Abstract
Background: Spinal cord injury (SCI) elicits robust neuroinflammation that eventually exacerbates the initial damage to the spinal cord. L-arginine is critical for the responsiveness of T cells, which are important contributors to neuroinflammation after SCI. Furthermore, L-arginine is the substrate for nitric oxide (NO) production, which is a known inducer of secondary damage. Methods: To accomplish systemic L-arginine depletion, repetitive injections of recombinant arginase-1 (rArg-I) were performed. Functional recovery and histopathological parameters were analyzed. Splenic immune responses were evaluated by flow cytometry. Pro-inflammatory gene expression and nitrite concentrations were measured. Results: We show for the first time that systemic L-arginine depletion improves locomotor recovery. Flow cytometry and immunohistological analysis showed that intraspinal T-cell infiltration was reduced by 65%, and peripheral numbers of Th1 and Th17 cells were suppressed. Moreover, rArg-I treatment reduced the intraspinal NO production by 40%. Histopathological analyses revealed a 37% and 36% decrease in the number of apoptotic neurons and neuron-macrophage/microglia contacts in the spinal cord, respectively. Conclusions: Targeting detrimental T-cell responses and NO-production via rArg-I led to a reduced neuronal cell death and an improved functional recovery. These findings indicate that L-arginine depletion holds promise as a therapeutic strategy after SCI.
Highlights
Spinal cord injury (SCI) is a devastating event characterized by the permanent loss of locomotor, sensory, and autonomic functions below the level of the injury
Mice subjected to rArg-I therapy showed a statistical enhancement of functional recovery compared to the vehicle group at the end of the 28-day observation period (Figure 1B)
To investigate whether systemic L-arginine depletion results in local arginine depletion, we investigated the local in vivo nitrite production in the spinal cord 7 dpi, at the peak of iNOS expression [44]
Summary
Spinal cord injury (SCI) is a devastating event characterized by the permanent loss of locomotor, sensory, and autonomic functions below the level of the injury. Local cells (e.g., microglia and astrocytes) are predominant, yet over the course of days, peripheral immune cell infiltration occurs [3,4,5,6]. Lymphocytes accumulate in the spinal cord days after trauma and remain chronically present [2,3]. Some researchers suggested that the presence of autoreactive T cells is beneficial and promotes functional. Spinal cord injury (SCI) elicits robust neuroinflammation that eventually exacerbates the initial damage to the spinal cord. L-arginine is the substrate for nitric oxide (NO) production, which is a known inducer of secondary damage
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