Therapeutic Strategies Targeting Caspase Inhibition Following Spinal Cord Injury in Rats

Ozawa, Hiroshi; Keane, Robert W.; Marcillo, Alexander; Diaz, P; Dietrich, W. Dalton

doi:10.1006/exnr.2002.7998

Cited by 50 publications

(27 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The anti-caspase-3 activity of rMSC is attributable to downregulation of apoptotic proteins of the extrinsic pathway, which altered the number of caspase-3-positive cells. Similar to our studies, reduction of caspase activity by synthetic peptide-based inhibitors has been demonstrated to attenuate neuronal apoptosis and the spread of secondary damage in animal models of CNS trauma (39,40).…”

Section: Discussionsupporting

confidence: 88%

Mesenchymal Stem Cells from Rat Bone Marrow Downregulate Caspase-3-mediated Apoptotic Pathway After Spinal Cord Injury in Rats

et al. 2007

View full text Add to dashboard Cite

Mesenchymal stem cells have been intensively studied for their potential use in reparative strategies for neurodegenerative diseases and traumatic injuries. We used mesenchymal stem cells (rMSC) from rat bone marrow to evaluate the therapeutic potential after spinal cord injury (SCI). Immunohistochemistry confirmed a large number of apoptotic neurons and oligodendrocytes in caudal segments 2mm away from the lesion site. Expression of caspase-3 on both neurons and oligodendrocytes after SCI was significantly downregulated by rMSC. Caspase-3 downregulation by rMSC involves increased expression of FLIP and XIAP in the cytosol and inhibition of PARP cleavage in the nucleus. Animals treated with rMSC had higher BBB scores and better recovery of hind limb sensitivity. Treatment with rMSC had a positive effect on behavioral outcome and histopathological assessment after SCI. The ability of rMSC to incorporate into the spinal cord, differentiate and to improve locomotor recovery hold promise for a potential cure after SCI.

show abstract

Section: Discussionsupporting

confidence: 88%

Mesenchymal Stem Cells from Rat Bone Marrow Downregulate Caspase-3-mediated Apoptotic Pathway After Spinal Cord Injury in Rats

et al. 2007

View full text Add to dashboard Cite

show abstract

“…This genetic rationale, however, fails to explain rat substrain differences observed in the literature. [7][8][9] Substrain differences in experimental nervous system models in rats have been reported for neuropathic pain behavior, startle reflex, and spinal noradrenergic neuron projections. [10][11][12] Nothing, however, has been reported on rat substrain differences in outcome after experimental spinal cord injury.…”

Section: Introductionmentioning

confidence: 99%

Rat Substrains Differ in the Magnitude of Spontaneous Locomotor Recovery and in the Development of Mechanical Hypersensitivity after Experimental Spinal Cord Injury

Kjell

Sándor

Josephson

et al. 2013

Journal of Neurotrauma

View full text Add to dashboard Cite

A number of different rodent experimental models of spinal cord injury have been used in an attempt to model the pathophysiology of human spinal cord injury. As a result, interlaboratory comparisons of the outcome measures can be difficult. Further complicating interexperiment comparisons is the fact that the rodent response to different experimental models is strain-dependent. Moreover, the literature is abundant with examples in which the same injury model and strain result in divergent functional outcomes. The objective of this research was to determine whether substrain differences influence functional outcome in experimental spinal cord injury. We induced mild contusion spinal cord injuries in three substrains of Sprague-Dawley rats purchased from three different European breeders (Scanbur, Charles River, and Harlan) and evaluated the impact of injury on spontaneous locomotor function, hypersensitivity to mechanical stimulation, and bladder function. We found that Harlan rats regained significantly more hindlimb function than Charles River and Scanbur rats. We also observed substrain differences in the recovery of the ability to empty the bladder and development of hypersensitivity to mechanical stimulation. The Harlan substrain did not show any signs of hypersensitivity in contrast to the Scanbur and Charles River substrains, which both showed transient reduction in paw withdrawal thresholds. Lastly, we found histological differences possibly explaining the observed behavioral differences. We conclude that in spite of being the same strain, there might be genetic differences that can influence outcome measures in experimental studies of spinal cord injury of Sprague-Dawley rats from different vendors.

show abstract

“…This includes the early infiltration of the injured spinal cord with neutrophils followed by microglial activation and persistent lymphocytic involvement chronically (67). Proand anti-apoptotic mechanisms are in play after SCI, and therapeutic strategies to regulate or inhibit apoptosis have been shown to improve outcome after experimental SCI (70,71). Inhibition of apoptosis by estrogen was shown to improve functional recovery after SCI in adult male rats through calpain inhibition (72).…”

Section: Review Of Animal Modelsmentioning

confidence: 99%

Pediatric Spinal Cord Injury in Infant Piglets: Description of a New Large Animal Model and Review of the Literature

Kuluz

Samdani

Benglis

et al. 2010

The Journal of Spinal Cord Medicine

View full text Add to dashboard Cite

Objective: To develop a new, clinically relevant large animal model of pediatric spinal cord injury (SCI) and compare the clinical and experimental features of pediatric SCI. Methods: Infant piglets (3-5 weeks old) underwent contusive SCI by controlled cortical impactor at T7. Severe complete SCI was induced in 6 piglets, defined as SCI with no spontaneous return of sensorimotor function. Eight piglets received incomplete SCI, which was followed by partial recovery. Somatosensory evoked potentials, magnetic resonance imaging, neurobehavioral function, and histopathology were measured during a 28-day survival period. Results: Mean SCI volume (defined as volume of necrotic tissue) was larger after complete compared with incomplete SCI (387 ± 29 vs 77 ± 38 mm 3 , respectively, P , 0.001). No functional recovery occurred after complete SCI. After incomplete SCI, piglets initially had an absence of lower extremity sensorimotor function, urinary and stool retention, and little to no rectal tone. Sensory responses recovered first (1-2 days after injury), followed by spontaneous voiding, lower extremity motor responses, regular bowel movements, and repetitive flexion-extension of the lower extremities when crawling. No piglet recovered spontaneous walking, although 4 of 8 animals with incomplete injuries were able to bear weight by 28 days. In vivo magnetic resonance imaging was performed safely, yielded high-resolution images of tissue injury, and correlated closely with injury volume seen on histopathology, which included intramedullary hemorrhage, cellular inflammation, necrosis, and apoptosis. Conclusion: Piglets performed well as a reproducible model of traumatic pediatric SCI in a large animal with chronic survival and utilizing multiple outcome measures, including evoked potentials, magnetic resonance imaging, functional outcome scores, and histopathology.

show abstract

Therapeutic Strategies Targeting Caspase Inhibition Following Spinal Cord Injury in Rats

Cited by 50 publications

References 27 publications

Mesenchymal Stem Cells from Rat Bone Marrow Downregulate Caspase-3-mediated Apoptotic Pathway After Spinal Cord Injury in Rats

Mesenchymal Stem Cells from Rat Bone Marrow Downregulate Caspase-3-mediated Apoptotic Pathway After Spinal Cord Injury in Rats

Rat Substrains Differ in the Magnitude of Spontaneous Locomotor Recovery and in the Development of Mechanical Hypersensitivity after Experimental Spinal Cord Injury

Pediatric Spinal Cord Injury in Infant Piglets: Description of a New Large Animal Model and Review of the Literature

Contact Info

Product

Resources

About