Amiloride Improves Locomotor Recovery after Spinal Cord Injury

Abstract

Amiloride is a drug approved by the United States Food and Drug Administration, which has shown neuroprotective effects in different neuropathological conditions, including brain injury or brain ischemia, but has not been tested in spinal cord injury (SCI). We tested amiloride's therapeutic potential in a clinically relevant rat model of contusion SCI inflicted at the thoracic segment T10. Rats receiving daily administration of amiloride from 24 h to 35 days after SCI exhibited a significant improvement in hindlimb locomotor ability at 21, 28, and 35 days after injury, when compared to vehicle-treated SCI rats. Rats receiving amiloride treatment also exhibited a significant increase in myelin oligodendrocyte glycoprotein (MOG) levels 35 days after SCI at the site of injury (T10) when compared to vehicle-treated controls, which indicated a partial reverse in the decrease of MOG observed with injury. Our data indicate that higher levels of MOG correlate with improved locomotor recovery after SCI, and that this may explain the beneficial effects of amiloride after SCI. Given that amiloride treatment after SCI caused a significant preservation of myelin levels, and improved locomotor recovery, it should be considered as a possible therapeutic intervention after SCI.

The Cancer Drug Tamoxifen: A Potential Therapeutic Treatment for Spinal Cord Injury

“…TMX effects on oligodendrocyte/myelin levels can explain the improvement in BBB scores. We have shown that loss of myelin levels at the lesion site in chronically injured spinal cords is correlated with BBB scores, 56 in agreement with other findings. 57 Further, we have also demonstrated that even modest increases in myelin (i.e., MOG) levels by *12% at the lesion site lead to substantial improvements of locomotor recovery.…”

“…57 Further, we have also demonstrated that even modest increases in myelin (i.e., MOG) levels by *12% at the lesion site lead to substantial improvements of locomotor recovery. 56 Therefore, our finding that TMX increases levels of all major myelin proteins (MBP, CNPase, MOG), and oligodendrocyte numbers by *20% at T10 can explain the observed improvement in hind-limb motor recovery (by *3 BBB scores).…”

Effect of amiloride on endoplasmic reticulum stress response in the injured spinal cord of rats

“…Based on the above results, we here used amiloride, a therapeutic agent that has been shown to have cytoprotective and ER stress‐modulating effects in various models of neurological diseases, including SCI (Friese et al ., ; Arias et al ., ; Durham‐Lee et al ., ).…”

“…Among the few studies that investigated the effects of amiloride in an SCI model, one report showed that amiloride had neuroprotective effects in an in vitro model of SCI (Agrawal & Fehlings, ). Another study reported improvements in hindlimb function and increased myelin oligodendrocyte glycoprotein in a rat SCI model (Durham‐Lee et al ., ). Similarly, in our current study, significant improvements in hindlimb function were observed after amiloride administration in a rat SCI model, possibly brought about by the reduced cell death revealed by TUNEL assays.…”

“…Amiloride is a potassium‐sparing diuretic approved by the Food and Drug Administration (FDA) to treat hypertension in the United States. In recent years, its neuroprotective effects against SCI (Durham‐Lee et al ., ) and neurodegenerative diseases, such as Parkinson's disease (Arias et al ., ) and multiple sclerosis (Friese et al ., ), have been reported.…”