Clomethiazole (ZENDRA, CMZ) improves hind limb motor function and reduces neuronal damage after severe spinal cord injury in rat.
Clomethiazole (CMZ) has a neuroprotective effect in experimental focal and global forebrain ischemia. This neuroprotective effect may depend on its ability to enhance GABA receptor activity. We have studied the effect of pretreatment with CMZ on motor function recovery and nerve cell damage after spinal cord injury (SCI). Rats were randomized and 30 min before SCI they received a single intraperitoneal dose of CMZ (150 mg/kg) or saline. The spinal cord was injured with a 50 g (4.5 g/mm2) load, applied over the exposed dura, through a curved rectangular plate (2.2 x 5.0 mm) for 5 min at T8-9. The animals became paraplegic 1 day after injury. The rats were evaluated for recovery of hind limb motor function. All animals recovered to some extent over the observation period of 12 weeks. However, hind limb motor function was significantly better in the animals pretreated with CMZ. At 12 weeks the rats were killed and perfused/fixed for morphological investigations. Microtubule-associated protein 2 (MAP2) immunostaining was used to stain neurons and dendrites and Luxol-fast blue to stain myelinated tracts of the white matter. The injured segment of the spinal cord showed severe atrophy, distortion, cavitation and necrosis of grey and white matter. Compared to uninjured controls the transverse sectional area was reduced to 32.7 +/- 4% in untreated animals but only to 38.5% +/- 4.1 in CMZ-treated animals. MAP2 staining showed that, compared to uninjured controls, grey matter was reduced to 7.4 +/- 2.7% in saline-treated injured animals and to 22.7 +/- 5.4% in CMZ-treated rats. Our results thus show that in this model CMZ improves hind limb motor function and attenuates the morphological damage to the spinal cord.
Department of Genetics and Pathology, Uppsala University Hospital, Sweden. Mohammad.Farooque@patologi.uu.se
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Farooque
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Isaksson
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Jackson
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Olsson
D000818:Animals; D002719:Chlormethiazole / Q000627:therapeutic use*; D004396:Coloring Agents; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006614:Hindlimb / Q000502:physiology*; D007150:Immunohistochemistry; D007211:Indoles; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects*; D009186:Myelin Sheath / Q000187:drug effects / Q000473:pathology; D009409:Nerve Crush; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*
D004396:Coloring Agents; D005904:Glial Fibrillary Acidic Protein; D007211:Indoles; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D002719:Chlormethiazole; C018588:Luxol Fast Blue MBS