Stability, Disposition, and Penetration of Catalytic Antioxidants Mn-Porphyrin and Mn-Salen and of Methylprednisolone in Spinal Cord Injury

Abstract

This study measured the time courses of concentration changes following administration of the catalytic antioxidants Mn (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) and Mn (III) 3-methoxy N, N' bis (salicyclidene) ethylenediamine chloride (EUK-134) in blood and cerebrospinal fluid (CSF) of rats with a spinal cord injury (SCI) and sham controls. Parallel measurements were made for methylprednisolone, the only drug presently used clinically for treating SCI. The time courses kinetically characterized the agents in their stability, disposition, and ability to penetrate the blood–spinal cord barrier (BSB). In both the SCI and control groups, MnTBAP was stable in CSF and in blood across the collection periods (10 h and 24 h, respectively) following administration. In the blood, [EUK-134] and [methylprednisolone] rapidly declined to near basal concentrations at 4 h and 2 h, respectively, post-administration. Therefore the order of stability in CSF and blood was MnTBAP >> EUK-134 > methylprednisolone. The maximum CSF/blood concentration ratios for EUK-134, methylprednisolone and MnTBAP post-administration were: 32 ± 3.1%, 19.2 ± 6.4%, and 4.42 ± 0.73% in the injured rats, and 22 ± 6.5%, 17.8 ± 2.9%, and 1.0 ± 0.5% in the sham control animals. This suggests an order of BSB penetration of EUK-134 > methylprednisolone >> MnTBAP. Despite much lower penetration by MnTBAP compared with EUK-134 and methylprednisolone, a lower dose of MnTBAP because of its stability provided a higher concentration in CSF than did the other agents given at higher doses. This finding supports further exploration of MnTBAP as a potential treatment for SCI.

Mn (III) tetrakis (4-benzoic acid) porphyrin scavenges reactive species, reduces oxidative stress, and improves functional recovery after experimental spinal cord injury in rats: comparison with methylprednisolone

“…We also demonstrated that the MP’s blood–spinal cord barrier penetrating ratio was much higher than MnTBAP (20% versus 4%) [50]. However, our results of behavioral tests demonstrated that with lower ability of penetrating the blood–spinal cord barrier, MnTBAP reached appropriate targets and more effectively improved the functional recovery than the standard treatment of SCI by MP, further supporting the candidacy of MnTBAP in treating SCI.…”

“…The standard regimen of MPSS, given intravenously (iv), consists of 30 mg/kg as a bolus dose followed by 5.4 mg/kg/h as a maintenance dose. The maximum MP concentration ratio of cerebrospinal fluid to blood is nearly 20% following iv administration [50]. According to this ratio, a 6 mg/kg bolus dose and a 1.08 mg/kg/h maintenance dose of MPSS given intrathecally equals the standard clinical regimen of MPSS given iv.…”

The effect of a polyurethane-based reverse thermal gel on bone marrow stromal cell transplant survival and spinal cord repair

“…The ability to scavenge ROS may be exerted through its urethane groups [28,29]. Possibly ESHU’s antioxidant effects may be increased with higher concentrations [46]. Our observations point at antioxidation as a potential mechanism of ESHU-promoted BMSC transplant survival.…”

The temporal and spatial profiles of cell loss following experimental spinal cord injury: effect of antioxidant therapy on cell death and functional recovery

“…We compared the penetrating ability of MnTBAP to methylprednisolone (MP), the only drug used clinically to treat SCI. We found that, despite the much lower penetration of the blood-spinal cord barrier (BSB) by MnTBAP compared with MP, its higher stability allows a lower dose of MnTBAP to produce a higher concentration in the CSF than does higher doses of MP [ 42 ]. Moreover, we demonstrated that MnTBAP (10 mg/kg) given intraperitoneally (i.p.)…”