Neuroprotective Effects of a Potent Sodium Channel Blocker, HFI-1, in a Rat Model of Spinal Cord Injury

Robert Weston, Bevyn Jarrott. Howard Florey Institute, Parkville, Australia.

Spinal cord injury (SCI) from car accidents often leads to permanent paraplegia and quadriplegia, and increased costs to society. Research is focusing on developing drugs to minimise the effects of SCI. Thus we undertook a study of a mexiletine analogue, HFI-1, which has a sodium channel blocking pharmacophore linked to an antioxidant moiety, to assess it as a neuroprotective compound. This modification increases not only the lipophilicity of HFI-1 compared to mexiletine that should favour entry into the CNS but also its potency by ∼ 80 times as measured with an in vitro sodium channel binding assay (Postma & Catterall, 1984). For in vivo assessment of HFI-1, male Hooded Wistar rats were anaesthetised (2% isoflurane in 98% oxygen), and a laminectomy performed at spinal level T12. An inflatable balloon catheter was inserted rostral, underneath the vertebra, to T10 and inflated for 5 minutes, causing reversible paraplegia (Feldblum et al 2000). Rats in this model demonstrate a slow, graded return of hindlimb motor function over 15 days, which allows an assessment of the actions of putative neuroprotective compounds. Rats had almost complete functional recovery by 15d. HFI-1 (30mg/kg, i.p.; n = 5) or vehicle (n = 4) was administered at 3h after the injury and twice daily thereafter, until killed. Behavioural tests were conducted every 3 days. At 15d post-injury, rats were anaesthetised and perfused transcardially to fix the spinal cords. Sections were cut and processed to examine the size of the cyst and modulatory effects of HFI-1 on lesion formation. HFI-1 treatment decreased significantly the recovery time in behavioural outcomes following SCI, as seen in the ladder walking test, BBB scale and inclined ledged beam; with differences from untreated rats at 9d and 12d (P<0.05). These differences remained significant from untreated rats for the remainder of the study (P<0.05). Vehicle-treated rats only showed significantly improved function in the behavioural outcomes at 12d and 15d post-SCI. HFI-1 also reduced the volume of damage following SCI by ∼50%, These data indicate that HFI-1 could be a promising neuroprotective compound for the treatment of SCI.

Feldblum, S. et al (2000) J Neurotrauma, 17:1079-1093.
Postma, SW & Catterall WA (1984) Mol Pharmacol 25: 219-227.