Comparative effects of glibenclamide and riluzole in a rat model of severe cervical spinal cord injury

Abstract

Both glibenclamide and riluzole reduce necrosis and improve outcome in rat models of spinal cord injury (SCI). In SCI, gene suppression experiments show that newly upregulated sulfonylurea receptor 1 (Sur1)-regulated NCCa- ATP channels in microvascular endothelial cells are responsible for “persistent sodium currents” that cause capillary fragmentation and “progressive hemorrhagic necrosis”. Glibenclamide is a potent blocker of Sur1-regulated NCCa-ATP channels (IC50,6–48 nM). Riluzole is a pleotropic drug that blocks “persistent sodium currents” in neurons, but in SCI, its molecular mechanism of action is uncertain. We hypothesized that riluzole might block the putative pore-forming subunits of Sur1-regulated NCCa-ATP channels, Trpm4. In patch clamp experiments, riluzole blocked Sur1-regulated NCCa-ATP channels in endothelial cells and heterologously expressed Trpm4 (IC50,31 μM). Using a rat model of cervical SCI associated with high mortality, we compared the effects of glibenclamide and riluzole administered beginning at 3 h and continuing for 7 days after impact. During the acute phase, both drugs reduced capillary fragmentation and progressive hemorrhagic necrosis, and both prevented death. At 6 weeks, modified (unilateral) Basso, Beattie, Bresnahan locomotor scores were similar, but measures of complex function (grip strength, rearing, accelerating rotarod) and tissue sparing were significantly better with glibenclamide than with riluzole. We conclude that both drugs act similarly, glibenclamide on the regulatory subunit, and riluzole on the putative pore-forming subunit of the Sur1-regulated NCCa-ATP channel. Differences in specificity, dose-limiting potency, or in spectrum of action may account for the apparent superiority of glibenclamide over riluzole in this model of severe SCI.

Improving the Efficiency and Efficacy of Glibenclamide in Limiting Progressive Hemorrhagic Necrosis Following Traumatic Spinal Cord Injury

“…6 Lesion expansion is prevented by blocking Sur1, either pharmacologically with glibenclamide or repaglinide, 4 or by gene suppression with antisense oligodeoxynucleotide or gene deletion of Abcc8, 8 or by blocking Trpm4, either pharmacologically with flufenamic acid 7 or riluzole, 9 or by gene suppression with antisense oligodeoxynucleotide or gene deletion of Trpm4. 7 In the present study examining acute outcomes at 24 h, in three other series from our laboratory examining outcomes at 1 or 6 weeks, 4,8,10 and in one series from an independent laboratory, 22 glibenclamide treatment beginning shortly after trauma was found to be highly effective in reducing lesion size and improving neurological function.…”

“…This dosing regimen was found previously to significantly ameliorate progressive hemorrhagic necrosis [8][9][10] without producing clinically relevant hypoglycemia or any other toxicity. 4,12,13 Unlike our previous study, in which a 3-h treatment delay was used, 9 here we used an early treatment time because our principal goal was to validate MRI for measuring early lesion expansion. The formulation of glibenclamide (#G2539; Sigma, St Louis, MO, USA) in dimethyl sulfoxide (DMSO) and the preparation of mini-osmotic pumps have been described in detail.…”

“…4,[8][9][10] Female Long-Evans rats (B11 weeks; 250-300 gm; Harlan) were anesthetized (Ketamine, 60 mg kg À1 plus Xylazine, 7.5 mg kg À1 , intraperitoneally (IP)). On the left side, the entire lamina of C7 and the dorsal half of the pedicle of C7 were removed.…”

The effect of preexisting hypertension on early neurologic results of patients with an acute spinal cord injury

“…11 This is largely due to an increased awareness of the complications associated with high dose steroid use, and the failure of subsequent studies to confirm the results of the NASCIS II. [11][12][13][14][15][16][17][18][19] Although alternative neuroprotective pharmacologic treatments, such as riluzole, are being developed and have shown promise in animal trials, [20][21][22][23] clinical trials are still in the early stages. 24,25 Although the use of different neuroprotective medications is unclear, one of the widely available and accepted treatments used to limit the secondary injury from an acute SCI is ensuring spinal cord perfusion with induced hypertension (HTN).…”

Translation of the rat thoracic contusion model; part 2 — forward versus backward locomotion testing

“…It is known from their use in other SCI models that more severely injured animals barely recover function, if at all, as assessed with these tests, which is suggestive of a relatively high requirement of supraspinal motor control. [7][8][9][10] In order to further increase the requirement of supraspinal motor control on locomotion testing and decrease the impact of basic intrinsic pattern generator-based spinal locomotion circuitry, the backward locomotion rotating rod test was developed. Backward locomotion is hypothesized to be more specific for supraspinal, voluntary and conscious locomotion as brainstem stimulation in decerebrated quadrupeds was only able to elicit forward, but not backward, walking patterns.…”