Stability, disposition, and penetration of catalytic antioxidants Mn-porphyrin and Mn-salen and of methylprednisolone in spinal cord injury.
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.
Department of Neurology, University of Texas Medical Branch, 301 University Blvd., Rt. 0881, Galveston, TX 77555-0881, USA.
Liqin
L
Wu
Yichu
Y
Shan
Danxia
D
Liu
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D020134:Catalytic Domain / Q000187:drug effects; D004355:Drug Stability; D008297:Male; D008345:Manganese / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D008665:Metalloporphyrins; D008775:Methylprednisolone / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D011524:Protoporphyrins / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012459:Salicylates; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000378:metabolism*
D000975:Antioxidants; C433928:EUK-134; D008665:Metalloporphyrins; C542902:Mn-salen; D009942:Organometallic Compounds; D011524:Protoporphyrins; D012459:Salicylates; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; C038654:manganese protoporphyrin; D008345:Manganese; D008775:Methylprednisolone