Abstract
Nogo receptor-1 (NgR1) signaling is involved in the limitation of axonal regeneration following spinal cord injury (SCI) through collapsing the growth cone and inhibiting neurite outgrowth. Lateral olfactory tract usher substance (LOTUS), a NgR antagonist, suppresses these pathological conditions. A previous report demonstrated the positive effects of LOTUS expression on motor function through raphespinal tract regeneration using pan-neuronally LOTUS-overexpressing transgenic mice. However, this report used a hemi-section model, which does not represent the majority of clinical SCI cases, and lacked a detailed histological analysis of other descending tracts. To determine the true therapeutic effects of LOTUS, we used a more clinically relevant contusive SCI model in female transgenic mice. Definitive tracing analyses revealed that LOTUS promoted the extensive regeneration of the reticulospinal tract across the lesion site and suppressed axonal dieback of corticospinal tract (CST). A significant increase in raphespinal tract fibers was seen from the subacute to the chronic phase after the injury, strongly suggesting that LOTUS promoted translesional elongation of this tract. Furthermore, histological analyses revealed that LOTUS had a neuroprotective effect on the injured spinal cord through suppressing cellular apoptosis during the acute phase. These neuroprotective and regenerative effects contributed to significant motor functional recovery and restoration of the motor evoked potential (MEP). Therefore, LOTUS application could prove beneficial in the treatment of SCI by promoting axonal regeneration of some descending fibers, reducing axonal dieback of CST fibers and encouraging motor function recovery.
Highlights
Natural recovery following spinal cord injury (SCI) is extremely limited in mammalian adults (Schwab, 2010) due to the inhibition of axonal regeneration controlled by Nogo receptor-1 (NgR1) signaling (Fournier et al, 2001)
We evaluated the effect of Lateral olfactory tract usher substance (LOTUS) on spinal contusive injury using transgenic mice overexpressing LOTUS by focusing on axonal regeneration in various tract fibers, such as the corticospinal, reticulospinal and raphespinal tracts, using tracing and various histologic methods
In LOTUS-Tg mice, HA-positive cells were costained with neuronal nuclear protein (NeuN), a neuronal marker, but not glial fibrillary acidic protein (GFAP), an astrocyte marker (Fig. 1C,D), indicating that overexpressed LOTUS was expressed in neuronal cells
Summary
Natural recovery following spinal cord injury (SCI) is extremely limited in mammalian adults (Schwab, 2010) due to the inhibition of axonal regeneration controlled by Nogo receptor-1 (NgR1) signaling (Fournier et al, 2001). Kim et al (2004) demonstrated locomotor recovery after SCI by inhibiting a common receptor of all ligands using NgR1-lacking mice. Mice lacking MAG or OMgp failed to regenerate the CST following SCI (Bartsch et al, 1995; Ji et al, 2008). This animal model exhibited regeneration of the raphespinal tract, which plays an important role in the formation of connections with the motor neural circuit after SCI (Liang et al, 2015).
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