A rat model of spinal cord ischemic injury (original) (raw)
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Ischemia-reperfusion model in rat spinal cord: cell viability and apoptosis signaling study
International journal of clinical and experimental pathology, 2015
This work aimed at determining the ideal ischemia time in an in vitro ischemia-reperfusion model of spinal cord injury. Rat spinal cord slices were prepared and then exposed or not to oxygen deprivation and low glucose (ODLG) for 30, 45, 60, 75 and 90 minutes. Cell viability was assessed by triphenyltetrazolium (TTC), lactate dehydrogenase (LDH) release, and fluorochrome dyes specific for cell dead (ethidium homodimer) using the apotome system. Glutamate release was enzymatically measured by a fluorescent method. Gene expression of apoptotic factors was assessed by real time RT-PCR. Whereas spinal cord slices exposed to ODLG exhibited mild increase in fluorescence for 30 minutes after the insult, the 45, 60, 75 and 90 minutes caused a 2-fold increase. ODLG exposure for 45, 60, 75 or 90 minutes, glutamate and LDH release were significantly elevated. nNOS mRNA expression was overexpressed for 45 minutes and moderately increased for 60 minutes in ODLG groups. Bax/bcl-xl ratio, caspase ...
Experimental Neurology, 2004
A number of previous studies indicated that ischemia -reperfusion injury causes two distinct types of cell death-necrosis and apoptosis-in the central nervous system. It was also implicated that the intensity of injury can somehow affect the cell death mechanisms. By occluding the descending thoracic aorta with or without simultaneously induced hypovolemic hypotension in rats, we established a model of experimental spinal cord ischemia -reperfusion (I/R) in which the injury severity can be controlled. Recordings of carotid blood pressure (CBP) and spinal cord blood flow (SCBF) showed that aortic occlusion induced dramatic CBP elevation but SCBF drop in both the normotensive (NT) and hypotensive (HT) groups of rats. However, the HT group demonstrated significantly lower SCBF during aortic occlusion, and much slower elevation of SCBF after reperfusion, and extremely poor neurological performance. Spinal cord lesions were characterized by infarction associated with extensive necrotic cell death, but little apoptosis and caspase-3 activity. In contrast, in the NT group, I/R injury resulted in minor tissue destruction associated with persistent abundant apoptosis, augmented caspase-3 activity, and favorable functional outcome. The relative sparing of motoneurons in the ventral horns from apoptosis might have accounted for the minor functional impairment in the NT group. The severity of I/R injury was found to have substantial impact on the histopathological changes and cell death mechanisms, which correlate with neurological performance. Our results implicate that injury severity and duration after injury are two critical factors to be considered in therapeutic intervention. D
Chapter 4 Cell death in models of spinal cord injury
Progress in Brain Research, 2002
Current treatments for acute spinal cord injury are based on animal models of human spinal cord injury (SCI). These models have shown that the initial traumatic injury to cord tissue is followed by a long period of secondary injury that includes a number of cellular and biochemical cascades. These secondary injury processes are potential targets for therapies. Continued refinement of rat and mouse models of SCI, along with more detailed analyses of the biology of the lesion in these models, points to both necrotic and apoptotic mechanisms of cell death after SCI. In this chapter, we review recent evidence for long-term apoptotic death of oligodendrocytes in long tracts undergoing Wallerian degeneration following SCI. This process appears to be related closely to activation of microglial cells. It is has been thought that microglial cells might be the source of cytotoxic cytokines, such as tumor necrosis factor-c~ (TNF-a), that kill oligodendrocytes. However, more recent evidence in vivo suggests that TNF-c~ by itself may not induce necrosis or apoptosis in oligodendrocytes. We review data that suggests other possible pathways for apoptosis, such as the neurotrophin receptor p75 which is expressed in both neurons and oligodendrocytes after SCI in rats and mice. In addition, it appears that microglial activation and TNF-c~ may be important in acute SCI. Ninety minutes after a moderate contusion lesion, microglia are activated and surround dying neurons. In an 'atraumatic' model of SCI, we have now shown that TNF-a appears to greatly potentiate cell death mediated by glutamate receptors. These studies emphasize that multiple mechanisms and interactions contribute to secondary injury after SCI. Continued study of both contusion models and other new approaches to studying these mechanisms will be needed to maximize strategies for acute and chronic therapies, and for neural repair.
Spinal Cord Injury: Current Mammalian Models
American Journal of Neuroscience, 2013
It is estimated that approximately 2.5 million people are affected by Spinal Cord Injury (SCI), with more than 130,000 new cases reported each year (International Campaign for Cures of Spinal Cord Injury Paralysis). Although there is currently no cure for SCI, various strategies including rehabilitative, cellular and molecular therapies have been tested in a variety of animal models. But questions remain as to the validity of animal models and whether they relate to the clinical conditions found in humans. This review aims to look at the different and most current models that are used to study SCI and their potential uses in mimicking the human condition. Several different animals models have been developed to study the problems of SCI, allowing exploration of mechanisms and properties of specific pathways such as; the MAPK pathway and spinal cord diseases such as; Syringomyelia and Central Cord Syndrome to name a few to be elucidated. SCI is complicated by cavitation and a glial scar that lines the cavity, reducing the possibility of axon regeneration. Mammalian models, particularly in mice and rats, have been used for many years to study the impact of SCI and potential therapies, however, questions remain as to the validity of these models and their potential usefulness.
Traumatic Spinal Cord Injury: An Overview of Pathophysiology, Models and Acute Injury Mechanisms
Frontiers in Neurology
Traumatic spinal cord injury (SCI) is a life changing neurological condition with substantial socioeconomic implications for patients and their care-givers. Recent advances in medical management of SCI has significantly improved diagnosis, stabilization, survival rate and well-being of SCI patients. However, there has been small progress on treatment options for improving the neurological outcomes of SCI patients. This incremental success mainly reflects the complexity of SCI pathophysiology and the diverse biochemical and physiological changes that occur in the injured spinal cord. Therefore, in the past few decades, considerable efforts have been made by SCI researchers to elucidate the pathophysiology of SCI and unravel the underlying cellular and molecular mechanisms of tissue degeneration and repair in the injured spinal cord. To this end, a number of preclinical animal and injury models have been developed to more closely recapitulate the primary and secondary injury processes of SCI. In this review, we will provide a comprehensive overview of the recent advances in our understanding of the pathophysiology of SCI. We will also discuss the neurological outcomes of human SCI and the available experimental model systems that have been employed to identify SCI mechanisms and develop therapeutic strategies for this condition.
KB-2796, a calcium channel blocker, ameliorates ischemic spinal cord damage in rabbits
Neurochemical Research, 1994
The effect of the calcium channel blocker (KB-2796) on metabolic and functional recovery in rabbit spinal cord after 20, 30, and 40 rain ischemia and 4 days of recovery was investigated. The drug was given intraperitoneally in three different doses, 10, 20, or 50 mg/kg pre-or post-ischemia of 20, 30, or 40 min duration. Both higher doses 20 and 30 mg/kg completely recovered energy state and significantly improved neurological functions in the spinal cord following 20 and 30 min ischemia. Partial protection was observed even after 40 min ischemia. The protective effect of KB-2796 exceeds the effect of calcium blockers previously used in experimental spinal cord ischemia.
Journal of Molecular Histology, 2012
Spinal cord ischemia belongs to serious and relatively frequent diseases of CNS. The aim of the present study was to find out the vulnerability of nitrergic neurons to 15 min transient spinal cord ischemia followed by 1 and 2 weeks of reperfusion. We studied neuronal nitric oxide synthase (nNOS) and nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) in structural elements of lumbosacral spinal cord along its rostrocaudal axis. In addition, a neurological deficit of experimental animals was evaluated. Spinal cord ischemia, performed on the rabbit, was induced by abdominal aorta occlusion using Fogarty catheter introduced into the right femoral artery for a period of 15 min. After surgical intervention the animals survived for 7 and 14 days. nNOS-immunoreactivity (nNOS-IR) was measured by immunohistochemical and NADPHd-positivity by histochemical method, and both immunohistochemical and histochemical stainings were quantified by densitometric analyses. Neurological deficit was evaluated according Zivin 0 s criteria. The number of nNOS-IR and/or NADPH-d positive neurons and the density of neuropil were markedly increased in superficial dorsal horn (laminae I-III) after 15 min ischemia and 7 days of reperfusion. However, ischemia followed by longer time of survival (14 days) returned the number of nNOS-IR and NADPH-d positive neurons to control. In the pericentral region (lamina X) containing interneurons and crossing fibers of spinal tracts, than in lamina VII and in dorsomedial part of the ventral horn (lamina VIII) we recorded a decreased number of nNOS-IR and NADPH-d positive neurons after both ischemia/reperfusion periods. In the medial portion of lamina VII and dorsomedial part of the ventral horn (lamina VIII) we observed many necrotic loci. This area was the most sensitive to ischemia/reperfusion injury. Fifteen minute ischemia caused a marked deterioration of neurological function of hind limbs, often developing into paraplegia. A quantitative immunohistochemical and histochemical study have shown a strong vulnerability of nitrergic neurons in intermediate zone to transient spinal cord ischemia.
Spinal Cord Injury: Pathophysiology, Multimolecular Interactions, and Underlying Recovery Mechanisms
International Journal of Molecular Sciences
Spinal cord injury (SCI) is a destructive neurological and pathological state that causes major motor, sensory and autonomic dysfunctions. Its pathophysiology comprises acute and chronic phases and incorporates a cascade of destructive events such as ischemia, oxidative stress, inflammatory events, apoptotic pathways and locomotor dysfunctions. Many therapeutic strategies have been proposed to overcome neurodegenerative events and reduce secondary neuronal damage. Efforts have also been devoted in developing neuroprotective and neuro-regenerative therapies that promote neuronal recovery and outcome. Although varying degrees of success have been achieved, curative accomplishment is still elusive probably due to the complex healing and protective mechanisms involved. Thus, current understanding in this area must be assessed to formulate appropriate treatment modalities to improve SCI recovery. This review aims to promote the understanding of SCI pathophysiology, interrelated or interl...