Increased levels of
ubiquitin and
heat shock protein (HSP) 72 kD are often seen in
spinal cord injury (SCI). However, their roles in cell injury or survival are not well known. Thus, we have investigated the possible relationship between
ubiquitin and HSP expressions in relation to cell injury in healthy animals, or following nanoparticle (NP) intoxication in SCI animals. A focal SCI was inflicted on the T10-11 segments over the right dorsal horn; animals were allowed to survive from 5 to 8 h after
trauma. Separate groups of rats were exposed to SiO2, Ag, or Cu NPs for 7 days and subjected to SCI on the eighth day. A marked increase in
ubiquitin or HSP immunoreactive cells occurred in the T9 to T12 segments 5 h after the injury, which further extended to the T4 and L5 after 8 h of survival. At this time, a marked increase in blood-spinal cord barrier (BSCB) permeability to
Evans blue and radioiodine, accompanied by an intense
edema formation, was observed. Changes were further exacerbated in NP-treated traumatized rats. The most marked expressions of
ubiquitin and HSP in SCI were seen in rats treated with SiO2, followed by Ag, and Cu NPs. Treatment with
H-290/51 (50 mg/kg p.o., 30 to 60 min after injury) or
carfilzomib (1 mg/kg, i.v., 30 to 60 min after
trauma) significantly reduced the
ubiquitin or HSP expressions, as well as the BSCB breakdown, the
edema formation, and the cell injury in the cord both 5 and 8 h after the injury, in normal animals. However, a double dose of
H-290/51 (100 mg/kg) or
carfilzomib (2 mg/kg) is needed to reduce cord pathology or
ubiquitin and HSP expressions in traumatized animals treated with NPs.
H-290/51 showed superior beneficial effects in reducing cord pathology in SCI than
carfilzomib. These observations are the first to demonstrate that (i) NP-treated traumatized animals induce a widespread BSCB leakage,
edema formation, and cord pathology as well as an overexpression of
ubiquitin and HSP, (ii) high doses of
antioxidant compounds or
proteasome inhibitors are required for neuroprotection in the NP-exposed traumatized group, and (iii)
ubiquitin and HSP expressions play a key role in neuronal injury in SCI, not reported earlier.