has been reported to have a strong angiogenic effect. In our previous study using a rat model of stroke, we showed the neuroprotective, angiogenic and motor recovery effects of COACl. Spinal cord injury (SCI) induces severe motor dysfunction and lowers the quality of life. In our recent study, we demonstrated that acute-phase administration of COA-Cl protects against spinal cord damage and facilitates motor recovery after SCI. In this study, we hypothesized that acute-phase administration of COA-Cl post-SCI also induces early neovascularization and participates in motor function recovery. SCI was induced using a drop device in rats. Rats with SCI were divided into 2 groups: COA-Cl and vehicle groups (n = 5 in each group). COACl was intraperitoneally injected (6 mg/kg in saline) once a day for 5 days immediately after SCI. In the vehicle group, only saline was administered, with the same dosing regimen as that in the COA-Cl group. Fourteen days after SCI, motor function was evaluated based on Basso–Beattie–Bresnahan scoring and the inclined plane test. To evaluate angiogenesis, cryosections of the spinal cord were immunostained with anti-laminin antibody. Motor function significantly improved in the COA-Cl group compared with that in the vehicle group; concomitantly, both the number and volume of blood vessels significantly increased in the COA-Cl group compared with those in the vehicle group. In conclusion, acute-phase administration of COA-Cl results in motor function recovery, which may be attributed to angiogenic effects

Data from: Rehabilitative skilled forelimb training enhances axonal remodeling in the corticospinal pathway but not the brainstem-spinal pathways after photothrombotic stroke in the primary motor cortex

Task-specific rehabilitative training is commonly used for chronic stroke patients. Axonal remodeling is believed to be one mechanism underlying rehabilitation-induced functional recovery, and significant roles of the corticospinal pathway have previously been demonstrated. Brainstem-spinal pathways, as well as the corticospinal tract, have been suggested to contribute to skilled motor function and functional recovery after brain injury. However, whether axonal remodeling in the brainstem-spinal pathways is a critical component for rehabilitation-induced functional recovery is not known. In this study, rats were subjected to photothrombotic stroke in the caudal forelimb area of the primary motor cortex and received rehabilitative training with a skilled forelimb reaching task for 4 weeks. After completion of the rehabilitative training, the retrograde tracer Fast blue was injected into the contralesional lower cervical spinal cord. Fast blue-positive cells were counted in 32 brain areas located in the cerebral cortex, hypothalamus, midbrain, pons, and medulla oblongata. Rehabilitative training improved motor performance in the skilled forelimb reaching task but not in the cylinder test, ladder walk test, or staircase test, indicating that rehabilitative skilled forelimb training induced task-specific recovery. In the histological analysis, rehabilitative training significantly increased the number of Fast blue-positive neurons in the ipsilesional rostral forelimb area and secondary sensory cortex. However, rehabilitative training did not alter the number of Fast blue-positive neurons in any areas of the brainstem. These results indicate that rehabilitative skilled forelimb training enhances axonal remodeling selectively in the corticospinal pathway, which suggests a critical role of cortical plasticity, rather than brainstem plasticity, in task-specific recovery after subtotal motor cortex destruction

Rehabilitative skilled forelimb training enhances axonal remodeling in the corticospinal pathway but not the brainstem-spinal pathways after photothrombotic stroke in the primary motor cortex.

Task-specific rehabilitative training is commonly used for chronic stroke patients. Axonal remodeling is believed to be one mechanism underlying rehabilitation-induced functional recovery, and significant roles of the corticospinal pathway have previously been demonstrated. Brainstem-spinal pathways, as well as the corticospinal tract, have been suggested to contribute to skilled motor function and functional recovery after brain injury. However, whether axonal remodeling in the brainstem-spinal pathways is a critical component for rehabilitation-induced functional recovery is not known. In this study, rats were subjected to photothrombotic stroke in the caudal forelimb area of the primary motor cortex and received rehabilitative training with a skilled forelimb reaching task for 4 weeks. After completion of the rehabilitative training, the retrograde tracer Fast blue was injected into the contralesional lower cervical spinal cord. Fast blue-positive cells were counted in 32 brain areas located in the cerebral cortex, hypothalamus, midbrain, pons, and medulla oblongata. Rehabilitative training improved motor performance in the skilled forelimb reaching task but not in the cylinder test, ladder walk test, or staircase test, indicating that rehabilitative skilled forelimb training induced task-specific recovery. In the histological analysis, rehabilitative training significantly increased the number of Fast blue-positive neurons in the ipsilesional rostral forelimb area and secondary sensory cortex. However, rehabilitative training did not alter the number of Fast blue-positive neurons in any areas of the brainstem. These results indicate that rehabilitative skilled forelimb training enhances axonal remodeling selectively in the corticospinal pathway, which suggests a critical role of cortical plasticity, rather than brainstem plasticity, in task-specific recovery after subtotal motor cortex destruction

Data

Dat

Distribution of Fast blue-positive neurons.

<p>(A) The sagittal brain atlas indicating the level of the section in B (purple line; i-viii). (B) Representative pictures of the brain sections in the cerebral cortex (i, ii and iii), thalamus and hypothalamus (iv), midbrain (v), pons (vi) and medulla oblongata (vii and viii). The neurons projecting to the contralesional spinal cord at C7-8 were labeled with Fast blue. Infarct is indicated with a red line and the observed area of Fast blue-positive cells are indicated with a purple line. The names of the brain areas are abbreviated as follows: Rostral forelimb area (RFA), caudal forelimb area (CFA), secondary sensory area (S2), hypothalamic area (Hyt), mesencephalic tegmental area (Mes. Teg.), red nucleus (RN), nucleus reticularis pontis (NRPN) mesencephalic trigeminal nuclei (Mes. Trig.), deep cerebellar nuclei (Cbll), nucleus reticularis gigantocellularis (NRGi), nucleus reticularis parvocellularis (NRPa), spinal trigeminal nuclei (Sp. Trig.), vestibular nuclei (Vest), dorsal medullary reticular nucleus (MdD), and ventral medullary reticular nucleus (MdV). Scale bar = 1 mm.</p

Summary of the histological changes induced by rehabilitative skilled forelimb training.

<p>Summary of the histological changes induced by rehabilitative skilled forelimb training.</p