Modeling chronic cervical spinal cord injury in aged rats for cell therapy studies

Advanced age at the time of spinal cord injury (SCI) exacerbates damage from reactive oxygen species (ROS). Mechanisms underlying this age-dependent response are not well understood and may arise from decreased antioxidant defense. We investigated how spinal cord levels of the antioxidant glutathione (GSH), and its regulation, change with age and SCI. GSH is used by GSH peroxidase to sequester ROS and is recycled by GSH reductase. Male and female, 4- and 14-month-old (MO) mice received a 60 kDyn contusion SCI, and the levels of GSH and its regulatory enzymes were evaluated at one and three days post-injury (dpi). The mice with SCI were treated with N-acetylcysteine-amide (NACA; 150 mg/kg), a cysteine supplement that increases GSH, to determine effects on functional and histological outcomes. GSH was decreased with older age in sham mice, and an SCI-dependent depletion was observed in 4-MO mice by three dpi. Neither age nor injury affected the abundance of proteins regulating GSH synthesis or recycling. GSH peroxidase activity, however, increased after SCI only in 4-MO mice. In contrast, GSH peroxidase activity was increased in 14-MO sham mice, indicating that spinal cords of older mice have an elevated oxidative state. Indeed, 14-MO sham mice had more oxidized protein (3-nitrotyrosine [3-NT]) within their spinal cords compared with 4-MO sham mice. Only 4-MO mice had significant injury-induced increases in 3-NT at three dpi. NACA treatment restored GSH and improved the redox environment in injured 4- and 14-MO mice at one dpi; however, three days of NACA delivery did not improve motor, sensory, or anatomical deficits at 28 dpi in 4-MO mice and trended toward toxicity in all outcomes in 14-MO mice. Our observation suggests that GSH levels at acute stages of SCI play a minimal role in age-dependent outcomes reported after SCI in mice. Collective results implicate elements of injury occurring after three dpi, such as inflammation, as key regulators of age-dependent effects.

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“… 5 , 7 , 10 , 11 Several other reports have corroborated our assertations that older animals perform worse after SCI. 41 , 58–60 …”

Section: Discussionmentioning

confidence: 99%

Advanced Age and Neurotrauma Diminish Glutathione and Impair Antioxidant Defense after Spinal Cord Injury

Stewart

Glaser

Mott

et al. 2022

Journal of Neurotrauma

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“…Studies in aged individuals are appropriate, given the increasing incidence of SCI in elderly populations and their reduced recovery capacity. In this sense, studies including both sexes are increasing, and some articles using aged animals have been recently published [ 64 , 68 ].…”

Section: Discussionmentioning

confidence: 99%

“…The animals experimented on showed very high mortality rates, both at SCI induction and with iPSC–NSC treatment, due to their age-related frailty, even though we found that the transplanted cells survived for one month in the spinal cord of aged animals, and no signs of tumor development or adverse reactions were noted. Nevertheless, no locomotor improvement was observed after transplantation [ 64 ].…”

Section: Ipsc For Sci Repairmentioning

confidence: 99%

Pluripotent Stem Cells for Spinal Cord Injury Repair

Martín-López

Fernández‐Muñoz

Cánovas

2021

Cells

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Spinal cord injury (SCI) is a devastating condition of the central nervous system that strongly reduces the patient’s quality of life and has large financial costs for the healthcare system. Cell therapy has shown considerable therapeutic potential for SCI treatment in different animal models. Although many different cell types have been investigated with the goal of promoting repair and recovery from injury, stem cells appear to be the most promising. Here, we review the experimental approaches that have been carried out with pluripotent stem cells, a cell type that, due to its inherent plasticity, self-renewal, and differentiation potential, represents an attractive source for the development of new cell therapies for SCI. We will focus on several key observations that illustrate the potential of cell therapy for SCI, and we will attempt to draw some conclusions from the studies performed to date.

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“…Furlan (2021) identified a significant positive correlation between older age at the time of SCI and improved motor scores at 1-year post-injury. While at first, this appears to contradict pre-clinical studies that find worse outcomes with older age (Gwak et al, 2004a;Genovese et al, 2006;Siegenthaler et al, 2008a,b;Fenn et al, 2014;Hooshmand et al, 2014;Zhang et al, 2015Zhang et al, , 2016Zhang et al, , 2019Takano et al, 2017;von Leden et al, 2017;Martín-López et al, 2021;Stewart et al, 2021b), there are several important caveats to consider. First, it is interesting to note that the original publication reported a significant increase in mortality within 1-year of SCI among individuals 50 years or older at the time of injury (Bracken et al, 1985).…”

Section: Age At Time Of Spinal Cord Injury and The Clinical Populationmentioning

confidence: 95%

Improving translatability of spinal cord injury research by including age as a demographic variable

Stewart

Jones

Gensel

2022

Front. Cell. Neurosci.

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Pre-clinical and clinical spinal cord injury (SCI) studies differ in study design, particularly in the demographic characteristics of the chosen population. In clinical study design, criteria such as such as motor scores, neurological level, and severity of injury are often key determinants for participant inclusion. Further, demographic variables in clinical trials often include individuals from a wide age range and typically include both sexes, albeit historically most cases of SCI occur in males. In contrast, pre-clinical SCI models predominately utilize young adult rodents and typically use only females. While it is often not feasible to power SCI clinical trials to test multi-variable designs such as contrasting different ages, recent pre-clinical findings in SCI animal models have emphasized the importance of considering age as a biological variable prior to human experiments. Emerging pre-clinical data have identified case examples of treatments that diverge in efficacy across different demographic variables and have elucidated several age-dependent effects in SCI. The extent to which these differing or diverging treatment responses manifest clinically can not only complicate statistical findings and trial interpretations but also may be predictive of worse outcomes in select clinical populations. This review highlights recent literature including age as a biological variable in pre-clinical studies and articulates the results with respect to implications for clinical trials. Based on emerging unpredictable treatment outcomes in older rodents, we argue for the importance of including age as a biological variable in pre-clinical animal models prior to clinical testing. We believe that careful analyses of how age interacts with SCI treatments and pathophysiology will help guide clinical trial design and may improve both the safety and outcomes of such important efforts.

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Modeling chronic cervical spinal cord injury in aged rats for cell therapy studies

Cited by 10 publications

References 44 publications

Advanced Age and Neurotrauma Diminish Glutathione and Impair Antioxidant Defense after Spinal Cord Injury

Advanced Age and Neurotrauma Diminish Glutathione and Impair Antioxidant Defense after Spinal Cord Injury

Pluripotent Stem Cells for Spinal Cord Injury Repair

Improving translatability of spinal cord injury research by including age as a demographic variable

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