Neonatal Rats Exhibit a Predominantly Anti-Inflammatory Response following Spinal Cord Injury

Abstract

It has been reported that children may respond better than adults to a spinal cord injury (SCI) of similar severity. There are known biomechanical differences in the developing spinal cord that may contribute to this “infant lesion effect,” but the underlying mechanisms are unknown. Using immunohistochemistry, we have previously demonstrated a different injury progression and immune cell response after a mild thoracic contusion SCI in infant rats, as compared to adult rats. Here, we investigated the acute inflammatory responses using flow cytometry and ELISA at 1 h, 24 h, and 1 week after SCI in neonatal (P7) and adult (9 weeks) rats, and locomotor recovery was examined for 6 weeks after injury. Adult rats exhibited a pronounced pro-inflammatory response characterized by neutrophils and M1-like macrophage infiltration and Th1 cytokine secretion. Neonatal rats exhibited a decreased pro-inflammatory response characterized by a higher proportion of M2-like macrophages and reduced Th1 cytokine responses, as compared to adults. These results suggest that the initial inflammatory response to SCI is predominantly anti-inflammatory in very young animals.

Comparative model of minimal spinal cord injury reveals a rather anti‐inflammatory response in the lesion site as well as increased proliferation in the central canal lining in the neonates compared to the adult rats

“…Furthermore, we observed differences in the reaction of immune cells and astrocytes between neonatal and mature nervous tissue at the lesion site. First, we observed decreased activation of microglia and/or accumulation of phagocytes at the lesion site in neonatal spinal cord compared with mature nervous tissue, a finding in line with previous observations (Kitade et al., 2023; Sutherland et al., 2017, 2021). Besides the lower inflammatory response at both the cellular and humoral levels, transient activation of neonatal microglia could contribute to scar‐free healing through the secretion of several components of the extracellular matrix, which forms bridges that ligate the borders of the lesion site (Li et al., 2020).…”

“…Numerous clues indicate that the limited endogenous regenerative potential of the adult nervous system is the result of the interplay between the inflammatory actions of immune and glial cells and the inhibitory nature of mature nervous tissue, especially in mammals. After an injury of the nervous system, there is extensive secondary damage to the tissue and attenuated activity of endogenous precursors (Kitade et al, 2023;Li et al, 2020;Okano et al, 2005;Peretto & Bonfanti, 2014;Sutherland et al, 2021). Thus, it may be assumed that the anti-inflammatory response to pathological stimuli, the local microenvironment, and the activity of progenitors residing in the spinal cord at earlier stages of phylogenesis and/or ontogenesis (Cigliota et al, 2023;Coskun et al, 2008;Johansson et al, 1999;Shihabuddin et al, 2000) could be responsible for the greater regenerative potential compared with the adult mammalian spinal cord (Ming & Song, 2011;Rodríguez-Barrera et al, 2021).…”

“…Moreover, clinical practice has revealed that the spinal cord of children recovers more efficiently than the adult spinal cord (Pape, 2012), likely due to less extensive secondary damage in earlier stages of development (Yuan et al, 2013). This phenomenon has been termed the "infant lesion effect" (Bregman & Goldberger, 1983;Sutherland et al, 2017Sutherland et al, , 2021. Knowledge gained by comparing regeneration in juvenile and adult animals (or even different animal species) could draw attention to factors that should be removed or added for more effective regenerative therapy of adult mammals.…”

“…To our knowledge, there are very few experimental studies exploring the reaction of neonatal or juvenile spinal cord to injury. The majority of these studies employed SCI models such as mild weightdrop contusion (Sutherland et al, 2017(Sutherland et al, , 2021Wingrave et al, 2004), hemisection (Hasegawa et al, 2016), vertebral dislocation (Lau et al, 2013), spinal cord crush (Cigliola et al, 2023;Kitade et al, 2023;Li et al, 2020), or manually executed incisions (Li et al, 2016). These approaches are associated with at least one of the two most common disadvantages: (i) the impossibility to execute the impact so that there is a similar extent of damage in animals at different ontogenetic stages; and/or (ii) the severity of injury often disrupts spinal architecture at the lesion site and prevents effective histological examination or single-cell analysis of the lesioned spinal segment.…”

Effectiveness of two extended-release buprenorphine formulations during postoperative period in neonatal rats

“…Postoperative analgesia is a critical component of laboratory animal medicine as untreated pain causes distress [ 1 ] and can impact research results [ 2 ]. Neonatal rodents are used for variety of survival surgical procedures, including stereotaxic [ 3 – 5 ], spinal [ 6 , 7 ], and thoracic [ 8 , 9 ] surgeries which are known to evoke pain responses. Untreated pain in neonates can lead to long-term behavioral changes [ 10 , 11 ], such as altered development of pain perception, neurodevelopmental functioning, and social-emotional functioning [ 12 ].…”