Apoptosis as a mechanism of neuronal cell death following acute experimental spinal cord injury

Lou, Jueren; Lenke, Lawrence G.; Ludwig, Fredrick J.; O’Brien, Michael F.

doi:10.1038/sj.sc.3100632

Cited by 125 publications

(83 citation statements)

References 17 publications

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“…A number of studies have provided compelling evidence of widespread apoptosis of neurons, oligodendroglia, and microglia following SCI (Katoh et al, 1996;Li et al, 1996;Crowe et al, 1997;Shuman et al, 1997;Emery et al, 1998;Hayashi et al, 1998;Lou et al, 1998;Yong et al, 1998). An excellent review by Beattie et al provides a summary of current findings (Beattie et al, 2000).…”

Section: Traumatic Spinal Cord Injurymentioning

confidence: 99%

Apoptotic Cell Death Following Traumatic Injury to the Central Nervous System

Springer¹

2002

BMB Reports

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Apoptotic cell death is a fundamental and highly regulated biological process in which a cell is instructed to actively participate in its own demise. This process of cellular suicide is activated by developmental and environmental cues and normally plays an essential role in eliminating superfluous, damaged, and senescent cells of many tissue types. In recent years, a number of experimental studies have provided evidence of widespread neuronal and glial apoptosis following injury to the central nervous system (CNS). These studies indicate that injury-induced apoptosis can be detected from hours to days following injury and may contribute to neurological dysfunction. Given these findings, understanding the biochemical signaling events controlling apoptosis is a first step towards developing therapeutic agents that target this cell death process. This review will focus on molecular cell death pathways that are responsible for generating the apoptotic phenotype. It will also summarize what is currently known about the apoptotic signals that are activated in the injured CNS, and what potential strategies might be pursued to reduce this cell death process as a means to promote functional recovery.

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Section: Traumatic Spinal Cord Injurymentioning

confidence: 99%

Apoptotic Cell Death Following Traumatic Injury to the Central Nervous System

Springer¹

2002

BMB Reports

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“…Both caspases and calpains are members of a group of proteases; the former is a calcium-independent protease, and the latter is a calcium-dependent protease. Laboratory findings and clinical evidence have suggested that caspases and calpains have an important role in the progression of programmed cell death and that multiple molecular pathways can lead independently to that type of cell death 15,[22][23][24]32 The activation of 1 protease can lead to the cleavage and activation of additional enzymes of the same or other proteases, and an amplified protease cascade results 46 .…”

Section: Introductionmentioning

confidence: 99%

Calpain inhibitor AK 295 inhibits calpain-induced apoptosis and improves neurologic function after traumatic spinal cord injury in rats

et al. 2009

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SummaryBackground. An increase in the level of intracellular calcium activates the calcium-dependent neutral protease calpain, which in turn leads to cellular dysfunction and cell death after an insult to the central nervous system. In this study, we evaluated the effect of a calpain inhibitor, AK 295, on spinal cord structure, neurologic function, and apoptosis after spinal cord injury (SCI) in a murine model.Methods. Thirty albino Wistar rats were divided into 3 groups of 10 each: the sham-operated control group (group 1), the spinal cord trauma group (group 2), and the spinal cord trauma plus AK 295 treatment group (group 3). After having received a combination of ketamine 60 mg/kg and xylazine 9 mg/kg to induce anesthesia, the rats in groups 2 and 3 were subjected to thoracic trauma by the weight drop technique (40 g-cm). One hour after having been subjected to that trauma, the rats in groups 2 and 3 were treated with an intraperitoneal injection of either dimethyl sulfoxide 2 mg/kg or AK 295 2 mg/kg. The effects of the injury and the efficacy of AK 295 were determined by an assessment of the TUNEL technique and the results of examination with a light microscope. The neurologic performance of 5 rats from group 2 and 5 from group 3 was assessed by means of the inclined plane technique and the modified Tarlov's motor grading scale 1, 3, and 5 days after spinal cord trauma.Findings. Light-microscopic examination of spinal cord specimens from group 2 revealed hemorrhage, edema, necrosis, and vascular thrombi 24 hours after trauma. Similar (but less prominent) features were seen in specimens obtained from group 3 rats. Twenty-four hours after injury, the mean apoptotic cell numbers in groups 1 and 2 were zero and 4.57 ± 0.37 cells, respectively. In group 3, the mean apoptotic cell number was 2.30 ± 0.34 cells, a value significantly lower than that in group 2 (P < .05). Five days after trauma, the injured rats in group 2 demonstrated significant motor dysfunction (P < .05). In comparison, the motor scores exhibited by group 3 rats were markedly better (P < .05).Conclusions. AK 295 inhibited apoptosis via calpaindependent pathways and provided neuroprotection and improved neurologic function in a rat model of SCI. To our knowledge, this is the first study to evaluate the use of AK 295, a calpain inhibitor, after SCI. Our data suggest that AK 295 might be a novel therapeutic compound for the neuroprotection of tissue and the recovery of function in patients with a SCI.KEY WORDS: AK 295. Apoptosis. Calpain inhibitor. Secondary damage. Spinal cord trauma.El inhibidor de la calpaina AK 295 inhibe la apoptosis inducida por calpaina y mejora la función neurológica tras traumatismo medular en ratas ResumenIntroducción. Una lesión en el sistema nervioso central origina un incremento en los niveles de calcio intracelular que activa la proteasa neutral calciodependiente calpaina, que a su vez conduce a la producción de disfunción y muerte celular. En este estudio evaluamos el efecto de un inhibidor de la calpaina, AK 295, so...

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“…Studies of apoptosis in white matter after dorsal cordotomy or after transection suggest that glial apoptosis occurs, at least in part, as a consequence of axonal degeneration (10,11). Several studies have implicated the apoptotic role of caspases in the injured spinal cord (12)(13)(14)(15)(16)(17)(18)(19)(20)(21). An increase in the number of cells expressing Fas was observed within 72 hours of SCI (22).…”

Section: Introductionmentioning

confidence: 99%

Umbilical Cord Blood Stem Cell Mediated Downregulation of Fas Improves Functional Recovery of Rats after Spinal Cord Injury

Dasari

Spomar

et al. 2007

Neurochem Res

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Human umbilical cord blood stem cells (hUCB), due to their primitive nature and ability to develop into nonhematopoietic cells of various tissue lineages, represent a potentially useful source for cellbased therapies after spinal cord injury (SCI). To evaluate their therapeutic potential, hUCB were stereotactically transplanted into the injury epicenter, one week after SCI in rats. Our results show the presence of a substantial number of surviving hUCB in the injured spinal cord up to five weeks after transplantation. Three weeks after SCI, apoptotic cells were found especially in the dorsal white matter and gray matter, which are positive for both neuron and oligodendrocyte markers. Expression of Fas on both neurons and oligodendrocytes was efficiently downregulated by hUCB. This ultimately resulted in downregulation of caspase-3 extrinsic pathway proteins involving increased expression of FLIP, XIAP and inhibition of PARP cleavage. In hUCB-treated rats, the PI3K/Akt pathway was also involved in antiapoptotic actions. Further, structural integrity of the cytoskeletal proteins α-tubulin, MAP2A&2B and NF-200 has been preserved in hUCB treatments. The behavioral scores of hind limbs of hUCB-treated rats improved significantly than those of the injured group, showing functional recovery. Taken together, our results indicate that hUCB-mediated downregulation of Fas and caspases leads to functional recovery of hind limbs of rats after SCI.

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Apoptosis as a mechanism of neuronal cell death following acute experimental spinal cord injury

Cited by 125 publications

References 17 publications

Apoptotic Cell Death Following Traumatic Injury to the Central Nervous System

Apoptotic Cell Death Following Traumatic Injury to the Central Nervous System

Calpain inhibitor AK 295 inhibits calpain-induced apoptosis and improves neurologic function after traumatic spinal cord injury in rats

Umbilical Cord Blood Stem Cell Mediated Downregulation of Fas Improves Functional Recovery of Rats after Spinal Cord Injury

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