Abstract
After spinal cord injury (SCI), secondary injury results in an expanding area of glial cell apoptosis. Oligodendrocyte precursor cells (OPCs) actively proliferate after SCI, but many of these cells undergo apoptosis. One of the factors that exacerbates secondary injury is endoplasmic reticulum (ER) stress. In this study, we tested the effects of amiloride treatment on the fate of OPCs during secondary injury in rats. Amiloride is an FDA-approved diuretic for treating hypertension, which in rats enhances ER stress response and suppresses the apoptosis of glial cells after SCI. A severe contusive SCI was induced in Sprague-Dawley rats using an infinite horizon (IH)-impactor (200 kdyne). Beginning 24 h after SCI, 10 mg/kg of amiloride or phosphate buffered saline (PBS) was intraperitoneally administered daily for a period of 14 days. At 7, 14, 28, and 56 days after SCI, animals were subsequently euthanized in order to analyze the injured spinal cord. We labeled proliferating OPCs and demonstrated that amiloride treatment led to greater numbers of OPCs and oligodendrocytes in the injured spinal cord. Increased myelin basic protein (MBP) expression levels were observed, suggesting that increased numbers of mature oligodendrocytes led to improved remyelination, significantly improving motor function recovery.
Highlights
Spinal cord injury (SCI) is a permanently debilitating injury that lowers the quality of life, for the patient, and their family members
We have been searching for a treatment that inhibits the apoptosis of oligodendrocyte precursor cells (OPCs) in the injured spinal cord, which in turn would reduce the expansion of secondary injury, and improve function through increased remyelination
The group treated with amiloride had improved motor function compared to the control group up to 28 days after injury. In this follow-up study, we use the same amiloride treatment and study the tested animals up to 56 days after injury to examine the following points: (1) does the increase in OPCs lead to increased oligodendrocytes; (2) does the increase in oligodendrocytes lead to improved remyelination; and (3) is there further improvement in motor function after 28 days, and what effect does amiloride treatment have on allodynia after spinal cord injury (SCI)?
Summary
Spinal cord injury (SCI) is a permanently debilitating injury that lowers the quality of life, for the patient, and their family members. We have been searching for a treatment that inhibits the apoptosis of OPCs in the injured spinal cord, which in turn would reduce the expansion of secondary injury, and improve function through increased remyelination. It was shown that lowering the ER stress response of OPCs leads to increased apoptosis during the secondary injury phase of SCI. Studies have demonstrated that the administration of amiloride, which enhances the ER stress response, decreased OPC apoptosis [11,12]. In our previous study by Kuroiwa, et al [9], we demonstrated that amiloride administration increased GRP78 expression and decreased CHOP expression within the spinal cord, which decreased neural cell apoptosis and led to an increase of OPCs in the injured spinal cord. In this follow-up study, we use the same amiloride treatment and study the tested animals up to 56 days after injury to examine the following points: (1) does the increase in OPCs lead to increased oligodendrocytes; (2) does the increase in oligodendrocytes lead to improved remyelination; and (3) is there further improvement in motor function after 28 days, and what effect does amiloride treatment have on allodynia after SCI?
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